Heteroaromatic indolesulfonamides

Abstract

The present disclosures relate to compounds that can be useful as modulators of splicing factor RBM39. Also disclosed herein are pharmaceutical compositions that can include a compound of Formula (I), the use and preparation thereof.

Description

HETEROAROMATIC INDOLESULFONAMIDESINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63 / 562663, filed March 7, 2024 and 63 / 717248, filed November 6, 2024.REFERENCE TO SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEED018WOSequenceListing.xml.xml, created on February 28, 2025, which is approximately 17.5 kb in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUNDField

[0003] The present disclosure relates generally to the fields of chemistry and medicine. More specifically, the present disclosure relates to the field of small molecule drugs for the treatment of cancer.Description of the Related Art

[0004] Aryl sulfonamides can act as molecular glues to induce aggregation between two or more proteins to modulate biological functions. More particularly, Indisulam and E7820 are both associated with the degradation of splicing factor RBM39 to achieve anticancer effects. In the presence of indisulam or E7820, RBM39 associates with the E3 ligase CUL4-DDB1-DDA1-DCAF15, leading to RBM39 polyubiquitination and proteasomal degradation. Indisulam and E7820 have been investigated in multiple phase I and II clinical trials involving advanced cancers with modest clinical responses. Therefore, a need exists for new sulfonamide compounds with more potent anticancer activity.SUMMARY

[0005] Some embodiments disclosed herein include a method of treating a cancer in a subject, wherein the cancer is characterized by a gene fusion mutation, comprising administering to a subject in need thereof an effective amount of a RBM39 degrader.

[0006] In some embodiments, the RBM39 degrader is a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof,points of attachment to form a fused bicyclic ring;Y is O or NH;Z1, Z2and Z3are each independently C(Rla) or N; each Rlais independently selected from the group consisting of H, halogen, -(Ci-Cejalkyl and -(C i-Cejhaloalkyl;R2is H, -(Ci-C6)alkyl or -C(O)R6;R3is a -(Ci-Ce)alkyl, furan, thiophene, a 5-mcmbcrcd monocyclic nitrogcn-containing heteroaryl, or a 6-12 membered nitrogen-containing bicyclic heterocyclyl; wherein the -(Ci-Ce)alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl and the 6-12 membered nitrogen-containing bicyclic heterocyclyl can be optionally substituted with one or two or three substituents selected from R4; each R4is independently selected from -Rxl, -Rx2, -(Ci-Ce)alkyl, -(Ci-Cejhaloalkyl, -(Ci-C6)alkoxy, -CN, halogen, -NH2, -N((Ci-C6)alkyl)2, -NHC(O)(Ci-C6)alkyl, -NHBoc, -(CH2)nS(O)2(Ci-C6)alkyl and -C(O)Rzl;R5ais selected from the group consisting of -H, -CN, halogen, -(Ci-C6)alkyl, -(Ci-Ce)haloalkyl, -(C2-C6)alkcnyl, -(C2-C6)alkynyl, and 4-7 membered monocyclic heterocyclyl;R5bis -(Ci-C6)alkyl; orR5ais taken together with R5band the atom to which R5aand R5bare attached to form an optionally substituted 3-7 membered monocyclic cycloalkyl;R6is H or -(Ci-Ce) alkyl;R7aand R7bare each independently selected from the group consisting of H, halogen, -CN, -(Ci-C6)alkyl, -(Ci-C6)alkoxy, 3-7 membered monocyclic cycloalkyl and -(Ci-Ce)haloalkyl; or R7ais taken together with R7band the atom to which R7aand R7bare attached to be -C(=O);Rxlis selected from the group consisting of C3-C7 cycloalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclyl(Ci-C6 alkyl), wherein the cycloalkyl, heterocyclyl and heterocyclyl(alkyl) are each optionally substituted with Ryl;Rx2is selected from the group consisting of -(Ci-C6)alkyl, -(Ci-Ce) alkoxy, -(Ci-C6)alkylamino, and amino; wherein the -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, -(Ci-C6)alkylamino, and amino are optionally substituted with one or two Ry2;Rylis selected from the group consisting of H, -CN, -OH, -C(O)O(Ci-C6)alkyl, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, 5-10 membered heterocyclyl, BOC, -C(O)(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -CH2S(O)2(Ci-C6)alkyl and -CH2CN; each Ry2is independently selected from the group consisting of -CN, -OH, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, -N((Ci-C6)alkyl)2, -CH2CN, -C(O)CH2CH2N((Ci-C6)alkyl)2, -C(O)(5-10 membered heterocyclyl) and -(CH2)nS(O)2(Ci- C6)alkyl; n is 0, 1, 2, 3 or 4; and

[0007] Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

[0008] Other embodiments disclosed herein include a method of preventing, treating, or ameliorating one or more cancers in a subject, by administering the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. The cancers include, but are not limited to, colorectal cancer (CRC), pleural mesothelioma (PM), cutaneous squamous cell carcinoma (CSCC); tumor mutation burden high (TMB-H), Bacillus Calmette-Guerin bladder cancer, endometrial carcinoma (EC), esophageal squamous cell carcinoma (ESCC), Merkel cell carcinoma (MCC), hepatocellular carcinoma (HCC), primary mediastinal large B cell lymphoma (PMBCL), cervical cancer, urothelial carcinoma, classical Hodgkin’s lymphoma, head and neck squamous cell carcinoma, liver cancer, gastric cancer, prostate cancer, sarcoma, melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, renal cell carcinoma, triple negative breast cancer, luminal B breast cancer, colon cancer, ovarian cancer, pancreatic cancer and glioblastoma.

[0009] Other embodiments disclosed herein include a method of treating a cancer in a subject, wherein the cancer is characterized by a gene fusion mutation, by administering an RBM39 degrader disclosed herein, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof. The gene fusion mutations include, but are not limited to, BCR-ABL1 , ETV6- RUNX1, TCF3-PBX1, RBM15-MKL1, RUNX1-RUNX1T1(AML1-MTG8), PML-RARA, CBFB-MYH11, NPM1-ALK, TRMT11-GRIK2, CCNH-C5orf30, ETV6-NTRK3, 0DZ4- NRG1, TBL1XR1-RGS17, MYB-NFIB, MAST-fusions, NOTCH-fusions, IGH-MYC, IGK- MYC, IGL-MYC, RSPO2-EIF3E, RSPO2-PTPRK, EWSR1-FLI1, EWSR1-ERG, BCL2- IGH, MAN2A1-FER, FGFR3-TACC3, FIG-ROS1, EML4-ALK1, ESRRA-C1 lorf20, BRAF- KIAA1549, TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR-TP53BP1, RPS10-HPR, APAK9-BRAF, RET-CCDC6, PAX8- PPARG, TFG-NTRK1, and TPM3-NTRK1.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 illustrates a CTG assay for Compound 1 in A-673 cells.

[0011] FIG. 2A shows the dose response against RBM39 protein in A-673 cells treated with a serial dilution of Compound 1 for 6 h.

[0012] FIG. 2B shows a time course study against RBM39 protein in A-673 cells treated with Compound 1 (5 pM) for 6 or 24 h.

[0013] FIG. 3 shows detection of EWS-FLI1 fusion protein using FLI antibody in A-673 cells treated with Compound 1 (5 pM) for 6-48 h.

[0014] FIG. 4 shows plasma concentrations of Compound 1 and Compound 143 over 8 hours following oral administration in female BALB / c mice.

[0015] FIG. 5 shows telencephalon concentrations of Compound 1 and Compound 143 over 8 hours following oral administration in female BALB / c mice.

[0016] FIG. 6 shows inhibition of cell growth by Compound 1 and Compound 143 in HCT116 colorectal cells in a CellTiter-Glo® luminescent cell viability assay.

[0017] FIG. 7 shows inhibition of cell growth by Compound 1 and Compound 143 in SH-SY-5Y neuroblastoma cells in a CellTiter-Glo® luminescent cell viability assay.

[0018] FIG. 8 shows inhibition of cell growth by Compound 1 and Compound 143 in A-673 Ewing sarcoma cells in a CellTiter-Glo® luminescent cell viability assay.

[0019] FIG. 9A illustrates dysregulation of EWSR1-FLI1 fusion gene splicing following treatment with Compound 1 (5 pM).

[0020] FIG. 9B shows statistical analysis results of RNA sequencing RT-PCR products of A-673 cells treated with Compound 1 (5 pM) for 24 h.

[0021] FIG. 10 shows dysregulation of Trim27 and BRCA1 gene splicing by Compound 1 (5 pM) treatment in A-673 cells.

[0022] FIG. 11 shows down regulation and / or mis-splicing of multiple genes in A- 673 cells treated with Compound 1 (5 pM).

[0023] FIG. 12 shows reduction of RBM39 and EWS-FLI1 in a Western Blot analysis of NOD scid mice inoculated with A-673 cells and treated with Compound 1.

[0024] FIG. 13 shows three EWS-FLI1 isoforms identified via PCR after treatment of NOD scid mice inoculated with A-673 cells with Compound 1.

[0025] FIG. 14 shows partial cell growth inhibition in SK-PN-DW (type I fusion) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0026] FIG. 15A shows cell growth inhibition in SK-N-MC (variant 7 / 6; type I- like fusion) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0027] FIG. 15B shows Western Blot showing RBM39 reduction and a shift of the EWS-FLI1 fusion band to a lower molecular weight in SK-N-MC (variant 7 / 6; type I-like fusion) Ewing sarcoma cells treated with Compound 1 (5 pM) for 24 h.

[0028] FIG. 16 shows cell growth inhibition in TC71 (type I fusion) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0029] FIG. 17 shows cell growth inhibition in SCCH-196 (type 1 fusion) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0030] FIG. 18A shows a Western Blot showing RBM39 reduction and a shift of the EWS-FLI1 fusion band to a lower molecular weight in SK-PN-DW (type I fusion), A673 (type I fusion) and SK-N-MC (type I-like fusion) Ewing sarcoma cells treated with Compound 1 (5 pM) for 24 h.

[0031] FIG. 18B shows a Western Blog showing RBM39 reduction, but no change in the EWS-FLI fusion band for TC-71 (type I fusion) Ewing sarcoma cells with Compound 1 (5 pM) for 24 h. SCCH-196 (type I fusion) Ewing sarcoma cells treated with Compound 1 (5 pM) for 24 h showed RBM39 reduction and a shift of the EWS-FLI1 fusion band to a lower molecular weight.

[0032] FIG. 19 shows cell growth inhibition in RD-ES (type II) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0033] FIG. 20 shows cell growth inhibition in SK-NEP-1 (type II) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0034] FIG. 21 shows a Western Blot showing RBM39 reduction but change in the EWS-FLI1 fusion band in RD-ES (type II) and SK-NEP-1 (type II) Ewing sarcoma cells treated with Compound 1 (5 pM) for 24 h.

[0035] FIG. 22A shows no cell growth inhibition in SK-ES-1 (type II) Ewing sarcoma cells treated with Compound 1 (5 pM).

[0036] FIG. 22B shows a Western Blot showing no RBM39 expression in SK-ES- 1 (type II) Ewing sarcoma cells and no change in the EWS-FLI1 fusion band following treatment with Compound 1 (5 pM) for 24 h.DETAILED DESCRIPTION

[0037] In some embodiments, provided herein are indole and thiazole-containing sulfonamide compounds that act as modulators of RBM39. Various embodiments of these compounds include compounds having the structure of Formula (I) as described above or pharmaceutically acceptable salts thereof. The structure of Formula (I) encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0038] In some embodiments of compounds of Formula (I):A is se ilected j fromand represents points of attachment to form a fused bicyclic ring;Y is O or NH;Z1, Z2and Z3are each independently C(Rla) or N; each Rlais independently selected from the group consisting of H, halogen, -(Ci-C6)alkyl and -(Ci-C6)haloalkyl;R2is H, -(Ci-C6)alkyl or -C(O)R6;R3is a -(Ci-Ce)alkyl, furan, thiophene, a 5-membered monocyclic nitrogen-containing heteroaryl, or a 6-12 membered nitrogen-containing bicyclic heterocyclyl; wherein the -(Ci-Ce)alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl and the 6-12 membered nitrogen-containing bicyclic heterocyclyl can be optionally substituted with one or two or three substituents selected from R4; each R4is independently selected from -Rxl, Rx2, -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Ci-C6)alkoxy, -CN, halogen, -NH2, -N((Ci-C6)alkyl)2, -NHC(O)(Ci-C6)alkyl, -NHBoc, -(CH2)nS(O)2(Ci-C6)alkyl and -C(O)Rzl;R5ais selected from the group consisting of -H, -CN, halogen, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, and 4-7 membered monocyclic heterocyclyl;R5bis -(Ci-C6)alkyl; orR5ais taken together with R5band the atom to which R5aand R5bare attached to form an optionally substituted 3-7 membered monocyclic cycloalkyl;R6is H or -(Ci-C6)alkyl;R7aand R7bare each independently selected from the group consisting of H, halogen, -CN, -(Ci-C6)alkyl, -(Ci-C6)alkoxy, 3-7 membered monocyclic cycloalkyl and -(Ci-C6)haloalkyl; or R7ais taken together with R7band the atom to which R7aand R7bare attached to be -C(=O);Rxlis selected from the group consisting of C3-C7 cycloalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclyl(Ci-C6 alkyl), wherein the cycloalkyl, heterocyclyl and heterocyclyl(alkyl) are each optionally substituted with Ryl;Rx2is selected from the group consisting of -(Ci-C6)alkyl, -(Ci-Ce) alkoxy, -(Ci-C6)alkylamino, and amino; wherein the -(Ci-C6)alkyl, -(Ci-Ce)alkoxy, -(Ci-C6)alkylamino, and amino are optionally substituted with one or two Ry2;Rylis selected from the group consisting of H, -CN, -OH, -C(O)O(Ci-C6)alkyl, -(Ci-Ce)alkyl, -(Ci-C6)haloalkyl, -(Ci-Ce)alkoxy, 5-10 membered hctcrocyclyl, BOC, -C(O)(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -CH2S(O)2(Ci-C6)alkyl and -CH2CN; each Ry2is independently selected from the group consisting of -CN, -OH, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, -N((Ci-C6)alkyl)2, -CH2CN, -C(O)CH2CH2N((Ci-C6)alkyl)2, -C(O)(5-10 membered heterocyclyl) and -(CH2)nS(O)2(Ci- C6)alkyl; n is 0, 1, 2, 3 or 4; andIn some embodiments, the compound is not

[0039] Some exemplary structures of Formula (I), or pharmaceutically acceptable salts thereof, include those of Formulas (II) through (VI):

[0040] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, at least one of Z1, Z2and Z3can be N. In some embodiments, Z3can be N. In some embodiments, Z1can be N. In other embodiments, Z2can be N. In other embodiments, Z1and Z3can be N. In other embodiments, Z1, Z2and Z can each independently be C(Rla). In some embodiments, Z1can be C(Rla). In other embodiments, Z2can be C(Rla). In still other embodiments, Z3can be C(Rla).

[0041] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, Rlacan be -(Ci-C6)alkyl. In other embodiments, Rlacan be -CH3. In some embodiments, Z1can be C(Rla) and Rlacan be -(Ci-C6)alkyl, such as -CH3. In still other embodiments, Rlacan be halogen. In other embodiments, Rlacan be -(C 1 -C6)haloalkyl .

[0042] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R2can be H. In other embodiments, R2can be-(Ci-C6)alkyl. In other embodiments, R2is -C(O)R6. In still other embodiments, R2can be -C(O)(Ci-C6)alkyl.

[0043] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R3can be a 5-membered monocyclic nitrogen-containing heteroaryl optionally substituted with one or two or three substituents selected from R4.

[0044] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R5acan be -CN. In other embodiments, R5acan be halogen. In other embodiments, R5acan be -(Ci-C6)haloalkyl. In still other embodiments, R5acan be -(Ci-C6)alkyl. In other embodiments, R5acan be a 4-7 membered heterocyclyl.

[0045] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R7acan be -CN. In other embodiments, R7acan be halogen. In other embodiments, R7acan be -(Ci-C6)haloalkyl. In still other embodiments, R7acan be-(Ci-C6)alkyl.

[0046] In some embodiments of compounds of Formula (I) or theirpharmaceutically acceptable salts, A1can be . In other embodiments, A1can be4. In still other embodiments, A can beF0047] In some embodiments of compounds of Formula (I) or Formula (II) or their pharmaceutically acceptable salts, X1can be O, S, or N(R4). In some embodiments of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) or their pharmaceutically acceptable salts, X1can be O or S. In some embodiments of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) or their pharmaceutically acceptable salts, X1can be O. In some embodiments of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) or their pharmaceutically acceptable salts, X1can be S. In some embodiments of Formula (I), Formula (II), Formula (III), Formula (V) or Formula (VI) or their pharmaceutically acceptable salts, X2can be N or C(R4). In other embodiments of Formula (I), Formula (II), Formula (III), Formula (V) or Formula (VI) or their pharmaceutically acceptable salts, X2can be N. In someembodiments of Formula (I), Formula (II), Formula (III), Formula (V) or Formula (VI) or their pharmaceutically acceptable salts, X2can be C(R4). In some embodiments of Formula (I) or Formula (II) or their pharmaceutically acceptable salts, X3can be C(R4) or N. In some embodiments of compounds of Formula (I) or Formula (VI) or their pharmaceutically acceptable salts, X3can be S or O or N(R4). In some embodiments of compounds of Formula (I) or Formula (VI) or their pharmaceutically acceptable salts, X3can be S. In some embodiments of compounds of Formula (I) or Formula (VI) or their pharmaceutically acceptable salts, X3can be O.

[0048] In some embodiments of compounds of Formula (I) or theirR5aR7a LR5bR7b \HN^Z pharmaceutically acceptable salts, A1can be

[0049] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R5bcan be -(Ci-Ce)alkyl.

[0050] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R5acan be taken together with R5band the atom to which R5aand R5bare attached to form an optionally substituted 3-7 membered monocyclic cycloalkyl. In some embodiments, R5acan be taken together with R5band the atom to which R5aand R5bare attached to form an optionally substituted cyclopropyl.

[0051] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R3can be -(Ci-C6)alkyl optionally substituted with one or two or three substituents selected from R4.

[0052] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, each R4can be independently -H, halogen, -CN, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, -(CH2)nS(O)2(Ci-C6)alkyl or -C(O)Rzl.

[0053] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R4can be CH3. In other embodiments, R4can be CD3. In still other embodiments, R4can be NH2. In other embodiments, R4can be NHBoc. In yet other embodiments, R4can be NHC(O)(Ci-Cfi)alkyl.

[0054] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R4can be -Rxl. In some embodiments, -Rxlcan be selected

[0055] In some embodiments of compounds of Formula (I) or their phamraceutically acceptable salts, Rylcan be -H. In other embodiments, Rylcan be-(Ci-C6)alkyl. In still other embodiments, Rylcan be -CN. In some embodiments, Rylcan beCH2CN. In other embodiments, Rylcan be BOC. In other embodiments, Rylcan be-C(O)(Ci-C6)alkyl. In still other embodiments, Rylcan be -(CH2)nS(O)2(Ci-C6) lkyl. In some embodiments, n can be 0. In other embodiments, n can be 1. In other embodiments, n can be 2. In other embodiments, n can be 3. In other embodiments, n can be 4. In other embodiments, Rylcan be heterocyclyl. In some embodiments, Rylcan

[0056] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R4can be -Rx2. In some embodiments, Rx2can be selectedembodiments, Rx2caneach Ry2can independently be -H, -OH, -CN,-(Ci-C6)alkoxy, -N((Ci-C6)alkyl)2, or -(CH2)aS(O)2(Ci-C6)alkyl. In other embodiments, Rx2each Ry2can be -(Ci-C6)alkyl. In some embodiments, each Ry2can be -OH. In some embodiments, Rx2canIn some embodiments, Rx2can beIn some embodiments, Ry2can be -CN or-CH2CN. In other embodiments, Ry2can be -(CH2)nS(O)2(Ci-C6)alkyl. In still other embodiments, Rx2caneach Ry2can independently be -(Ci-C6)alkyl,-CH2CN, -C(O)CH2CH2N((Ci-C6)alkyl)2, -(CH2)nS(O)2(Ci-C6)alkyl, or -CH2CH2S(O)2(Ci-C6)alkyl.

[0057] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R3can be -(Ci-C6)alkyl, such as -CH3. In other embodiments, R3can be isopropyl. In other embodiments, R3can be -(Ci-C6)alkyl substituted with R4and R4can be -Rxl. In some embodiments, Rxlcan beor

[0058] In some embodiments of compounds of Formula (1) or their pharmaceutically acceptable salts, R3can be a 6-12 membered nitrogen-containing bicyclic heterocyclyl optionally substituted with one or two or three substituents selected from R4. In some embodiments, the 6-12 membered nitrogen-containing bicyclic heterocyclyl can beselected from the group consisting of:some embodiments, R4is -CN.

[0059] In some embodiments of compounds of Formula (I), the compound can be a compound selected from the group consisting of:andpharmaceutically acceptable salt of any of the foregoing.

[0060] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound having the structure:

[0061] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof arc included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0062] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

[0063] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise, (including pharmaceutically acceptable salts of any of the foregoing).Definitions

[0064] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the ail to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0065] ‘Solvate” refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0066] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts can also be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases that contain sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in loss of a labile hydrogen from the compound to afford the salt form including an inorganic cation such as Li+, Na+, K+, Mg2+and Ca2+and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0067] As used herein, “Cato Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” or “C1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2-, and (CH3)3C-.

[0068] The term “halogen” or “halo,” as used herein, means any one of the radiostable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0069] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as “Ci-4 alkyl” or similar designations. By way of example only, “Ci-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0070] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl as is defined above, such as “C1-9 alkoxy”, including but not limited to methoxy, ethoxy, n- propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

[0071] As used herein, “alkylthio” refers to the formula -SR wherein R is an alkyl as is defined above, such as “C1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1 -methylethylmercapto(isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec -butylmercapto, tertbutylmercapto, and the like.

[0072] As used herein, “alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as “C2-4 alkenyl” or similar designations. By way of example only, “C2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen- 1-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl- propen-l-yl, 2-methyl-propen-l-yl, 1-ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta- 1,3-dienyl, buta- 1,2, -dienyl, and buta-l,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

[0073] As used herein, “alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as “C2-4 alkynyl” or similar designations. By way of example only, “C2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn- 1-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

[0074] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as “C1-4 heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0075] As used herein, “alkylene” means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as “C1-4 alkylene” or similar designations. By way of example only, “C1-4 alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan- 1,1 -diyl, propylene, propan- 1,1 -diyl, propan-2, 2-diyl, 1-methyl-ethylene, butylene, butan- 1 , 1 -diyl, butan-2, 2-diyl, 2-methyl-propan- 1,1 -diyl, 1- methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1- ethyl-ethylene.

[0076] As used herein, “alkenylene” means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carboncarbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as “C2-4 alkenylene” or similar’ designations. By way of example only, “C2-4 alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1- diyl, propenylene, propen- 1,1 -diyl, prop-2-en- 1,1 -diyl, 1-methyl-ethenylene, but-l-enylene, but-2-enylene, but-l,3-dienylene, buten- 1,1 -diyl, but- 1,3-dien- 1,1 -diyl, but-2-en- 1,1 -diyl, but- 3-en- 1,1 -diyl, l-methyl-prop-2-en- 1,1 -diyl, 2-methyl-prop-2-en- 1,1 -diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl- propenylene, 2-methyl-propen- 1,1 -diyl, and 2,2-dimethyl-ethen-l,l-diyl.

[0077] The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0078] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as “Ce-io aryl,” “Ce or C10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0079] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as “Ce-io aryloxy” or “C6-10 arylthio” and the like, including but not limited to phenyloxy.

[0080] An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as “C7-14 aralkyl” and the like, including but not limited to benzyl,2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C alkylene group).

[0081] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0082] A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl,3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, 34yanate34ylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C alkylene group).

[0083] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6 carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3 -dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro [4.4] nonanyl.

[0084] A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0085] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0086] As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0087] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar’ designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl,imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, pipcrazinyl, dioxopipcrazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-pipcridonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3- oxathianyl, 1 ,4-oxathiinyl, 1,4-oxathianyl, 2H- 1,2-oxazinyl, trioxanyl, hexahydro- 1,3,5- triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3- oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro- 1 ,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0088] A “(heterocyclyl) alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0089] As used herein, “acyl” refers to -C(=O)R, wherein R is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, CMO aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0090] An “O-carboxy” group refers to a “-OC(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0091] A “C-carboxy” group refers to a “-C(=O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH).

[0092] A “cyano” group refers to a “-CN” group.

[0093] A “cyanato” group refers to an “-OCN” group.

[0094] An “isocyanato” group refers to a “-NCO” group.

[0095] A “thiocyanato” group refers to a “-SCN” group.

[0096] An “isothiocyanato” group refers to an “ -NCS” group.

[0097] A “sulfinyl” group refers to an “-S(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0098] A “sulfonyl” group refers to an “-SO2R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0099] An “S-sulfonamido” group refers to a “-SO2NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0100] An “N-sulfonamido” group refers to a “-N(RA)SO2RB” group in which RA and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0101] An “O-carbamyl” group refers to a “-OC(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0102] An “N-carbamyl” group refers to an “-N(RA)C(=O)ORB” group in which RA and RB are each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0103] An “O-thiocarbamyl” group refers to a “-OC(=S)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0104] An “N-thiocarbamyl” group refers to an “-N(RA)C(=S)ORB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0105] A “C-amido” group refers to a “-C(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0106] An “N-amido” group refers to a “-N(RA)C(=O)RB” group in which RA and RB arc each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0107] An “amino” group refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2).

[0108] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0109] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.

[0110] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substituents independently selected from Ci-Ce alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), C3- C7-carbocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-Ce alkyl, C1-C6 alkoxy, Ci- Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 3-10 membered heterocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl(Ci-C6)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and C1-C6 haloalkoxy), 5-10 membered hctcroaryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), halo, cyano, hydroxy, Ci-Ce alkoxy, Ci-Ce alkoxy(Ci-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-C6)alkyl (e.g., -CF3), halo(Ci-C6)alkoxy (e.g., -OCF3), Ci-Ce alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=0). Unless otherwise indicated, wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0111] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CFhCH CFhjCFF-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0112] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where ring A is a heterocyclyl ring containing the depicted nitrogen.

[0113] Similarly, when two “adjacent” R groups arc said to form a ring “together with the atoms to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups arc the recited ring. For example, when the following substructure is present:and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:where A is an aryl ring or a carbocyclyl containing the depicted double bond.

[0114] Wherever a substituent is depicted as a di -radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AE- orincludes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0115] As used herein, "isosteres" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The followingstructures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated.The atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.

[0116] It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is also contemplated that the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s) or is / are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.

[0117] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.

[0118] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0119] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes,monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

[0120] An “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0121] “Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.Methods of Preparation

[0122] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are bothhereby incorporated herein by reference in their entirety. The routes shown and described herein arc illustrative only and arc not intended, nor arc they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the ait will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0123] Scheme A provides a general synthetic scheme for the synthesis of compounds of Formula 1.SCHEME A

[0124] To a solution of substituted heteroaromatic sulfonyl chloride (1.00 eq) in dichloromethane (0.500 mL) is added pyridine (2.00 eq) and 7-amino-4-substituted- 1 H-indole- 3-carbonitrile or other substitution (1.00 eq). The mixture is stirred at 20 °C for 1 h. The reaction mixture is concentrated under reduced pressure to remove solvent. The crude product is purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:43%-73% B over 10 min) and lyophilized to afford the desired heteroaromatic indole sulfonamide.Administration and Pharmaceutical Compositions

[0125] The compounds are administered at a therapeutically effective dosage. While human dosage levels have yet to be optimized for the compounds described herein, generally, a daily dose may be from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg, from about 0.05 mg / kg to about 50 mg / kg of body weight, or from about 0.075 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg per day or less to about 7000 mg per day or more, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state beingtreated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0126] Administration of the compounds disclosed herein, or the pharmaceutically acceptable salts thereof, can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0127] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0128] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0129] Some examples of substances, which can serve as pharmaceutically - acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt;gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0130] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0131] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 h), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0132] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere withthe inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0133] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0134] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0135] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0136] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0137] Compositions described herein may optionally include other drug actives.

[0138] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0139] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.

[0140] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0141] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but arc not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

[0142] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

[0143] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0144] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxy toluene.

[0145] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0146] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co- solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0147] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodiumformaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0148] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0149] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, a daily dose may be from about 0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg of body weight, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.Methods of Treatment

[0150] The compounds disclosed herein and / or pharmaceutically acceptable salts thereof can effectively modulate RNA splicing by RBM39. Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.

[0151] Some embodiments include methods of treating cancer with the compounds and compositions comprising compounds described herein. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof. In some embodiments, a subject can be an animal, e.g., a mammal, a human. Example cancers include, but are not limited to, colorectal cancer (CRC), pleural mesothelioma (PM), cutaneous squamous cell carcinoma (CSCC); tumor mutation burden high (TMB-H), Bacillus Calmette-Guerin bladder cancer, endometrial carcinoma (EC), esophageal squamous cell carcinoma (ESCC), Merkel cell carcinoma (MCC), hepatocellular carcinoma (HCC), primary mediastinal large B cell lymphoma (PMBCL), cervical cancer, urothelial carcinoma, classical Hodgkin’s lymphoma, head and neck squamous cell carcinoma, liver cancer, gastric cancer, prostate cancer, sarcoma, melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, renal cell carcinoma, triple negative breast cancer, luminal B breast cancer, colon cancer, ovarian cancer, pancreatic cancer, intrahepatic cholangiocarcinoma, bladder cancer and glioblastoma.

[0152] Some embodiments include methods of treating cancer with the compounds and compositions comprising compounds described herein, wherein the cancer can be characterized by a gene fusion mutation. Example cancers that can be characterized by a gene fusion mutation include, but are not limited to, acute lymphoblastic leukemia, acute megakary oblast leukemia, acute myeloid leukemia, anaplastic large T-cell lymphoma, breast carcinoma, Burkitt lymphoma, chronic myeloid leukemia, colorectal carcinoma, Ewing’s sarcoma, fibrosarcoma, follicular lymphoma, glioblastoma multiforme, hepatocellular carcinoma, lung cancer, esophageal adenocarcinoma, ovarian adenocarcinoma, pilocytic astrocytoma, intrahepatic cholangiocarcinoma, bladder cancer, prostate carcinoma, and thyroid carcinoma. Example fusion genes include, but are not limited to, BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, RBM15-MKL1, RUNX1-RUNX1T1(AML1-MTG8), PML-RARA, CBFB- MYH11, NPM1-ALK, TRMT11-GRIK2, CCNH-C5orf30, ETV6-NTRK3, ODZ4-NRG1,TBL1XR 1-RGS 17, MYB-NFIB, MAST-fusions, NOTCH-fusions, IGH-MYC, IGK-MYC, IGL-MYC, RSPO2-EIF3E, RSPO2-PTPRK, EWSR1-FLI1, EWSR1-ERG, BCL2-IGH, MAN2A1-FER, FGFR3-TACC3, FIG-ROS1, EML4-ALK1, ESRRA-Cl lorf20, BRAF- KIAA1549, TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR-TP53BP1, RPS10-HPR, APAK9-BRAF, RET-CCDC6, PAX8- PPARG, TFG-NTRK1, and TPM3-NTRK1.

[0153] In some embodiments, the methods of treating cancer with the compounds and compositions described herein can dysregulate EWSR-FLI1 fusion gene splicing. In some embodiments, dysregulation of EWSR-FLI fusion gene splicing can include skipping RNA splicing of Exon 6 and / or Exon 7 of FLU in the EWSR1-FLI1 fusion gene. In some embodiments, expression of EWS-FLI1 fusion protein can be reduced.

[0154] In some embodiments, the methods of treating cancer with the compounds and compositions described herein can include obtaining a biological sample from the subject and identifying the gene fusion mutation. In some embodiments, the gene fusion mutation can be Type I EWS-FLI1, wherein exons 1-7 of EWSR1 are fused to exons 6-9 of FLU, also referred to as a 7 / 6 fusion. In a Type II EWS-FLI1 fusion, exons 1-7 of EWSR1 are fused to exons 5-9, also known as a 7 / 5 fusion.

[0155] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, including the compounds and compositions comprising compounds described herein (e.g., compounds of Formula (I)). Non-limiting examples of RBM39 degraders are described in the following illustrative publications. The preparation and use of N-(3-cyano-4-methyl-lH- indol-7-yl)-3-cyanobenzenesulfonamide is described in U.S. Pat. No. 8,772,269 (Owa), which is incorporated herein by reference in its entirety. The preparation and use of substituted N- (lH-indol-7-yl)benzenesulfonamides is described in International Publication Nos. WO 2022 / 169755 (Greenlee), WO 2022 / 173805 (Greenlee) and WO 2023 / 059899 (Greenlee), which are incorporated herein by reference in their entirety. The preparation and use of pyrazolesulfonamides is described in International Publication No. WO 2020 / 210139 (Estrada), which is incorporated herein by reference in its entirety. The preparation and use of tricyclic sultams and sulfamides is described in International Publication Nos. WO 2023 / 064058 (Wehn) and WO 2023 / 064152 (Caldwell), which are incorporated by referencein their entirety. The preparation and use of other sulfonamide derivatives that are RBM39 degraders is described in U.S. Application Nos. 2009 / 0047365 (Owa) and 2010 / 0291592 (Semba) and International Publication Nos. WO 2019 / 147783 (Gray) and WO 2024 / 039689 (Saeed), which are incorporated herein by reference in their entirety.

[0156] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be N-(3-cyano-4-methyl-lH-indol-7-yl)-3- cyanobenzenesulfonamide.

[0157] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:, or a pharmaceutically acceptable salt thereof, wherein ring A can be an optionally substituted monocyclic or bicyclic aromatic ring; ring B can be an optionally substituted 6-membered cyclic unsaturated hydrocarbon or 6- membered unsaturated heterocycle containing a nitrogen atom as a heteroatom; ring C can be an optionally substituted 5-membered heterocycle containing one or two nitrogen atoms; W can be a single bond, or -CH-CH-; X can be -NCR1) - or an oxygen atom; Y can be a carbon atom or a nitrogen atom; and Z can be -N(R2)- or a nitrogen atom, wherein R1and R2each independently can be, identically or differently, a hydrogen atom or a lower alkyl group.

[0158] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein E can be -O-, -N(CH ) -, -CH2-, -CH2CH2-, or -CH2O-; D can be -CH2- or -O-; Rlacan be a hydrogen atom or a halogen atom; and R2acan be a halogen atom or a trifluoromethyl group.

[0159] In other embodiments, the RBM39 degrader can be a compound having the structure:, or a pharmaceutically acceptable salt thereof, wherein J can be -O- or -NH-, Rlbcan be a hydrogen atom, a halogen atom, an optionally substituted Ci-Ce alkyl group, an optionally substituted C1-C4 alkoxy group, an optionally substituted C1-C4 alkylthiogroup, -CF3, -OCF3, -SCF3, an optionally substituted C1-C4 alkoxy carbonyl group, a nitro group, an azido group, -O(SO2)CH , -N(CH3)2, a hydroxyl group, a phenyl group, a substituted phenyl group, a pyridinyl group, a thienyl group, a furyl group, a quinolinyl group or a triazole group; R2bcan be a hydrogen atom, a halogen atom, a cyano group, -CF3, an optionally substituted Ci-Ce alkyl group, an optionally substituted C1-C4 alkoxy carbonyl group, an optionally substituted C1-C4 alkoxy group, an optionally substituted phenyl group or an optionally substituted quinolinyl group; R3bcan be a hydrogen atom or an optionally substituted C1-C4 alkoxy group; R4bcan be a hydrogen atom or an optionally substituted C1-C6 alkyl group (provided that at least one of Rband R4bis a hydrogen atom); R5bcan be a hydrogen atom, a halogen atom, an optionally substituted Ci-Ce alkyl group, -CF3 or a nitro group; R6bcan be a hydrogen atom, a halogen atom or an optionallysubstituted Ci-Ce alkyl group (provided that when R6bis an optionally substituted Ci-Ce alkyl group, R5bis a hydrogen atom and R7bis a halogen atom), R7bcan be a halogen atom, an optionally substituted Ci-Ce alkyl group or -CF3 (provided that when either R5bor R7bis an optionally substituted Ci-Ce alkyl group or when R7bis a halogen atom or an optionally substituted Ci-Ce alkyl group, either one of R5bor R6bis a hydrogen atom).

[0160] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure;, or a pharmaceutically acceptable salt thereof.In other embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 nd having the structure:pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein R1can be selected from chloro, bromo, fluoro, and iodo; R2can be selected from H, chloro, fluoro and methyl; R3can be selected from H, chloro, fluoro, cyano and methyl; R5can be selected from H and Ci-Ce alkyl; R6can be selected from -CO2CH3,-CH2OCH3, CH2S(O)CI-C6 alkyl, ((optionally substituted 3 to 7-membered heterocyclyl)oxy)Ci-C6 alkyl, optionally substituted C1-C6 alkoxy )Ci-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3 to 7-membered heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10-membered heteroaryl, (optionally substituted 3 to 7-membered heterocyclyl)Ci-Ce alkyl, (optionally substituted Ce-Cio aryl)Ci- Ce alkyl, (optionally substituted 5 to 10-membered heteroaryl)Ci-C6 alkyl, and

[0162] In other embodiments, the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein R can be an optionally substituted-5,6; -6,5; -6,6; -6,7 bicyclic ring system; R1can be selected from chloro, bromo, fluoro and iodo; and R2can be selected from H, chloro, fluoro, and methyl.

[0163] In yet other embodiments, the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein R1can be selected from chloro, bromo, fluoro, and iodo; R2can be selected from H, chloro, fluoro, and methyl; R3can be selected from H, chloro, fluoro, cyano, and methyl; R4can be selected fromwherein R5can be selected from optionally substituted C3 to C7 cycloalkyl, optionally substituted 4 to 12-membered heterocyclyl, optionally substituted Ce-Cio aryl, and substituted Ci-Cs alkyl; wherein the Ci-Cs alkyl can be substituted with at least one substituent selected from halo, Ci-Ce alkoxy, (optionally substituted C3-C7 cycloalkyl amino)carbonyl, (Ci-Ce alkoxycarbonyl)(Ci-C6 alkyl)amino,(Ci-C6alkyl)(Ci-C6 alkyl)N-, Ci-Ce alkylsulfonyl, optionally substituted 4 to 8-membered hctcrocyclyl, optionally substituted bcnzo[d][l,3]dioxolyl, optionally substituted benzooxazolonyl, optionally substituted tetrahydroquinolinyl, optionally substituted tetrahydroisoquinolinyl, optionally substituted Ce-Cio aryl, optionally substituted isoindolinyl, and optionally substituted 5 to 10-membered heteroaryl;wherein R6can be selected from H and CH3; R7can be selected from optionally substituted C3-C7 cycloalkyl, optionally substituted 2,3-dihydro-lH-indenyl, optionally substituted 3 to 7- membered heterocyclyl, and substituted C1-C5 alkyl; wherein the C1-C5 alkyl can be substituted with at least one substituent selected from optionally substituted C1-C6 alkoxy, optionally substituted 4 to 8-membered hetercyclyoxy, -C(O)NR8R9, C1-C6 alkylsulfonyl, optionally substituted C3-C7 cycloalkyl, optionally substituted bicyclooctatrienyl, optionally substituted 4 to 8-membered heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted dihydrobenzodioxinyl, and optionally substituted 5- to 10-membered heteroaryl; wherein R8and R9together with the nitrogen atom to which they are attached can form an optionally substituted 5-6 membered heterocyclyl; or alternatively, R6and R7together with the nitrogen atom to which they are attached can form a group selected from optionally substituted 4 to 12- membered optionally substituted heterocyclyl, and optionally substituted 4,5,6,7-tetrahydro- 1 H-imidazo [4,5-c]pyridinyl.

[0164] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader,wherein the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein X can be N or CRe; R1can be hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or halo; R2can be hydrogen, halo, or cyano; R3can be hydrogen, C1-C4 alkyl, halo, cyano, C1-C4 fluoroalkyl, -(C1-C4 alkyl)OH, or -NRaRb, wherein Raor Rbindependently can be hydrogen, C3-C6 cycloalkyl, heterocycloalkyl, or C1-C4 alkyl, or R7Rband the nitrogen atom they are attached to can form a 5 or 6-membered ring optionally independently substituted by one or more substituents selected from halo, C1-C4 alkyl, cyano, hydroxy, and -O(Ci-C4 alkyl); R4can be hydrogen, Ci-Ce alkyl, C1-C10 heteroalkyl, C1-C4 fluoroalkyl, -(Ci-C4)alkylNH2, C3-Ce cycloalkyl, -(C1-C4 alkyl)(C.3-C6 cycloalkyl), -(C1-C4 alkyl)phenyl, phenyl, heteroaryl, -(Ci-C; alkyl)heteroaryl, C2-C5 alkenyl, -(Cj-Q alkyl)heterocycloalkyl. heterocycloalkyl, -C0-C4 alkylS(-O)?.(Ci-C4 alkyl), -S(-O)2phenyl, -Sf-Ohheteroaryl, -C0-C4 alkylC(~O)heterocycioalkyl, -C0-C4 alkyl C(~O)NRaRb, -(C0-C4 alkyl)C(~O)O(Ct -Ch alkyl), -(C0-C4 alkyl)C(-O)Ct-C4alkyl, -(C0-C4 alkyl)C(-O)OH or -(Ci-Cs alkyl)OH, wherein R,j can be substituted with 0, I , 2, or .3 substituents selected from deuterium, halo, hydroxy, — ((2o- C4alkyl)O(Ci-C4 alkyl), -C1-C4 alkyl, -(Co-C4alkyl)cyano, -S(=O)2(Ci-C4 alkyl), -C0-C4 alkylC(=O)NRaRb, -C(=O)O(C’.-C4alkyl), C1-C4 fluoroalkyl oxo, -(C1-C4 alky 1)011, and -NH2, wherein each of Raand R° can be independently substituted with 0, 1, 2, or 3 hydrogen, C3-C6 cycloalkyl, heterocycloalkyl or C1-C4 alkyl; R< can be hydrogen, halo, -NH2 or Cj-C4alkyl; i<6 can be hydrogen, halo or C1-C4 alkyl; and R? can be hydrogen, halo, heteroalkyl, Ci-C.4 alkyl, -(C0-C4 aIkyI)O(Ci-C4alkyl), -(C1-C4 alkyl)(C3-C6cycloalkyl), C3-C6cycloalkyl, -(C:-C4alkyl Iheterocycloalkyl, or heterocycloalkyl.

[0165] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:pharmaceutically acceptable salt thereof, wherein:W can be NRaor CRaRn; Rbcan be hydrogen, or (Ci-C4)alkyl; Racan be selected fromH, (Ci-C6) alkyl, -(Ci-C6)alkylOH, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl,(C2-Cs)alkenyl, cycloalkyl((Co-C6)alkyl), aryl((Co-C6)alkyl), heterocycloalkyl((Co-C6)alkyl), heteroaryl((Co-C6)alkyl), ((Co-C6)alkyl)amino((Ci-C6)alkyl), and((Ci-C6)alkyl)carbonylamino((Ci-C6)alkyl), wherein Rais substituted with 0, 1, 2 or 3 R4substituents; each R4can be independently selected from (Ci-C6)alkylcarbonyl, cyano, (Ci-C6)haloalkyl, halogen, oxo, (Ci-C6)alkyl, (Ci-C6)alkoxy((C0-C6)alkyl, -SO2(Ci-C6alkyl), amino, hydroxy, amino(Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarboxy, and -(Ci-C6)alkylOH, provided that when Rais (Ci-C6)alkoxy(Ci-Ce)alkyl), R4is other than (Ci-Ce)alkoxy((Co- Ce)alkyl; each n independently can be 1, 2, or 3; Z can be CH or N; X can be CH or N; R1can be H, (Ci-C6)alkyl, cyano, -(Ci-CelOH, halogen, or (Ci-C6)haloalkyl; and R2can be H, (Ci-C6)alkyl, cyano, -(CI-C6)OH, halogen, or (Ci-C6)haloalkyl.

[0166] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:, or a pharmaceutically acceptable salt thereol, wherein:R1can be selected from H, (Ci-C6)alkyl, aminocarbonyl(Ci- C6)alkylaminocarbonyl(Co-C6)alkyl, carboxy(Ci-C6)alkyl, hydroxycarbonyl(Co-C6)alkyl), and (Ci-C6)alkoxycarbonyl(Co-Ce)alkyl); R2can be H, -(Ci-Ce)alkyl, cyano, -(Ci-Ce)OH, halogen, or (Ci-C6)haloalkyl; R3can be H, -(Ci-Ce)alkyl, cyano, -(CI-C6)0H, halogen, or (Ci-C6)haloalkyl; R4can be selected from (Ci-C6)alkoxy((Ci-C6)alkyl), heterocycloalkyl((Co- Ce)alkyl), heteroaryl((Co-C6)alkyl), -C(=O)(Ci-C6)alkyl-(O-(Ci-C6)alkyl)n, and -(Ci-C6)alkyl-(O-(Ci-C6))n, wherein R4is substituted with 0, 1, 2, or 3 R5substituents; each n independently can be 1, 2, 3, or 4; each R5independently can be selected from cyano, (Ci-C6)haloalkyl, halogen, hydroxy, oxo, (Ci-Ce)alkyl, (Ci-C6)alkoxy(Co-C6)alkyl, -SO2(Ci-C6)alkyl, amino, -C(=O)(Ci-C6)alkyl-(O-(Ci-C6)alkyl)m, -(Ci-C6)alkyl-(O-(Ci- C6) lkyl)m, amino(Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarboxy, (Ci-C6)alkylcarbonyl, and -(Ci-C6)alkylOH, wherein each R5independently can be substituted with 0, 1, 2 or 3 R6substituents; each R6independently can be selected from amino, (Ci-C6)alkylcarboxy, (Ci-C4)alkyl, halogen and hydroxy; each m independently can be 1, 2, or 3; and provided that when R4is (Ci-C6)alkoxy((Ci-C6)alkyl), heterocycloalkyl((Co-C6)alkyl), or heteroaryl((Co- Ce)alkyl) then R1is other than hydrogen.

[0167] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader can be a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein:RN1can be H or Ci-ealkyl optionally substituted with 1 , 2, or 3 R7;RN2can be H or Ci-ealkyl optionally substituted with 1 , 2, or 3 R7;X1can be OR1or N;X2can be CR3or N;X3can be CR4or N;R1can be H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, halo, OH, or ON, and the Ci-ealkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R2can be H, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci.6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci.6alkyl;R3can be H, Ci-6alkyl, Ci-ehaloalkyl, Ci-ealkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R4can be H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R3can be H, Ci-6alkyl, Ci-ehaloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-ealkyl; each RNis independently H, Ci-6alkyl optionally substituted with 1 , 2, or 3 R7, or Ca-iocycloalkyl;Het can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1 , 2, or 3 ring hctcroatoms selected from O, S, and N and optionally substituted with 1 , 2, or 3 R6;each R6can be independently halo, CN, Ci-ealkyl, Cnehaloalkyl, Cnealkoxy, NRNRN, COOH, C(O)NRNRN, Ci-6alkylcnc-C(O)ORN, Ci-6alkylcnc-C(O)NRNRN, SO2NRNRN, P(O)(RN)(RN), C(O)-5- or 6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, Ci-ealkylene-Ca-iocycloalkyl, Ca-iocycloalkyl, 4-6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, Ce-ioaryl, or 5- or 6- membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, wherein the Ca-iocycloalkyl, 4-6-membered heterocycloalkyl, Ce-ioaryl, or 5- or 6-membered heteroaryl can optionally be substituted with 1 , 2, or 3 R7and each Ci-ealkyl, Ci-ealkylene, or Ci-ealkoxy can be optionally substituted with 1 or 2 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-ealkyl; and each R7is independently OH, halo, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, NH2, NH(Ci-6alkyl), or N(Ci-6alkyl)2.

[0168] In some embodiments, an RBM39 degrader can be E7820, indisulam, chloroquinoxaline sulfonamide (CQS), tasisulam, or dCeMMl.

[0169] In some embodiments, the method of treating cancer characterized by a fusion gene mutation, includes administering an effective amount of an RBM39 degrader, wherein the RBM39 degrader may be selected from;

[0170] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the degradation or reduction of RBM39 protein.

[0171] In some embodiments, the method of administering one or more of the compounds disclosed herein results in increased expression of immunogenic ncocpitopcs.

[0172] In some embodiments, the method of administering one or more of the compounds disclosed herein results in increased CD8+T cell expansion. In someembodiments, the method includes administering a pharmaceutically acceptable salt thereof of one or more compounds disclosed herein.

[0173] In some embodiments, the subject is a human.

[0174] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.

[0175] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein, with an additional medicament. By “coadministration,” it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.

[0176] Some embodiments further include administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy. In some embodiments, the immunotherapy includes administration of an immune checkpoint inhibitor.Immune Checkpoint Inhibitors

[0177] In some embodiments, one or more immune checkpoint inhibitor may be co-administered with a compound of Formula (I). A review describing immune checkpoint pathways and the blockade of such pathways with immune checkpoint inhibitor compounds is provided by Pardoll in Nature Reviews Cancer (April 2012), pages 252-264, which is incorporated herein by reference in its entirety. Immune check point inhibitor compounds display anti-tumor activity by blocking one or more of the endogenous immune checkpoint pathways that downregulate an anti-tumor immune response. The inhibition or blockade of an immune checkpoint pathway typically involves inhibiting a checkpoint receptor and ligand interaction with an immune checkpoint inhibitor compound to reduce or eliminate the down regulation signal and resulting diminishment of the anti-tumor response.

[0178] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound inhibits the signaling interaction between an immune checkpoint receptor and the corresponding ligand of the immune checkpoint receptor. The immune checkpoint inhibitor compound can act by blocking activation of the immune checkpoint pathway by inhibition (antagonism) of an immune checkpoint receptor (some examples of receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or by inhibition of a ligand of an immune checkpoint receptor (some examples of ligands include PD-L1 and PD-L2). In such embodiments, the effect of the immune checkpoint inhibitor compound is to reduce or eliminate down regulation of certain aspects of the immune system anti-tumor response in the tumor microenvironment.

[0179] The Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; which are incorporated herein by reference in their entirety). Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA. PD-1 is suggested to exist as a monomer, lacking the unpaired cysteine residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.

[0180] The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72, which is incorporated herein by reference in its entirety). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is important for B7-1 and B7-2 binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD- L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carteret al. (2002) Eur. J. Immunol. 32:634- 43; which are incorporated herein by reference in their entirety). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9, which is incorporated herein by reference in its entirety).

[0181] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745; which arc incorporated herein by reference in their entirety). The interaction between PD-1 and PD-L1 can act as an immune checkpoint, whichcan lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and / or immune evasion by cancerous cells (Dong ct al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100; which are incorporated herein by reference in their entirety). Immune suppression can be reversed by inhibiting the local interaction of PD- 1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat’l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66; which are incorporated herein by reference in their entirety).

[0182] The immune checkpoint receptor cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is expressed on T-cells and is involved in signaling pathways that reduce the level of T-cell activation. It is believed that CTLA-4 can downregulate T-cell activation through competitive binding and sequestration of CD80 and CD86. In addition, CTLA-4 has been shown to be involved in enhancing the immunosuppressive activity of TRegcells.

[0183] The immune checkpoint receptor programmed death 1 (PD-1) is expressed by activated T-cells upon extended exposure to antigen. Engagement of PD-1 with its known binding ligands, PD-L1 and PD-L2, occurs primarily within the tumor microenvironment and results in downregulation of anti-tumor specific T-cell responses. Both PD-L1 and PD-L2 are known to be expressed on tumor cells. The expression of PD-L1 and PD-L2 on tumors has been correlated with decreased survival outcomes.

[0184] The immune checkpoint receptor T cell membrane protein 3 (TIM-3) is expressed on Thl and Tel cells, but not other T-cells. Interaction of TIM-3 with its ligand, galectin-9, produces a Thl cell death signal. TIM-3 has been reported to play a role in maintaining T-cell exhaustion and blockade of TIM-3 has been shown to restore activity to exhausted T-cells.

[0185] The immune checkpoint receptor B- and T-lymphocyte attenuator (BTLA) receptor is expressed on both resting and activated B-cells and T-cells. Activation of BTLA when combined with its ligand HVEM (herpes virus entry mediator) results in downregulation of both T-cell activation and proliferation. HVEM is expressed by certain tumors (e.g., melanoma) and tumor- associated endothelial cells.

[0186] The immune checkpoint receptors known as killer cell immunoglobulin- like receptors (KIR) are a polymorphic family of receptors expressed on NK cells and some T-cells and function as regulators of immune tolerance associated with natural killer (NK) cells. Blocking certain KIR receptors with inhibitor compounds can facilitate the destruction of tumors through the increased activity of NK cells.

[0187] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 Daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor compound is an antibody. In some embodiments, the antibody is a monoclonal antibody, specifically a human or a humanized monoclonal antibody.

[0188] Monoclonal antibodies, antibody fragments, and antibody derivatives for blocking immune checkpoint pathways can be prepared by any of several methods known to those of ordinary skill in the art, including but not limited to, somatic cell hybridization techniques and hybridoma, methods. Hybridoma generation is described in Antibodies, A Laboratory Manual, Harlow and Lane, 1988, Cold Spring Harbor Publications, New York, which is incorporated herein by reference in its entirety. Human monoclonal antibodies can be identified and isolated by screening phage display libraries of human immunoglobulin genes by methods described for example in U.S. Pat. Nos. 5,223,409, 5,403,484, 5,571,698, 6,582,915, and 6,593,081, which are incorporated herein by reference in their entirety. Monoclonal antibodies can be prepared using the general methods described in U.S. Pat. No. 6,331,415 (Cabilly), which is incorporated herein by reference in its entirety.

[0189] As an example, human monoclonal antibodies can be prepared using a XenoMouse™ (Abgenix, Freemont, Calif.) or hybridomas of B cells from a XenoMouse. A XenoMouse is a murine host having functional human immunoglobulin genes as described in U.S. Pat. No. 6,162,963 (Kucherlapati), which is incorporated herein by reference in its entirety.

[0190] Methods for the preparation and use of immune checkpoint antibodies are described in the following illustrative publications. The preparation and therapeutic uses of anti-CTLA-4 antibodies are described in U.S. Pat. No. 7,229,628 (Allison), U.S. Pat. No. 7,311,910 (Linsley), and U.S. Pat. No. 8,017,144 (Korman), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti-PD-1 antibodies are described in U.S. Pat. No. 8,008,449 (Korman) and U.S. Patent Application No. 2011 / 0271358(Freeman), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti-PD-Ll antibodies arc described in U.S. Pat. No. 7,943,743 (Korman), which is incorporated herein by reference in its entirety. The preparation and therapeutic uses of anti-TIM-3 antibodies are described in U.S. Pat. No. 8,101,176 (Kuchroo) and U.S. Pat. No. 8,552,156 (Tagayanagi), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti-LAG-3 antibodies are described in U.S. Patent Application No. 2011 / 0150892 (Thudium) and International Publication Number W02014 / 008218 (Lonberg), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti-KIR antibodies are described in U.S. Pat. No. 8,119,775 (Moretta), which is incorporated herein by reference in its entirety. The preparation of antibodies that block BTLA regulated inhibitory pathways (anti-BTLA antibodies) are described in U.S. Pat. No. 8,563,694 (Mataraza), which is incorporated herein by reference in its entirety.

[0191] In some embodiments, the one or more immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4. In some embodiments, the immune checkpoint inhibitor is a PD- 1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a binding ligand of PD-L1. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0192] In some embodiments, the one or more immune checkpoint inhibitor as described herein includes a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In some embodiments, the first and the second immune checkpoint inhibitor are independently an inhibitor of PD-1, PD-L1 or CTLA-4. In some embodiments, the first immune checkpoint inhibitor is a PD- 1 inhibitor, and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0193] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, spartalizumab, or any combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor may include an anti-PD-1 HuMAbs can be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3 and 5F4, all of which are described in U.S. Pat. No. 8,008,449, which isincorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAbs can be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 1 1E6, 12B7, and 13G4, all of which are described in U.S. Pat. No. 7,943,743, which is incorporated herein by reference in its entirety.

[0194] In some embodiments, the one or more immune checkpoint inhibitor may be incorporated in a pharmaceutically acceptable formulation. In some embodiments, the one or more immune checkpoint inhibitor is incorporated in a pharmaceutically acceptable aqueous formulation. Examples of acceptable aqueous formulations include isotonic buffered and pH 4.5-8 adjusted saline solutions such as Lactated Ringer’s Solution and the like.

[0195] In some embodiments, the immune checkpoint inhibitor compound is incorporated in a pharmaceutically acceptable liposome formulation, wherein the formulation is a passive or targeted liposome formulation. Examples of methods for the preparation of suitable liposome formulations of antibodies are described U.S. Pat. No. 5,399,331 (Loughrey), U.S. Pat. No. 8,304,565 (Wu) and U.S. Pat. No. 7,780,882 (Chang), which are incorporated herein by reference in their entirety.

[0196] In some embodiments, the one or more immune checkpoint inhibitor may be an antibody. In some embodiments, the antibody is a dry, lyophilized solid that is reconstituted with an aqueous reconstitution solvent prior to use. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected directly into a tumor. In some embodiments, the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected into the peritumoral region surrounding a tumor. The peritumoral region may contain antitumor immune cells. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intravenous injection or infusion. In some embodiments, the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by subcutaneous injection or intradermal injection. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intraperitoneal injection or lavage.

[0197] The precise amount of immune checkpoint inhibitor compound incorporated in a particular method or therapeutic combination of the disclosure may vary according to factors known in art such as for example, the physical and clinical status of the subject, the method of administration, the content of the formulation, the physical and chemical nature of the immune checkpoint inhibitor compound, the intended dosing regimen or sequence. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.

[0198] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the ail and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.EXAMPLESGeneral procedures

[0199] It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

[0200] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in their entirety) and the like. All the intermediate compounds were used without further purification unless otherwise specified.

[0201] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4thEd., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

[0202] The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase-based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application.

[0203] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.

[0204] The following abbreviations have the indicated meanings:AC2O = acetic anhydrideACN = acetonitrileAcOH = acetic acidAcOK = potassium acetateBOC = tert-butoxycarbonylBOC2O = di-tert-butyldicarbonateBu = butyl clogP = calculated partition coefficientDCM = dichloromethaneDIE A = W / V-diisopropylethylamineDIPEA = A,A-diisopropylethylamineDMAP = 4-dimethylaminopyridineDMF = dimethylformamideDMSO = dimethyl sulfoxideESI = electrospray ionizationEt = EthylFA = formic acidFBS = fetal bovine serumHATU = hexafluorophosphate benzotriazole tetramethyl uraniumHBSS = Hank’s Balanced Salt SolutionHCHO = formaldehydeHEPES = 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acidHOAc = acetic acidHPLC = high performance liquid chromatographyLCMS = liquid chromatography mass spectrometryLHMDS = lithium bis(trimethylsilyl)amideLogP = octanol / water partition coefficientMDCK = Madin Darby canine kidneyMDR1 = multidrug resistance gene-1MS = mass spectrometryMW = molecular weightNADPH = reduced nicotinamide adenine dinucleotide phosphateNCS = N-ChlorosuccinimideNMR = nuclear magnetic resonancePBS = phosphate-buffered salinePd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)CL = bis(diphenylphosphino)ferrocene]dichloropalladium(II)Ph = phenylPK = pharmacokineticPy = pyridineTBS-C1 = tert-butylchlorodimethylsilaneTEA = triethylamineTFA = trifluoracetic acidTHF = tetrahydrofuranTLC = thin-layer chromatography

[0205] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the ait in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.General Example. Preparative HPLC

[0206] Preparative HPLC were carried out under one of the following conditions:1) Column: Welch ultimate Cl 8 150*25mm * 7pm; mobile phase: [water(FA)- ACN];gradient:37%-67% B over 10 min;2) column: Waters Xbridge 150*25mm 10pm; mobile phase: [water(NH4HCOa)- ACN] gradient: 11%-41% B over 18 min; or3) column: Waters Xbridge C18 150*50mm* 10pm; mobile phase: [water(NH3H O)- ACN] gradient: 12%-42% B over 10 min.Example 1. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-methyl-thiazole-5- sulfonamide (Compound 1)Compound 1

[0207] To a solution of 2-mcthylthiazolc-5- sulfonyl chloride (100 mg, 506 pmol, 1.00 eq) and 7-amino-4-methyl-lH-indole-3-carbonitrile (95.3 mg, 557pmol, 1.10 eq) in dichloromethane (2.00 mL) was added pyridine (80.0 mg, 1.01 mmol, 81.7 pL, 2.00 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and collected the filter cake. The crude product was triturated with ethyl acetate (3.00ml) at 25 °C for 10 min to give the A-(3-cyano-4-methyl- 1 H-indol-7-yl)-2-methyl-thiazole-5-sulfonamide (48.34 mg, 143.97 pmol, 28.46% yield, 99% purity) as a red solid. MS (ESI) m / z 333.0 [M+H]+. 'H NMR (400 MHz, DMSO-^6) d = 11.99 (s, 1H), 10.28 (s, 1H), 8.19 (d, J = 3.2 Hz, 1H), 7.90 (s, 1H), 6.88 (d, 7= 7.6 Hz, 1H), 6.72 (d, J= 7.6 Hz, 1H), 2.68 (s, 3H), 2.61 (s, 3H).Example 2, Synthetic Scheme of Compound 2Compound 2Example 2,1, Preparation of 2-methyloxazole-5-sulfinic acid

[0208] To a solution of 2-methyloxazole (200 mg, 2.41 mmol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added n-Butyllithium (2.5 M, 1.44 mL, 1.50 eq) dropwise at - 78 °C and stirred 30 min. under nitrogen, and then sulfur dioxide (154 mg, 2.41 mmol, 1.00 eq) was bubbled into at -65 °C for 30 min. The reaction mixture was warmed to 20°C slowly and stirred for 2 h. A solution of 2-methyloxazole-5-sulfinic acid (400 mg, crude) in tetrahydrofuran (2.00 mL) was obtained as a yellow liquid and it used into next step directly. Example 2,2, Preparation of 2-methyloxazole-5-sulfonyl chloride

[0209] To a solution of 2-methyloxazole-5-sulfinic acid (395 mg, 2.42 mmol, 1.00 eq) in tetrahydrofuran (3.00 mL) was added 1 -chloropyrrolidine-2, 5-dione (969 mg, 7.26 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL). The combined organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum cthcr / cthyl acetate = 3 / 1) to give 2-methyloxazole-5-sulfonyl chloride (180 mg, 912 pmol, 37% yield, 92% purity) as a yellow oil. ’H NMR (400 MHz, CDC13) <5 = 7.75 (s, 1H), 2.66 (s, 3H).Example 2,3. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-methyl-oxazole-5- sulfonamide (Compound 2)Compound 2

[0210] To a solution of 2-methyloxazole-5-sulfonyl chloride (50.0 mg, 275 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (43.6 mg, 551 pmol, 44.5 pL, 2.00 eq) and 7-amino-4-methyl-177-indole-3-carbonitrile (47.1 mg, 275 pmol, 1.00 eq). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:22%-52% B over 8 min) and lyophilized to afford A-(3-cyano-4-methyl-lH-indol-7-yl)-2-methyl-oxazole-5-sulfonamide (30.66 mg, 95.66 pmol, 34.74% yield, 98.7% purity) as a purple solid. MS (ESI) m / z 317.2 [M+H]+.{H NMR (400 MHz, acetone) 6 = 11.39 - 11.05 (m, 1H), 8.15 (s, 1H), 7.36 (s, 1H), 7.01 - 6.81 (m, 2H), 2.71 (s, 3H), 2.51 (s, 3H).Example 3. Synthetic Scheme of Compound 3Compound 3Example 3.1. Preparation of 2-(2-bromothiazol-5-yl)-morpholino-methanone

[0211] To a solution of 2-bromothiazole-5-carboxylic acid (1.50 g, 7.21 mmol, 1.00 eq) in dimethylformamide (15.0 mL) was added morpholine (690 mg, 7.93 mmol, 697 pL, 1.10 eq) , 6>-(7-azabenzotriazol- l-yl)-A^M / V, / V-tetramethyluroniumhexafluorophosphate (2.74 g, 7.21 mmol, 1.00 eq) and / V, / V-diisopropylethylamine (1.86 g, 14.4 mmol, 2.51 mL, 2.00 eq) at 20°C. The mixture was stirred at 20°C for 16 h. The mixture was poured into water(30.0 mL), extracted with dichloromethane (70mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL. Petroleum ether / Ethyl acetate=100 / l to 5 / 1), TLC (petroleum ether / ethyl acetate =l:l,R=0.5,P=0.3). (2-Bromothiazol-5-yl)-morpholino-methanone (1.00 g, 3.57 mmol, 49% yield, 98% purity) was obtained as a white solid.JH NMR (400 MHz, DMSO- d6) 6 = 8.02 (s, 1H), 3.63 (s, 8H).Example 3.2, Preparation of 3-[2-[(4-methoxyphenyl)methylsulfanyl]thiazol-5-yl]- morpholino-mcthanoncsolution of (2-bromothiazol-5-yl)-morpholino-methanone (500 mg, 1.80 mmol, 1.00 eq) in dimethylformamide (5.00 mL) was added (4- methoxyphenyl)methanethiol (306 mg, 1.98 mmol, 276 pL, 1.10 eq) and potassium carbonate (498 mg, 3.61 mmol, 2.00 e<?)at 20°C. The mixture was stirred at 100°C for 4h. The mixture was poured into water (30.0 mL), extracted with dichloromethane (70.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 1 / 1), TLC (Petroleum ether / Ethyl acetate =0:l,Rf(R=0.5,P=0.3)). [2-[(4-Methoxyphenyl)methylsulfanyl]thiazol-5-yl]-morpholino-methanone (600 mg, crude) was obtained as a white solid. MS (ESI) m / z 351.2 [M+H]+.Example 3.3. Preparation of 5-(morpholine-4-carbonyl)thiazole-2-sulfonyl chlorideof [2-[(4-methoxyphenyl)methylsulfanyl]thiazol-5-yl]- morpholino-methanone (200 mg, 570 pmol, 1.00 eq) in acetic acid (3.00 mL) and water (1.00 mL) was added 1 -chloropyrrolidine-2, 5-dione (333 mg, 2.50 mmol, 4.37 eq) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was poured into water(20.0 mL), extracted with dichloromethane (50 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. 5-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride (155 mg, crude) was obtained as a white oil. MS (ESI) m / z 297.0 / 289.9 [M+H]+.Example 3.4, Preparation of N-(3-cyano-4-methyl-1H-indol-7-yl)-5-(morr)holine-4- carbonyl)thiazolc-2-sulfonamidc (Compound 3)Compound 3

[0214] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (30.0 mg, 175 pmol, 1.10 eq) in dichloromethane (1.00 mL) was added pyridine (25.2 mg, 318 pmol, 25.7 pL, 2.00 eq) and 5-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride (47.2 mg, 159 pmol, 1.00 eq) at 20°C. The mixture was stirred at 20°C for 16 h. The mixture was poured into water (10.0 mL), and extracted with dichloromethane (20.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by >rep-HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:24%-54% B over 15 min ). A-(3-cy ano-4- methyl- lH-indol-7-yl)- 5-(morpholine-4-carbonyl)thiazole-2-sulfonamide (5.86 mg, 13.38 pmol, 8.40% yield, 98.55% purity) was obtained as pink solid. MS (ESI) m / z 432.2 [M+H]+.JH NMR (400 MHz, DMSO- d6) = 12.12 - 12.03 (m, 1H), 10.87 (s, 1H), 8.37 - 8.26 (m, 1H), 8.19 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.73 (d, J= 8.0 Hz, 1H), 3.60 (dd, J = 4.8, 18.4 Hz, 8H), 2.60 (s, 3H). Example 4, Preparation of N-(3,4-dichloro-lH-indol-7-yl)-2-methyl-thiazole-5-sulfonamide (Compound 4)Compound 4

[0215] To a solution of 2-mcthylthiazolc-5-sulfonyl chloride (30.0 mg, 152 pmol, 1.20 eq) 3,4-dichloro- l / f-indol-7-aminc (30.0 mg, 126 pmol, 1.00 eq, HC1) in dichloromethane (0.500 mL) was added Pyridine (20.0 mg, 253 pmol, 20.4 pL, 2.00 eq). The mixture wasstirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC (column: Welch ultimate C18 150*25mm* 7pm;mobile phase: [water(FA)-ACN];gradient:37%-67% B over 10 min) and desired fraction was collected and lyophilized to give the A-(3,4-dichloro-177-indoL7-yl)-2- methyl-thiazole-5-sulfonamide (25.7 mg, 70.8 pmol, 56.1% yield, 100% purity) as a pink solid. MS (ESI) m / z 362.1 / 364.1 / 363.1 [M+H]+.!H NMR (400 MHz, DMSO-76) 3 = 11.43 (s, 1H), 10.53 - 10.21 (m, 1H), 7.93 (s, 1H), 7.53 (d, J= 2.0 Hz, 1H), 6.99 (d, 7= 8.0 Hz, 1H), 6.79 (d, 7 = 8.0 Hz, 1H), 2.66 (s, 3H).Example 5. Preparation of N-(3-(difhioromethyl)-4-methyl-lH-indol-7-yl)-2-methylthiazole- 5-sulfonamide (Compound 5)Compound 5

[0216] To a solution of 3-(difluoromethyl)-4-methyl-lH-indol-7-amine (28.4 mg, 145 pmol, 0.450 eq) and pyridine (50.9 mg, 644 pmol, 51.9 pL, 2.00 eq) in dichloromethane (0.800 mL) was added dropwise a solution of 2-methylthiazole-5- sulfonyl chloride (65 mg, 322 pmol, 1.00 eq) in dichloromethane (0.200 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was poured into water (10.0 mL) and extracted with dichloromethane (10.0 ml x 3). The combined organic phase was washed with brine (20.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)- ACN];gradient:36%-66% B over 8 min ). N-(3-(difluoromethyl)-4-methyl-lH-indol-7-yl)-2- methylthiazole-5-sulfonamide (7.24 mg, 15.03 pmol, 4.67% yield, 98.67% purity) was obtained as a gray solid. MS (ESI) m / z 475.1 / 477.1 / 476.1 [M+H]+. 'H NMR (400 MHz, CDCh) 3 = 11.3 (s, 1H), 10.2 (s, 1H), 7.9 (s, 1H), 7.7 (s, 1H), 7.38-7.10 (m, 1H), 6.8 (d, J = 8.4 Hz, 1H), 6.70 (d, 7=7.6Hz, 1H), 2.67 (s, 3H), 2.51 (s, 3H).Example 6. Synthetic Scheme of Compound 6Compound 6Example 6.1. Preparation of 2-methylthiazole-5-sulfinic acid

[0217] To a solution of 2-methylthiazole (1.00 g, 10.1 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added n-butyllithium (2.5 M, 6.05 mL, 1.50 eq) dropwise at - 78 °C and stirred 30 min under nitrogen, and then sulfur dioxide (646 mg, 10.1 mmol, 1.00 eq) was bubbled into at -65 °C for 30 min. The reaction mixture was warmed to 20 °C slowly and stirred for 2 h. The crude product 2-methylthiazole-5-sulfinic acid (2.00 g, crude) in tetrahydrofuran (20.0 mL) was obtained as a yellow liquid. The mixture was used into the next step without further purification.Example 6.2. Preparation of 2-methylthiazole-5-sulfonyl chloride

[0218] To a solution of 2-methylthiazole-5-sulfinic acid (2.00 g, 11.2 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added N- chloro-succinimide (4.47 g, 33.5 mmol, 3.00 cq) at 0°C and stirred another 12 h at 20°C. The reaction mixture was quenched by addition water (20.0 mL) at 0 °C, and then extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 3 / 1) and concentrated under reduced pressure to give the 2-methylthiazole-5-sulfonyl chloride (1.30 g, 6.25 mmol, 56% yield, 95% purity) asa yellow oil. MS (ESI) m / z 198.0 / 200.0 [M+H]+.!H NMR (400 MHz, CDCW) d = 8.32 (s, 1H), 2.85 (s, 3H).Example 6.3. Preparation of N-(4-chloro-3-cvano-lH-indol-7-yl)-2-methyl-thiazole-5- sulfonamide (Compound 6)Compound 6

[0219] To a solution of 2-methylthiazole-5-sulfonyl chloride (37.1 mg, 188 pmol, 1.20 eq) and 7-amino-4-chloro-lH-indole-3-carbonitrile (30.0 mg, 157 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added pyridine (24.8 mg, 313 pmol, 25.3 pL, 2.00 eq). The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water(NH4HCO3)-ACN];gradient:l l%-41% B over 18 min) and lyophilized to give the JV-(4-chloro-3-cyano- lH-indol-7-yl)-2-methyl-thiazole-5- sulfonamide (9.20 mg, 26.0 pmol, 16.6% yield, 99.8% purity) as a white solid. MS (ESI) m / z 353.0 / 354.9 / 354.1 [M+H]+. ’H NMR (400 MHz, DMSO-< / 6) d = 12.34 (s, 1H), 10.50 (s, 1H), 8.33 (s, lH), 7.93 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.91 - 6.79 (m, 1H), 2.68 (s, 3H).Example 7, Synthetic SchemeCompound 7Example 7.1. Preparation of ethyl 2-(5-bromothiazol-2-yl)acetate

[0220] To a solution of 5-bromo-2-methyl-thiazole (1.50 g, 8.42 mmol, 1.00 eq) in tetrahydrofuran (15.0 mL) was added lithium bis(trimethylsilyl)amide (1 M, 18.5 mL, 2.20 eq). The mixture was stirred at -78 °C for 0.5 h. Diethyl carbonate (1.20 g, 10.2 mmol, 1.23 mL, 1.21 eq) was added and stirred at 0 °C for 4 h. After the end of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (50 mL x 3). The organic was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 3 / 1) to give ethyl 2-(5-bromothiazol-2-yl)acetate (550 mg, 2.20 mmol,26% yield) as a yellow oil. ’H NMR (400 MHz, DMSO-d6) 6 = 7.87 - 7.74 (m, 1H), 4.20 -4.10 (m, 4H), 1.21 (t, 7 = 7.2 Hz, 3H).Example 7.2. Preparation of 2-[5-[(4-methoxyphenyl)methylsulfanyl1thiazol-2-yl1acetate

[0221] Ethyl 2-(5-bromothiazol-2-yl)acetate (500 mg, 2.00 mmol, 1.00 eq), (4- methoxyphenyl)methanethiol (462 mg, 3.00 mmol, 417 pL, 1.50 eq), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg, 200 pmol, 0.100 eq), diisopropylethylamine (775 mg, 6.00 mmol, 1.04 mL, 3.00 eq) and tris(dibenzylideneacetone)dipalladium(0) (183 mg, 200 pmol, 0.100 eq) were taken up into a microwave tube in dimethylformamide (5.00 mL). The sealed tube was heated at 120 °C for 1.5 h under microwave. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 3 / 1) to give ethyl 2-[5-[(4- methoxyphenyl)methylsulfanyl]thiazol-2-yl] acetate (490 mg, 1.52 mmol, 75% yield) as a yellow oil . MS (ESI) m / z 324.1 [M+H]+.Example 7,3. Preparation of 2-[5-[(4-methoxyphenyl)methylsulfanyl]thiazol-2-yl]ethanol

[0222] To a solution of ethyl 2-[5-[(4-methoxyphenyl)methylsulfanyl]thiazol-2- yl]acetate (220 mg, 680 pmol, 1.00 eq) in ethanol (3.00 mL) was added sodium tetrahydroborate (66.9 mg, 1.77 mmol, 2.60 eq) in portion at 0 °C. The mixture was warmedto 20 °C and stirred at 20 °C for 2 h. The mixture was quenched by adding saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic layer was concentrated under vacuum to give a crude product. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 3 / 1) to give 2-[5-[(4- methoxyphenyl)methylsulfanyl]thiazol-2-yl]ethanol (150 mg, 533 pmol, 78% yield) as a yellow oil.JH NMR (400 MHz, CDCL) d = 7.44 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.90 (s, 2H), 3.80 (s, 3H), 3.15 (t, J= 5.6 Hz, 2H).Example 7,4, Preparation of 2-(2-methoxyethy l)-5- [ (4- methoxyphenyDmethylsulfanyllthiazole

[0223] To a solution of 2-[5-[(4-methoxyphenyl)methylsulfanyl]thiazol-2- yl]ethanol (100 mg, 355 pmol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added sodium hydride (15.6 mg, 391 pmol, 60% purity, 1.10 eq) at 0 °C. The mixture was stirred at 0 °C for 10 min. Methyl iodide (60.5 mg, 426 pmol, 26.6 pL, 1.20 eq) was added to the mixture at 0°C and stirred at 20 °C for 2 h. The mixture was poured in water (20.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic phase was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 3 / 1 ) to give 2-(2-methoxyethyl)-5-[(4-methoxyphenyl)methylsulfanyl]thiazole (40.0 mg, 130 pmol, 36% yield, 96% purity) as a yellow oil. MS (ESI) m / z 296.2 [M+H]+. Example 7.5. Preparation of 2-(2-methoxyethyl)thiazole-5-sulfonyl chloride0-20°C, 0.5 h

[0224] To a solution of 2-(2-methoxyethyl)-5-[(4- methoxyphenyl)methylsulfanyl]thiazole (22 mg, 74.5 pmol, 1.00 eq) in acetic acid (0.300 mL) and water (0.100 mL) was added / V-chlorosuccinimidc (39.8 mg, 298 pmol, 4.00 eq) at 0 °C .The mixture was stirred at 20°C for 0.5 h. The mixture was poured into water (2.00 mL) and extracted with dichloromethane (0.500 mL). A solution of 2-(2-methoxyethyl)thiazole-5-sulfonyl chloride (18.0 mg, 38.0 pmol, 51 % yield, 51 % purity) in dichloromethane (0.5 mL) was obtained as a yellow liquid. The solution was used in the next step directly. MS (ESI) m / z 242.1 [M+H]+.Example 7,6. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(2- methoxyethyl)thiazole-5-sulfonamide (Compound 7)Compound 7

[0225] To a solution of 2-(2-methoxyethyl)thiazole-5-sulfonyl chloride (18.0 mg, 74.5 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added pyridine (17.7 mg, 223 pmol, 18.0 pL, 3.00 eq) and 7-amino-4-methyl-lH-indole-3-carbonitrile (12.8 mg, 74.5 pmol, 1.00 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phcnomcncx luna Cl 8 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:30%-60% B over 8 min) and lyophilized to afford A-(3-cyano-4-methyl-lH-indol-7-yl)-2-(2-methoxyethyl)thiazole-5- sulfonamide (9.32 mg, 24.11 pmol, 32.38% yield, 97.4% purity) as a yellow solid. MS (ESI) m / z 377.1 [M+H]+.JH NMR (400 MHz, DMSO-d6) <5 = 11.97 (s, 1H), 10.26 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.93 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.71 (d, 7 = 7.6 Hz, 1H), 3.62 (t, J= 6.0 Hz, 2H), 3.28 - 3.14 (m, 5H), 2.60 (s, 3H).Example 8. Synthetic Scheme of Compound 8Compound 8Example 8.1. Preparation of 2-S-((2-methylthiazol-5-yl)methyl) ethanethioateACN, 35°C, 2 h

[0226] To a solution of 5-(chloromethyl)-2-methyl-thiazole (400 mg, 2.71 mmol, 1.00 eq) in acetonitrile (6.00 mL) was added ethanethioic S-acid (227 mg, 2.98 mmol, 213 pL, 1.10 eq), potassium carbonate (749 mg, 5.42 mmol, 2.00 eq) and sodium iodide (40.6 mg, 271 pmol, 0.100 eq) at 16°C. The mixture was stirred at 35°C for 2h. The reaction mixture was quenched by addition water (30 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (50 mL x 2), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 50 mL / min). S-[(2-methylthiazoL5- yl)methyl] ethanethioate (450 mg, 2.40 mmol, 88% yield) was obtained as a yellow oil.NMR (400 MHz, DMSO-d6) 6 = 7.48 (s, 1H), 4.30 (s, 2H), 2.58 (s, 3H), 2.37 (s, 3H). Example 8.2, Preparation of 3-(2-mcthylthiazol-5-yl)mcthancsulfonyl chloride

[0227] l-chloropyiTolidine-2, 5-dione (185 mg, 1.38 mmol, 3.70 eq) was solved in acetonitrile (0.840 mL) and hydrochloric acid (2.00 M, 93.4 pL, 0.500 eq) at 0°C. S-[(2- methylthiazol-5-yl)methyl] ethanethioate (70.0 mg, 373 pmol, 1.00 eq) was solved inacetonitrile (0.84 mL), which was added to the mixture at 0°C for 5 min. The mixture was stirred at 15°C for 10 min. The mixture was poured into water (10 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (3x5 mL). The organic layers were combined and washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. Model LCMS showed desired mass detected. The crude compound was used into the next step without further purification. (2-methylthiazol-5- yl)methanesulfonyl chloride (80 mg, crude) was obtained as a yellow solid.Example 8.3. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-l-(2-methylthiazol-5- vDmethanesulfonamide (Compound 8)Compound 8

[0228] To a solution of (2-methylthiazol-5-yl)methanesulfonyl chloride (51.4 mg, 170 pmol, 1.00 eq) in dichloromethane (5 mL) was added PYRIDINE (26.9 mg, 340 pmol, 27.5 pL, 2.00 eq). 7-amino-4-mcthyl-lH-indolc-3-carbonitrilc (29.1 mg, 170 pmol, 1.00 eq) was added to the mixture at 0°C. The mixture was stirred at 15°C for 2h. The mixture was poured into water (10 mL), separated the organic phase and the aqueous phase was extracted with dichloromethane (3 x 5 mL). The organic layers were combined and washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by prep-HPLC (Column: Waters Xbridge 150*25mm 10pm; Condition: water( NH4HCO3)-ACN; B%: 10%-40%; FlowRate(ml / min): 25.) to give desired compound. N-(3- cyano-4-methyl-lH-indol-7-yl)-l-(2-methylthiazol-5-yl)methanesulfonamide (21.46 mg, 61.95 pmol, 36.43% yield, 100% purity) was obtained as a brown solid. MS (ESI) m / z 347.1 [M+H]+. ’H NMR (400 MHz, DMSO-rfo) 3 = 11.99 - 11.75 (m, 1H), 9.64 (s, 1H), 8.20 (s, 1H), 7.48 (s, 1H), 7.12 (d, J= 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 2.64 (s, 3H), 2.61 (s, 3H).Example 9. Synthetic Scheme of Compound 9,Compound 9Example 9.1. Preparation of 3-chloro-lH-indol-7-aminc

[0229] To a solution of 3-chloro-7-nitro- 1 H-indolc (200 mg, 1.02 mmol, 1.00 eq) and iron (227 mg, 4.07 mmol, 4.00 eq) in ethanol (2.00 mL) was added ammonium chloride (435 mg, 8.14 mmol, 8.00 eq) and water (2.00 mL), the mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification, the residue was directly used to the next step reaction. 3-chloro- 1 / ¥- indol-7-amine (200 mg, crude) was obtained as a black oil. MS (ESI) m / z 167.3 / 169.3 [M+H]+. Example 9.2, Preparation of N-(3-chloro-lH-indol-7-yl)-2-methylthiazole-5-sulfonamide (Compound 9)Compound 9

[0230] To a solution of 3-chloro-lH-indol-7-amine (50.0 mg, 300 pmol, 1.00 eq) and 2-methylthiazole-5-sulfonyl chloride (59.6 mg, 300 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added pyridine (490 mg, 6.19 mmol, 0.50 mL, 20.6 eq), the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by p / 'ep-HPLC (column: Phenomenexluna C18 150*25mm* 10pm; mobile phase: [water(FA)-ACN]; gradient:30%-60% B over 10 min). A-(3-chloro-lH- indol-7-yl)-2-methylthiazole-5-sulfonamide (11.95 mg, 36.12 pmol, 12.03% yield, 99.07% purity) was obtained as a yellow solid. MS (ESI) m / z 328.2 / 330.1 [M+H]+.JH NMR (400 MHz, DMSO-J6) <5 = 1 L05 (s, 1H), 10.61 - 10.01 (m, 1H), 7.93 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.11 - 6.97 (m, 1H), 6.91 (d, 7= 7.2 Hz, 1H), 2.65 (s, 3H).Example 10. Synthetic Scheme of Compound 10Compound 10Example _ 10.L Preparation _ of _ 5 - [(4-methoxyphenyl)methylsulfany 1] -2-(trifluoromethyl)thiazole

[0231] A mixture of 5-bromo-2-(trifluoromethyl)thiazole (450 mg, 1.94 mmol, 1.00 eq), (4-methoxyphenyl)methanethiol (359 mg, 2.33 mmol, 324 pL, 1.20 eq), tris(dibenzylideneacetone)dipalladium(0) (178 mg, 194 pmol, 0.100 eq), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (112 mg, 194 pmol, 0.100 eq) and N,N- diisopropylethylamine (752 mg, 5.82 mmol, 1.01 mL, 3.00 eq) in dioxane (9.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 5 h under nitrogen atmosphere. The mixture was extracted with ethyl acetate (15.0 mL), washed with brine (15.0 mL), dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 20 / 1) and concentrated under reduced pressure to remove solvent to give the 5-[(4- methoxyphenyl)methylsulfanyl]-2-(trifluoromethyl)thiazole (550 mg, 1.71 mmol, 88% yield, 95% purity) as an off-white oil.NMR (400 MHz, DMSO-ri6) d = 7.99 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.90 - 6.85 (m, 2H), 4.21 (s, 2H), 3.73 (s, 3H).Example 10.2. Preparation of 2-(trifluoromethyl)thiazole-5-sulfonyl chloride

[0232] To a solution of 5-[(4-methoxyphenyl)methylsulfanyl]-2- (trifluoromethyl)thiazole (50.0 mg, 164 pmol, 1.00 eq) in water (0.250 mL) was added 1- chloropyrrolidine-2,5-dione (65.6 mg, 491 pmol, 3.00 eq) and acetic acid (262 mg, 4.37 mmol, 0.250 mL, 26.7 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give the 2-(trifluoromethyl)thiazole- 5-sulfonyl chloride (30.0 mg, crude) as a white solid.Example 10.3. Preparation of N-( 3-cyano-4-methyl- 1 H-indol-7 -yl)-2- (trifluoromethyl)thiazole-5-sulfonamide (Compound 10)Compound 10

[0233] To a solution of 2-(trifhioromethyl)thiazole-5-sulfonyl chloride (30.0 mg, 119 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added Pyridine (18.9 mg, 238 pmol, 19.2 pL, 2.00 eq) and 7-amino-4-methyl-l / / -indole-3-carbonitrile (20.4 mg, 119 pmol, 1.00 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by / c -HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:43%- 73% B over 10 min) and lyophilized to afford the A-(3-cyano-4-methyl-177-indol-7-yl)-2- (trilluoromethyl)thiazole-5-sulfonamide (6.08 mg, 15.0 pmol, 12.5% yield, 95.0% purity) as a yellow solid. MS (ESI) m / z 387.1 [M+H]+.1H NMR (400 MHz, DMSO-76) d' = 12.09 (s, 1H), 10.72 (s, 1H), 8.40 - 8.31 (m, 1H), 8.21 - 8.10 (m, 1H), 6.86 (d, 7 = 7.6 Hz, 1H), 6.74 (d, 7 = 7.6 Hz, 1H), 2.60 (s, 3H).Example 11. Preparation of N-(3,4-dichloro-l H-indol-7-yl)-2-(trifluoromethyl)thiazole-5- sulfonamide (Compound 11 )Compound 11

[0234] To a solution of 2-(trifluoromethyl)thiazole-5-sulfonyl chloride (30.0 mg, 119 pmol, 1.00 eq) in dichloromcthanc (0.500 mL) was added pyridine (18.9 mg, 238 pmol, 19.3 pL, 2.00 eq) and 3,4-dichloro-lH-indol-7-amine (23.9 mg, 119 pmol, 1.00 eq). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by p / ep-HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)-ACN];gradient:25%-55% B over 14 min) and lyophilized to give the 2V-(3,4-dichloro-lH-indol-7-yl)-2- (trifluoromethyl)thiazole-5-sulfonamide (4.65 mg, 11.2 pmol, 9.40% yield, 99.8% purity) as a brown solid. MS (ESI) m / z 413.9 [M+H]+. ‘H NMR (400 MHz, DMSO-d6) 3 = 11.51 (s, 1H), 10.89 - 10.64 (m, 1H), 8.34 (s, 1H), 7.46 (s, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.0 Hz, 1H).Example 12, Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(l-methyl-4- piperidyl)thiazole-5-sulfonamide (Compound 12)Compound 12

[0235] To a solution of N-(3-cyano-4-methyl- lH-indol-7-yl)-2-(4- pipcridyl)thiazolc-5-sulfonamidc (20.0 mg, 49.8 pmol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added formaldehyde (2.99 mg, 99.6 pmol, 2.74 pL, 2.00 eq) and sodium triacetoxyhydroborate (31.7mg, 149 pmol, 3.00 eq) at 16°C. The mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)-ACN];gradient:9%-39% B over 10 min ). A-(3-cyano-4-methyl- lH-indol-7-yl)-2-(l-methyl-4-piperidyl)thiazole-5-sulfonamide (8.81 mg, 21.05 pmol, 42.27% yield, 99.30% purity) was obtained as a white solid. MS (ESI) m / z 461.2 [M+H]+.!H NMR (400 MHz, DMSO-ri6) 3 = 12.05 - 11.68 (m, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 6.87 - 6.67 (m, 2H), 6.16 - 6.14 (m, 1H), 3.10 - 2.99 (m, 3H), 2.55 (s, 3H), 2.42 (s, 5H), 2.11 - 1.99 (m, 2H), 1.80 - 1.67 (m, 2H).Example 13. Synthetic Scheme of Compound 13Compound 13Example 13.1. Preparation of 2-(di 11 uoromcthyl)-5-( (4- methoxy benzyl )(hio)thiazolc

[0236] To a solution of 5-bromo-2-(difluoromethyl)thiazole (300 mg, 1.40 mmol, 1.00 eq) in dioxane (6.00 mL) was added (4-methoxyphenyl)methanethiol (432 mg, 2.80 mmol, 390 pL, 2.00 eq), A(A-diisopropylethylamine (362 mg, 2.80 mmol, 488 pL, 2.00 eq), tris(dibenzylideneacetone)dipalladium(0) (256 mg, 280 pmol, 0.200 eq) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (81.1 mg, 140 pmol, 0.100 eq) at 20°C, the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (50 mL). And thenextracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. The crude product was purified by prep- HPLC(column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)- ACN];gradient:56%-76% B over min), which was determined by LCMS. The desired fraction was lyophilized. 2-(difluoromethyl)-5-((4-methoxybenzyl)thio)thiazole (200 mg, 696 pmol, 49% yield) was obtained as a yellow liquid. MS (ESI) m / z 288.2. [M+H]+.JH NMR (400 MHz, chloroform) 8 ppm 7.58 - 7.63 (m, 1 H), 7.12 (d, 7=8.3 Hz, 2 H), 6.80 - 6.91 (m, 2 H), 6.58 - 6.76 (m, 1 H), 3.95 - 4.02 (m, 2 H), 3.77 - 3.85 (m, 3 H).Example 13.2. Preparation of 2-(difluoromethyl)thiazole-5-sulfonyl chloride,

[0237] To a solution of 2-(difluoromethyl)-5-((4-methoxybenzyl)thio)thiazole (100 mg, 348 pmol, 1.00 eq) in acetic acid (1.5 mL) and water (0.5 mL) was added 1- chloropyrrolidine-2, 5-dione (185 mg, 1.39 mmol, 4.00eq) at 0°C,the mixture was stirred at 25°C for 1 h. The mixture was diluted with ice water (20 mL). And then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. It was not purified and used for the next step. 2- (difluoromethyl)thiazole-5-sulfonyl chloride (80 mg, crude) was obtained as a yellow liquid. Example 13.3. Preparation of N-(3-chloro-lH-indol-7-yl)-2-(difluoromethyl)thiazole-5- sulfonamide (Compound 13)Compound 13

[0238] To a solution of 3-chloro- lH-indol-7-amine (34.2 mg, 205 pmol, 1.20 eq) in dichloromethane (1.00 mL) was added pyridine (27.0 mg, 342 pmol, 27.6 pL, 2.00 eq) and 2-(difluoromethyl)thiazole-5-sulfonyl chloride (40.0 mg, 171 pmol, 1.00 eq) at 0°C,themixture was stirred at 20°C for 10 min. The mixture was concentrated in vacuum to give a crude product. The crude product was purified by pre -HPLC(column: Waters Xbridge C18 15O*5Omm* 10pm;mobile phase: [water(NH3H2O)-ACN];gradient:8%-38% B over 10 min). The desired fraction was lyophilized. A-(3-chloro-177-indol-7-yl)-2-(difluoromethyl)thiazole- 5-sulfonamide (23.57 mg, 62.85 pmol, 36.71% yield, 97% purity) was obtained as a yellow solid. MS (ESI) m / z 363.9. [M+H]+. ’ H NMR (400 MHz, DMSO-76) 8 ppm 11.17 (s, 1 H), 10.60 (s, 1 H), 8.31 (s, 1 H), 7.50 (d, 7=2.4 Hz, 1 H), 7.19 - 7.42 (m, 2 H), 7.05 (t, 7=8.0 Hz, 1 H), 7.05 (t, 7=8.0 Hz, 1 H), 6.85 (d, 7=7.2 Hz, 1 H).Example 14. Preparation of N-(3,4-dichloro-lH-indol-7-yl)-2-(difluoromethyl)thiazole-5- sulfonamide (Compound 14)Compound 14

[0239] To a solution of 3,4-dichloro- 1 H-indol-7-aminc (40.66 mg, 171 pmol, 1.00 eq, hydrochloric acid) in dichloromethane (1.00 mL) was added pyridine (27.0 mg, 342 pmol, 27.6 pL, 2.00 eq) and 2-(difluoromethyl)thiazole-5-sulfonyl chloride (40.0 mg, 171 pmol, 1.00 eq) at 0°C, the mixture was stirred at 20°C for 10 min. The mixture was concentrated in vacuum to give a crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge C18 15O*5Omm* 10pm;mobile phase: [water(NH3H2O)-ACN];gradient:12%-42% B over 10 min). The desired fraction was lyophilized. A-(3,4- dichloro-lH-indol-7-yl)-2-(difluoromethyl)thiazole-5-sulfonamide (24.95 mg, 62.02 pmol, 36.23% yield, 99% purity) was obtained as a yellow solid. MS (ESI) m / z 416.0 / 414.1 [M+H]+. H NMR (400 MHz, DMSO-6?6) 8 ppm 11.58 (s, 1 H), 10.65 (s, 1 H), 8.32 (s, 1 H), 7.59 (d, 7=2.4 Hz, 1 H), 7.38 (t, 7=53.6 Hz, 1 H), 7.04 (d, 7=8.0 Hz, 1 H), 6.76 (d, 7=8.0 Hz, 1 H).Examples 15 and 16. Synthetic Scheme of Compound 15 and Compound 16Example 15.1. Preparation of tert-butyl 5-(thiazol-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate,2, , oc

[0240] A mixture of tert-butyl 5-(4,4,5,5-tetramethyLl,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-l(2H)-carboxylate (3.00 g, 9.70 mmol, 1.00 eq), 2-bromothiazole (1.59 g, 9.70 mmol, 874 pL, 1.00 eq), sodium carbonate (2.57 g, 24.3 mmol, 2.50 eq) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (710 mg, 970 pmol. 0.100 eq) in dioxane (50.0 mL) and water (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL) and dried with sodium sulfate solid and filtered. Then the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Sepa Flash® Silica Flash Column, Eluent of 0~ 10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound tert-butyl 5-(thiazol-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.60 g, 5.59 mmol, 57% yield, 93% purity) was obtained as a white solid. 'H NMR (400 MHz, CDCI3) <5 = 7.75 (d, J= 3.2 Hz, 1 H), 7.21 (d, J = 3.2 Hz, 1H), 6.72 (s, 1H), 4.44 (s, 2H), 3.59 (t, J = 5.6 Hz, 2H),2.36 (s, 2H), 1.50 (s, 9H).Example 15.2, Preparation of tert-butyl 3-(thiazol-2-yl)piperidine-l -carboxylate' MeOH, 50 C, 24 hBoc Boc

[0241] To a solution of tert-butyl 5-(thiazol-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (1.60 g, 6.01 mmol, 1.00 eq) in methanol (30.0 mL) was added Pd / C (639 mg, 600 pmol, 10% purity, 0.100 eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 Psi) at 50 °C for 24 h. The suspension was filtered through a pad of Celite and filter cake was washed with methanol (50.0 mL x 2). The combined filtrates were concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound tert-butyl 3-(thiazol-2-yl)piperidine-l -carboxylate (860 mg, 3.11 mmol, 51.7% yield, 97% purity) was obtained as a white solid. 'H NMR (400 MHz, CDCI3) 8 = 7.72 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 4.49 - 4.22 (m, 1H), 4.03 (d, J = 12.0 Hz, 1H), 3.27 - 3.14 (m, 1H), 3.07 (s, 1H), 2.95 - 2.80 (m, 1H), 2.22 (dd, J = 3.6, 9.2 Hz, 1H), 1.89 - 1.72 (m, 2H), 1.70 - 1.55 (m, 1H), 1.47 (s, 9H).Example 15.3. Preparation of tert-butyl 3-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l- carboxylateBocBoc

[0242] To a solution of tert-butyl 3-(thiazol-2-yl)pipcridinc-l -carboxylate (860 mg, 3.20 mmol, 1.00 eq in tetrahydrofuran (10.0 mL) was added n-butyllithium (2.50 M, 1.92 mL, 1.50 eq) dropwise at -78 °C and stirred 30 min under nitrogen, and then sulfur dioxide (205 mg, 3.20 mmol, 1.00 eq) was bubbled into at -65 °C for 30 min. The reaction mixture was warmed to 15 °C slowly and stirred at 20 °C for 1 h. / V-chloro- succinimide (1.29 g, 9.66 mmol, 3.00 eq) was added to the mixture at 0 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was poured into water and extracted with dichloromethane (50.0 mL x3). The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Scpa Flash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl 3-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l -carboxylate (930 mg, 2.41 mmol, 74.8% yield, 95% purity) was obtained as a colorless oil. MS (ESI) m / z 367.0 [M+H]+.Example 15.4, Preparation of tert-butyl 3-(5-(N-(4-chloro-lH-indol-7-yl)sulfamoyl)thiazol-2- yDpiperidine- 1 -carboxylate

[0243] To a solution of tert-butyl 3-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l- carboxylate (80 mg, 218 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (86.2 mg, 1.09 mmol, 88.0 pL, 5.00 eq) and 4-chloro- l / T-indol-7-amine (36.3 mg, 218 pmol, 1.00 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with water (5.00 mL) and extracted with dichloromethane (5.00 mL x 2). The combined organic layers were dried with sodium sulfate solid and filtered. Then the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 18 mL / min). Compound tert-butyl 3-(5-( -(4-chloro-lH-indol-7-yl)sulfamoyl)thiazol-2- yl)piperidine- 1 -carboxylate (90 mg, 173 pmol, 79.7% yield, 96% purity) was obtained as a white solid. MS (ESI) m / z 497.2 [M+H]+.Example 15.5. Preparation of N-(4-chloro-1H-indol-7-yl)-2-(piperidin-3-yl)thiazole-5- sulfonamidc (Compound 15)Compound 15

[0244] To a solution of tert-butyl 3-(5-(A-(4-chloro-lH-indol-7- yl)sulfamoyl)thiazol-2-yl)piperidine-l -carboxylate (90 mg, 181 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added hydrochloric acid / dioxane (4.00 M, 1.00 mL, 22.0 eq). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuum to get a crude product. The residue was purified by prep-HPLC (column: Phcnomcncx luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN] gradient: 15%-45% B over 15 min). The aqueous solution was lyophilized in vacuo to get A-(4-chloro-lH-indol-7-yl)-2-(piperidin-3- yl)thiazole-5-sulfonamide (4.95 mg, 11.1 pmol, 6.10% yield, 98.9% purity, formic acid salt) as a white solid. MS (ESI) m / z 397.1 [M+H]+.NMR (400 MHz, DMSO-de+^O) <5 = 8.19 (s, 1H), 7.81 (s, 1H), 7.16 (d, J = 3.2 Hz, 1H), 6.83 - 6.77 (m, 1H), 6.74 - 6.68 (m, 1H), 6.26 (d, J= 3.2 Hz, 1H), 3.35 - 3.23 (m, 2H), 3.14 (d, J = 12.0 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.81 (dt, 7 = 3.2, 12.0 Hz, 1H), 2.10 - 2.00 (m, 1H), 1.84 - 1.72 (m, 1H), 1.71 - 1.54 (m, 2H). Example 16.1. Preparation of N-(4-chloro-lH-indol-7-yl)-2-(l-methylpiperidin-3-yl)thiazole-Compound 16

[0245] To a solution of 2V-(4-chloro-lH-indol-7-yl)-2-(piperidin-3-yl)thiazole-5- sulfonamide (40.0 mg, 101 pmol, 1.00 eq) in tetrahydrofuran (0.500 mL) was added potassiumacetate (29.6 mg, 303 pmol, 3.00 eq), acetic acid (18.1 mg, 303 pmol, 17.3 pL, 3.00 eq) and formaldehyde (16.3 mg, 202 pmol, 15.0 pL, 2.00 eq). The mixture was stirred at 25 °C for 1 h. sodium triacetoxyhydroborate (21.3 mg, 101 pmol. 1.00 eq) was added and the mixture was stirred at 25 °C for 1 h. The mixture was blown dry with nitrogen. The residue was purified by p / e -HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)- ACN];gradient:18%-48% B over 10 min). The aqueous solution was lyophilized in vacuo. Compound W(4-chloro- 1 H-indol-7-yl )-2-( 1 -methylpiperidin-3-yl)thiazole-5-sulfonamide (8.63 mg, 21.00 pmol, 20.84% yield) was obtained as a yellow gum. MS (ESI) m / z 411.1 [M+H]+. ‘H NMR (400 MHz, DMSO-d6) d = 11.07 (s, 1H), 10.39 - 9.75 (m, 1H), 7.95 (s,1H), 7.36 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.41 (s, 1H), 3.29 - 3.23 (m, 2H), 2.93 - 2.73 (m, 1H), 2.42 (d, J= 8.0 Hz, 2H), 2.26 (s, 3H), 1.86 (d, J= 6.4 Hz, 1H), 1.67 - 1.39 (m, 3H).Example 17, Synthetic Scheme of Compound 17Compound 17Example 17.1. Preparation of 4-thiazol-2-ylmorpholine

[0246] To a solution of 2-bromothiazole (500 mg, 3.05 mmol, 275 pL, 1.00 eq) in morpholine (4.95 g, 56.8 mmol, 5.00 mL, 18.6 eq). The mixture was stirred at 120 °C for 9 h. The reaction mixture was quenched by addition concentrated hydrochloric acid (I M 10.0 mL at 0 °C), and then extracted with ethyl acetate (20.0 mL). The combined organic layers werewashed with brine (15.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=l / O to 3 / 1) and concentrated under reduced pressure to give the 4-thiazol-2-ylmorpholine (500 mg, 2.79 mmol, 91% yield, 95% purity) as a yellow oil.!H NMR (400 MHz, DMSO-d6) <5 = 7.19 (d, J = 3.6 Hz, 1H), 6.88 (d, J= 3.6 Hz, 1H), 3.73 - 3.67 (m, 4H), 3.38 - 3.32 (m, 4H).Example 17,2, Preparation of 2-morpholinothiazole-5-sulfonyl chloride

[0247] A mixture of 4-thiazol-2-ylmorpholine (100 mg, 587 pmol, 1.00 eq) in sulfurochloridic acid (1.75 g, 15.0 mmol, 1.00 mL, 25.6 eq) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched by addition water (10.0 mL) at 0 °C, and then extracted with ethyl acetate (20.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the 2-morpholinothiazole-5- sulfonyl chloride (50 mg, crude) was obtained as a white solid.Example 17,3. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-morpholino-thiazole-5- sulfonamide (Compound 17)Compound 17

[0248] To a solution of 2-morpholinothiazole-5- sulfonyl chloride (40.0 mg, 149 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added Pyridine (11.8mg, 149 pmol, 12.0 pL, 1.00 eq) and 7-amino-4-methyl-lH-indole-3-carbonitrile (25.5 mg, 149 pmol, 1.0 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:26%-56% B over 10 min) and lyophilized to give the AA(3-cyano-4-methyl-177-indol-7-yl)-2- morpholino-thiazolc-5- sulfonamide (7.40 mg, 18.2 pmol, 12.2% yield, 99.1% purity) as a pink solid. MS (ESI) m / z 404.3 [M+H]+. ‘H NMR (400 MHz, DMSO-t / 6) <5 = 12.09 - 11.72 (m, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 6.91 - 6.77 (m, 2H), 3.67 (t, J = 4.8 Hz, 4H), 3.42 - 3.39 (m, 4H), 2.58 (s, 3H).Examples 18 and 19. Synthetic Scheme of Compound 18 and Compound 19Example 18.1. Preparation of tert-butyl (5-bromothiazol-2-yl)carbamate

[0249] To a solution of 5-bromothiazol-2-amine (5.00 g, 27.9 mmol, 1.00 eq) in dichloromethane (60.0 mL) was added 4-dimethylaminopyridine (341 mg, 2.79 mmol, 0.100 eq) and di-tert-butyldicarbonate (9.14 g, 41.8 mmol, 9.62 mL, 1.50 eq) at 16°C. The mixture was stirred at 16°C for 2 h. The mixture was poured into water (100 mL) and extracted with dichloromethane (100 mLx3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum cthcr / Ethyl acctatc= 100 / 1to 100 / 1 , TLC(petroleum ether: ethyl acetate=10:l), Rf(R=0.2 ,P=0.6)). The crude product was triturated with Petroleum ether at 20 °C for 15 min. The mixture was filtered, and the filter cake was collected. Tert-butyl (5-bromothiazol-2-yl)carbamate (4.7 g, 16.84 mmol, 60.29% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO-rfd) <5 = 11.73 (s, 1H), 7.43 (s, 1H), 1.48 (s, 9H).Example 18.2. Preparation of tert-butyl (5-((4-methoxybenzyl)thio)thiazol-2-yl)carbamate, , ,

[0250] To a solution of tert-butyl (5-bromothiazol-2-yl)carbamate (1.00 g, 3.58 mmol, 1.00 eq and (4-methoxyphenyl)methanethiol (662 mg, 4.30 mmol, 598 pL, 1.20 eq) in dioxane (10.0 mL) was added N,N-diisopropylethylamine (462 mg, 3.58 mmol, 623 pL, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (414 mg, 716 pmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium(0) (205 mg, 358 pmol, 0.100 eq) at 16 °C. The mixture was stirred at 100 °C for 16 h. The mixture was stirred at 100 °C for 16 h. The mixture was poured into water (50 mL) and extracted with dichloromethane (50 mLx3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum cthcr / Ethyl acctatc=100 / l to 10 / 1, TLC(pctrolcum ether:ethyl acetate=5:l), Rf(R=0.7 ,P=0.3)). Tert-butyl (5-((4-methoxybenzyl)thio)thiazol-2- yl)carbamate (590 mg, 1.67 mmol, 46% yield) was obtained as a yellow solid.JH NMR (400 MHz, CDCh) <5 = 7.12 — 7.03 (m, 3H), 6.86 - 6.74 (m, 2H), 3.85 (s, 2H), 3.79 (s, 3H), 3.71 (s,1H), 1.54 (s, 9H).Example 18.3. Preparation of tert-butyl (5-(chlorosulfonyl)thiazol-2-yl)carbamate

[0251] To a solution of tert-butyl (5-((4-methoxybenzyl)thio)thiazol-2- yl)carbamate (100 mg, 283 pmol, 1.00 eq) in acetic acid (4.00 mL), water(1.00 mL) anddichloromethane (1.00 mL) was added / V-chlorosuccinimide (113.65 mg, 851.13 pmol, 3 eq) at 0 °C. The mixture was stirred 16 °C for 2 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layer was washed with brine (10 mL), dried over with sodium sulfate and concentrated in vacuum. Tert-butyl (5- (chlorosulfonyl)thiazol-2-yl)carbamate (80.0 mg, crude) was obtained as a yellow solid.Example 18.4, Preparation of tert-butyl (5-(N-(3-cyano-4-methyl-lH-indol-7- yl)sulfamoyl)thiazol-2-yl)carbamate (Compound 18)Compound 18

[0252] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (41.2 mg, 240 pmol, 0.900 eq) in dichloromethane (1.00 mL) was added pyridine (211 mg, 2.68 mmol, 216 pL, 10.0 eq) and tert-butyl (5-(chlorosulfonyl)thiazol-2-yl)carbamate (80.0 mg, 267 pmol, 1.00 eq) at 0 °C. The mixture was stirred at 16 °C for 10 min. The mixture was poured into water (5.00 mL) and extracted with dichloromethane (15.0 mLx2). The combined organic layer was concentrated in vacuum. The crude product was purified by prep- HPLC(column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:35%-65% B over 8 min ). Tert-butyl (5-(N-(3-cyano-4-methyl-lH-indol-7-yl)sulfamoyl)thiazol-2-yl)carbamate (40 mg, 90.43 pmol, 33.77% yield, 98% purity) was obtained as a yellow solid, 8.06 mg of product was used for delivery. MS (ESI) m / z 434.0 / 334.0 [M+H]+. 'H NMR (400 MHz, CDCh) d = 9.63 (s, 1H), 9.33 - 9.01 (m, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.50 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.67 - 6.56 (m, 2H), 2.76 (s, 3H), 1.52 (s, 9H).Example 19.1. Preparation of 2-amino-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5- sulfonamidc (Compound 19)Compound 19

[0253] To a solution of tert-butyl (5-(N-(3-cyano-4-methyl-lH-indol-7- yl)sulfamoyl)thiazol-2-yl)carbamate (25.0 mg, 57.6 pmol, 1.00 eq) in dichloromethane (0.5 mL) was added hydrochloric acid / dioxane (4 M, 1 mL, 69.3 eq) at 16°C. The mixture was stirred at 16°C for 0.5 h. LCMS showed reactant 1 remained, trifluoroacetic acid (153 mg, 1.35 mmol, 0.1 mL, 23.3 eq) was added to the mixture. The resulting mixture was stirred at 16 °C for 2.5 h. The mixture was concentrated in vacuum. The mixture was purification by prep-HPLC (column: Phenomenex Luna C18 150*30mm*5pm;mobile phase: [water(HCl)- ACN];gradient:18%-48% B over 10 min ). 2-amino-N-(3-cyano-4-methyl-lH-indol-7- yl)thiazole-5-sulfonamide (8.48 mg, 24.67 pmol, 42.78% yield, 97% purity) was obtained as an off-white solid. MS (ESI) m / z 334.2 [M+H]+. ‘H NMR (400 MHz, DMSO-J6) 3 = 11.95 (d, 7 = 2.4 Hz, 1H), 9.89 (s, 1H), 8.18 (d, J = 3.2 Hz, 1H), 8.04 - 7.68 (m, 2H), 7.26 (s, 1H), 6.91 - 6.81 (m, 2H), 2.60 (s, 3H).Example 20, Preparation of N-(3-chloro-4-methyl-lH-indol-7-yl)-2-methyl-thiazole-5- sulfonamide (Compound 20)Compound 20

[0254] To a solution of 3-chloro-4-methyl-lH-indol-7-amine (50.0 mg, 276 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (65.7 mg, 830 pmol, 67.0 pL, 3.00 eq) and 2-methylthiazole-5-sulfonyl chloride (60.2 mg, 304 pmol, 1.10 eq) at 0°C. The mixture was stirred at 0°C for Ih. The mixture was concentrated under reduced pressure togive a residue. The crude product was purified by prep- HPLC(column: Phenomenex luna C18 150*25mm* 10pm;mobilc phase: [watcr(FA)-ACN];gradicnt:40%-70% B over 8 min ). A-(3-chloro-4-methyl-lH-indol-7-yl)-2-methyl-thiazole-5-sulfonamide was obtained as a solid. MS (ESI) m / z 342.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) d = 11.05 (s, 1H), 10.13(s, 1H), 7.91 (s, 1H), 7.41 (d, J = 2.8 Hz, 1H), 6.74 - 6.65 (m, 2H), 2.67 (s, 3H), 2.63 (s, 3H).Example 21, Synthetic Scheme of Compound 21Compound 21Example 21,1. Preparation of 2,4-dimethylthiazole-5-sulfonyl chloride

[0255] To a solution of 2,4-dimethylthiazole (200 mg, 1.77 mmol, 1.00 eq) added to sulfurochloridic acid (877 mg, 7.52 mmol, 500 pL, 4.26 eq) at 0 °C under N2, and then the mixture was stirred at 140 °C for 16 h under N2. Pentachloro-phosphane (735 mg, 3.53 mmol, 2.00 eq) added to the mixture at 120°C, and then the mixture was stirred at 120°C for Ih. The reaction mixture was poured into water and extracted with dichloromethane 50.0 mL x 3. The organic layer was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). 2,4- Dimethylthiazole-5- sulfonyl chloride (370 mg, 1.73 mmol, 97% yield, 99% purity) was obtained as a yellow oil. MS (ESI) m / z 212.2 / 214.2 [M+H]+.Example 21 ,2, Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2,4-dimethylthiazole-5- sulfonamide (Compound 21)Compound 21

[0256] To a solution of 2,4-dimethylthiazole-5-sulfonyl chloride (49.5 mg, 234 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added 7-amino-4-methyl-lH-indole-3- carbonitrile (40.0 mg, 234 pmol, 1.00 eq) and pyridine (55.4 mg, 701 pmol, 56.6 pL, 3.00 eq) at 16°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into water (20 mL), and then extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over sodium sulphate, filtered, and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)-ACN];gradient:15%-45% B over 10 min).N-(3-cyano-4-methyl-lH-indol-7-yl)- 2,4-dimethyl-thiazole-5-sulfonamide (22.87 mg, 66.02 pmol, 28.25% yield, 100% purity) was obtained as a yellow solid. MS (ESI) m / z 347.2 [M+HJ+. ’H NMR (400 MHz, DMSO-dd) d = 11.95 (d, J = 1.2 Hz, 1H), 10.20 (s, 1H), 8.18 (s, 1H), 6.86 (d, 7 = 7.6 Hz, 1H), 6.65 (d, 7 =7.6 Hz, 1H), 2.61 (s, 3H), 2.59 (s, 3H), 2.18 (s, 3H).Example 22. Synthetic Scheme of Compound 22NCS, HOAc _(1.2 eq) pyridine, DCM, 20°CExample 22, L Preparation of 2-bromo-4-methylthiazole-5-carboxylic acid

[0257] of ethyl 2-bromo-4-methylthiazole-5-carboxylate (2.00 g,8.00 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added lithium hydroxide (671 mg, 16.0 mmol, 2.00 eq), water (2 mL) and ethanol (1.00 mL) at 20 °C, the mixture was stirred at 50 °C for 16 h. The mixture was acidified by concentrated hydrochloric acid (1 M) adjust to H-2. and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuum. 2-bromo-4-methylthiazole-5- carboxylic acid (1.6 g, crude) was obtained as a yellow solid. MS (ESI) m / z 221.9 / 223.9. [M+H]+. ’H NMR (400 MHz, DMSO-d6) <5 ppm 13.27 - 14.14 (m, 1 H) 2.61 (s, 3 H). Example 22,2, Preparation of (2-bromo-4-methylthiazol-5-yl)(morpholino)methanone

[0258] To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (500 mg, 2.25 mmol, 1.00 cq) in dimethylformamide (5.00 mL) was added O-(7-azabcnzotriazol-l-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.28 g, 3.38 mmol, 1.50 eq) and N,N- diisopropylethylamine (582 mg, 4.50 mmol, 784 pL, 2.00 eq) at 20°C,the mixture was stirred at 20°C for 30 min, and then added morpholine (235 mg, 2.70 mmol, 237 pL, 1.20 eq) at 20°C ,the mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (100 mL). And then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=100:l to 1:1. (2-bromo-4-methylthiazol-5-yl)(morpholino)methanone (500 mg, 1.72 mmol, 76% yield) was obtained as a yellow solid. MS (ESI) m / z 291.0 / 292.9. [M+H]+. ’H NMR (400 MHz, DMSO-76) d ppm 3.56 - 3.63 (m, 4 H) 3.50 (s, 4 H) 2.33 (s, 3 H).Example 22,3 Preparation of (2-((4-methoxybenzyl)thio)-4-methylthiazol-5- yl)(morpholino)methanone

[0259] To a solution of (2-bromo-4-methylthiazol-5-yl)(morpholino)methanone (500 mg, 1.72 mmol, 1.00 cq) in dioxane (8.00 mL) was added N,N-diisopropylcthylaminc (443 mg, 3.43 mmol, 598 pL, 2.00 eq) , (4-methoxyphenyl)methanethiol (529 mg, 3.43 mmol, 478 pL, 2.00 eq) , 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (99.3 mg, 171 pmol, 0.100 eq) and tris(dibenzylideneaeetone)dipalladium(0) (314.50 mg, 343 pmol, 0.200 eq) at 20°C,the mixture was stirred at 100°C for 2 h under nitrogen. The mixture was diluted with water (100 mL). And then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=100:l to 1:1. (2-((4-methoxybenzyl)thio)-4-methylthiazol-5- yl)(morpholino)methanone (500 mg, 1.37 mmol, 79.88% yield) was obtained as a yellow solid. MS (ESI) m / z 365.3ppm 7.36 (d, 7=8.4 Hz, 2 H)6.90 (d, 7=8.4 Hz, 2 H) 4.43 (s, 2 H) 3.74 (s, 3 H) 3.59 (d, 7=4.4 Hz, 4 H) 3.48 (s, 4 H) 2.31 (s, 3 H).Example 22,4, Preparation of 4-methyl-5-(morr>holine-4-carbonyl)thiazole-2-sulfonyl chloride

[0260] To a solution of (2-((4-methoxybenzyl)thio)-4-methylthiazol-5- yl)(morpholino)methanone (100 mg, 274 pmol, 1.00 eq) in acetic acid (3 mL) and water (1.00 mL) was added 1 -chloropyrrolidine-2, 5-dione (146 mg, 1.10 mmol, 4.00 eq) at 0°C,the mixture was stirred at 20°C for 1 h. The mixture was diluted with ice water (10.0 mL). And then extracted with dichloromethane (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. It was not purified and used for the next step. 4-methyl-5-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride (80.0 mg, crude) was obtained as a yellow oil. MS (ESI) m / z 311.0 / 313.0. [M+H]+.Example 22,5. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-4-methyl-5-(morpholine- 4-carbonyl)thiazole-2-sulfonamide (Compound 22)Compound 22

[0261] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (48.4 mg, 283 pmol, 1.10 eq) in dichloromethane (1.00 mL) was added pyridine (20.3 mg, 257 pmol, 20.7 pL, 1.00 eq) and 4-methyl-5-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride (80.0 mg, 257 pmol, 1.00 eq) at 0°C, the mixture was stirred at 0°C for 10 min. The mixture was diluted with water (20.0 mL). And then extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue.The crude product was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10pm;mobilc phase: [watcr(FA)-ACN];gradicnt:27%-57% B over 8 min). The desired fraction was lyophilized. A-(3-cyano-4-methyl-lH-indol-7-yl)-4-methyl-5-(morpholine-4- carbonyl)thiazole-2-sulfonamide (15.54 mg, 34.88 pmol, 13.55% yield, 100% purity) was obtained as a yellow solid. MS (ESI) m / z 446.0. [M+H]+.1H NMR (400 MHz, DMSO-tfo) ppm 12.06 (s, 1 H) 10.79 (s, 1 H) 8.20 (s, 1 H) 6.85 (d, 7=7.2 Hz, 1 H) 6.73 (d, 7=7.2 Hz, 1 H) 3.59 (s, 4 H) 3.33 - 3.52 (m, 4 H) 2.60 (s, 3 H) 2.40 (s, 3 H).Example 23. Synthetic Scheme of Compound 23H(2.0 eq)1 .tetraisopropoxytitanium toluene, 40°C, 16 h2.NaBH3CN, 0-20°C, 1 hCompound 23Example 23.1. Preparation of N,N-dimethyl-l-(thiazol-2-yl)ethan-l-amineH(2.0 eq)1 .tetraisopropoxytitaniumtoluene, 40°C, 16 h 2.NaBH3CN, 20°C, 1 h

[0262] To a solution of l-thiazol-2-ylethanone (1.00 g, 7.86 mmol, 815 pL, 1.00 eq) , N-methylmethanamine (2 M, 7.86 mL, 2.00 eq) and tetraisopropoxytitanium (4.82 g, 16.9 mmol, 5.00 mL, 2.15 eq) in toluene (10.0 mL)the mixture was stirred at 40°C for 16 h, And then added sodium cyanoborohydride (1.98 g, 31.4 mmol, 4.00 eq) at 20°C,the mixture was stirred at 20°C for 1 h. The mixture was diluted with water (50 mL). And then extracted with ethyl acetate (2 x 50.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. The crude product was purified by n? -HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)-ACN];gradient:6%-36% B over 10 min). The desired fraction was lyophilized. A,A^-dimethyL l-thiazol-2-yl-cthanaminc (120 mg, 768.01 pmol, 9% yield) was obtained as a yellow liquid.

[0263] MS (ESI) m / z 179.1. [M+Na]+.JH NMR (400 MHz, CHLOROFORM) d ppm 7.71 (d, 7=3.2 Hz, 1 H) 7.28 (d, 7=3.2 Hz, 1 H) 3.96 (q, 7=6.8 Hz, 1 H) 2.32 (s, 6 H) 1.48 (d, 7=6.8 Hz, 3 H).Example 23.2, Preparation of 2-(l-(dimethylamino)ethyl)thiazole-5 -sulfonyl chloride

[0264] To a solution of N,N-dimethyl-l-(thiazol-2-yl)ethan-l -amine (100 mg, 640 pmol, 1.00 eq) in tetrahydrofuran (3.00 mL) was added n-butyllithium (2.5 M, 384 pL, 1.50 eq) at -78°C. The mixture was stirred at -78 °C for 0.5 h. sulfur dioxide (41.0 mg, 640 pmol, 1.00 eq) was bubbled into at-65°C for 30 min. The reaction mixture was warmed to 20°C slowly and stirred for 2 h. The mixture was stirred at 20 °C for 1 h. The mixture was diluted with ice water (20.0 mL). And then extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. It was not purified and used for the next step. 2-[l-(dimethylamino)ethyl]thiazole-5-sulfinic acid (141 mg, crude) was obtained as a yellow oil. MS (ESI) m / z 221.1. [M+H]+.

[0265] To a solution of 2-[l-(dimethylamino)ethyl]thiazole-5-sulfinic acid (141 mg, 640 pmol, 1.00 eq) in tetrahydrofuran (3.00 mL) was added 1 -chloropyrrolidine-2, 5-dione (256 mg, 1.92 mmol, 3.00 eq) at 0°C,the mixture was stirred at 20°C for 16 h. The mixture was diluted with ice water (20.0 mL). And then extracted with dichloromethane (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. It was not purified and used for the next step. 2-(l- (dimethylamino)ethyl)thiazole-5- sulfonyl chloride (80.0 mg, 314 pmol, 49% yield) was obtained as a yellow oil. MS (ESI) m / z 255.1 / 257.1. [M+H]+.Example _ 23.3. _ Preparation _ of _ N-(3-cyano-4-methyl- 1 H-indol-7-yl)-2-( 1 -(dimcthylamino)cthyl)thiazolc-5-sulfonamidc (Compound 23)Compound 23

[0266] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (26.8 mg, 157 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (24.8 mg, 314 pmol, 25.3 pL, 2.00 eq) and 2-(l-(dimethylamino)ethyl)thiazole-5- sulfonyl chloride (80.0 mg, 157 pmol, 1.00 eq) at 0°C,the mixture was stirred at 0°C for 20 min. The mixture was diluted with water (20.0 mL). And then extracted with dichloromethane (2 x 20.0 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuum to give a residue. The crude product was purified by / 'c -HPLC (column: Waters Xbridge C18 150*50mm* 10pm;mobile phase: [water(NH3H2O)-ACN];gradient:3%-33% B over 10 min).The desired fraction was lyophilized. A-(3-cyano-4-methyl-lH-indol-7-yl)-2-(l-(dimethylamino)ethyl)thiazole-5- sulfonamide (7.99 mg, 20.31 pmol, 12.93% yield, 99% purity) was obtained as a yellow solid. MS (ESI) m / z 390.0. [M+H]+.!H NMR (400 MHz, DMSO-tfc) d ppm 11.84 - 11.96 (m, 1 H) 10.10 - 10.29 (m, 1 H) 8.16 (s, 1 H) 7.86 - 8.01 (m, 1 H) 6.81 - 6.95 (m, 1 H) 6.67 - 6.78 (m, 1 H) 3.88 - 4.05 (m, 1 H) 2.60 (s, 3 H) 2.17 (s, 6 H)1.28 (d, 7=6.0 Hz, 3 H).Example 24. Synthetic Scheme of Compound 24Compound 24Example 24,1, Preparation of 5-((4-methoxybenzyl)thio)thiazole-2-carbaldehyde, ,

[0267] A mixture of (4-methoxyphenyl)methanethiol (386 mg, 2.50 mmol, 348 pL, 1.20 eq), 5-bromothiazole-2-carbaldehyde (400 mg, 2.08 mmol, 1.00 eq), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 208 pmol, 0.100 eq), tris(dibenzylideneacetone)dipalladium(0) (191 mg, 208 pmol, 0.100 tv / )and N,N- diisopropylethylamine (808 mg, 6.25 mmol, 1.09 mL, 3.00 eq) in dioxane (4.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100°C for 3hr under nitrogen atmosphere. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1- 1 / 1). Compound 5- [(4-methoxyphenyl)methylsulfanyl]thiazole-2- carbaldehyde (380 mg, 1.32 mmol, 63% yield, 92% purity) was obtained as a white solid. ’ HNMR (400 MHz, chloroform) 3 = 9.84 (s, 1H), 7.79 (S, 1H), 7.19 - 7.16 (m, 2H), 6.86-6.83(m, 2H), 4.09 (s, 2H), 3.78 (s, 3H).Example 24,2, Preparation of l-((5-((4-methoxybenzyl)thio)thiazol-2-yl)methyl)pyrrolidine- 3-carbonitrile

[0268] To a solution of pyrrolidine-3-carbonitrile (130 mg, 980 pmol, 1.30 eq, HC1) in tetrahydrofuran (5.00 mL) was added potassium acetate (222 mg, 2.26 mmol, 3.00 eq) at 20°C. The mixture was stirred at 20°C for 20 min. 5-((4-methoxybenzyl)thio)thiazole-2- carbaldehyde (200 mg, 754 pmol, 1.00 eq) and acetic acid (90.5 mg, 1.51 mmol, 86.3 pL, 2.00 eq), sodium triacetoxyhydroborate (320 mg, 1.51 mmol, 2.00 eq) was added to the mixture at 20°C. The resulting mixture was stirred at 20°C for 2 h. The mixture was poured into water (30.0 mL), and then extracted with ethyl acetate (50.0 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =10 :l-4 :1, petroleum ether / ethyl acetate =3:1, Rl(Rf=0.6), Pl (Rf=0.2)) to give a residue, which was determined by HNMR. l-((5-((4-methoxybenzyl)thio)thiazol-2-yl)methyl)pyrrolidine-3- carbonitrile (160 mg, 416.81 pmol, 55.30% yield, 90% purity) was obtained as a yellow solid.!H NMR (400 MHz, chloroform) 3 = 7.37 (s, 1H), 7.03 (s, 2H), 6.75 - 6.73 (m, 2H), 3.84 (s, 3H), 3.72 (s, 4H), 3.03 - 2.92 (m, 2H), 2.78 - 2.70 (m, 3H), 2.27 - 2.16 (m, 1H), 2.13 - 2.04 (m, 1H).Example 24,3. Preparation of 2-((3-cvanopyrrolidin-l-yl)methyl)thiazole-5-sulfonyl chloride

[0269] To a solution of l-[[5-[(4-methoxyphenyl)methylsulfanyl]thiazol-2- yl]mcthyl]pyrrolidinc-3-carbonitrilc (100 mg, 289 mol, 1.00 eq) in dichloromcthanc (1.00 mL) and Water (1.00 mL), acetic acid (3.15 g, 52.4 mmol, 3.00 mL, 181 e )was added 1- chloropyrrolidine-2,5-dione (193 mg, 1.45 mmol, 5.00 eq) at 0°C. The mixture was stirred at 20°C for 2 h. The mixture was poured into water (20.0 mL), and then extracted with dichloromethane (10.0 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. It was not purified and used for the next step. 2-((3- cyanopyrrolidin-l-yl)methyl)thiazole-5-sulfonyl chloride (80.0 mg, 274 pmol, 94% yield) was obtained as a white solid.Example 24,4. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-((3-cyanopyrrolidin-l- yl)methyl)thiazole-5-sulfonamide (Compound 24)Compound 24

[0270] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (46.9 mg, 274 mol, 1.00 eq) and pyridine (65.1 mg, 822 pmol, 66.4 pL, 3.00 eq) in dichloromethane (3.00 mL) was added 2-((3-cyanopyrrolidin-l-yl)methyl)thiazole-5-sulfonyl chloride (80.0 mg, 274 pmol, 1.00 eq) at 0°C. The mixture was stirred at 20°C for 2 h. The mixture was poured into water (30.0 mL), and then extracted with dichloromethane (30.0 mL x 3). The combined organic layers were washed with 1 N hydrochloric acid (10.0 mL), brine (20.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give a residue, which was determined by LCMS. The residue was purified by prep-HPLC (column: Waters Xbridge C18 15O*5Omm* 10pm;mobile phase: [water(NH3H20)-ACN];gradient:0%-30% B over 10 min). N-(3-cyano-4-methyl-lH-indol-7-yl)-2-((3-cyanopyrrolidin-l-yl)methyl)thiazole-5- sulfonamide (3.61 mg, 8.46 mol, 3.09% yield, 100% purity) was obtained as a white solid. MS (ESI) m / z 425.0 [M-H]+ JH NMR (400 MHz, chloroform) 3 = 9.70 - 9.60 (m, 1H), 7.88 (s, 1H), 7.82 (d, J= 3.2 Hz, 1H), 6.86 (d, J= 8.0 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.60 (d, J= 8.0 Hz, 1H), 4.08 - 3.95 (m, 2H), 3.16 - 2.86 (m, 4H), 2.77 (s, 4H), 2.37 - 2.15 (m, 2H).Example 25 and Example 26. Synthetic Scheme of Compound 25 and Compound 26Compound 25 Compound 26of tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate

[0271] To a solution of 2-bromothiazole (9.00 g, 54.8 mmol, 4.95 mL, 1.00 eq) in dioxane (100 mL) and water (10.0 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (20.3 g, 65.8 mmol, 1.20 eq), potassium carbonate (15.1 g, 109 mmol, 2.00 eq and tetrakis[triphenylphosphine]palladium(0) (1.00 g, 865 pmol, 1.58e"2eq) at 16 °C. The mixture was stirred at 100°C for 22 h. The reaction mixture was quenched by addition water (50.0 mL), and then extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over [sodium sulfate], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOi, Petroleum ether / Ethyl acetate=100 / lto 10 / l(TLC(petroleum ether: ethyl acetate=5:l), Rf(R=0.5, P=0.3) ). Tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-l(2 / / )-carboxylate (5.20 g, 19.5 mmol, 35% yield) was obtained as a yellow oil. ’H NMR (400 MHz, CDCE) 8 = 7.76 (d, J= 3.2 Hz, 1H), 7.23 (d, J= 3.2 Hz, 1H), 6.58 (s, 1H), 4.17 - 4.07 (m, 2H), 3.64 (t, J= 5.2 Hz, 2H), 2.71 (br d, J= 1.2 Hz, 2H), 1.49 (s, 9H).Example 25.2. Preparation of tert-butyl 4-(thiazol-2-yl)piperidine-1 -carboxylateBoc Boc

[0272] To a solution of tert-butyl 4-(thiazol-2-yl)-3,6-dihydropyridine-l(27 )- carboxylate (5.00 g, 18.7 mmol, 1.00 eq) in methanol (50.0 mL) was added palladium / carbon (1.50 g, 1.41 mmol, 10% purity, 7.51C2eq) at 16 °C. The mixture was stirred at 16 °C for 16 h under hydrogen (37.9 mg, 18.7 mmol, 1.00 eq) (15 psi). The mixture was filtered and washed with methanol (500 mL). The fdtrate was concentrated in vacuum. The residual was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / lto 0 / l(TLC(petroleum ether:ethyl acetate=l:l), Rf(R=0.6, P=0.3)). Tert-butyl 4-(thiazol-2-yl)piperidine-l- carboxylate (2.40 g, 8.94 mmol, 47% yield) was obtained as colorless oil.NMR (400 MHz, DMSO-tfc) 6 =7.72 (d, J= 3.2 Hz, 1H), 7.61 (d, J= 3.6 Hz, 1H), 4.03 - 3.94 (m, 2H), 3.21 (tt, 7= 3.6, 11.6 Hz, 1H), 2.90 (d, J = 0.8 Hz, 2H), 2.06 - 2.00 (m, 2H), 1.55 (dq, 7= 4.0, 12.4 Hz, 2H), 1.41 (s, 9H).Example 25.3. Preparation of tert-butyl 4-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l- carboxylate

[0273] To a solution of tert-butyl 4-(thiazol-2-yl)piperidine-l -carboxylate (200 mg, 745 pmol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added n-butyllithium (2 M, 447 pL, 1.20 eq) at -78°C. The mixture was stirred at -78 °C for 0.5 h. Sulfur dioxide (47.7 mg, 745 pmol, 1.00 eq) was bubbled into the mixture at -65 °C for 30 min (15 psi). The reaction mixture was warmed to 20°C slowly and stirred for 2 h. / V-chloro succinimide (199 mg, 1.49 mmol, 2.00 eq) was added to the mixture at 20 °C. The mixture was stirred at 20 °C for 15 h. The mixture was poured into water and extracted with dichloromethane (50 mLx3). The organic layer was concentrated under reduced pressure to give a residue. Tert-butyl 4-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l -carboxylate (210 mg, crude) was obtained as a colorless oil. 'H NMR (400 MHz, DMSO-rT) 6 = 7.61 (s, 1H), 4.03 - 3.90 (m, 2H), 3.14 (tt, J = 3.6, 11.4 Hz, 1H), 2.95 - 2.81 (m, 2H), 2.07 - 1.92 (m, 2H), 1.57 - 1.47 (m, 2H), 1.41 - 1.40 (m, 2H), 1.40 (s, 9H).Example 25.4, Preparation of tert-butyl 4-[5-[(3-cyano-4-methyl-lH-indol-7- yl)sulfamoyl1thiazol-2-yl]piperidine-l-carboxylate (Compound 25)

[0274] To a solution of tert-butyl 4-(5-(chlorosulfonyl)thiazol-2-yl)piperidine-l- carboxylate (100 mg, 272 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added 7-amino- 4-methyl- I H-i ndolc-3-carbonitri Ic (51.3 mg, 299 pmol, 1.10 eq), pyridine (43.1 mg, 545 pmol, 44.0 pL, 2.00 e< / )at 20°C. The mixture was stirred at 20°C for 5min . The mixture was concentrated under reduced pressure to give a residue. Tert-butyl 4-[5-[(3-cyano-4-methyl- 1 H-indol-7-yl) sulfamoyl ]thiazol-2-yl (piperidine- 1 -carboxylate (85.0 mg, crude) was obtained as a white solid. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:47%-77% B over 11 min ). Tert-butyl 4-[5-[(3-cyano-4-methyl- 17Tindol-7-yl)sulfamoyl]thiazol-2-yl]piperidine- 1- carboxylate (2.15 mg, 4.23 pmol, 7.07% yield, 98.72% purity) was obtained as a yellow gum. MS (ESI) m / z 402.2 [M+H]+.!H NMR (400 MHz, DMSO-d6) d = 8.10 (s, 1H), 7.91 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.74 - 6.65 (m, 1H), 3.92 (d, J = 12.4 Hz, 2H), 3.26 - 3.14 (m, 1H), 2.94 - 2.76 (m, 2H), 2.57 (s, 3H), 1.99 - 1.88 (m, 2H), 1.51 - 1.40 (m, 2H), 1.40 - 1.32 (m, 9H).Example 26. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(4-piperidyl)thiazole-5- sulfonamidc (Compound 26)Compound 26

[0275] To a solution of tert-butyl 4-[5-[(3-cyano-4-methyl-17 / -indol-7- yl)sulfamoyl]thiazol-2-yl]piperidine-l -carboxylate (80.0 mg, 159 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added hydrochloric acid / dioxane (6 M, 2.00 mL, 75.2 eq) at 16°C. The mixture was stirred at 20°C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOpnpmobile phase: [water(FA)-ACN];gradient:6%-36% B over 10 min ). (V-(3-cyano-4-methyl-l H-indol-7-yl)-2-(4-piperidyl)thiazole-5-sulfonamide (35.77 mg, 89.09 pmol, 55.86% yield, 100% purity) was obtained as a white solid. 5.77 mg product for delivery. MS (ESI) m / z 402.2 [M+H]+.JH NMR (400 MHz, DMSO-Js) d = 12.02 - 11.72 (m, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.63 (br d, J = 7.6 Hz, 1H), 3.30 - 3.17 (m, 3H), 2.95 (t, J = 12.4 Hz, 2H), 2.49 (s, 3H), 2.09 (d, J = 13.2 Hz, 2H), 1.83 - 1.71 (m, 2H).Example 27, Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(piperidin-3-yl)thiazole-5- sulfonamide (Compound 27)Compound 27

[0276] To a solution of tert-butyl 3-(5-(W(3-cyano-4-methyl-lH-indoL7- yl)sulfamoyl)thiazol-2-yl)pipcridinc-l -carboxylate (108 mg, 215 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added hydrochloric acid / dioxane (4.00 M, 1.00 mL, 18.6 eq). The mixture was stirred at 15 °C for 1 h. The mixture was concentrated in vacuum. The residue was dissolved with acetonitrile (1.00 mL) and diluted with water (10.0 mL). The solution was lyophilized in vacuo. Compound Ar-(3-cyano-4-methyl-lH-indol-7-yl)-2- (piperidin-3-yl)thiazole-5-sulfonamide (90 mg, 203 pmol, 94.5% yield, 99% purity, hydrochloric acid salt) was obtained as a yellow solid. MS (ESI) m / z 402.1 [M+H]+.1H NMR (400 MHz, DMSO-tfc) 3 = 12.10 (d, J = 2.4 Hz, 1H), 10.48 (s, 1H), 9.07 - 8.75 (m, 2H), 8.20 (d, J= 3.2 Hz, 1H), 8.04 (s, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 8.0 Hz, 1H), 3.59 - 3.46 (m, 2H), 3.25 (d, J= 13.2 Hz, 1H), 3.17 - 3.06 (m, 1H), 2.89 (d, J= 9.2 Hz, 1H), 2.61 (s, 3H), 2.11 (d, J= 12.0 Hz, 1H), 1.93 - 1.58 (m, 3H).Example 28. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(l-methylpiperidin-3- yl)thiazole-5-sulfonamide (Compound 28)Compound 28

[0277] To a solution of A4(3-cyano-4-methyl-177-indol-7-yl)-2-(piperidin-3- yl)thiazole-5-sulfonamide (50.0 mg, 124 pmol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added potassium acetate (36.6 mg, 374 pmol, 3.00 eq), formaldehyde (20.2 mg, 249 pmol, 18.5 pL, 2.00 eq), acetic acid (22.4 mg, 374 pmol, 21.4 pL, 3.00 eq) and sodium triacetoxyhydroborate (26.4 mg, 124 pmol, 1.00 eq). The mixture was stirred at 25 °C for 2 h. The mixture was blown dry with nitrogen. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm 10pm;mobile phase: [water( NH4HCO3)-ACN] gradient: 13%- 43% B over 14 min). Compound W(3-cyano-4-methyl- l / / -indol-7-yl)-2-( 1-methy Ipiperidin- 3-yl)thiazole-5 -sulfonamide (22.79 mg, 54.8 pmol, 44.0% yield, 100% purity) was obtained as a white solid. MS (ESI) m / z 416.1 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6+D2O) 3 = 8.06(s, 1H), 7.88 (s, 1H), 6.77 (q, J = 8.0 Hz, 2H), 3.29 (s, 2H), 2.94 (d, J = 4.8 Hz, 1H), 2.67 (s, 1H), 2.56 (s, 3H), 2.38 (s, 1H), 2.33 (s, 3H), 1.90 (d, 7= 2.8 Hz, 1H), 1.71 - 1.38 (m, 3H).Example 29. Preparation of 2-(l-acetyl-4-piperidyl)-N-(3-cvano-4-methyl-lH-indol-7- yl)thiazole-5-sulfonamide (Compound 29)Compound 29

[0278] To a solution of Ac^O (8.39 mg, 82.2 pmol, 7.72 pL, 1.20 eq) in dichloromethane (0.50 mL) was added triethylamine (34.7 mg, 342 pmol, 47.6 pL, 5.00 eq) and N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(4-piperidyl)thiazole-5-sulfonamide (30.0 mg, 68.5 pmol, 1.00 eq, hydrochloric acid) at 0°C. The mixture was stirred at 15°C for 1 h. The reaction mixture was poured into water(10.0 mL) and extracted with dichloromethane (30mL x3), dried over[sodium sulfate], filtered and concentrated under reduced pressure to give a residue. The crude product was purified by Prep- HPLC(column: Waters Xbridge C18 150*50mm* 10pm;mobile phase: [water (NH4HCO3)-ACN] gradient: 11%-41% B over 10 min). 2-(l-acetyl-4-piperidyl)-N-(3-cyano-4-methyl-lH-indol-7-yl)thiazole-5-sulfonamide was obtained as solid. MS (ESI) m / z 444.1 [M+H]+.NMR (400 MHz, DMSO-d6) <5 = 8.10 (s, 1H), 7.96 - 7.83 (m, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 3.82 (d, 7 = 13.2 Hz, 1H), 3.28 (t, 7 = 10.8 Hz, 1H), 3.14 (t, 7 = 12.4 Hz, 1H), 2.68 (t, 7 = 12.4 Hz, 1H), 2.57 (s, 3H), 2.04 - 1.92 (m, 5H), 1.65 - 1.51 (m, 1H), 1.49 - 1.35(m, 1H).Example 30. Synthetic Scheme of Compound 3084 pmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added paraformaldehyde (80.0 mg, 584 pmol, 1.00 eq) and sodium triacetoxyhydroborate (371 mg, 1.75 mmol, 3.00 eq) at 16°C. The mixture was stirred at 25°Cfor 16h. The reaction mixture was poured into water (40mL) and extracted with ethyl acetate (60 mL x3). Dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC(column: Waters Xbridge 150*25mm I O immobile phase; [water (NH4HCO3)-ACN];gradient:24%- 54% B over 10 min ). 4-methyl-7-(methylamino)-lH-indole-3-carbonitrile (25 mg, 134.97 mol, 23.11% yield) was obtained as a yellow solid. 'H NMR (400 MHz, DMSOmfe) <5 = 11.65 (s, 1H), 8.07 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.34 (d, J = 3.6 Hz,1H), 3.30 (s, 3H), 2.81 (d, J = 4.0 Hz, 3H).Example 30.2, Preparation of N-(3-cyano-4-mcthyl-lH-indol-7-yl)-N,2-dimcthyl-thiazolc-5- sulfonamide (Compound 30)Compound 30

[0280] To a solution of 4-methyl-7-(methylamino)-lH-indole-3-carbonitrile (20.0 mg, 107 mol, 1.00 eq) in dichloromethane (1.00 mL) was added Py (25.6 mg, 323 pmol, 26.2pL, 3.00 eq) and 2-methylthiazole-5-sulfonyl chloride (23.5 mg, 1 18 pmol, 1.10 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (30 mL x3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column; Phenomenex luna C18 150*25mm* I O immobile phase: [water(FA)- ACN];gradient:31%-61% B over 11 min ). A-(3-cyano-4-methyl-177-indol-7-yl)-N,2- dimethyl-thiazole-5-sulfonamide (10.72 mg, 30.57 pmol, 28.31% yield, 98.78% purity) was

[0281] A mixture of methyl 2-bromothiazole-4-carboxylate (2.50 g, 11.3 mmol, 1.00 eq) in tetrahydrofuran (71.0 mL) and Lithium hydroxide monohydratc (1.00 M, 29.8 mL, 2.65 eq) was heated at 70° C for 1 h. The organic solvent was removed in vacuo. The residual aqueous solution was cooled to 0° C and acidified to H= I with IN HC1 solution. The mixture was filtered. The filter cake was washed with water and concentrated in vacuum. 2-Bromothiazole-4-carboxylic acid (2.20 g, 10.6 mmol, 94% yield) was obtained as a white solid.NMR (400 MHz, DMSO-tfc) 3 = 13.53 - 13.07 (m, 1H), 8.46 (s, 1H).Example 31.2. Preparation of (2-bromothiazol-4-yl)(moipholino)methanone

[0282] To a mixture of 2-bromothiazole-4-carboxylic acid ( 1.00 g, 4.81 mmol, 1.00 eq) and A'-diisopropylethylamine (1.86 g, 14.4 mmol, 2.51 mL, 3.00 eq) in dimethylformamide (15.0 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (2.19 g, 5.77 mmol, 1.20 eq). The mixture was stirred at 25°C for 30 min, then morpholine (461 mg, 5.29 mmol, 465 pL, 1.10 eq) was added. The mixture was stirred at 25°C for 1.5 h. The mixture was poured into water (40.0 mL) and extracted with ethyl acetate (20.0 ml x 3). The combined organic phase was washed with brine (20.0 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =20:80). (2- Bromothiazol-4-yl)-morpholino-methanone (1.30 g, 4.69 mmol, 98% yield) was obtained as a white solid. ‘H NMR (400 MHz, DMSO-d6) d = 8.16 (s, 1H), 3.63 (s, 8H).Example 31.3. Preparation of (2-((4-methoxybenzyl)thio)thiazol-4- yl)(morpholino)methanone

[0283] To a mixture of (2-bromothiazol-4-yl)-morpholino-methanone (500 mg, 1.80 mmol, 1.00 eq) and (4-methoxyphenyl)methanethiol (417 mg, 2.71 mmol, 377 pL, 1.50 eq) in dioxane (10.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (165 mg, 180 pmol, 0.100 eq), N,N-diisopropylethylamine (700 mg, 5.41 mmol, 943 pL, 3.00 eq) and Xantphos (104 mg, 180 pmol, 0.100 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =60:40). [2-[(4-Methoxyphenyl)methylsulfanyl]thiazol-4-yl]-morpholino-methanone (600 mg, 1.71 mmol, 95% yield) was obtained as a white solid.!H NMR (400 MHz, DMSO-rie) 6 = 8.02 (s, 1H), 7.33 (br d, J = 8.0 Hz, 2H), 6.89 (d, J= 8.0 Hz, 2H), 4.44 (s, 2H), 3.73 (s, 3H), 3.36 - 3.25 (m, 8H).Example 31.4, Preparation of 4-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride

[0284] Acetic acid (1.00 mL) was added to water (0.300 mL). [2-[(4- methoxyphenyl)methylsulfanyl]thiazol-4-yl]-morpholino-methanone (100 mg, 285 pmol, 1.00 eq) and 1 -chloropyrrolidine-2, 5-dione (152 mg, 1.14 mmol, 4.00 eq) were added to the mixture. The mixture was stirred at 0°C for Ih. The mixture was poured into sat. sodium bicarbonate (20.0 mL),and adjusted to pH=8, separated the organic phase and the aqueous phase was extracted with ethyl acetate (20.0 ml x 3). The organic layers were combined and washed with brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The crude can used to next step without any purification. 4-(morpholine-4- carbonyl)thiazole-2-sulfonyl chloride (84.0 mg, crude) was obtained as a yellow solid.Example 31.5. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-4-(morpholine-4- carbonyl)thiazole-2-sulfonamide (Compound 31)Compound 31

[0285] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (20.2 mg, 118 pmol, 1.00 eq) and pyridine (18.7 mg, 236 pmol, 19.0 pL, 2.00 eq) in dichloromethane (0.200 mL)was added dropwise a solution of 4-(morpholine-4-carbonyl)thiazole-2-sulfonyl chloride(35.0 mg, 118 pmol, 1 .00 eq) in dichloromethane (0.200 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was concentrated in vacuum. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)- ACN];gradient:25%-55% B over 8 min). A-(3-cyano-4-methyl-lH-indol-7-yl)-4- (morpholine-4-carbonyl)thiazole-2-sulfonamide (8.98 mg, 20.40 pmol, 17.29% yield, 98% purity) was obtained as a pink solid. MS (ESI) m / z 432.2 [M+H]+. ’H NMR (400 MHz, DMSO-ifc) 6 = 12.04 (s, 1H), 10.89 - 10.71 (m, 1H), 8.43 (s, 1H), 8.20 (br d, J - 2.4 Hz, 1H),6.85 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 3.75 - 3.52 (m, 4H), 3.43 (br d, J = 11.6 Hz,4H), 2.60 (s, 3H).Example 32, Synthetic Scheme of Compound 32Compound 32Example 32,1, Preparation of l-(thiazol-2-yl)cyclobutan-l-ol

[0286] To a solution of n-BuLi (2.50 M, 1 1 .3 mL, 1 .20 eq) in tetrahydrofuran (30.0 mL) was slowly added a solution of thiazole (2.00 g, 23.5 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) at -78 °C . The resulting mixture was stirred for 1 h and then cyclobutanone (3.29 g, 47.0 mmol, 3.51 mL, 2.00 eq) in tetrahydrofuran (7.00 mL) was added. The mixture was stirred for 2 h at -78 °C. Then saturated ammonium chloride (200 ml) was added, and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 ml x 3) and the combined organics were washed with water, brine (30.0 ml), dried (sodium sulfate) and concentrated. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=3 / l). l-thiazol-2-ylcyclobutanol (3.90 g, crude) was obtained as a yellow oil.{H NMR (400 MHz, DMSO- / 6) d = 7.73 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 3.2 Hz, 1H), 6.44 (s, 1H), 2.49 - 2.45 (m, 2H), 2.37 - 2.26 (m, 2H), 1.94 - 1.82 (m, 2H).Example 32.2. Preparation of 2-(l-chlorocyclobutyl)thiazole

[0287] A mixture of l-thiazol-2-ylcyclobutanol (2.47 g, 15.9 mmol, 1.00 eq) in thionyl chloride (9.90 mL) was stirred at 0°C for 2 h. The mixture was concentrated in reduced pressure. The residue was poured into sat. sodium bicarbonate (100 mL) and extracted with ethyl acetate (30.0 ml x 3). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=90 / 10). 2-(l-Chlorocyclobutyl)thiazole (2.30 g, 12.8 mmol, 80% yield, 96% purity) was obtained as a colorless oil. ‘H NMR (400 MHz, DMSO-d6) 3 = 7.85 - 7.81 (m, 2H), 3.04 - 2.98 (m, 2H), 2.82 - 2.75 (m, 2H), 2.22 (ttd, J = 5.6, 9.6, 10.8 Hz, 1H), 1.98 - 1.86 (m, 1H).Example 32,3. Preparation of 4-(l-(thiazol-2-yl)cyclobutyl)morpholine

[0288] A mixture of 2-(l-chlorocyclobutyl)thiazole (1.96 g, 11.3 mmol, 1.00 eq) in morpholine (30.0 mL) was stirred at 130 °C for 16 h. The mixture was poured into water (20.0 mL) and acidified with hydrochloric acid (1 M) to pH about 8. The resulting mixturewas extracted with ethyl acetate (20.0 ml x 3). The combined organic phase was washed with brine (20.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =85:15). 4-(l-thiazol-2-ylcyclobutyl)morpholine (1.00 g, 4.46 mmol, 39% yield) was obtained as a yellow solid.NMR (400 MHz, DMSO-< / 6) 6 = 7.79 (d, J = 3.3 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 3.60 - 3.51 (m, 4H), 2.41 - 2.28 (m, 8H), 1.85 - 1.66 (m, 2H).Example 32,4, Preparation of 2-(l-morpholinocyclobutyl)thiazole-5-sulfinic acid

[0289] To a solution of 4-(l-thiazol-2-ylcyclobutyl)morpholine (300 mg, 1.34 mmol, 1.00 eq) in tetrahydrofuran (6.00 mL) was added n-butyllithium (2.50 M, 802 pL, 1.50 eq) dropwise at -78 °C and stirred 30 min under nitrogen, and then sulfur dioxide (85.7 mg, 1.34 mmol, 1.00 eq) was bubbled into at -65°C for 30 min. The reaction mixture was warmed to 20°C slowly and stirred for 3 h. The mixture can used to next step without any work-up. The mixture can used to next step without any purification. A solution of 2-(l- morpholinocyclobutyl)thiazole-5-sulfinic acid (386 mg, crude) in THF (6.00 mL) was obtained as a yellow liquid. The solution was used to next step directly.Example 32,5. Preparation of 2-(l-morpholinocyclobutyl)thiazole-5-sulfonyl chloride

[0290] To a solution of 2-(l-morpholinocyclobutyl)thiazole-5-sulfinic acid (386 mg, 1.34 mmol, 1.00 eq) in tetrahydrofuran was added 1 -chloropyrrolidine-2, 5-dione (536 mg, 4.02 mmol, 3.00 eq) at 0 °C and stirred another 16 h at 20°C. The mixture was poured into water (10.0 mL) and extracted with dichloromethane (10.0 ml x 3). The combined organic phase was washed with brine (10.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate =5:1). 2-(l-morpholinocyclobutyl)thiazole-5- sulfonyl chloride (350 mg, 1.08 mmol, 81% yield) was obtained as a yellow oil. ’ H NMR (400 MHz, DMSO-rfe) 3 = 7.96(s, 1H), 3.89 (s, 4H), 3.08 - 2.96 (m, 4H), 2.59 - 2.55 (m, 2H), 1.99 - 1.92 (m, 2H), 1.83 - 1.69 (m, 2H).Example _ 32,6. _ Preparation _ of N-(3-cvano-4-methyl-lH-indol-7-yl)-2-(l- morpholinocvclobutyl)thiazole-5- sulfonamide (Compound 32)Compound 32

[0291] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (26.5 mg, 155 pmol, 1.00 eq) and pyridine (24.5 mg, 310 pmol, 25.0 pL, 2.00 eq) in dichloromethane (0.500 mL) was added dropwise a solution of 2-(l-morpholinocyclobutyl)thiazole-5-sulfonyl chloride (50.0 mg, 155 pmol, 1.00 eq) in dichloromethane (0.500 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was concentrated in vacuum. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)- ACN];gradient:30%-60% B over 8 min ). A-(3-cyano-4-methyl-177-indol-7-yl)-2-(l- morpholinocyclobutyl)thiazole-5- sulfonamide (30.52 mg, 66.70 pmol, 43.07% yield, 100% purity) was obtained as a pink solid. MS (ESI) m / z 458.2 [M+H]+.JH NMR (400 MHz, DMSO-ri6) <5 = 11.89 (d, J= 2.4 Hz, 1H), 10.17 (s, 1H), 8.16 (d, J = 3.2 Hz, 1H), 8.03 (s, 1H), 6.87 (d, 7= 8.0 Hz, 1H), 6.71 (d, 7 = 7.6 Hz, 1H), 3.54 (s, 4H), 2.61 (s, 3H), 2.44 (d, 7 = 10.8 Hz, 2H), 2.28 (s, 4H), 2.16 (t, 7= 8.8 Hz, 2H), 1.88 - 1.69 (m, 2H).Example 33. Synthetic Scheme of Compound 33Compound 33Example 33.1. Preparation of 2-methylthiazole-5-sulfonamide

[0292] To a solution of 2-methylthiazole-5-sulfonyl chloride (450 mg, 2.28 mmol, 1.00 eq) in dichloromethane (0.500 mL) was added ammonium hydroxide (4.10 g, 29.2 mmol, 4.50 mL, 25% purity, 12.8 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=l / O to 1 / 1) and concentrated under reduced pressure to remove solvent and give the 2-methylthiazole-5-sulfonamide (360 mg, 1.92 mmol, 84.3% yield, 95% purity) as a white solid. ’H NMR (400 MHz, DMSO-t / e) d' = 7.97 (s, 1H), 7.85 (s, 2H), 2.71 (s, 3H).Example 33.2, Preparation of N-[tert-butyl(dimethyl)silyl]-2-methyl-thiazole-5-sulfonamide

[0293] To a solution of 2-methylthiazole-5-sulfonamide (300 mg, 1 .68 mmol, 1 .00 cq) in tetrahydrofuran (7.00 mL) was added dropwisc sodium hydride (135 mg, 3.37 mmol, 60% purity, 2.00 eq) at 0°C. After addition, the mixture was stirred at this temperature for 30 min, and then tert-butylchlorodimethylsilane (1.27 g, 8.42 mmol, 1.04 mL, 5.00 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition water (10.0 mL) at 0 °C, and then extracted with ethyl acetate (10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 3 / 1) and concentrated under reduced pressure to give the A-[tert-butyl(dimethyl)silyl]-2-methyl- thiazole-5- sulfonamide (400 mg, 1.30 mmol, 77.2% yield, 95% purity) as a white solid.!H NMR (400 MHz, DMSO- / 6) 3 = 8.10 (s, 1H), 7.94 (s, 1H), 2.71 (s, 3H), 0.88 (s, 9H), 0.17 - 0.14 (m, 6H).Example 33.3. Preparation of tert-butyL[[chloro-(2-methylthiazol-5-yl)-oxo- sulfanylidene] aminol -dimethyl-silane

[0294] To a solution of dichloro(triphenyl)-phosphane (17.1 mg, 51.3 pmol, 1.50 eq ) in trichloromethane (0.100 mL) was added dropwise triethylamine (5.54 mg, 54.7 pmol, 7.61 pL, 1.60 eq) at 0 °C. After addition, the mixture was stirred at 20 °C for 15 min, and then A-[ / ert-butyl(dimethyl)silyl]-2-methyl-thiazole-5-sulfonamide (10.0 mg, 34.2 pmol, 1.00 eq) in trichloromethane (0.100 mL) was added drop wise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The crude product tert-butyl-[[chloro-(2-methylthiazol-5-yl)-oxo- sulfanylidene]amino]-dimethyl-silane (100 mg, crude) in trichloromethane (1.00 mL) was obtained as a yellow liquid. The mixture was used into the next step without further purification.Example 33.4, Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-morpholino-thiazole-5- sulfonamidc

[0295] To a solution of te -butyl-[[chloro-(2-methylthiazol-5-yl)-oxo- sulfanylidene]amino]-dimethyl-silane (10.0 mg, 32.2 pmol, 1.00 eq) and 7-amino-4-methyl- lH-indole-3-carbonitrile (5.51 mg, 32.2 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (5.09 mg, 64.3 pmol, 5.19 pL, 2.00 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL). The combined organic layers were washed with brine (5.00 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si CL. Petroleum ether / Ethyl acetate=l / O to 3 / 1) and concentrated under reduced pressure to remove solvent to give the 7-[[ / V-[tcrt- butyl(dimethyl)silyl]-S-(2-methylthiazol-5-yl)sulfonimidoyl]amino]-4-methyl-lH-indole-3- carbonitrile (25.0 mg, 48.8 pmol, 15% yield, 87% purity) as a white solid. MS (ESI) m / z 446.1 [M+H]+.Preparation of 33.5. Preparation of 4-methyl-7-[[(2-methylthiazol-5-yl)sulfonimidoyl]amino]- IH-indole- 3 -carbonitrile (Compound 33)Compound 33

[0296] To a solution of 7-[[Ar-[tert-butyl(dimethyl)silyl]-S-(2-methylthiazol-5- yl)sulfonimidoyl]amino]-4-methyl-lH-indole-3-carbonitrile (20.0 mg, 44.9 pmol, 1.00 eq) in dichloromethane (0.100 mL) was added dioxane (4 M, 11.2 pL, 1.00 eq). The mixture wasstirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by prep-HPLC (column: Phcnomcncx luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:23%-53% B over 8 min) and lyophilized to give the 4-methyl-7- [[(2-methylthiazol-5-yl) sulfonimidoyl] amino] -177- indole-3-carbonitrile (5.08 mg, 15.0 pmol, 33% yield, 98% purity) as a yellow gum. MS (ESI) m / z 354.0 [M+H]+. ’ H NMR (400 MHz, DMSO-d6) 3 = 11.83 - 11.57 (m, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.66 (br s, 2H), 6.86 - 6.80 (m, 1H), 6.79 - 6.72 (m, 1H), 2.68 (s, 3H), 2.54 (s, 3H)Example 34. Preparation of N-(5-(N-(3-cyano-4-methyl-lH-indol-7-yl)sulfamoyl)thiazol-2- vDacetamide (Compound 34)Compound 34

[0297] To a solution of 2-amino-A-(3-cyano-4-methyl-17 / -indol-7-yl)thiazole-5- sulfonamide (50.0 mg, 111 pmol, 1.00 eq, trifluoroacetic acid) in dichloromethane (1 mL) was added triethylamine (113 mg, 1.12 mmol, 155 pL, 10 eq) and acetic anhydride (11.4 mg, 111 pmol, 10.5 pL, 1.00 eq) at 0 °C. The mixture was stirred at 16 °C for 3.5 h. The mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mLx3). The combined organic layer was concentrated in vacuum. The crude product was purification by prep- HPLC(column: Phcnomcncx luna C18 150*25mm* 10pm;mobilc phase: [watcr(FA)- ACN];gradient:23%-53% B over 10 min ). N-(5-(N-(3-cyano-4-methyl-lH-indol-7- yl)sulfamoyl)thiazol-2-yl)acetamide (10.86 mg, 28.64 pmol, 25.63% yield, 99% purity) was obtained as a white solid. MS (ESI) m / z 376.0 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) 3 = 12.91 - 12.30 (m, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.14 (s, 2H), 7.59 (s, 1H), 7.09 - 6.92 (m, 2H), 2.72 - 2.67 (m, 3H), 1.86 (s, 3H).Example 35. Synthetic Scheme of Compound 35Compound 35Example 35.1. Preparation of 2-thiazol-2-ylpropan-2-ol

[0298] To a solution of 2-bromothiazole (2.00 g, 12.2 mmol, 1.10 mL, 1.00 eq) in tctrahydrofuran (25.0 mL) was added n-butyllithium (2.5 M, 5.37 mL, 1.10 eq at -78°C . The mixture was stirred at -78°C for0.5h, acetone (779 mg, 13.4 mmol, 986 pL, 1.10 eq) was added to the mixture , The mixture was stirred at -78°C for 1.5 h . The mixture was poured into water (50.0 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (3x60 mL). The organic layers were combined and washed with brine (50.0 mL), dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / l to 4 / 1) ,TLC (Petroleum ether / Ethyl acetate =1:1, Rf(R=0.2,P=0.3)). 2-thiazol-2-ylpropan-2-ol (750 mg, 5.24 mmol, 42.95% yield) was obtained as brown oil.NMR (400 MHz, DMSO-de) 8 = 7.74 (d, J = 3.2 Hz, 1H), 7.60 (d, 7= 3.2 Hz, 1H), 1.57 (s, 6H).Example 35.2. Preparation of 2-(l -hydroxy- l-methyl-ethyl)thiazole-5-sulfonyl chloride

[0299] To a solution of 2-thiazol-2-ylpropan-2-ol (300 mg, 2.09 mmol, 1.00 eq) in tetrahydrofuran (7.00 mL) was added n-butyllithium (2.5 M, 2.51 mL, 3.00 eq) dropwise at - 78°C; the mixture was stirred for 30 min at -78°C. Then sulfur dioxide (134 mg, 2.09 mmol, 1.00 eq) was introduced in this solution for 20 minutes below -30°C under 15 Psi. The solution was stirred for 0.5 h at 16°C. NCS (419 mg, 3.14 mmol, 1.50 eq) was added to the mixture at 16 °C. The solution was stirred for 16 h at 16°C. The mixture was poured into water (30.0 mL), separated the organic phase and the aqueous phase was extracted with ethyl acetate (3x60 mL). The organic layers were combined and washed with brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 3 / 1) ,TLC (Petroleum ether / Ethyl acetate =1:1, Rf (R=0.3,P=0.5)). 2-(l -hydroxy- l-methyl-ethyl)thiazole-5- sulfonyl chloride (100 mg, 413.71 pmol, 19.75% yield, 100% purity) was obtained as a white solid. MS (ESI) m / z 241.9 [M+H]+.Example 35.5. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(l-hydroxy-l-methyl- ethyl)thiazole-5-sulfonamide (Compound 35)Compound 35

[0300] To a solution of 2-(l -hydroxy- l-methyl-ethyl)thiazole-5-sulfonyl chloride(50.0 mg, 206 pmol, 1.10 eq) in dichloromethane (1.00 mL) was added pyridine (44.6 mg, 564 pmol, 45.5 pL, 3.00 eq) and 7-amino-4-methyl-lH-indole-3-carbonitrile (32.1 mg, 188 pmol,I .00 eq) at 0°C. The mixture was stirred at 0°Cfor 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC(column: Phenomenex luna C18 150*25mm* 10pm;mobile phase: [water(FA)-ACN];gradient:23%- 53% B over 10 min ). A-(3-cyano-4-methyl-lH-indol-7-yl)-2-(l -hydroxy- 1-methyL ethyl)thiazole-5-sulfonamide (8.81 mg, 23.36 pmol, 12.42% yield, 99.81% purity) was obtained as a white solid. MS (ESI) m / z 377.2 [M+H]+. ’H NMR (400 MHz, DMSO-ri6) <5 =I I.93 (s, 1H), 10.27 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.74 (d, J= 8.0 Hz, 1H), 6.30 (s, 1H), 2.62 (s, 3H), 1.47 (s, 6H).Example 36.1. Preparation of 2-(methyl-drithiazole

[0301] To a solution of thiazole (1.00 g, 11.8 mmol, 1.00 eq) in tetrahydrofuran (15.0 mL) was added dropwise n-butyllithium (2.5 M, 5.17 mL, 1.10 eq) at -78°C. trideuterio(iodo)methane (2.21 g, 15.3 mmol, 950 pL, 1.30 eq) was added at -60°C and stirred at 20°C for another 2 h. The mixture was quenched by adding saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50 mL x 2). The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1) to give 2-(methyl- <L?)thiazole (1.30 g, 12.7 mmol, 54% yield) as a yellow oil. ’H NMR (400 MHz, CHLOROFORM-rf) 6 = 7.65 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H).Example 36.2, Preparation of 3-2-(methyl-dj)thiazole-5-sulfonyl chloride

[0302] To a solution of 2-(methyl-6? )thiazole (1.20 g, 11.7 mmol, 1.00 eq) in tetrahydrofuran (15.0 mL) was added n-butyllithium (2.5 M, 7.99 mL, 1.70 eq) dropwise at - 78°C and stirred 30 min. under nitrogen, and then sulfur dioxide (752 mg, 11.7 mmol, 1.00 eq) was bubbled into at -65°C for 30 min. The reaction mixture was warmed to 20°C slowly and stirred for 3 h. N-chlorosuccinimide (2.89 g, 21.7 mmol, 3.00 eq) was added at 0°C. The mixture was stirred at 20°C for 12 h. The mixture was poured into water (100 mL) andextracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1) to give 2-(methyl-6??)thiazole-5-sulfonyl chloride (470 mg, 2.32 mmol, 32% yield, 99% purity) as a yellow oil.Example 36.3. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(methyl-d5)thiazole-5- sulfonamide (Compound 143)

[0303] To a solution of 2-(methyl-<7?)thiazole-5-sulfonyl chloride (50.0 mg, 249 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added pyridine (39.4 mg, 498 pmol, 40.2 pL, 2.00 eq) and 7-amino-4-methyl-l / / -indole-3-carbonitrile (42.7 mg, 249 pmol, 1.00 eq). The mixture was stirred at 20°C for 0.5 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLCicolumn: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 27%-57% B over 10 min) and lyophilized to give A-(3-cyano-4-methyl-177-indol-7-yl)-2-(methyl-6?3)thiazole-5-sulfonamide (58.52 mg, 174.47 pmol, 70.03% yield). MS (ESI) m / z 336.1 [M+H]+. ‘H NMR (400 MHz, DMSO-J6) <5 = 11.97 (br s, 1H), 10.44 - 10.12 (m, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.89 (s, 1H), 6.86 (d, J= 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 2.60 (s, 3H).Compound 91Example 37,1, Preparation of tert-butyl (5-bromothiazol-2-yl)carbamate

[0304] To a solution of 5-bromothiazol-2-amine (5.00 g, 27.9 mmol, 1.00 eq) in dichloromethane (60 mL) was added 4-dimethylaminopyridine (341 mg, 2.79 mmol, 0.100 eq) and di-tert-butyldicarbonate (9.14 g, 41.8 mmol, 9.62 mL, 1.50 eq) at 16 °C. The mixture was stirred at 16 °C for 2 h. The mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate= 100 / 1 to 10 / 1) .The crude product was triturated with Petroleum ether at 20 °C for 15 min. The mixture was filtered, and the filter cake was collected, tert-butyl (5-bromothiazol-2- yl)carbamate (5.6 g, 20.06 mmol, 71.83% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO-t / fi) d = 11.74 (br s, 1H), 7.44 (s, 1H), 1.51 - 1.47 (m, 9H)Example 37.2. Preparation of tert-butyl-(5-bromothiazol-2-yl)(methyl)carbamate

[0305] To a solution of sodium hydride (859 mg, 21.4 mmol, 60% purity, 1.20 eq) in dimethylformamide (30 mL) was added tert-butyl (5-bromothiazol-2-yl)carbamate (5.00 g, 17.9 mmol, 1.00 eq at 0 °C. The mixture was stirred at 0 °C for 0.5 h. lodomethane (3.05 g, 21.4 mmol, 1.34 mL, 1.20 eq was added to the mixture and stirred at 16 °C for 1 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / lto 10 / 1). TLC (petroleum ether:ethyl acctatc-5: 1 ); Rf (R=0.5; P=0.8). tert-butyl (5-bromothiazoL2- yl)(methyl)carbamate (5.1 g, 17.40 mmol, 97.12% yield) was obtained as a white solid. H NMR (400 MHz, CDCh) d = 7.33 (s, 1H), 3.50 (s, 3H), 1.58 (s, 9H).Example 37,3, Preparation of 5-bromo-N-methylthiazol-2-amine

[0306] To a solution of tert-butyl (5-bromothiazol-2-yl)(methyl)carbamate (5.00 g, 17.0 mmol, 1.00 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (7.68 g, 67.3 mmol, 5.00 mL, 3.95 eq) at 16 °C. The mixture was stirred at 16 °C for 2.5 h. The mixture was poured into water (50 mL) and adjusted to pH=8. Then extracted with dichloromethane (200 mL x 3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate= 100 / 1 to 10 / 1, TLC (petroleum ether:ethyl acetate=5:l) Rf(R=0.6, P=0.4)). 5-bromo-Af-mcthylthiazol-2-aminc (2.4 g, 12.43 mmol, 72.89% yield) was obtained as a yellow solid.JH NMR (400 MHz, DMSO-ifc) 6 = 7.69 (br s, 1H), 7.05 (s, 1H), 2.79 (d, 7 - 4.4 Hz, 3H).Example 37.4. Preparation of N-(5-bromothiazol-2-yl)-N-methylmethanesulfonamide

[0307] To a solution of solution of 5-bromo-AAmethylthiazol-2-amine (500 mg, 2.59 mmol, 1.00 eq) in dichloromethane (5 mL) was added triethylamine (262 mg, 2.59 mmol, 360 pL, 1.00 eq) and methanesulfonyl chloride (460 mg, 4.02 mmol, 310 pL, 1.55 eq) at 0 °C. The mixture was stirred at 16 °C for 1 h. The mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic layer was dried over with sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 3 / 1, TLC (petroleum ether: ethyl acetate=5:l), Rf(R=0.4, P=0.6)).JV-(5-bromothiazol-2-yl)-AA-mcthylrncthancsull'onamidc (450 mg, 1.66 mmol, 64.08% yield) was obtained as a yellow oil.NMR (400 MHz, DMSO-<7d) d = 7.10 (s, 1H), 2.80 (s, 3H), 2.30 (s, 3H).Example 37.5. Preparation of N-(5-((4-methoxybenzyl)thio)thiazol-2-yl)-N- methylmethanesulfonamide

[0308] To a solution of AL(5-bromothiazol-2-yl)- / V-mcthyhncthancsullbnamidc(100 mg, 368 pmol, 1.00 eq) and (4-methoxyphenyl)methanethiol (68.2 mg, 442 pmol, 61.6 pL, 1.20 eq) in dioxane (2 mL) was added / V, / V-diisopropylethylamine (47.6 mg, 368 pmol,64.2 pL, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (42.6 mg, 73.7 pmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium(0) (21.2 mg, 36.8 pmol, 0.100 eq) at 16 °C. Themixture was stirred at 100 °C for 16 h. The mixture was poured into water (50 mL) and extracted with dichloromcthanc(50 mL x 3). The combined organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 1 / 1, TLC (petroleum ether: ethyl acetate=l:l), Rf(R=0.7 ,P=0.3)). N-(5-((4- methoxybenzyl)thio)thiazol-2-yl)-iV-methylmethanesulfonamide (85 mg, 246.75 pmol, 66.91% yield) was obtained as a yellow gum.JH NMR (400 MHz, DMSO-afe) d = 7.34 (s, 1H), 7.13 (d, J= 8.4 Hz, 2H), 6.85 (d, J= 8.4 Hz, 2H), 3.98 (s, 2H), 3.72 (s, 3H), 3.36 (s, 3H), 3.22 (s, 3H).Example 37,6. Preparation of 2-(N-methylmethylsulfonamido)thiazole-5-sulfonyl chloride

[0309] To a solution of 2V-(5-((4-methoxybenzyl)thio)thiazol-2-yl)-.V- methylmethanesulfonamide (80.0 mg, 232 pmol, 1.00 eq) in acetic acid (3 mL), water (1 mL) and dichloromethane (1 mL) was added / V-chlorosuccin imide (124 mg, 928 pmol, 4.00 eq) at 0 °C. The mixture was stirred at 16 °C for 0.5 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (10 mL x 3), dried over sodium sulfate and concentrated in vacuum. 2-(A / - methylmethylsulfonamido)thiazole-5- sulfonyl chloride (60 mg, crude) was obtained as a yellow solid.Example _ 37,7, _ Preparation _ of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(N- mcthylmcthylsulfonamido)thiazolc-5- sulfonamide (Compound 91)Compound 91

[0310] To a solution of 7-amino-4-methyl-177-indole-3-carbonitrile (31.7 mg, 185 pmol, 0.900 eq) in dichloromethane (0.5 mL) was added pyridine (81.6 mg, 1.03 mmol, 83.2 pL, 5.00 eq) and 2-(Wmethylmethylsulfonamido)thiazole-5-sulfonyl chloride (60.0 mg, 206 pmol, 1.00 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was dried over with sodium sulfate and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters Xbridge 150*25mm I Op immobile phase: [water (NH4HC03)-ACN];gradient:20%-50% B over 10 min ). LCMS showed 90% desired mass was detected. The mix was purified by prep-TLC (petroleum ether: ethyl acetate=l:l, Rf=0.5). N- (3-cyano-4-mcthyl- 177-indol-7-yl)-2-(Wmcthylmcthylsulfonamido)thiazolc-5-sulfonamidc (10.91 mg, 25.64 pmol, 12.43% yield, 100% purity) was obtained as a white solid. MS (ESI) m / z 426.0 [M+H]+.1H NMR (400 MHz, DMSO- d6) 6 = 12.00 (br d, J = 2.0 Hz, 1H), 10.23 (s, 1H), 8.19 (d, 7= 2.8 Hz, 1H), 7.74 (s, 1H), 6.89 (d, 7 = 8.0 Hz, 1H), 6.78 (d, 7= 8.0 Hz, 1H), 3.41 (s, 3H), 3.33 (s, 3H), 2.61 (s, 3H).

[0311] Compounds 36-90, 92-142, and 144-151 were or can be prepared by similar methods to those described herein and are shown in Table 1.Table 1Example 38. HCT116 Cell Viability Assay

[0312] HCT116 colorectal cells were used in these experiments. HCT116 cells were obtained from ATCC. The CellTiter-Glo® Luminescent Cell Viability Assay Reagent was obtained from Promega.

[0313] Into a 96- well plate, 3000 HCT116 cells were seeded with 100 pL of media (McCoy’s 5A Medium supplemented with 10% FBS. 100 units penicillin, and 100 pg streptomycin per mL) 24 h before the experiment. For compound treatment, the liquid handling system-Pico machine was used to prepare all the compounds. Each master plate contained serial dilution of 2 compounds, including the control compound E7820. lOmM compound stock was added to each well of the assay plate to give final concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0 pM. Each concentration was tested in triplicate. After 72h, cell viability was determined using CellTiter-Glo Luminescent Cell Viability Assay Reagent following the manufacturer’s recommended protocol. Briefly, equilibrate the assay plate and its contents at room temperature for approximately 30 minutes. 100 pL of CellTiter-Glo reagent was added to each well of the assay plate and the contents were mixed for 2 minutes at 500 rpm on an orbital shaker to induce cell lysis (Fisherbrand). The plate was incubated at room temperature for 10 minutes to stabilize luminescent signal. Then the plate was immediately placed in a platereader (PerkinElmer Multimode Plate Reader Envision2105) and the luminescence signal (0.5 second per well integration time) was determined. IC50 values were calculated using GraphPad Prism 9 software.

[0314] Compounds described herein as exemplified in the Examples, showed IC50 values in the following ranges: A: IC50 < 500 nM; B: 500 nM < IC50 <1000 nM; C: IC50 > 1000 nM.Table 2Example 39: ADME StudiesGeneral Solubility Protocol:

[0315] Into a 96-well rack 15 pL of stock solution (10 mM) of each sample was placed. Into each vial of a cap-less Solubility Sample plate 485 pL of buffer was added. The assay was performed in duplicate. To each vial one stir stick was added and each vial was sealed using a molded PTFE / Silicone plug. The Solubility Sample plate was then transferredto an Eppendorf Thermomixer Comfort plate shaker and shake at 25°C at 1100 RPM for 2 h. After 2 h, the stir sticks were removed using a big magnet and the samples were transferred from the solubility sample plate into the filter plate. Using a vacuum manifold, all the samples were filtered. An aliquot of 5 pL was taken from the filtrate and 5 pL blank DMSO followed by addition of 490 pL of a mixture of H2O and acetonitrile containing an internal standard (1:1). The dilution factor may be changed according to the solubility value and the LC / MS signal response.General Liver Microsomes Stability Protocol:

[0316] A 100 pM test compound solution and PC solution (verapamil) was prepared by adding 2 pL of 10 mM stock solution in DMSO to 198 pL of 50% acetonitrile I 50% water.Step 1: Incubation

[0317] Two separate experiments were performed as follows:

[0318] a) With Cofactors (NADPH): 25 pL of 10 mM NADPH was added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. b) Without Cofactors (NADPH): 25 pL of 100 mM Phosphate buffer was added to the incubations. The final concentration of microsomes was 0.5 mg / mL. The mixture was prewarmed at 37°C for 10 minutes.

[0319] The reaction was started with the addition of 2.5 pL of 100 pM control compound or test compound solutions. Verapamil was used as positive control in this study. The final concentration of test compound or control compound was 1 pM. The incubation solution was incubated in a water bath at 37°C.Step 2. Reaction Quenching

[0320] Aliquots of 30 pL were taken from the reaction solution at 0.5, 15, 30, 45 and 60 min. The reaction was stopped by the addition of 5 volumes of cold acetonitrile with IS (100 nM alprazolam, 20011M caffeine and 100 nM tolbutamide).

[0321] Samples were then centrifuged at 3,220 g for 40 min. An aliquot of 100 pL of the supernatant was mixed with 100 pL of ultra-pure H2O and then used for LC-MS / MS analysis.General MDCK-MDR1 Assay Protocol:

[0322] To prepare transport buffer (HBSS with 10 mM HEPES, pH 7.4), 2.383 g of HEPES and 0.35 g sodium hydrogen carbonate was accurately weighed and added into 900 mL of pure water, then sonicated to dissolve the content. Into the solution was transferred 100 mL of 10 x HBSS, and the solution was placed on a stirrer. The pH of the solution was slowly adjusted with sodium hydroxide to 7.4, followed with filtering.

[0323] MDCK-MDR1 plate(s) were removed from the incubator. The monolayer was washed the monolayer twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Then the plate(s) were incubated at 37 °C for 30 minutes.

[0324] Propranolol was used as the high permeability marker. Digoxin was used as the substrate of breast cancer resistant protein (MDR1). Stock solutions of test compound(s) and digoxin in DMSO at 0.2 mM were prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to get 1 pM working solutions. Stock solutions of propranolol in DMSO at 1 mM was prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 pM working solutions.

[0325] To determine the rate of drug transport in the apical to basolateral direction, 125 pL of the working solution was added to the Transwell insert (apical compartment), and a 50 pL sample was immediately transferred from the apical compartment to 200 pL quenching solvents (acetonitrile with 100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (A-B). The plate was shaken at 1000 rpm for 10 minutes. The wells in the receiver plate (basolateral compartment) were filled with 235 pL of transport buffer. All incubations were performed in duplicate.

[0326] To determine the rate of drug transport in the basolateral to apical direction, 285 pL of the 1 pM working solution was added to the receiver plate wells (basolateral compartment), and a 50 pL sample was immediately transferred from the basolateral compartment to 200 pL quenching solvents (acetonitrile with 100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (B-A). Shake the plate at 1000 rpm 10 minutes. The Transwell insert (apical compartment) was filled with 75 pL of transport buffer. The apical to basolateral direction and the basolateral to apical direction were done at the same time.

[0327] The Trans well insert plate was inserted into the basolateral plate, transferred into the incubator and incubated at 37°C for 2 h.

[0328] At the end of the incubation, 50 pL samples from donor sides (apical compartment for Ap >BI flux, and basolatcral compartment for Bl >Ap flux) and receiver sides (basolateral compartment for Ap— >B1 flux, and apical compartment for Bl— >Ap flux) were transferred to wells of a new 96-well plate, followed by the addition of 4 volume of quenching solvents (acetonitrile with 100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide). Samples were Vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 pL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS / MS analysis.

[0329] To determine the Lucifer yellow leakage after 2-hour transport period, Lucifer yellow working solutions were prepared by diluting the stock solution with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 pM. To the apical compartment, 100 pL of the Lucifer yellow solution were added. The plate(s) were incubated at 37 °C for 30 minutes and 80 pL was directly removed from the apical and basolateral wells and transferred to new 96 wells plates. Lucifer yellow fluorescence (to monitor monolayer integrity) was measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission.Table 3: ADME PropertiesMV = no valueExample 40: Ewing Sarcoma A-673 Cell Viability StudiesA-673 Cell Proliferation Assay

[0330] Into a 96-well plate, 5000 A-673 cells were seeded with 100 pL of media (Dulbecco’s Modified Eagle Medium, supplemented with 10% fetal bovine serum, 100 units penicillin, and 100 pg streptomycin per mL). After 24 h, 10 mM compound stock was added to each well of the assay plate to give final concentrations of 10 pM, 3 pM, 1 pM, 0.3 pM, 0.1 pM, 0.03 pM, 0.01 pM, 0.003 pM and 0 pM using a liquid handling system-Pico machine. Dimethyl sulfoxide (DMSO) was normalized to 0.1% (v / v) across all wells and each concentration was tested in triplicate. After 72h of incubation, the plate was equilibrated at room temperature for approximately 30 min. To each well was added 100 pL of CellTiter- Glo® (CTG) reagent. The contents were mixed for 2 min at 500 rpm on an orbital shaker to induce cell lysis. The plate was incubated at room temperature for 10 min to stabilize the luminescent signal. The plate was then immediately placed in a plate reader (PerkinElmer Multimode Plate Reader Envision 2105) and the luminescence signal (0.5 seconds per well integration time) was determined. IC50 values were calculated using GraphPad Prism 9 software using a nonlinear regression analysis model with variable slope (four parameters).

[0331] The antitumor activity on A-673 cells was evaluated for effects on cell viability in an 8-point dose-response CTG assay. A representative result for Compound 1 is shown in Fig. 1. A dose-response inhibition of cell proliferation was observed for Compound 1. The average IC50 for Compound 1 was 0.18 pM.Example 41: RBM39 Protein Expression StudiesGeneral Western Blot Assay

[0332] Into a 12-well plate with 1 mL of culture media, 1 x 106A-673 cells were seeded. After 24 h, compounds were diluted in the growth medium and A-673 cells were refreshed with compound solutions for 6 h or 24 h. To normalize each well, 0.5% DMSO was added, including the vehicle control wells. Plates were washed once with cold phosphate- buffered saline (PBS) post-treatment and stored at -80°C until the western blot was conducted.

[0333] To each well of the 12-well plates, 150 pL of RIPA buffer supplied with protease cocktail and incubated for 10 min with constant shaking. The lysate was transferred to 1.7 mL tubes and placed on ice for 30 min. During the incubation on ice, the tubes were vortexed extensively for 15 seconds every 10 min. The cell lysate was spun at 14,000 rpm for15 min to remove insoluble cell debris. The lysate was transferred to another tube and the protein concentration was measured by the BCA (bicinchoninic acid) method. The cell lysate was mixed with 4X LDS loading buffer and 10X NuPAGE™ reducing agent. Samples were incubated on a heat block at 95 °C for 15 min.

[0334] For each sample, 20 pg was loaded in 4 to 12% gels. A chameleon ladder was loaded on the left side to monitor gel progression. Gels were run at 150 V for 65 min, and then removed from the cassette. Gels were soaked in water with gentle shaking for 10 min before transferring protein to membranes. Membrane transfer was conducted using PVDF (poly vinylidene difluoride) membranes. Membranes were blocked in LI-COR Intercept® (PBS) Blocking Buffer for 1-2 h. Primary antibodies were diluted in Intercept® (PBS) Blocking Buffer and incubated overnight at 4°C. Membranes were washed three times with TBST (tris-buffered saline with 0.1% Tween® 20) for five minutes each time. Membranes were detected by a LI-COR™ instrument.

[0335] Fig. 2A shows the dose response of Compound 1 against RBM39 protein in A-673 cells. Cells were treated with a serial dilution of Compound 1 for 6 h. A significant reduction in RBM39 protein expression was observed when cells were treated with 0.037 pM of Compound 1 for 6 h. Complete reduction was observed following treatment with 0.33 pM of Compound 1 for 6 h. As seen in Fig. 2B, in a time-course experiment, complete reduction of RBM39 protein expression was observed after 6 h of treatment with 5 pM of Compound 1, and RBM39 expression was not detected after continued treatment for 24 h.

[0336] Fig. 3 shows that compound 1 significantly affected the molecular weight of EWS-FLI 1 fusion protein detected with FLI- 1 antibody, which showed only one major band of about 70 kDa in the DMSO-treated group, but showed a new lower weight molecular band in the group treated with compound 1. The density of the lower molecular weight band in the group treated with compound 1 became stronger after treatment for 72 h.Example 42: Deuterated Derivative

[0337] Single dose PK parameters were also determined for Compound 143, a deuterated derivative of Compound 1, according to the methods described herein. The data in Table 4 show that Compound 143 demonstrates improved metabolic stability and permeability compared to Compound 1 and comparative compound E7820. Metabolic stability wasassessed by measuring the half-life of the test compounds in human and mouse liver microsomes. Compound 143 also demonstrated an improved efflux ratio in MDCK cells.Table 4Table 5Table 6

[0338] The data in Fig. 4 and Table 5 show that Compound 143 demonstrates an increase in plasma AUC after oral administration compared to Compound 1. As shown in Fig. 5 and Table 6, Compound 143 also exhibits a 2.5-fold increase in telencephalon AUC after oral administration compared to Compound 1.

[0339] Cell viability assays were performed in HCT116 cells, A673 human Ewing sarcoma cells and SH-S Y -5 Y neuroblastoma cells according to the procedures described herein to compare the potency of Compound 1 to Compound 143. For SH-SY-5Y neuroblastoma cells, 5000 cells were seeded into a 96-well plate with 100 L of media (Dulbecco’s ModifiedEagle Medium, supplemented with 10% fetal bovine serum, 100 units penicillin, and 100 pg streptomycin per mL). As shown in Fig. 6, no significant difference was observed between Compound 1 and Compound 143 for inhibiting cell growth in HCT116 cells. Compound 1 exhibits an IC50 of 0.2587 pM, whereas Compound 143 exhibits an IC50 of 0.2554 pM. No significant difference was observed for inhibition of SH-SY-5Y cell growth by Compound 1 and Compound 143 as shown in Fig. 7. For SH-SY-5Y cells, Compound 1 exhibits an IC50 of 0.1394 pM and Compound 143 exhibits an IC50 of 0.1397 pM. As shown in Fig. 8, no significant difference was observed for inhibition of growth in Human Ewing Sarcoma A673 for Compound 1 and Compound 143. In Human Ewing Sarcoma A673 cells, Compound 1 exhibits an IC50 of 0.1903 pM and Compound 143 exhibits an IC50 of 0.1899 pM.Example 43: Gene Splicing StudiesGeneral PCR and Sequencing Protocol

[0340] Into a 12-well plate with 1 mL of culture media, 1 x 106A-673 cells were seeded. After 24 h, compounds were diluted in the growth medium and A-673 cells were refreshed with compound solutions for 6 h or 24 h. To normalize each well, 0.5% DMSO was added, including the vehicle control wells. Cellular RNA was extracted from the plates using a PureLink™ RNA Mini Kit and the RNA concentration was measured with Nanodrop. Using a High-Capacity cDNA Reverse Transcription Kit, 2 pg of RNA was reverse transcribed in a 20 pL reaction. Obtained cDNA was diluted by 1-fold in water and 1 pL of cDNA was used to amplify target genes using DreamTaq Green PCR Master Mix (2X). PCR products were resolved in 2% agarose gels (E-Gel™ EX Agarose Gels) and imaged with an iBright FL 1500 Imaging System.

[0341] Fig. 9A shows the dysregulation of EWSR1-FLH fusion gene splicing in A-673 cells treated with 5 pM of Compound 1 for 24 h. Fig. 4A shows the RT-PCR products resolved in 2% agarose gels. Bands 4-6 were cut out and Sanger sequenced. Band 4 (SEQ ID NO 1) was confirmed as the intact sequence. Band 5 was shown to be missing FLU exon 7 and major band 6 (SEQ ID NO 3) lacked 41 amino acids found in the DMSO treatment group corresponding to FLU exons 6 and 7 (amino acids 272-312). Next generation PacBio sequel RNA sequencing of the total RT-PCT products revealed three major peaks corresponding to Bands 4, 5 and 6 as shown in Fig. 9B.

[0342] As seen in Figs. 10 and 1 1 , multiple other genes in A-673 cells treated with 5 pM of Compound 1 for 24 h, including Trim27 and BRCA1, were downrcgulatcd by treatment with Compound 1. A comparison of the DNA fragment size of the PCR-amplified gene and the exon skipped gene size for each gene is summarized in Table 7. Primers used in the gene-splicing analysis are listed in Table 8.Table 7: Fragment Size of PCR Product Compared to Skipped Exon Gene SizeTable 8: Primers used in Gene Splicing AnalysisExample 44: Ewing Sarcoma Cell Line Studies

[0343] A673 cells were inoculated subcutaneously on the right flank of NOD SCID mice. Mice were treated with 30 mg / kg of Compound 1 and vehicle twice per day orally when the tumor reached about 280 mm3. At 6 h post 5thdose, 6 tumor samples were collected for Western Blot analysis and RNA extraction / cDNA synthesis / PCR analysis.

[0344] As shown in Fig. 12, Western Blot analysis showed that both RBM39 and EWS-FLI1 were significantly reduced when treated with Compound 1. PCR analysis in Fig. 13 identified three EWS-FLI1 isoforms following treatment with Compound 1, including two lower molecular weight bands corresponding to loss of Exon 6 / 7.

[0345] CellTiter-Glo® luminescent cell viability assays were conducted for three type I fusion cell lines (A673, SK-PN-DW and SK-N-MC) and two type II fusion cell lines (RD-ES and SK-ES-1). Type I fusion consists of fusion of EWSR1 exons 1-7 to FLU exons6-9 of FLU . Type 2 fusion consists of fusion EWSR1 exons 1-7 to FLU exons 5-9. Western Blot measurements of expression levels of RBM39 and EWS-FLI1 fusion were taken before and after treatment with Compound 1 (5 pM) for 24 h.

[0346] As shown in Fig. 14, Ewing sarcoma cell line SK-PN-DW (type I) demonstrated weaker cell growth inhibition compared to A673 (Fig. 1). Following treatment with Compound 1, SK-PN-DW cells showed complete RBM39 degradation.

[0347] As shown in Fig. 15A, Ewing sarcoma cell line SK-N-MC (type Llike fusion) demonstrated complete cell growth inhibition (IC50: 539 nM). Following treatment with 5 pM of Compound 1, Western Blot analysis showed complete RBM39 degradation and the EWS-FLI1 fusion band was shifted to lower molecular weight (Fig. 15B).

[0348] As shown in Fig. 16, Ewing sarcoma cell line TC-71 (type I) demonstrated weaker cell growth inhibition (IC50: 1.119 pM) compared to A673. Ewing sarcoma cell line SCCH-196 (type I) also demonstrated complete cell growth inhibition (IC50: 89.7 nM) as shown in Fig. 17.

[0349] The Western Blot analysis in Figs. 18A and 18B showed complete RBM39 degradation (>95% degradation) for most of the type I fusion and type I- like fusion Ewing sarcoma cell lines, including SK-PN-DW, A673, SK-N-MC and SCCH-196. These cell lines also showed a change in the EWS-FLI1 fusion band indicating misfunction of ESWR1-FLI1 fusion gene splicing. In comparison, TC-71 degraded RBM39 to a lesser extent (70-80% degradation) and showed no change in the EWS-FLI1 fusion band. Four of five type I or type I-like EWS-FLI1 tested were misspliced by Western blot techniques when RBM39 is degraded, whereas neither of the tested type II Ewing sarcoma cell lines, SK-NEP1 and RD- ES, were misspliced.

[0350] Ewing sarcoma cell lines having type II fusion did not show similar cell growth inhibition after treatment with Compound 1. For the RD-ES cell line, partial inhibition (53.5% at 5 pM) was observed (Fig. 19). Western Blot analysis showed 70-80%RBM39 degradation, but the EWS-FLI1 fusion band remained without change (Fig. 21). The SK-NEP- 1 cell line similarly showed partial (54.5% at 5 pM)inhibition as seen in Fig. 20. Western Blot analysis (Fig. 21) showed some RBM39 degradation (> 80%) and no change in the EWS-FLI1 fusion band. The SK-ES-1 (type II) cell line showed no cell growth inhibition as seen in Fig.22A. Western Blow analysis (Fig. 22B) showed no RBM39 expression and no change in the EWS-FLI1 fusion band.

[0351] While some embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0352] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0353] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ willbe understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0354] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present technology. This includes the generic description of the present technology with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0355] All publications, patent applications, issued patents, and other documents (for example, journals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0356] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0357] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0358] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

[0359] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a cancer in a subject, wherein the cancer is characterized by a gene fusion mutation, comprising administering to a subject in need thereof an effective amount of a RBM39 degrader.

2. The method of Claim 1, wherein the RBM39 degrader is a compound of formulaA1is selected fromand * represents points of attachment to form a fused bicyclic ring;Y is O or NH;Z1, Z2and Z3are each independently C(Rla) or N; each R1ais independently selected from the group consisting of H, halogen, -(Ci-C6)alkyl and -(Ci-C6)haloalkyl;R2is H, -(Ci-C6)alkyl or -C(O)R6;R3is a -(Ci-Ce)alkyl, furan, thiophene, a 5-membered monocyclic nitrogen-containing heteroaryl, or a 6-12 membered nitrogen-containing bicyclic heterocyclyl; wherein the -(Ci-Ce)alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl and the 6-12 membered nitrogen-containing bicyclic heterocyclyl can be optionally substituted with one or two or three substituents selected from R4; each R4is independently selected from -Rxl, -Rx2, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, -CN, halogen, -NH2, -N((Ci-C6)alkyl)2, -NHC(O)(Ci-C6)alkyl, -NHBoc, -(CH2)„S(O)2(Ci-C6)alkyl and -C(O)Rzl;R5ais selected from the group consisting of -H, -CN, halogen, -(Ci-C6)alkyl, -(Ci-Ce)haloalkyl, -(C2-C6)alkcnyl, -(C2-C6)alkynyl, and 4-7 membered monocyclic heterocyclyl;R5bis -(Ci-C6)alkyl; orR5ais taken together with R5band the atom to which R5aand R5bare attached to form an optionally substituted 3-7 membered monocyclic cycloalkyl;R6is H or -(Ci-Ce) alkyl;R7aand R7bare each independently selected from the group consisting of H, halogen, -CN, -(Ci-C6)alkyl, -(Ci-C6)alkoxy, 3-7 membered monocyclic cycloalkyl and -(Ci-Ce)haloalkyl; or R7ais taken together with R7band the atom to which R7aand R7bare attached to be -C(=O);Rxlis selected from the group consisting of C3-C7 cycloalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclyl(Ci-C6 alkyl), wherein the cycloalkyl, heterocyclyl and heterocyclyl(alkyl) are each optionally substituted with Ryl;Rx2is selected from the group consisting of-(Ci-C6)alkyl, -(Ci-C6)alkoxy, alkylamino, and amino; wherein the -(Ci-C6)alkyl, -(Ci-Ce)alkoxy, alkylamino, and amino are optionally substituted with one or two Ry2;Rylis selected from the group consisting of H, -CN, -OH, -C(O)O(Ci-C6)alkyl, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, 5-10 membered heterocyclyl, BOC, -C(O)(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -CH2S(O)2(Ci-C6)alkyl and -CH2CN; each Ry2is independently selected from the group consisting of -CN, -OH, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)alkoxy, -N((Ci-C6)alkyl)2, -CH2CN, -C(O)CH2CH2N((Ci-C6)alkyl)2, -C(O)(5-10 membered heterocyclyl) and -(CH2)nS(O)2(Ci- C6)alkyl; n is 0, 1, 2, 3 or 4; and3. The method of Claim 2, where Z3is N.

4. The method of Claim 2 or 3, where Z1is N.

5. The method of any one of Claims 2-4, where Rlais -(Ci-C6)alkyl.

6. The method of Claim 5, wherein Rlais -CH3.

7. The method of any one of Claims 2-4, wherein Rlais halogen.

8. The method of any one of Claims 2-4, wherein Rlais -(Ci-C6)haloalkyl.

9. The method of any one of Claims 2-8, wherein R2is -H.

10. The method of any one of Claims 2-8, wherein R2is -(Ci-C6)alkyl.

11. The method of any one of Claims 2-8, wherein R2is -C(O)R6.

12. The method of Claim 11, wherein R2is -C(O)(Ci-Ce)alkyl.

13. The method of any one of Claims 2-12, wherein R3is a 5-membered monocyclic nitrogen-containing heteroaryl optionally substituted with one or two or three substituents selected from R4.

14. The method of any one of Claims 2-13, wherein R5ais -CN.

15. The method of any one of Claims 2-13, wherein R5ais halogen.

16. The method of any one of Claims 2-13, wherein R5ais -(Ci-C6)haloalkyl.

17. The method of any one of Claims 2-13, wherein R5ais -(Ci-Ce) alkyl.

18. The method of any one of Claims 2-13, wherein R5ais 4-7 membered monocyclic heterocyclyl.

19. The method of any one of Claims 2-18, wherein R7ais -CN.

20. The method of any one of Claims 2-18, wherein R7ais halogen.

21. The method of any one of Claims 2-18, wherein R7ais -(Ci-C6)haloalkyl.

22. The method of any one of Claims 2-18, wherein R7ais -(Ci-Ce) alkyl.

23. The method of any one of Claims 2-18, wherein A1isR7a\ ^NHN24. The method of any one of Claims 2-14 or 19-22, wherein A1is25. The method of any one of Claims 2-22, wherein A1is26. The method of claim 25, wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1is S, O, or N(R4); andX2, X3and X4are each independently C(R4) or N, provided that X1is N(R4) or at least one of X2, X3and X4is N.

27. The method of Claim 26, wherein X1is S.

28. The method of Claim 26 or 27, wherein at least one of X2and X3is N.

29. The method of Claim 26, wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1is O or S; andX2is C(R4) or N.

30. The method of Claim 29, wherein X2is C(R4).

31. The method of Claim 29, wherein X2is N.

32. The method of Claim 26, wherein the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1is O or S.

33. The method of Claim 32, wherein X1is S.

34. The method of Claim 32, wherein X1is O.

35. The method of Claim 26, wherein the compound is a compound of Formula (V), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1is S or O; andX2is C(R4) or N.

36. The method of Claim 35, wherein X1is S.

37. The method of Claim 35, wherein X1is O.

38. The method of any one of Claims 35-37, wherein X2is C(R4).

39. The method of any one of Claims 35-37, wherein X2is N.

40. The method of Claim 2, wherein the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1and X2are each independently C(R4) or N; andX3is S, O, or N(R4), provided that X3is N(R4) or at least one of X1and X2is N.

41. The method of Claim 40, wherein X3is S.

42. The method of Claim 40, wherein X3is O.

43. The method of Claim 40, wherein X3is N(R4).

44. The method of any one of Claims 40-43, wherein X2is N.

45. The method of any one of Claims 40-43, wherein X2is C(R4).

46. The method of any one of Claims 40-45, wherein X1is N.

47. The method of any one of Claims 40-45, wherein X1is C(R4).

48. The method of any one of Claims 2-22, wherein A1is49. The method of Claim 2 or 48, wherein R5bis -(Ci-Ce)alkyl.

50. The method of Claim 2 or 48, wherein R5ais taken together with Rbband the atom to which R5aand R5bare attached to form an optionally substituted 3-7 membered monocyclic cycloalkyl.

51. The method of Claim 50, wherein R5ais taken together with R5band the atom to which R5aand R5barc attached to form an optionally substituted cyclopropyl.

52. The method of any one of Claims 2-12, wherein R3is -(Ci-C6)alkyl optionally substituted with one or two or three substituents selected from R4.

53. The method of any one of Claims 2-52, wherein each R4is independently -H, halogen, -CN, -(Ci-Celalkyl, -(Ci-Celhaloalkyl, -(Ci-C6)alkoxy, -(CH2)nS(O)2(Ci-C6)alkyl or -C(O)Rzl.

54. The method of any one of Claims 2-53, wherein R4is CH3.

55. The method of any one of Claims 2-53, wherein R4is CD3.

56. The method of any one of Claims 2-53, wherein R4is NH2.

57. The method of any one of Claims 2-53, wherein R4is NHBoc.

58. The method of any one of Claims 2-53, wherein R4is NHC(O)(Ci-C6)alkyl.

59. The method of any one of Claims 2-52, wherein R4is -Rxl.

60. The method of Claim 59, wherein -Rxlis selected from the group consisting of61 . The method of Claim 59 or 60, wherein Rylis -H.

62. The method of Claim 59 or 60, wherein Rylis -(Ci-C6)alkyl.

63. The method of Claim 59 or 60, wherein Rylis -CN or -CH2CN.

64. The method of Claim 59 or 60, wherein Rylis BOC.

65. The method of Claim 59 or 60, wherein Rylis -C(O)(Ci-C6)alkyl.

66. The method of Claim 59 or 60, wherein Rylis -(CH2)nS(O)2(Ci-C6)alkyl.

67. The method of Claim 59 or 60, wherein Rylis heterocyclyl.

68. The method of Claim 67, wherein69. The method of any one of Claims 2-52, wherein R4is -Rx2.

70. The method of Claim 69, wherein -Rx2is selected from the group consisting of:

71. The method of Claim 70, whereineach Ry2is independently -H, -OH, -CN, -(Ci-Ce)alkoxy, -N((Ci-Ce)alkyl)2, or -(CH2)nS(O)2(Ci-C6)alkyl.

72. The method of Claim 70, whereineach Ry2is -(Ci-C6)alkyl.

73. The method of any one of Claims 70-72, wherein Ry2is -OH.

74. The method of Claim 70, wherein75. The method of Claim 70, wherein -Rx2is76. The method of any one of Claims 70-75, wherein Ry2is -CN or -CH2CN.

77. The method of Claim 75, wherein Ry2is -(CH2)nS(O)2(Ci-C6)alkyl.

78. The method of Claim 70, whereineach Ry2is independently-(Ci-C6)alkyl, -CH2CN, -C(O)CH2CH2N((Ci-C6)alkyl)2, or-(CH2)nS(O)2(Ci-C6)alkyl.

79. The method of Claim 52, wherein R3is -CH3.

80. The method of Claim 52, wherein R3is isopropyl.

81. The method of Claim 52, wherein R3is substituted with R4and R4is -Rxl.

82. The method of Claim 81, wherein83. The method of any one of Claims 2-12, wherein R3is a 6-12 membered nitrogencontaining bicyclic heterocyclyl optionally substituted with one or two or three substituents selected from R4.

84. The method of Claim 83, wherein the 6-12 membered nitrogen-containing bicyclic heterocyclyl is selected from the group consisting of:

85. The method of Claim 84, wherein R4is -CN.

86. The method of Claim 1, wherein the RBM39 degrader is N-(3-cyano-4-methyl-lH- indol-7-yl)-3-cyanobenzenesulfonamide, or a pharmaceutically acceptable salt thereof.

87. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein: ring A is an optionally substituted monocyclic or bicyclic aromatic ring; ring B is an optionally substituted 6-membered cyclic unsaturated hydrocarbon or 6- membered unsaturated heterocycle containing a nitrogen atom as a heteroatom; ring C is an optionally substituted 5-membered heterocycle containing one or two nitrogen atoms;W is a single bond, or -CH=CH-;X is -N R1) - or an oxygen atom;Y is a carbon atom or a nitrogen atom; andZ is -N(R2)- or a nitrogen atom, wherein R1and R2each independently, identically or differently, is a hydrogen atom or a lower alkyl group.

88. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein:E is -O-, -N(CH3) -, -CH2- -CH2CH2-, or -CH2O-;D is -CH2- or -O-;Rlais a hydrogen atom or a halogen atom; andR2ais a halogen atom or a trifluoromethyl group.

89. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein J is O or NH;Rlbis a hydrogen atom, a halogen atom, an optionally substituted Ci-Ce alkyl group, an optionally substituted C1-C4 alkoxy group, an optionally substituted C1-C4 alkylthiogroup, -CF3, -OCF3, -SCF3, an optionally substituted C1-C4 alkoxy carbonyl group, a nitro group, an azido group, -O(SO2)CH3, -N(CH3)2, a hydroxyl group, a phenyl group, a substituted phenyl group, a pyridinyl group, a thienyl group, a furyl group, a quinolinyl group or a triazole group;R2bis a hydrogen atom, a halogen atom, a cyano group, -CF3, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C4 alkoxy carbonyl group, an optionally substituted C1-C4 alkoxy group, an optionally substituted phenyl group or an optionally substituted quinolinyl group;R3bis a hydrogen atom or an optionally substituted C1-C4 alkoxy group;R4bis a hydrogen atom or an optionally substituted Ci-Ce alkyl group (provided that at least one of R3band R4bis a hydrogen atom);R5bis a hydrogen atom, a halogen atom, an optionally substituted Ci-Ce alkyl group, -CF3 or a nitro group;R6bis a hydrogen atom, a halogen atom or an optionally substituted Ci-Ce alkyl group (provided that when R6bis an optionally substituted Ci-Ce alkyl group, R5bis a hydrogen atom and R7bis a halogen atom);R7bis a halogen atom, an optionally substituted C1-C6 alkyl group or -CF3 (provided that when either R5bor R7bis an optionally substituted Ci-Ce alkyl group or when R7bis a halogen atom or an optionally substituted Ci-Ce alkyl group, either one of R5bor R6bis a hydrogen atom).

90. The method of Claim 1, wherein the RBM39 degrader is a compound having thepharmaceutically acceptable salt thereof.

91. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of chloro, bromo, fluoro, and iodo; R2is selected from the group consisting of H, chloro, fluoro and methyl;R3is selected from the group consisting of H, chloro, fluoro, cyano and methyl;R5is selected from the group consisting of H and Ci-Ce alkyl;R6is selected from the group consisting of -CO2CH3, -CH2OCH3, CH2S(O)Ci-Ce alkyl, ((optionally substituted 3 to 7-membered heterocyclyl)oxy)Ci-C6 alkyl, optionally substituted CI-C6alkoxy)Ci-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3 to 7-membered heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted 5 to 10-mcmbcrcd hctcroaryl, (optionally substituted 3 to 7-mcmbcrcd heterocyclyl)Ci-C6 alkyl, (optionally substituted C6-C10 aryljCi-Ce alkyl, (optionally substituted 5 to 10-membered heteroaryl)Ci-C6 alkyl,92. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein R is an optionally substituted-5,6; -6,5; -6,6; -6,7 bicyclic ring system;R1is selected from the group consisting of chloro, bromo, fluoro and iodo; and R2is selected from the group consisting of H, chloro, fluoro, and methyl.

93. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of chloro, bromo, fluoro, and iodo;R2is selected from the group consisting of H, chloro, fluoro, and methyl;R3is selected from the group consisting of H, chloro, fluoro, cyano, and methyl;R4is selected from the group consisting ofwherein:R5is selected from the group consisting of optionally substituted C3 to C7 cycloalkyl, optionally substituted 4 to 12-mcmbcrcd hctcrocyclyl, optionallysubstituted Ce-Cio aryl, and substituted Ci-Cs alkyl; wherein the Ci-Cs alkyl is substituted with at least one substituent selected from halo, Ci-Ce alkoxy, (optionally substituted C3-C7 cycloalkyl amino)carbonyl, (Ci-Ce alkoxycarbonyl)(Ci-C6 alkyl)amino, (Ci-Ce alkyl)(Ci-C6 alkyl)N-, Ci-Ce alkylsulfonyl, optionally substituted 4 to 8-membered heterocyclyl, optionally substituted benzo[d][l,3]dioxolyl, optionally substituted benzooxazolonyl, optionally substituted tetrahydroquinolinyl, optionally substituted tetrahydroisoquinolinyl, optionally substituted Ce-Cio aryl, optionally substituted isoindolinyl, and optionally substituted 5 to 10-membered heteroaryl; and, wherein:R6is selected from the group consisting of H and CH3;R7is selected from the group consisting of optionally substituted C3-C7 cycloalkyl, optionally substituted 2,3-dihydro-lH-indenyl, optionally substituted 3 to 7-membered heterocyclyl, and substituted C1-C5 alkyl; wherein the C1-C5 alkyl is substituted with at least one substituent selected from optionally substituted Ci-Ce alkoxy, optionally substituted 4 to 8-membered hetercyclyoxy, -C(O)NR8R9, Ci-Ce alkylsulfonyl, optionally substituted C3-C7 cycloalkyl, optionally substituted bicyclooctatrienyl, optionally substituted 4 to 8-membered heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted dihydrobenzodioxinyl, and optionally substituted 5 to 10-membered heteroaryl; wherein R8and R9together with the nitrogen atom to which they are attached form an optionally substituted 5-6 membered heterocyclyl; or alternatively, R6and R7together with the nitrogen atom to which they are attached form a group selected from optionally substituted 4 to 12- membered optionally substituted heterocyclyl, and optionally substituted 4,5,6,7-tetrahydro-lH- imidazo [4,5 -c] pyridiny 1.

94. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein:X is N or CR6;R1is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or halo;R2is hydrogen, halo, or cyano;R3is hydrogen, C1-C4 alkyl, halo, cyano, C1-C4 fluoroalkyl, -(C1-C4 alkyl)OH, or -NRaRb, wherein Raor Rbis independently hydrogen, C3-C6 cycloalkyl, heterocycloalkyl, or C1-C4 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, C1-C4 alkyl, cyano, hydroxy, and -O(Ci-C4 alkyl);R4is hydrogen, Ci-Ce alkyl, C1-C10 hctcroalkyl, C1-C4 fluoroalkyl, -(Ci-C4)alkylNH2, C3-C6 cycloalkyl, -(Cj-Q alkyl)(C13-C6 cycloalkyl), -(C: -C4alkyl jphenyk phenyl, heteroaryl, — (Ci-C4alkyl)heteroaryl, C2-C5 alkenyl, -(Cj-C4alkyl)heterocycloalkyl, heterocycloalkyl, -Cii-C: alkylS(™O)2(Cj "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(Ci-C4alkyl), -(C0-C4 alky l)C(=O)C> -C4alkyl, -(C0-C4 alkyl)C(=())OH or -(C;-C8alkyl)OH, wherein R4is substituted with 0, 1, 2, or 3 substituents selected from deuterium, halo, hydroxy, -(Co- C4alkyl)O(Ci-C4 alkyl), -Cj-C4alkyl. -(Co-Chal kyl Jcyano. -S(=O)2(Ci-C4alkyl), -C0-C4 alkylC(=O)NRaRb, -C(==O)O(Ci-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- C& cycloalkyl, heterocycloalkyl or C1-C4 alkyl;Ri is hydrogen, halo, -NH2or C1-C4 alkyl;Rs is hydrogen, halo or C1-C4 alkyl; andR ? is hydrogen, halo, heteroalkyl, C]-C4 alkyl, - (C0-C4 alkyl)O(Cj-C4 alkyl), -(C1-C4 alkyl)(C3-C& cycloalkyl), C3-C& cycloalkyl, -(Ci-C: alkyl)hctcrocycloalkyl, or heterocycloalkyl.

95. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:pharmaceutically acceptable salt thereof, wherein:W is NRaor CRilRu;Rbis hydrogen, or (Ci-C4)alkyl;Rais selected from H, (Ci-Ce) alkyl, -(Ci-Ce)alkylOH, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-Cs)alkenyl, cycloalkyl((Co-C6)alkyl), aryl((Co-Ce)alkyl), hctcrocycloalkyl((Co-C6)alkyl), hctcroaryl((Co-C6)alkyl), ((Co-C6)alkyl)amino((Ci-C6)alkyl), and ((Ci-C6)alkyl)carbonylamino((Ci-C6)alkyl), wherein Rais substituted with 0, 1, 2 or 3 R4substituents; each R4independently is selected from (Ci-C6)alkylcarbonyl, cyano, (Ci-Ce)haloalkyl, halogen, oxo, (Ci-C6)alkyl, (Ci-C6)alkoxy((Co-C6)alkyl, -SChCCi-Ce alkyl), amino, hydroxy, amino(Ci-C6)alkylcarbonyl, (Ci-Ce)alkylcarboxy, and -(Ci-C6)alkylOH, provided that when Rais (Ci-C6)alkoxy(Ci-C6)alkyl), R4is other than (Ci-C6)alkoxy((Co-C6)alkyl; each n independently is 1, 2, or 3;Z is CH or N;X is CH or N;R1is H, (Ci-Ce)alkyl, cyano, -(Ci-Ce)OH, halogen, or (Ci-C6)haloalkyl; andR2is H, (Ci-Ce)alkyl, cyano, -(Ci-Ce)OH, halogen, or (Ci-C6)haloalkyl.

96. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:, or a pharmaceutically acceptable salt thereof, wherein:R1is selected from H, (Ci-C6)alkyl, aminocarbonyl(Ci-C6)alkylaminocarbonyl(Co-Celalkyl, carboxy(Ci-C6)alkyl, hydroxycarbonyl(Co-C6)alkyl), and(Ci-C6)alkoxycarbonyl(Co-Ce)alkyl);R2is H, -(Ci-C6)alkyl, cyano, -(Ci-Ce)OH, halogen, or (Ci-C6)haloalkyl;R3is H, -(Ci-C6)alkyl, cyano, -(Ci-Ce)OH, halogen, or (Ci-C6)haloalkyl;R4is selected from (Ci-C6)alkoxy((Ci-Ce)alkyl), heterocycloalkyl((Co-Ce)alkyl), heteroaryl((Co-C6)alkyl), -C(=O)(Ci-C6)alkyl-(O-(Ci-C6)alkyl)n, and -(Ci-C6)alkyl-(O-(Ci- C6))n, wherein R4is substituted with 0, 1, 2, or 3 R5substituents; each n is independently 1, 2, 3, or 4; each R5independently is selected from cyano, (Ci-C6)haloalkyl, halogen, hydroxy, oxo, (Ci-Ce)alkyl, (Ci-C6)alkoxy(Co-C6)alkyl, -SO2(Ci-C6)alkyl, amino, -C(=0)(Ci-C6)alkyl- (0-(C i -C6)alkyl)m, -(C i -Ce)alky 1-(O-(C i -C6)alkyl)m, amino(C i -Ce)alky Icarbonyl,(Ci-C6)alkylcarboxy, (Ci-Celalkylcarbonyl, and -(Ci-C6)alkylOH, wherein each R5independently is substituted with 0, 1, 2 or 3 R6substituents; each R6independently is selected from amino, (Ci-C6)alkylcarboxy, (Ci-C4)alkyl, halogen and hydroxy; each m independently is 1, 2, or 3; and provided that when R4is (Ci-Ce)alkoxy((Ci- Ce)alkyl), heterocycloalkyl((Co-C6)alkyl), or heteroaryl((Co-C6)alkyl) then R1is other than hydrogen.

97. The method of Claim 1, wherein the RBM39 degrader is a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein:RN1is H or Ci-6alkyl optionally substituted with 1 , 2, or 3 R7;RN2is H or Ci-6alkyl optionally substituted with 1 , 2, or 3 R7;XUs OR1or N;X2is CR3or N;X3is CR4or N;R1is H, Ci-6alkyl, Ci-ehaloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-ealkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R2is H, Ci-6alkyl, Ci-ehaloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci.6alkyl;R3is H, Ci-6alkyl, Ci-ehaloalkyl, Ci-ealkoxy, halo, OH, or ON, and the Ci-ealkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R4is H, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-ealkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl;R3is H, Ci-6alkyl, Ci-ehaloalkyl, Ci-6alkoxy, halo, OH, or ON, and the Ci-6alkyl can optionally be substituted with 1 , 2, or 3 substituents independently selected from Ci-ealkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-6alkyl; each RNis independently H, Ci-6alkyl optionally substituted with 1 , 2, or 3 R7, or Ca-iocycloalkyl;Het is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heteroaryl comprising 1 , 2, or 3 ring hctcroatoms selected from O, S, and N and optionally substituted with 1 , 2, or 3 R6; eachR6is independently halo, CN, Cnealkyl, Ci-ehaloalkyl, Ci-e lkoxy, NRNRN, COOH, C(O)NRNRN, Ci-6alkylcnc-C(O)ORN, Ci-6alkylcnc-C(O)NRNRN, SO2NRNRN, P(O)(RN)(RN), C(O)-5- or 6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, Ci-ealkylene-Ca-iocycloalkyl, Ca-iocycloalkyl, 4-6-membered heterocycloalkyl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, Ce-ioaryl, or 5- or 6- membered heteroaryl comprising 1 , 2, or 3 ring heteroatoms selected from O, S, and N, wherein the C -iocycloalkyl, 4-6-membered heterocycloalkyl, Ce-ioaryl, or 5- or 6-membered heteroaryl can optionally be substituted with 1 , 2, or 3 R7and each Ci-6alkyl, Ci-ealkylene, or Ci-ealkoxy can be optionally substituted with 1 or 2 substituents independently selected from Ci-6alkoxy, OH, CN, CO2H, NRNRN, and CO2Ci-ealkyl; and each R7is independently OH, halo, CN, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, NH2, NH(Ci-6alkyl), or N(Ci-6alkyl)2.

98. The method of Claim 1, wherein the RBM39 degrader is selected from the group consisting of E7820, indisulam, chloroquinoxaline sulfonamide (CQS), tasisulam, and dCeMMl.

99. The method of any one of Claims 1-97, wherein the cancer is selected from the group consisting of: acute lymphoblastic leukemia, acute megakaryoblast leukemia, acute myeloid leukemia, anaplastic large T-cell lymphoma, breast carcinoma, Burkitt lymphoma, chronic myeloid leukemia, colorectal carcinoma, Ewing’s sarcoma, fibrosarcoma, follicular lymphoma, glioblastoma multiforme, hepatocellular carcinoma, lung cancer, esophageal adenocarcinoma, ovarian adenocarcinoma, pilocytic astrocytoma, intrahepatic cholangiocarcinoma, bladder cancer, prostate carcinoma, and thyroid carcinoma.

100. The method of Claim 1, wherein the gene fusion mutation comprises a gene fusion selected from the group consisting of: BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, RBM15-MKL1, RUNX1-RUNX1T1(AML1-MTG8), PML-RARA, CBFB-MYH11, NPM1- ALK, TRMT11-GRIK2, CCNH-C5orf30, ETV6-NTRK3, ODZ4-NRG1, TBL1XR1-RGS17, MYB-NFIB, MAST-fusions, NOTCH-fusions, IGH-MYC, IGK-MYC, IGL-MYC, RSPO2- EIF3E, RSPO2-PTPRK, EWSR1-FLI1, EWSR1-ERG, BCL2-IGH, MAN2A1-FER, FGFR3- TACC3, FIG-ROS1, EML4-ALK1, ESRRA-Cl lorf20, BRAF-KIAA1549, TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR- TP53BP1, RPS10-HPR, APAK9-BRAF, RET-CCDC6, PAX8-PPARG, TFG-NTRK1, and TPM3-NTRK1.

101. The method of Claim 100, wherein EWSR1-FLI1 fusion gene splicing is dysrcgulatcd.

102. The method of Claim 101, wherein administering the RBM39 degrader causes RNA splicing of Exon 6 and / or Exon 7 of FLU in the EWSR1-FLI1 fusion gene to be skipped.

103. The method of Claim 101, wherein administering the RBM39 degrader reduces expression of EWS-FLI1 fusion protein.

104. The method of any one of Claims 1-103, comprising obtaining a biological sample from the subject and identifying the gene fusion mutation.

105. The method of any one of Claims 1-104, wherein the gene fusion mutation is Type I or Type I like EWS-FLI1.

106. The method of Claim 2, wherein the RMB39 degrader is selected from the group consisting of:the foregoing.

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