Heteroaromatic indolesulfonamides

Abstract

The present disclosures relates to deuterated anti-cancer 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 INDOLESULFONAMIDESBACKGROUNDField

[0001] 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

[0002] 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

[0003] Some embodiments disclosed herein include a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof,l - 1. J X-A1is selected fromrepresents 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-Ce)alkyl and -(Ci-Ce)haloalkyl;R2is H, -(Ci-C6)alkyl or -C(O)R6;R3is a -(Ci-C6)alkyl, 5-10 membered monocyclic or bicyclic heteroaryl, or a 6-12 membered bicyclic heterocyclyl; wherein the 5-10 membered monocyclic or bicyclic 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-Ce)haloalkyl, -(Ci-C6)alkoxy, -CN, halogen, -NH2, -N((Ci-C6)alkyl)2, -NHC(O)(Ci-Ce)alkyl, -NHBoc, -(CH2)nS(O)2(Ci-C6)alkyl and -C(O)Rzl;R5ais selected from the group consisting of -H, -CN, halogen, -(Ci-Cb)alkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl and -(C2-C6)alkynyl;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-Ce)alkyl, -(Ci-Ce)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-Ce) alkylamino, and amino; wherein the -(Ci-C6)alkyl, -(Ci-Cejalkoxy, -(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-Ce)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;the compound comprises at least one deuterium; with the proviso that the compound is

[0004] Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

[0005] 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.

[0006] 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 subject in 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, 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-Cllorf20, BRAF-KIAA1549, TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR-TP53BP1, RPS10-HPR, AGAP9-BRAF, RET-CCDC6, PAX8-PPARG, TFG-NTRK1, and TPM3-NTRK1.DETAILED DESCRIPTION

[0007] 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:

[0008] In some embodiments of compounds of Formula (I):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, 5-10 membered monocyclic or bicyclic heteroaryl, or a 6-12 membered bicyclic heterocyclyl; wherein the -(Ci-C6)alkyl, 5-10 membered monocyclic or bicyclic heteroaryl and the 6-1 membered 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)nS(O)2(Ci-C6)alkyl and -C(O)Rzl;R5ais selected from the group consisting of -H, -CN, halogen, -(Ci-Ce) alkyl, -(Ci-Ce)haloalkyl, -(C2-Ce)alkenyl and -(C2-Ce)alkynyl;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-Ce)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-Ce 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, -(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-Ce)alkyl, -(Ci-Ce)alkyl, -(Ci-C6)haloalkyl, -(Ci-Ce)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;the compound comprises at least one deuterium; with the proviso that the compound is

[0009] Some exemplary structures of Formula (I), or pharmaceutically acceptable salts thereof, include those of Formulas (II) through (VI):

[0010] 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 Z3can 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).

[0011] 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-Ce)alkyl, such as -CH3. In other embodiments, Z1can be C(Rla) and Rlacan be -CD3. In some embodiments, Z1can be C(Rla) and Rlacan be -CH2D. In other embodiments, Z1can be C(Rla) and Rlacan be -CHD2. In still other embodiments, Rlacan be halogen. In other embodiments, Rlacan be -(Ci-C6)haloalkyl. In other embodiments, Rlacan be deuterium (D). In some embodiments,Z1can be C(Rla) and Rlacan be deuterium. In other embodiments, Z2can be C(Rla) and Rlacan be deuterium. In still other embodiments, Z3can be C(Rla) and Rlacan be deuterium.

[0012] 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. In other embodiments, R2can be deuterium (D).

[0013] 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.

[0014] 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-Ce)haloalkyl. In still other embodiments, R5acan be -(Ci-C6)alkyl.

[0015] 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. In other embodiments, R7acan be deuterium (D).

[0016] In some embodiments of compounds of Formula (I) or their.! pharmaceutically acceptable salts, A1can be. In other embodiments, A1can beIn still other embodiments, A can be In other embodiments, A1can

[0017] 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 ofFormula (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 some embodiments 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.

[0018] In some embodiments of compounds of Formula (I) or theirpharmaceutically acceptable salts, A1can be

[0019] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R5bcan be -(Ci-Ce)alkyl.

[0020] 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.

[0021] 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.

[0022] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, each R4can be independently -H, halogen, -CN, -(Ci-C6)alkyl, -(Ci-Ce)haloalkyl, -(Ci-C6)alkoxy, -(CH2)nS(O)2(Ci-Ce)alkyl or -C(O)Rzl.

[0023] 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-C6)alkyL

[0024] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R4can be -Rxl. In some embodiments, -Rxlcan be selected

[0025] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, Rylcan be -H. In other embodiments, Rylcan be -(Ci-Ce)alkyl. In still other embodiments, Rylcan be -CN. In some embodiments, Rylcan be -CH2CN. 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)alkyl. In some embodiments, n can be 0. In other embodiments, n can be 1. In other embodiments, n canbe 2. In other embodiments, n can be 3. In other embodiments, n can be 4. In otherembodiments, Rylcan be heterocyclyl. In some embodiments, Rylcan

[0026] 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-Ce)alkoxy, -N((Ci-Ce)alkyl)2, or -(CH2)nS(O)2(Ci-C6)alkyl. In other embodiments, Rx2each Ry2can be -(Ci-Ce)alkyl. In some embodiments, each Ry2can be -OH. In some embodiments, Rx2canIn someembodiments, Rx2can be. In some embodiments, Ry2can be -CN or -CH2CN. In other embodiments, Ry2can be -(CH2)nS(O)2(Ci-C6)alkyl. In still otherembodiments, Rx2caneach Ry2can independently be -(Ci-Ce)alkyl, -CH2CN. -C(O)CH2CH2N((Ci-C6)alkyl)2. -(CH2)nS(O)2(Ci-C6)alkyl, or -CH2CH2S(O)2(Ci-C6)alkyl.

[0027] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R3can be -(Ci-Ce)alkyl, such as -CH3. In other embodiments, R3can be isopropyl. In other embodiments, R3can be -(Ci-Ce)alkyl substitutedwith R4and R4can be -Rxl. In some embodiments, Rxlcan beor

[0028] In some embodiments of compounds of Formula (I) 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:-CN. In other embodiments, R4can be -(Ci-Ce)alkyl, such as -CH3. In other embodiments, R4can be halogen, such as fluoro or chloro.

[0029] In some embodiments of compounds of Formula (I) or their pharmaceutically acceptable salts, R3can be a 5-10 membered monocyclic heteroaryl optionally substituted with one or two or three substituents selected from R4. In other embodiments, R3can be a 6-10 membered bicyclic heteroaryl optionally substituted with one or two or three substituents selected from R4. In some embodiments, the 6-10 membered bicyclic heteroaryl can be an 8-membered nitrogen-containing fused bicyclic heteroaryl. In some embodiments, the 8-membered nitrogen-containing fused bicyclic heteroaryl can beoptionally substituted with one or two or three substituents selected from R4,wherein X1can be O or S, such that R3can beIn other embodiments, 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 be an 8-membered nitrogencontaining fused bicyclic heterocyclyl, wherein the 8-membered nitrogen-containing fused bicyclic heterocyclyl can be optionally substituted with one or two or three substituents selected from R4. In some embodiments, the 8-membered nitrogen-containing fused bicyclicheterocyclyl can be selected fromother embodiments, the 8-membered nitrogen-containing fused bicyclic heterocyclyl can beoptionally substituted with one or two or three substituents selected from R4, wherein X2can be CH2, NR8, or SO2; and R8can be selected from -(Ci-Ce)alkyl, -C(O)(Ci-Ce)alkyl, -OC(O)N(R9)2 and -SO2R9, wherein R9can be H, -(Ci-C6)alkyl, and -(Ci-C6)haloalkyl. In someembodiments, X1can be S and X2can be CH2, such that R3can beIn otherembodiments, X1can be S and X2can be SO2, such that R3can beembodiments, X1can be S, X2can be NR8, such that R8In some embodiments, R8can be -(Ci-Ce)alkyl, such as -CH3. In other embodiments, R8can be -C(O)(Ci-Ce)alkyl, such as -C(O)CH3. In still other embodiments, R8can be -OC(O)N(R9)2 such as OC(O)NH2. In some embodiments, R8can be -SO2R9, such as -SO2CH3. In other embodiments, the 8-membered nitrogen-containing fused bicyclic heterocyclyl can beoptionally substituted with one or two or three substituents selected from R4, wherein X1can be O or S; X3can be N or CH; X4can be N or CR4; and m and n each independently can be 1 or 2. In some embodiments, X1can be S, X3and X4can each be N, and m and n can each be 1, suchthat R3can beIn some embodiments, R3can be substituted with at least one R4,such that R3can be. In some embodiments, R4can be -(Ci-C6)alkyl, such as from -CH3.

[0030] In some embodiments of compounds of Formula (I), the compound can be a compound selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing.

[0031] In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, cannot be a compound having the structure:some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof,cannot be a compound having the structure:

[0032] 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 are 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.

[0033] 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.

[0034] 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

[0035] 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 art 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.

[0036] “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.

[0037] 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, for example, 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).

[0038] 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” grouprefers 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-.

[0039] 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.

[0040] 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 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as “C1-4 alkyl” or similar designations. By way of example only, “C1-4 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.

[0041] 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.

[0042] 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.

[0043] 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 having2 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.

[0044] 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 having 2 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.

[0045] 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.

[0046] 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 “Ci-4 alkylene” or similar designations. By way of example only, “Ci-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.

[0047] 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-l,3-dien-l,l-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 -methylpropenylene, 2-methyl-propen- 1,1 -diyl, and 2,2-dimethyl-ethen-l,l-diyl.

[0048] 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.

[0049] 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 Cio aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0050] 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 “Ce-io arylthio” and the like, including but not limited to phenyloxy.

[0051] 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 C1-4 alkylene group).

[0052] 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.

[0053] 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, isothiazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).

[0054] 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 10 carbon 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.

[0055] 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.

[0056] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0057] 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.

[0058] 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 joinedtogether 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, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 277-1,2-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.

[0059] 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.

[0060] 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, Ce-io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0061] An “O-carboxy” group refers to a “-OC(=O)R” group in which R is 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.

[0062] 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).

[0063] A “cyano” group refers to a “-CN” group.

[0064] A “26yanate” group refers to an “-OCN” group.

[0065] An “isocyanato” group refers to a “-NCO” group.

[0066] A “thiocyanato” group refers to a “-SCN” group.

[0067] An “isothiocyanate” group refers to an “ -NCS” group.

[0068] 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.

[0069] 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, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.

[0070] An “S-sulfonamido” group refers to a “-SC>2NRARB” 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.

[0071] An “N- sulfonamide” 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] An “N-amido” group refers to a “-N(RA)C(=O)RB” 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.

[0078] 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).

[0079] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0080] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.

[0081] 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 meantthat the group is substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-C6alkenyl, Ci-Ce alkynyl, Ci-Ce heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce 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-Ce)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 Ci-Ce haloalkoxy), 5-10 membered heteroaryl(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-Ce)alkyl (i.e„ ether), aryloxy, sulfhydryl (mercapto), halo(Ci-Ce)alkyl (e.g., -CF3), halo(Ci-Ce)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, thiocyanato, 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.

[0082] 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-. -CH2CH(CH3)CH2-. and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0083] 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 nototherwise 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.

[0084] Similarly, when two “adjacent” R groups are 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 are 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.

[0085] 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 substituentdepicted 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.

[0086] 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 following structures 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.

[0087] 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.

[0088] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.

[0089] “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.

[0090] 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.

[0091] 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).

[0092] “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 patientwill 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

[0093] 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 both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art 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.

[0094] Scheme A provides a general synthetic scheme for the synthesis of compounds of Formula 1.SCHEME A

[0095] 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 C18 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

[0096] 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 being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0097] 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.

[0098] 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 byreference 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.

[0099] The term “pharmaceutically acceptable earner” 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.

[0100] 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.

[0101] 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.

[0102] 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 asingle 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.

[0103] 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 earners 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 with the 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).

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] Compositions described herein may optionally include other drug actives.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are 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.

[0113] 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.

[0114] 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 bebetween 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.

[0115] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0116] 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.

[0117] 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.

[0118] 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, sodium formaldehyde, 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 Phann 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.

[0119] 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.

[0120] 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

[0121] 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.

[0122] 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), esophagealsquamous 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.

[0123] 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 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. 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, 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-ALK, ESRRA-Cllorf20, BRAF-KIAA1549, TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR-TP53BP1, RPS10-HPR, AGAP9-BRAF, RET-CCDC6, PAX8-PPARG, TFG-NTRK1, and TPM3-NTRK1.

[0124] 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 FLI1 in the EWSR1-FLI1 fusion gene. In some embodiments, expression of EWS-FLI1 fusion protein can be reduced.

[0125] 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.

[0126] 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:pharmaceutically acceptable salt of any of the foregoing.

[0127] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the degradation or reduction of RBM39 protein.

[0128] In some embodiments, the method of administering one or more of the compounds disclosed herein results in increased expression of immunogenic neoepitopes.

[0129] In some embodiments, the method of administering one or more of the compounds disclosed herein results in increased CD8+T cell expansion. In some embodiments, the method includes administering a pharmaceutically acceptable salt thereof of one or more compounds disclosed herein.

[0130] In some embodiments, the subject is a human.

[0131] 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.

[0132] 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.

[0133] 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

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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; Carter et 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).

[0138] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida. Y. etal. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec.29) Immunol. Immunother. 56(5):739-745; which are incorporated herein by reference in their entirety). The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can 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 et 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).

[0139] The immune checkpoint receptor cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is expressed on T-cells and is involved in signaling pathways that reducethe 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] Methods for the preparation and use of immune checkpoint antibodies are described in the following illustrative publications. The preparation and therapeutic uses of anti-CTUA-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 are 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 (Uonberg), 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.

[0148] 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.

[0149] 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.

[0150] 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 is incorporated 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, IB 12, 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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 art 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

[0156] 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.

[0157] 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.

[0158] 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. Wilts Protecting Groups in Organic Synthesis, 4thEd., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

[0159] 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.

[0160] 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.

[0161] The following abbreviations have the indicated meanings:AC2O = acetic anhydrideACN = acetonitrileAcOH = acetic acidAcOK = potassium acetateBOC = tert-butoxycarbonylBOC2O = di-z -butyldicarbonateBu = butylclogP = calculated partition coefficientDCM = dichloromethaneDIEA = N,N-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)-1-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)Cl2 = bis(diphenylphosphino)ferrocene]dichloropalladium(II)Ph = phenylPK = pharmacokineticPy = pyridineTBS-C1 = tert-butylchlorodimethylsilaneTEA = triethylamineTFA = trifluoracetic acidTHF = tetrahydrofuranTLC = thin-layer chromatography

[0162] 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 art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.General Example. Preparative HPLC

[0163] Preparative HPLC were carried out under one of the following conditions: 1) Column: Welch ultimate C18 150*25mm * 7μm; mobile phase: [water(FA)-ACN];gradient:37%-67% B over 10 min;2) column: Waters Xbridge 150*25mm 10μm; mobile phase: [water(NH4HCO3)-ACN] gradient: 11 %-41 % B over 18 min; or3) column: Waters Xbridge C18 150*50mm* 10μm; mobile phase: [water(NH3H2O)-ACN];gradient:12%-42% B over 10 min.Example 1. Synthetic Scheme of Compound 101101Example 1.1. Preparation of thiazol-2-ylmethan-d-ol

[0164] To a solution of thiazole-2-carbaldehyde (5.00 g, 44.2 mmol, 3.88 mL, 1.00 eq) in tetrahydrofuran (50.0 mL) was added lithium;tetradeuterioalumanuide (2.50 M, 26.5 mL, 1.50 eq) at 0°C under nitrogen, then the mixture was stirred at 25 °C for 2 hours under nitrogen. The reaction mixture was quenched by addition deuterium oxide (5.0 mL) at 0°C, and then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (IS CO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 30.0 mL / min) to give thiazol-2-ylmethan-d-ol (1.30 g, 10.2 mmol, 23.1% yield, 91.2% purity) as a yellow solid. Deuterated ratio=96.3%.1H NMR (400 MHz, CDCl3-d) <5 = 7.75 (d, J= 3.2 Hz, 1H), 7.33 (d, J= 3.2 Hz, 1H), 4.98 - 4.94 (m, 1H), 3.08 - 2.70 (m, 1H)Example 1.2, Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole

[0165] To a solution of thiazol-2-ylmethan-d-ol (1.20 g, 10.3 mmol, 1.00 eq) in dichloromethane (12.0 mL) was added tert-butylchlorodimethylsilane (2.02 g, 13.4 mmol, 1.65 mL, 1.30 eq) and imidazole (1.05 g, 15.5 mmol, 1.50 eq), the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (20.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (IS CO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 40.0 mL / min) to give 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole (2.30 g, 9.48 mmol, 91.8% yield, 95.0% purity) as a yellow oil. Deuterated ratio=96.6%. 'H NMR (400 MHz, DMSO-d6) S = 7.75 (d, J= 3.2 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 3.90 (s, 1H), 0.94 -0.90 (m, 9H), 0.84 (s, 6H).Example 1.3. Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole-5-sulfonyl chloride

[0166] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole (2.10 g, 9.11 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was dropwise added n-butyllithium (2.50 M, 3.46 mL, 0.95 eq) at -78°C under nitrogen atmosphere, the mixture was stirred at -78°C for 1 hour. Then this mixture was passed sulfur dioxide (55.6 mg, 868 pmol) gas continuously and the reaction was stirred at -40°C for 0.5 hour. Then 1 -chloropyrrolidine-2, 5-dione (3.65 g, 27.3 mmol, 3.00 eq) was added and the reaction was stirred at 25°C for 12 hours. Thereaction mixture was quenched by addition ammonium chloride (20.0 mL) at 0 °C, and then diluted with water 50.0 mL and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 40.0 mL / min) to give 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole-5-sulfonyl chloride (1.02 g, 3.10 mmol, 34.0% yield, 100% purity) as a yellow solid. Deuterated ratio=99.1%.1H NMR (400 MHz, CDCl3-d) 3 = 8.38 (s, 1H), 4.98 (t, J= 2.0 Hz, 1H), 0.99 (s, 9H), 0.23 - 0.15 (m, 6H).Example 1.4. Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)-N-(3-cyano-4-methyl- 1 H-indol-7-yl)thiazole-5 - sulfonamide

[0167] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)thiazole-5-sulfonyl chloride (1.00 g, 3.04 mmol. 1.00 eq) and 7-amino-4-methyl- 1 H-indole-3-carbonitrile (520 mg, 3.04 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added pyridine (360 mg, 4.56 mmol, 368 pL, 1.50 eq), the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water 50.0 mL and extracted with dichloromethane (20.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 2), dried over sodium sulfate, 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 0-50% Ethyl acetate / Commercial hexanes gradient @ 20.0 mL / min) to give 2-(((tert-butyldimethylsilyl)oxy)methyl-d)-N-(3-cyano-4-methyl-lH-indol-7-yl)thiazole-5-sulfonamide (1.20 g, 2.56 mmol, 84.3% yield, 99.0% purity) as a yellow solid. Deuterated ratio=98.9%. 'H NMR (400 MHz, CDCl3-d) 6 = 9.69 (s, 1H), 7.90 (s, 1H), 7.81 (d, J= 3.2 Hz,1H), 6.87 - 6.82 (m, 2H), 6.58 (d, 7 = 7.6 Hz, 1H), 4.88 (s, 1H), 2.75 (s, 3H), 0.93 (s, 9H), 0.11 (s, 6H).Example 1.5. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(hvdroxymethyl-d)thiazole-5-sulfonamide

[0168] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d)- / V-(3-cyano-4-methyl-1 H-indol-7-yl)thiazole-5-sulfonamide (1.00 g. 2.16 mmol, 1.00 eq) in dimethylformamide (10 mL) was added potassium fluoride (1.25 g, 21.6mmol, 10.0 eq), the mixture was stirred at 40°C for 2 hours. The reaction mixture was adjusted pH to 4-5 with hydrochloric acid (1.0 M) at 0°C, and then diluted with water 30.0 mL and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 2), dried over sodium sulfate, 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% methanol / dichloromethane @ 20.0 mL / min) to give N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(hydroxymethyl-d)thiazole-5-sulfonamide (680 mg, 1.92 mmol, 89.2% yield, 98.9% purity) as a yellow solid. Deuterated ratio=98.9%. 'H NMR (400 MHz, DMSO-d6) 3 = 11.98 (s, 1H), 10.28 (s, 1H), 8.19 (d, J= 3.2 Hz, 1H), 7.97 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.72 (d. J = 7.6 Hz, 1H). 6.33 (d, 7= 6.0 Hz, 1H), 4.71 (d, 7= 5.6 Hz, 1H), 2.61 (s, 3H).Example 1.6. Preparation of 2-(bromomethyl-d)-N-(3-cyano-4-methyl-lH-indol-7-yl)thiazole-5-sulfonamide

[0169] To a solution of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-(hydroxymethyl-d)thiazole-5-sulfonamide (300 mg, 859 mol, 1.00 eq) in dimethylformamide (3.00 mL) was added phosphorus tribromide (465 mg, 1.72 mmol, 2.00 eq, the mixture was stirred at 25 °C for 0.5 hours under nitrogen atmosphere. The reaction mixture was adjust pH to 7-8 with sodium bicarbonate at 0°C, and then diluted with water (30.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure at 30°C to give 2-(bromomethyl-d)-N-(3-cyano-4-methyl-lH-indol-7-yl)thiazole-5-sulfonamide (354 mg, crude) as a yellow oil. Deuterated ratio=98.4%. MS (ESI) m / z 412.0 [M+H]+.Example 1.7. Preparation of N-(3-cvano-4-methyl-lH-indol-7-yl)-2-(methyl-d)thiazole-5-sulfonamide (Compound 101)

[0170] To a solution of 2-(bromomethyl-d)-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5-sulfonamide (300 mg, 728 μmol, 1.00 eq) in tetrahydrofuran (3.00 mL) was added palladium on carbon (74.8 mg, 70.3 μmol, 10% purity), the mixture was stirred at 20°C for 1 hour under hydrogen (15 Psi). The reaction mixture was filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD01-Phenomenex luna C18 150*25mm* 10μm;mobile phase: [H2O(0.225% FA)- ACN];gradient:20%-50% B over 16.0 min) to give Compound 101 (74.55 mg, 223 μmol, 30.6% yield, 99.7% purity) as a white solid. Deuterated ratio=98.4%. MS (ESI) m / z 334.0 [M+H]+. 'H NMR (400 MHz, DMSO-d6) d = 11.97 (s, 1H), 10.27 (s, 1H), 8.19 (d, 7= 3.2 Hz, 1H), 7.90 (s, 1H), 6.88 (d. J= 8.0 Hz, 1H), 6.72 (d, J= 8.0 Hz. 1H). 2.66 (s, 2H). 2.61 (s, 3H).Example 2, Synthetic Scheme of Compound 102102Example 2,1, Preparation of thiazol-2-ylmethan-d2-ol

[0171] To a solution of methyl thiazole-2-carboxylate (5.0 g, 34.9 mmol, 1.0 eq) in dry tetrahydrofuran (50.0 mL) was added lithium;tetradeuterioalumanuide (1.0 M, 22.7 mL, 0.65 eq) at 0-5 °C under nitrogen atmosphere, the mixture was stirred at 20 °C for 12 h. Thereaction mixture was quenched by addition D2O (699 mg, 34.9 mmol, 1.0 eq) and ammonium chloride saturated solution (10.0 mL) at 0-5 °C, then filtered and the filtrate was extracted with ethyl acetate / ethanol (10 / 1, 15 mL x 5). The combined organic layers were 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 0-37% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford thiazol-2-ylmethan-d2-ol (1.79 g, 15.18 mmol, 43.48% yield, 99% purity) as a white solid. Deuterated ratio=99.83%.JH NMR (400 MHz, DMSO-rf6) 5 = 7.73 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 5.99 (s, 1H).Example 2.2. Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole

[0172] To a solution of thiazol-2-ylmethan-d2-ol (1.59 g, 13.6 mmol, 1.0 eq) in dichloromethane (45.0 mL) was added tert-butylchlorodimethylsilane (2.66 g, 17.6 mmol, 2.17 mL, 1.3 eq) and imidazole (1.39 g, 20.4 mmol, 1.50 eq), the mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (20.0 mL x 3). The combined organic layers were 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 / Commercial hexanes gradient @ 80 mL / min) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole (3.79 g, 13.10 mmol, 96.54% yield, 80% purity) as a yellow oil. Deuterated ratio=98.63%.NMR (400 MHz, DMSO-d6) δ = 7.76 (d, J= 3.2 Hz, 1H), 7.66 (d, J= 3.2 Hz, 1H), 0.92 (s, 9H), 0.18 -0.06 (m, 6H).Example 2,3, Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole-5-sulfonyl chloride

[0173] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole (3.49 g, 15.1 mmol, 1.0 eq) in tetrahydrofuran (70.0 mL) was added n-BuLi (2.50 M, 5.73 mL, 0.95 eq) at -78 °C under nitrogen atmosphere. The reaction was stirred at -78 °C for 1 h. To the reaction flask was passed SO2 continuously and the reaction was stirred at 0 °C for 0.5 h. Then 1 -chloropyrrolidine-2, 5-dione (6.04 g, 45.2 mmol, 3.0 eq) was added at 0 °C and the reaction was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition ammonium chloride solution 100 mL at 0 °C. and then diluted with water 100 mL and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~7% Ethyl acetate / Commercial hexanes gradient @ 60 mL / min) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole-5-sulfonyl chloride (750 mg, 2.25 mmol, 14.92% yield, 99% purity) as a colorless oil. Deuterated ratio=99.83%.NMR (400 MHz, DMSO-d6) δ = 7.77 - 7.57 (m, 1H), 0.92 (s, 9H), 0.13 - 0.08 (m, 6H).Example 2.4. Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-N-(3-cyano-4-methyL 1 H-indol-7-yl)thiazole-5 -sulfonamide

[0174] To a solution of 7-amino-4-methyl-lH-indole-3-carbonitrile (389 mg, 2.27 mmol, 1.0 eq) in dichloromethane (10.0 mL) was added 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)thiazole-5-sulfonyl chloride (0.75 g, 2.27 mmol, 1.0 eq) and pyridine (719 mg, 9.09 mmol, 734 pL, 4.0 eq) at 5 °C. The reaction was stirred at 25 °C for 0.8 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (10.0 mL x 1), ethyl acetate (10 mL x 2), the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silicagel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~18%Ethylacetate / Commercial hexane gradient @ 80 mL / min) to afford 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5-sulfonamide (0.97 g, 1.59 mmol, 69.79% yield, 76% purity) as a yellow solid. Deuterated ratio=99.83%. 'H NMR (400 MHz, DMSO-d6) 8 = 11.93 (d, J= 2.4 Hz, 1H). 10.23 (s, 1H), 8.18 (d, J= 3.2 Hz, 1H), 8.02 (s, 1H). 6.91 - 6.82 (m, 1H), 6.73 (d, J = 7.6 Hz. 1H), 2.60 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H).Example 2,5. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(hydroxymethyl-d2)thiazole-5-sulfonamide

[0175] A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5-sulfonamide (0.97 g, 2.09 mmol, 1.0 eq) and potassium fluoride (1.21 g, 20.9 mmol, 10 eq) in dimethylformamide (10.0 mL) was stirred at 25 °C for 12 h, then stirred at 40 °C for 2 h. The mixture was diluted with water (0.5 mL). The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3) to afford N-(3-cyano-4-methyl-1H-indol-7-yl)-2-(hydroxymethyl-d2)thiazole-5-sulfonamide (623 mg, 1.74 mmol, 83.47% yield, 98% purity) as a white solid. Deuterated ratio=99.83%. 'H NMR (400 MHz, DMSO-d6) 5 = 11.97 (s. 1H), 10.29 (d. J= 2.0 Hz, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.72 (d, J= 7.6 Hz, 1H), 6.29 (s, 1H), 2.60 (s, 3H).Example 2,6. Preparation of 2- (bromometh yl-d2)-N-(3-cvano-4-methyl- lH-indol-7-yl)thiazole-5-sulfonamide

[0176] To a solution of N-(3-cyano-4-methyl-1H-indol-7-yl)-2-(hydroxymethyl-d2)thiazole-5-sulfonamide (0.44 g, 1.26 mmol, 1.0 eq) in dimethylformamide (4.5 mL) was added tribromophosphane (1.02 g, 3.77 mmol, 0.35 mL, 3.0 eq). The reaction was stirred at 25 °C for 1 h. The mixture was quenched by addition warmed water (10 mL), then poured into a mixture of ethyl acetate (10.0 mL) and saturated sodium bicarbonate (20.0 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(bromomethyl-d2)-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5-sulfonamide (1.02 g, 1.23 mmol, 98.27% yield, 50% purity) as a yellow oil. Deuterated ratio=99.83%.1H NMR (400 MHz, DMSO-d6) 8 = 12.00 (s, 1H), 10.38 (s, 1H), 8.19 (d, J = 3.2 Hz, 1H), 8.05 (s. 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 2.61 (s, 3H).Example 2,7. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl)-2-(methyl-d2)thiazole-5-sulfonamide (Compound 102)102

[0177] A mixture of 2-(bromomethyl-d2)-N-(3-cyano-4-methyl-1H-indol-7-yl)thiazole-5-sulfonamide (0.3 g, 472 pmol, 1.0 eq) and Pd / C (100 mg, 94.0 pmol, 10% purity) in tetrahydrofuran (10.0 mL) was stirred at 25 °C for 1 h under hydrogen atmosphere (15 psi). The mixture was filtered and washed with dichloromethane (30.0 mL), the filtrate was concentrated. The mixture was diluted with dimethylsulfoxide (2.0 mL), then purified by prep-HPLC (column: CDOl-Phenomenex lunaC18 150*25mm* 10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:27%-57% B over 11.0 min) to afford Compound 102 (76.23 mg, 216.65 pmol. 45.92% yield, 95.041% purity) as a yellow solid. Deuterated ratio=99.83%. MS (ESI) m / z 335.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 = 11.97 (s, 1H), 10.27 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 6.87 (d, J = 6.8 Hz, 1H), 6.72 (d, J = 4.8 Hz, 1H), 2.64 (s, 1H), 2.60 (s, 3H).Example 3. Synthetic Scheme of Compound 103103Example 3.1. Preparation of 2-methylthiazole-4-d

[0178] To a solution of 4-bromo-2-methylthiazole (300 mg, 1.68 mmol, 1.0 eq) in deuterated methanol (5.0 mL) was added dry palladium on carbon (150 mg, 141 pmol, 10% purity). The mixture was stirred at 60°C for 6 h under deuterium gas (15 Psi). The reaction mixture was filtered and the filtrate was concentrated to afford 2-methylthiazole-4-d (270 mg, 1.46 mmol, 86% yield, 98% purity, 98.16% deuterated ratio, DBr salt) as a light pink solid.1H NMR (400 MHz, CD3OD) 8 = 8.01 (s, 1H), 3.01 (s, 3H).Example 3.2. Preparation of 2-methylthiazole-5-sulfonyl chloride-4-d

[0179] To a solution of 2-methylthiazole-4-d (118 mg, 648 pmol, DBr salt, 1.0 eq) in tetrahydrofuran (5.0 mL) was added n-butyllithium (2.5 M, 493 pL, 1.9 eq) at -78°C under nitrogen atmosphere. The reaction was stirred at -78°C for 0.5 h. To the reaction flask was passed sulfur dioxide continuously and the reaction was stirred at 0°C for 0.5 h. Then N-Chlorosuccinimide (260 mg, 1.94 mmol, 3 eq) was added at 0°C and the reaction was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition saturated, ammonium chloride aqueous. (10 mL) at 0°C, extracted by ethyl acetate (5 mL x2), the combined organic phase were dried over anhydrous sodium sulfate, filtered and 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 / Commercial hexanes gradient @ 12 mL / min) to afford 2-methylthiazole-5-sulfonyl chloride-4-d (40.0 mg, 191 pmol, 30% yield, 95% purity, 95.18% deuterated ratio) as a colorless oil.1H NMR (400 MHz, CDCl3) 8 = 2.85 (s, 3H).Example 3.3. Preparation of N-(3-cvano-4-methyl-lH-indol-7-yl)-2-methylthiazole-5-sulfonamide-4-d (Compound 103)103

[0180] To a mixture of 7-amino-4-methyl-1H-indole-3-carbonitrile (41.4 mg, 242 pmol, 1.2 eq) and 2-methylthiazole-5-sulfonyl chloride-4-d (40.0 mg, 201 pmol, 1.0 eq) in dichloromethane (1.0 mL) was added pyridine (31.9 mg, 403 pmol, 2.0. eq). The mixture was stirred at 20°C for 0.5 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: CDOl-Phenomenex luna C18 150*25mm* 10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:26%-56% B over 11.0 min) to afford Compound 103 (46.48 mg, 138.09 pmol, 68.59% yield, 99.055% purity, 95.34% deuterated ratio) as a yellow solid. MS (ESI) m / z 333.9 [M+H]+.NMR (400 MHz, DMSO-d6) 8 = 11.97 (s, 1H), 10.27 (s, 1H), 8.19 (d, 7= 3.2 Hz, 1H), 6.87 (d, 7= 8.0 Hz, 1H), 6.72 (d, 7= 8.0 Hz, 1H), 2.68 (s, 3H), 2.61 (s, 3H).Example 4. Synthetic Scheme of Compound 104Example 4.1. Preparation of CD3B(OH)21. CD3MglB(OMe)3- — - ► CD3B(OH)22. HCI

[0181] To a solution of B(OMe)3(2.5 g. 24.06 mmol, 2.4 eq.) in THF (25 mL) was added CD3MgI (1 M in Et2O, 10 mL, 1.00 eq.) at -78°C under N2. The reaction was stirred at -78°C for 2 h. Then the reaction was allowed to warm to room temperature and stirred for 0.5 h, after which aqueous HCI solution (1 M, 5 mL, 0.5 equiv) was added and the reaction was stirred at 15 °C for 1 h. The solution was diluted with EA (30 mL), washed with brine (25 mLx2), dried over Na2SO4, filtered and concentrated under vacuum to give CD3B(OH)2(200 mg) as a yellow solid, which was used directly in the next step without further purification. Yield: 31.3%.Example 4.2. Preparation of methyl 4-(methyl-d3)-1H-indole-7-carboxylate

[0182] To a solution of compound methyl 4-bromo-1H-indole-7-carboxylate (1.5 g. 5.90 mmol) in dioxane (30 mL) and H2O (6 mL) was added (methyl-d3) boronic acid (600 mg, 1.50 eq.), Pd(dppf)Cl2(430 mg, 0.10 eq.) and Na2CO3(1.25 g, 2.00 eq.). The reaction was stirred at 90 °C for 8 h under N2. The mixture was quenched by the addition of water (30 mL), extracted with EA (30 mLx3). The organic layer was concentrated under vacuum and purified by column chromatographed on silica gel (PE: EA = 5:1) to give methyl 4-(methyl-d3)-1H-indole-7-carboxylate (0.8 g) as a yellow solid. LCMS m / z 193.1 (M+l).Example 4.3. Preparation of 4-(methyl-d3)-1H-indole-7-carboxylic acid

[0183] To a solution of methyl 4-(methyl-d3)-1H-indole-7-carboxylate (500 mg) in THF (10 mL) and EtOH (10 mL) was added H2O (4 mL) and NaOH (300 mg, 4.00 eq.). The reaction was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure, diluted with water (10 mL) and the pH was adjusted to 1~2 with 1 N HC1 solution. The mixture was filtered and the filter cake was dried under vacuum to give 4-(methyl-d3)-1H-indole-7-carboxylic acid (300 mg) as a white solid. LCMS m / z 177.1 (M-l).Example 4.4. Preparation of tert-butyl (4-(methyl-d3)-1H-indol-7-yl)carbamate

[0184] To a solution of 4-(methyl-d3)-1H-indole-7-carboxylic acid (1 g, 5.61 mmol) in ‘BuOH (20 mL) was added DPPA (3 g, 2.00 eq.) and TEA (2.2 g, 3.00 eq.). The reaction was stirred at 85 °C for 3 h under N2. The mixture was concentrated under vacuum and purified by column chromatographed on silica gel (PE: EA = 10:1) to give tert-butyl (4-(methyl-d3)-1H-indol-7-yl)carbamate (800 mg) as a white solid. LCMS m / z 250.1 (M+l).Example 4.5. Preparation of 7-amino-4-(methyl-d3)-1H-indole-3-carbonitrile

[0185] To a solution of tert-butyl (4-(methyl-d3)-1H-indol-7-yl)carbamate (800 mg) in EA (2 mL) was added HC1 / EA (4 M, 10 mL). The reaction was stirred at 25 °C for 2 h. The solvent was removed under reduced pressure, washed with PE: EA=10: 1 (20 mL) and dried under vacuum to give 7-amino-4-(methyl-d3)-1H-indole-3-carbonitrile (400 mg, crude) as a brown oil, which was used directly in the next step without further purification. LCMS m / z 175.1 (M+l).Example 4.6. Preparation of N-(3-cyano-4-(methyl-d3)-1H-indol-7-yl)-2-methylthiazole-5-sulfonamide (Compound 104)

[0186] To a solution of 7-amino-4-(methyl-d3)-1H-indole-3-carbonitrile (200 mg,) in DCM (15 mL) was added pyridine (570 mg, 5.00 eq.), followed by 2-methylthiazole-5-sulfonyl chloride (574 mg, 2.00 eq.). The reaction was stirred at 25 °C for 1 h. The mixture was quenched by the addition of aqueous NH4CI solution (20 mL), extracted with DCM (15 mLx3). The organic layer was concentrated under vacuum and purified by Prep-HPLC to give Compound 104 (43 mg) as a yellow solid.1H NMR (600 MHz, DMSO-d6): 11.99 (s, 1H), 10.28 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.71 (d, J -7.8 Hz, 1H), 2.68 (s. 3H). LCMS m / z 336.1 (M+l).Example 5. Synthetic Scheme of Compound 105

[0187] To a solution of 4-methyl-7-nitro-1H-indole (6.0 g, 34.1 mmol, 1.0 eq) in dry dimethylformamide (60 mL) was added sodium hydride (4.09 g. 102 mmol, 60% purity, 3.0 eq) at 0-5 °C under nitrogen atmosphere, after stirred for 0.3 h, TosCl (13.0 g, 68.1 mmol,2.0 eq) was added at 0-5 °C, the mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched by addition saturated ammonium chloride (200 mL) at 0-5 °C, and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (15 mL) at 25 °C for 30 min, then filtered and washed with ethyl acetate (15 mL), the filtrate was concentrated and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min), this batch was combined with filter cake and concentrated to afford 4-methyl-7-nitro-1-tosyl-1H-indole (9.9 g, 29.37 mmol, 86.23% yield, 98% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 8.04 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H). 7.74 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.27 (d, J= 8.0 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 2.54 (s, 3H), 2.39 (s, 3H).Example 5.2, Preparation of 2-bromo-4-methyl-7-nitro-l-tosyl-lH-indole

[0188] To a solution of 4-methyl-7-nitro-1-tosyl-1H-indole (8.8 g, 26.6 mmol, 1.0 eq) in tetrahydrofuran (140 mL) was added lithium diisopropylamide (2.0 M, 12.0 mL, 1.5 eq at -75 °C under nitrogen atmosphere slowly, after stirred at -75 °C for 0.3 h, a solution of 1,2-dibromo-1,1,2,2-tetrachloro-ethane (10.4 g, 32.0 mmol. 3.84 mL, 1.2 eq) in tetrahydrofuran (50 mL) was added at -75 °C, the mixture was stirred for 1 h under nitrogen atmosphere. The reaction mixture was added ammonium chloride saturated solution (100 mL) at 0 °C, then diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD27-Phenomenex luna C18 250*70mm,10 um;mobile phase: [H2O(0.225% FA)-ACN];gradient:50%-80% B over 20.0 min), then concentrated and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to affordcompound 2-bromo-4-methyl-7-nitro-l -tosyl- l / 7-indole (8.21 g, 19.66 mmol, 73.80% yield, 98% purity) as a brown solid.1H NMR (400 MHz, DMSO-d6) 8 = 7.85 (d, J = 8.4 Hz, 1H), 7.51 - 7.45 (m. 2H), 7.43 - 7.33 (m, 4H). 2.48 (s, 3H), 2.37 (s, 3H).Example 5.3. Preparation of 4-methyl-7-nitro-l-tosyl-lH-indole-2-d

[0189] A mixture of 2-bromo-4-methyl-7-nitro-1-tosyl-1H-indole (500 mg, 1.22 mmol, 1 eq), palladium acetate (27.4 mg, 122 uimol. 0.1 eq), sodium;deuterioformate (166 mg, 2.44 mmol, 2.0 eq) and triphenylphosphine (64.1 mg, 244 pmol, 0.2 eq) in dry dimethylformamide (10 mL) and dry acetonitrile (3.3 mL) was stirred at 65 °C for 12 h under nitrogen atmosphere. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-22% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford compound 4-methyl-7-nitro-1-tosyl-1H-indole-2-d (4.17 g, 10.70 mmol, 87.55% yield, 85% purity) as a yellow solid. Deuterated ratio=96.54%.1H NMR (400 MHz, DMSO-d6) 8 = 7.79 (d, J = 8.4 Hz, 2H), 7.74 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 2H), 7.31 - 7.23 (m, 1H), 7.12 (s. 1H), 2.54 (s, 3H). 2.39 (s, 3H).Example 5.4. Preparation of 4-methyl-7-nitro-lH-indole-2-d

[0190] A mixture of 4-methyl-7-nitro-l -tosyl- I / 7-indole-2-<7 (2.0 g, 6.04 mmol, 1.0 eq) and potassium hydroxide (1.69 g, 30.2 mmol, 5.0 eq) in methanol (60 mL) was stirred at 70 °C for 2 h. The reaction mixture was diluted with saturated ammonium chloride (30 mL), extracted with ethyl acetate (3 x 20 mL), the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford compound 4-methyl-7-nitro- 1 H-indole-2- (860 mg, 4.85 mmol. 80.42% yield. 100% purity) as a yellow solid. Deuterated ratio=95.90%.1H NMR (400 MHz, DMSO-d6) δ = 11.87 (s, 1H), 8.02 (d, J= 8.0 Hz, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 1.6 Hz, 1H), 2.61 (s, 3H).Example 5.5. Preparation of 4-methyl-lH-indol-2-d-7-amine

[0191] A mixture of 4-methyl-7-nitro-1H-indole-2-J (860 mg, 4.85 mmol, 1.0 eq), ammonium chloride (4.17 M, 5.82 mL, 5.0 eq) and ferrous powder (2.71 g, 48.5 mmol, 10 eq) in methanol (27 mL) was stirred at 60 °C for 5 h. The mixture was filtered and washed with methanol (20 mL), dichloromethane (50 mL), the filtrate was concentrated to afford compound 4-methyl-lH-indol-2-rf-7-amine (714 mg, crude) as a green solid. Deuterated ratio=75.05%.Example 5.6. Preparation of tert-butyl (4-methyl-lH-indol-7-yl-2-d)carbamate

[0192] To a solution of 4-methyl-lH-indol-2-<7-7 -amine (714 mg, 4.85 mmol, 1 eq) in methanol (16 mL) was added triethylamine (1.96 g, 19.4 mmol, 2.70 mL, 4.0 eq) and di-tert-butyl decarbonate (4.76 g, 21.8 mmol, 5.01 mL, 4.5 eq), the mixture was stirred at 25 °C for 1 h. The mixture was diluted with brine (50 mL), extracted with ethyl acetate (3x 20mL), the combined organic layers were concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-7% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford compound tert-butyl (4-methyl-lH-indol-7-yl-2-<7)carbamate (895 mg, 3.58 mmol, 73.86% yield, 99% purity) as a white solid. Deuterated ratio=89.48%.1H NMR (400 MHz, DMSO-d6) δ = 10.75 (s, 1H), 8.87 (s, 1H), 7.37 - 7.22 (m, 1H), 6.70 (dd, J= 0.8, 7.6 Hz, 1H), 6.41 (d, J= 2.0 Hz, 1H), 2.40 (s, 3H), 1.50 (s, 9H).Example 5.7. Preparation of tert-butyl (3-cyano-4-methyl-lH-indol-7-yl-2-d)carbamate

[0193] To a solution of tert-butyl (4-methyl-l / / -indol-7-yl-2-( )carbamate (895 mg, 2.90 mmol, 1 eq) in dimethylformamide (18 mL) was added sulfurisocyanatidic chloride (492 mg, 3.47 mmol, 302 pL, 1.2 eq) at 0-5 °C, the mixture was stirred at 25 °C for 12 h. The reaction mixture was then diluted with water (180 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were 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 0-15% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford compound tert-butyl (3-cyano-4-methyl- lH-indol-7-yl-2-d)carbamate (630 mg, 2.22 mmol, 76.63% yield, 95.9% purity) as a white solid. Deuterated ratio=98.85%. 'H NMR (400 MHz, DMSO-rf6) 5 = 11.80 (s, 1H), 9.14 - 8.88 (m, 1H), 7.38 (d, J= 7.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 2.59 (s. 3H), 1.49 (s, 9H).Example 5.8. Preparation of 7-amino-4-methyl-lH-indole-3-carbonitrile-2-d

[0194] A mixture of tert-butyl (3-cyano-4-methyl-lH-indol-7-yl-2-d)carbamate (200 mg, 734 pniol, 1.0 eq) and hydrochloric acid (2 M in dioxane, 2 m, 5.45 eq) in dichloromethane (2.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated at 35 °C, then added saturated ammonium chloride (10 mL), extracted with ethyl acetate (3 x 10 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue to afford compound 7-amino-4-methyl-lH-indole-3-carbonitrile-2-(Z (140 mg, 731.69 pmol, 99.63% yield, 90% purity) as a white solid. Deuterated ratio=83.15%.(400 MHz. DMSO-nfe) 5 = 11.78 (s, 1H). 6.69 - 6.62 (m, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.10 (s, 2H), 2.49 (s, 3H).Example 5.9. Preparation of 2-methylthiazole-5-sulfonyl chloride

[0195] To a solution of 2-methylthiazole (1.00 g. 10.1 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added n-butyllithium (2.50 M, 4.84 mL, 1.20 eq) at -78°C under nitrogen atmosphere, the mixture was stirred at -78°C for 30 min, then inject sulfur dioxide gas slowly at -20°C, the mixture was stirred at 20°C for 1 hour under nitrogen atmosphere, then jV-chlorosuccinimide (2.69 g, 20.2 mmol, 2.00 eq) was added, the mixture was stirred at 25 °C for 12 hours under nitrogen atmosphere. The reaction mixture was quenched by addition ammonium chloride solution (20.0 mL) at 0 °C, and then diluted with water (100 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 50.0 mL / min) to give the title compound (1.4 g, 6.87 mmol, 68.1% yield, 97% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.92 (s, 1H), 2.75 (s, 3H).Example 5.10. Preparation of N-(3-cyano-4-methyl-lH-indol-7-yl-2-d)-2-methylthiazole-5-sulfonamide (Compound 105)105

[0196] A mixture of 7-amino-4-methyl- 1 H-indole-3-carbonitrile-2-(7 (140 mg, 813 pmol, 1.0 eq), 2-methylthiazole-5- sulfonyl chloride (161 mg, 813 pmol, 1.0 eq) and Pyridine (129 mg, 1.63 mmol, 131 pL, 2.0 eq) in dichloromethane (2.0 mL) and tetrahydrofuran (4.0 mL) was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (8.0 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150*25*7um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:7%-37% B over 11.0 min) to give the title compound (94.35 mg, 279.37 pmol, 34.37% yield, 98.72% purity) as a white solid. MS (ESI) m / z 334.1 [M+H] +. Deuterated ratio=98.84%.1H NMR (400 MHz, DMSO-d6) δ = 11.97 (s, 1H), 10.26 (s, 1H), 7.89 (s, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 2.68 (s, 3H), 2.60 (s, 3H).Example 6. Preparation of N-(3-cyano-4-(methyl-d3)-lH-indol-7-yl)-2-(methyl-d3)thiazole-5-sulfonamide (Compound 106)

[0197] To a solution of 7-amino-4-(methyl-d3)-1H-indole-3-carbonitrile (200 mg,) in DCM (15 mL) was added pyridine (570 mg, 5.00 eq.), followed by 2-(methyl-d3)thiazole-5-sulfonyl chloride (574 mg, 2.00 eq.). The reaction was stirred at 25 °C for 1 h. The mixture was quenched by the addition of aqueous NH4CI solution (20 mL), extracted with DCM (15 mLx3). The organic layer was concentrated under vacuum and purified by Prep-HPLC to give Compound 106 (30 mg) as a yellow solid. 'H NMR (600 MHz, DMSO-d6): 11.98 (s, 1H), 10.28 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.71 (d. J = 7.8 Hz, 1H). LCMS m / z 339.1 (M+l).Example 7. Preparation of N-(3-cvano-4-methyl-lH-indol-7-yl)-2-methyl-thiazole-5-sulfonamide (Comparative Compound A)Comparative Compound A

[0198] To a solution of 2-methylthiazole-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) indichloromethane (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 Comparative Compound A (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-d6) 3 = 11.99 (s, 1H), 10.28 (s, 1H). 8.19 (d, J = 3.2 Hz, 1H), 7.90 (s. 1H), 6.88 (d, J = 7.6 Hz. 1H). 6.72 (d, J = 7.6 Hz, 1H), 2.68 (s, 3H), 2.61 (s, 3H).

[0199] Compounds 107-109, were or can be prepared by similar methods to those described herein and are shown in Table 1.Table 1Example 8. Cell Viability Assays

[0200] 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.

[0201] 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) 24h 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, 0.001, 0.003, 0.002 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 plate reader (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. Results from these experiments for Comparative Compound A are shown in Table 2.Table 2Example 9: ADME StudiesGeneral Liver Microsomes Stability Protocol:

[0202] 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

[0203] Two separate experiments were performed as follows:

[0204] 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.

[0205] 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

[0206] 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, 200 nM caffeine and 100 nM tolbutamide).

[0207] 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:

[0208] 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.

[0209] 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.

[0210] 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 M working solutions.

[0211] To determine the rate of drug transport in the apical to basolateral direction, 125 pL of the working solution was added to the Trans well 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.

[0212] 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.

[0213] The Transwell insert plate was inserted into the basolateral plate, transferred into the incubator and incubated at 37 °C for 2 h.

[0214] At the end of the incubation, 50 pL samples from donor sides (apical compartment for Ap— > B1 flux, and basolateral compartment for Bl— > Ap flux) and receiver sides (basolateral compartment for Ap^-Bl 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.

[0215] 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 Properties

[0216] Deuteration at different positions (groups) of Comparative Compound A lead to various changes to its metabolic stability and MDCK permeability readouts. As shown in Table 3, Compound 106 has significantly better metabolic stability than Comparative Compound A.

[0217] 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.

[0218] 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.

[0219] 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 anddescribed 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’ will be 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.

[0220] 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.

[0221] 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.

[0222] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0223] 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.

[0224] 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.

[0225] 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 compound of Formula (I)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-Ce)alkyl and -(Ci-Ce)haloalkyl;R2is H, -(Ci-C6)alkyl or -C(O)R6;R3is a -(Ci-Ce)alkyl, 5-10 membered monocyclic or bicyclic heteroaryl, or a 6-12 membered bicyclic heterocyclyl; wherein the -(Ci-C6)alkyl, 5-10 membered monocyclic or bicyclic heteroaryl and the 6-12 membered 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-Ce)haloalkyl, -(Ci-C6)alkoxy, -CN, halogen, -NH2, -N((Ci-C6)alkyl)2, -NHC(O)(Ci-Ce)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 and -(C2-C6)alkynyl;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-Ce)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-Ce alkyl), wherein the cycloalkyl, heterocyclyl and heterocyclyl(alkyl) are each optionally substituted with Ryl;Rx2is selected from the group consisting of -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, -(Ci-Ce) 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-Ce)alkyl, -(Ci-Ce)alkyl, -(Ci-C6)haloalkyl, -(Ci-Ce)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-Ce)alkyl)2, -C(O)(5-10 membered heterocyclyl) and -(CH2)nS(O)2(Ci-C6)alkyl;n is 0, 1, 2, 3 or 4;the compound comprises at least one deuterium; with the proviso that the compound is2. The compound of Claim 1, wherein Z1is C(Rla).

3. The compound of Claim 2, wherein Rlain Z1is -(Ci-Ce)alkyl.

4. The compound of Claim 3, wherein Rlain Z1is -CH3.

5. The compound of Claim 3, wherein Rlain Z1is -CD3, -CHD2 or -CH2D.

6. The compound of any one of Claims 1-5, wherein Z2is C(Rla).

7. The compound of Claim 6, wherein Rlain Z2is D (deuterium).

8. The compound of any one of Claims 1-7, wherein Z3is C(Rla).

9. The compound of Claim 8, wherein Rlain Z3is deuterium (D).

10. The compound of any one of Claims 1-9, wherein R2is deuterium (D).

11. The compound of any one of Claims 1-10. wherein R3is a 5-membered monocyclic nitrogen-containing heteroaryl optionally substituted with one or two substituents selected from R4.

12. The compound of Claim 11, wherein each R4is independently selected from the group consisting of -CH3, deuterium (D), -CD3, -CHD2 and -CH2D.

13. The compound of any one of Claims 1-12, wherein R7ais deuterium (D).

14. The compound of any one of Claims 1-13, wherein R5ais -CN.

15. The compound of any one of Claims 1-14, wherein A1is16. The compound of any one of Claims 1-14, wherein the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, having the structure:wherein:X1is O or S.

17. The compound of Claim 16, wherein X1is S.

18. The compound of Claim 1, wherein the compound is selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing.

19. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, and excipient.

20. A method of treating cancer in a subject comprising administering to a subject in need thereof an effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof.

21. The method of Claim 20, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormonal therapy, or antiviral therapy.

22. A compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

23. The compound of Claim 22, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormonal therapy, or antiviral therapy.

24. Use of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in treating cancer.

25. The use of Claim 24, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormonal therapy, or antiviral therapy.

26. 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 compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof.

27. The method of Claim 26, 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.

28. The method of Claim 26, 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-AEK, TRMT11-GRIK2, CCNH-C5orf30, ETV6-NTRK3, ODZ4-NRG1, TBE1XR1-RGS17, MYB-NFTB, MAST-fusions, NOTCH-fusions, IGH-MYC, 1GK-MYC, IGL-MYC, RSPO2-EIF3E, RSPO2-PTPRK, EWSR1-FLI1, EWSR1-ERG, BCL2-IGH, MAN2A1-FER, FGFR3-TACC3, FIG-ROSE EML4-ALK1, ESRRA-Cllorf20, BRAF-KIAA1549. TMPRSS2-ERG, TMPRSS2-ETV1, TMPRSS2-ETV4, SLC45A2-AMACR, TMEM135-CCDC67, MTOR-TP53BP1, RPS10-HPR, AGAP9-BRAF, RET-CCDC6, PAX8-PPARG, TFG-NTRK1, and TPM3-NTRK1.

29. The method of Claim 28, wherein EWSR1-FLI1 fusion gene splicing is dysregulated.

30. The method of Claim 29, wherein administering the compound causes RNA splicing of Exon 6 and / or Exon 7 of FLU in the EWSR1-FLI1 fusion gene to be skipped.

31. The method of Claim 29, wherein administering the compound reduces expression of EWS-FLI1 fusion protein.

32. The method of any one of Claims 26-31, comprising obtaining a biological sample from the subject and identifying the gene fusion mutation.

33. The method of any one of Claims 26-32, wherein the gene fusion mutation is Type I or Type I like EWS-FLI1.

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