WO2023049691A1 - Cdk7 inhibitors and methods of treating cancer - Google Patents

Abstract

Compounds of Formula (I) and pharmaceutically active salts thereof are provided, where the variables in Formula (I) are described herein. Such compounds and salts are CDK7 inhibitors that are useful for treating conditions characterized by excessive cellular proliferation, such as cancer and tumors.

Description

CDK7 INHIBITORS AND METHODS OF TREATING CANCER INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial No. 63/261,546, filed September 23, 2021, which is hereby incorporated herein by reference in its entirety. BACKGROUND Field [0002] The present application relates generally to compounds that are CDK7 inhibitors and methods of using them to treat conditions characterized by excessive cellular proliferation, such as cancer and tumors. Description [0003] Cyclin-dependent kinase 7 (CDK7) is a protein in the cyclin-dependent protein kinase (CDK) family. It forms a complex with cyclin H and MAT1 that is involved in T-loop phosphorylation and driving cell cycle progression. CDK7 is also involved in the regulation of transcription as a component of transcription factor TFIIH. See Sava, G.P. et al, “CDK7 Inhibitors as Anticancer Drugs,” Cancer and Metastasis Reviews (2020) 39:805-823. [0004] A number of compounds of varying chemical structure that inhibit CDK7 have been evaluated for their ability to treat cancer and/or tumors. For example, Table 1 illustrates several selective CDK7 inhibitors that have progressed to Phase I/II clinical trials involving patients with advanced solid malignancies: C S

CDK7 Inhibitor Structure

[0005] The clinical advances of multiple compounds represent milestones in the development of CDK7 inhibitors. However, there remains a need for improved compounds that inhibit the activity of CDK7. SUMMARY [0006] Various embodiments provide compounds of the Formula (I) and methods of using them. [0007] An embodiment provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR^5a, or NR^5aR^5b; R³ is substituted or unsubstituted C3-C8 cycloalkyl or C3-C8 heterocyclyl, wherein the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶; R⁴ is halogen, CN, alkyl, cycloalkyl, -NR⁷R⁸, OR⁶, -CO2R⁶, or -C(O)-NR⁷R⁸; each R^5a, R^5b, and R⁶ is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; R⁷ and R⁸ are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; wherein the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR⁶, CN, alkyl, NHR^5a, or NR^5aR^5b; or R⁷ and R⁸, along with the N to which they are connected, are taken together to form an unsubstituted or substituted C₃-C₈ heterocyclyl wherein the substituted C₃-C₈ heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶; X is N or CR⁹; Q₁ is C or N; Q2 is CH or N; Q3 is CH, N, or NH; provided that when Q1 is N, then Q3 is N;

; each R¹⁰ is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; Y and Z are independently N or CH, and each n is independently 0, 1, 2, 3, or 4. [0008] Another embodiment provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0009] Another embodiment provides a method for treating a cancer or a tumor comprising administering an effective amount of a compound as described herein, or a pharmaceutically active salt thereof, or a pharmaceutical composition of as described herein, to a subject having the cancer or the tumor. [0010] These and other embodiments are described in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS [0011] FIG. 1 illustrates a general synthetic scheme for preparing compounds of the Formula (I). [0012] FIG. 2 illustrates a reaction scheme for making 7-bromo-3-(2,5- dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (Intermediate 2). [0013] FIG. 3 illustrates a reaction scheme for making 3-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (Intermediate 5). [0014] FIG. 4 illustrates a reaction scheme for making 3-(2-(((3S,6S)-6- Methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1-oxidophospholan-1- yl)-1H-indole-6-carbonitrile (Example 1). [0015] FIG. 5 illustrates a reaction scheme for making 3-(5-Chloro-2-(((3S,6S)-6- methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophospholan-1-yl)-1H-indole-6- carbonitrile (Example 8). [0016] FIG. 6 illustrates a reaction scheme for making N-(3,5-dimethylisoxazol-4- yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrrolo[2,3-b]pyridine-6-carboxamide (Example 18). [0017] FIG. 7 illustrates a reaction scheme for making N-(3,5-dimethylisoxazol-4- yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H- indole-6-carboxamide (Example 28). Detailed Description [0018] Cyclin-dependent kinases (CDKs) are a major class of kinases and are important in cancer cell proliferation and deregulated oncogenic transcription. CDK7 binds to cyclin H and MATI to form a trimeric cyclin-activating kinase (CAK) that performs its function by phosphorylating other CDKs involved in cell-cycle control. These complexes control specific transitions between two subsequent phases in the cell cycle. CDK7 is implicated in both temporal control of the cell cycle and transcriptional activity. CDK7 is implicated in the transcriptional initiation process by phosphorylation of Rbp1 subunit of RNA Polymerase II (RNAPII). Uncontrolled cell proliferation and deregulated transcription is a cancer hallmark. Targeting CDK7 selectively may offer an advantage by simultaneously inhibiting active transcription and cell-cycle progression. Therefore, CDK7 is a promising target for the treatment of cancer, in particular aggressive and hard to-treat cancers. Definitions [0019] 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. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0020] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amine group, a di-substituted amine group, a mono-substituted amine(alkyl) and a di-substituted amine(alkyl). [0021] As used herein, “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed. [0022] If two “R” groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^a and R^b of an NR^aR^b group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:

[0023] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 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 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. [0024] As used herein, the term “alkylene” refers to a bivalent fully saturated straight chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene. An alkylene group may be represented by , followed by the number of carbon atoms, followed by a “*”. For example,

to represent ethylene. The alkylene group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 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 alkyl having 1 to 12 carbon atoms. The alkylene group could also be a lower alkyl having 1 to 4 carbon atoms. An alkylene group may be substituted or unsubstituted. For example, a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C_3-6 monocyclic cycloalkyl group (e.g.,

[0025] The term “alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2- butenyl and the like. An alkenyl group may be unsubstituted or substituted. [0026] The term “alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted. [0027] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. [0028] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted. [0029] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. [0030] As used herein, “heteroaryl” refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted. [0031] Those skilled in the art understand that the partial circle in the fused “A” ring of the following moiety indicates that the “A” ring is aromatic:

[0032] For example, when any one or more of Q1, Q2 and Q3 is nitrogen, the above moiety is a heteroaryl group. Similarly, when Q₁, Q₂ and Q₃ are all carbon, the above moiety is an aryl group. [0033] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-) and nitrogen (e.g., -N=, -NH- or -N(alkyl)-). A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non- adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include 2-azaspiro[3.3]heptane, 2- oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane. [0034] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenylalkyl, 3-phenylalkyl and naphthylalkyl. [0035] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs. [0036] A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl). [0037] As used herein, the term “hydroxy” refers to a –OH group. [0038] As used herein, “alkoxy” refers to the Formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non- limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted. [0039] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0040] A “cyano” group refers to a “-CN” group. [0041] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine. [0042] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. [0043] An “O-carbamyl” group refers to a “-OC(=O)N(R_AR_B)” group in which R_A and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted. [0044] An “N-carbamyl” group refers to an “ROC(=O)N(R_A)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted. [0045] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted. [0046] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and R_A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted. [0047] A “C-amido” group refers to a “-C(=O)N(RARB)” group in which RA and R_B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted. [0048] An “N-amido” group refers to a “RC(=O)N(R_A)-” group in which R and R_A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted. [0049] An “S-sulfonamido” group refers to a “-SO₂N(R_AR_B)” group in which R_A and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted. [0050] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0051] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted. [0052] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted. [0053] A “nitro” group refers to an “–NO2” group. [0054] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted. [0055] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. [0056] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0057] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri- haloalkyl and polyhaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted. [0058] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2- fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted. [0059] The terms “amino” and “unsubstituted amino” as used herein refer to a –NH2 group. [0060] A “mono-substituted amine” group refers to a “-NHR_A” group in which R_A can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The R_A may be substituted or unsubstituted. A mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-C₁-C₆ alkylamine group, a mono- arylamine group, a mono-C6-C10 arylamine group and the like. Examples of mono-substituted amine groups include, but are not limited to, −NH(methyl), −NH(phenyl) and the like. [0061] A “di-substituted amine” group refers to a “-NR_AR_B” group in which R_A and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. R_A and R_B can independently be substituted or unsubstituted. A di-substituted amine group can include, for example, a di-alkylamine group, a di-C1-C6 alkylamine group, a di-arylamine group, a di-C6-C10 arylamine group and the like. Examples of di-substituted amine groups include, but are not limited to, −N(methyl)₂, −N(phenyl)(methyl), −N(ethyl)(methyl) and the like. [0062] As used herein, “mono-substituted amine(alkyl)” group refers to a mono-substituted amine as provided herein connected, as a substituent, via a lower alkylene group. A mono-substituted amine(alkyl) may be substituted or unsubstituted. A mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl) group, a mono-C1-C6 alkylamine(C1-C6 alkyl) group, a mono-arylamine(alkyl group), a mono- C6-C10 arylamine(C1-C6 alkyl) group and the like. Examples of mono-substituted amine(alkyl) groups include, but are not limited to, −CH₂NH(methyl), −CH₂NH(phenyl), −CH2CH2NH(methyl), −CH2CH2NH(phenyl) and the like. [0063] As used herein, “di-substituted amine(alkyl)” group refers to a di-substituted amine as provided herein connected, as a substituent, via a lower alkylene group. A di-substituted amine(alkyl) may be substituted or unsubstituted. A di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-C1-C6 alkylamine(C1-C6 alkyl) group, a di-arylamine(alkyl) group, a di-C6-C10 arylamine(C1-C6 alkyl) group and the like. Examples of di-substituted amine(alkyl)groups include, but are not limited to, −CH2N(methyl)2, −CH2N(phenyl)(methyl), −NCH2(ethyl)(methyl), −CH2CH2N(methyl)2, −CH2CH2N(phenyl)(methyl), −NCH2CH2(ethyl)(methyl) and the like. [0064] Where the number of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0065] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.” [0066] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2- oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH₃ ⁺) and the positive charge can be balanced by a negatively charged counterion (such as Cl- ). [0067] The term “CDK7 inhibition” and similar terms refer to inhibiting the activity or function of a CDK7 protein. Similarly, the term “CDK7 inhibitor” refers to an agent (including small molecules and proteins) that inhibits the function of CDK7 protein. As will be understood by those of skill in the art, there are numerous methods of evaluating protein binding interactions, including, but not limited to co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR) and fluorescence polarization/anisotropy. [0068] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. [0069] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium). [0070] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. 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. [0071] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0072] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. [0073] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. [0074] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. Compounds [0075] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

[0076] R¹ and R² in Formula (I) can each independently be hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR^5a, or NR^5aR^5b. In an embodiment, at least one of R¹ and R² is hydrogen. In another embodiment, at least one of R¹ and R² is halogen. In another embodiment, at least one of R¹ and R² is CN. In another embodiment, at least one of R¹ and R² is alkyl, e.g., C_1-3 alkyl. In another embodiment, at least one of R¹ and R² is alkoxy, e.g., C1-3 alkoxy. In another embodiment, at least one of R¹ and R² is haloalkyl, e.g., C1-3 haloalkyl. In another embodiment, at least one of R¹ and R² is hydroxyalkyl, e.g., C1-3 hydroxyalkyl. In another embodiment, at least one of R¹ and R² is cycloalkyl, e.g., C_3-6 cycloalkyl. In another embodiment, at least one of R¹ and R² is NHR^5a. In another embodiment, at least one of R¹ and R² is NR^5aR^5b. In another embodiment, at least one of R¹ and R² is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl. [0077] R³ in Formula (I) can be a substituted or unsubstituted C₃-C₈ cycloalkyl or C3-C8 heterocyclyl. In various embodiments, the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶. In an embodiment, R³ is substituted C3-C8 cycloalkyl. In an embodiment, R³ is unsubstituted C3-C8 cycloalkyl. In an embodiment, R³ is substituted C3-C8 heterocyclyl. In an embodiment, R³ is unsubstituted C3- C₈ heterocyclyl. In an embodiment, R³ is piperidinyl, methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxaazaspirodecyl. [0078] R⁴ in Formula (I) can be halogen, CN, alkyl, cycloalkyl, -NR⁷R⁸, OR⁶, - CO₂R⁶, or -C(O)-NR⁷R⁸. In an embodiment, R⁴ is halogen. In an embodiment, R⁴ is CN. In an embodiment, R⁴ is alkyl, e.g., C1-3 alkyl. In an embodiment, R⁴ is cycloalkyl, e.g., C1-3 cycloalkyl. In an embodiment, R⁴ is -NR⁷R⁸. In an embodiment, R⁴ is OR⁶. In an embodiment, R⁴ is -CO2R⁶. In an embodiment, R⁴ is -C(O)-NR⁷R⁸. In various embodiments, R⁷ and R⁸ of R⁴ are each independently unsubstituted alkyl, e.g., C1-3 alkyl. In other embodiments, the R⁷ and R⁸ of R⁴, along with the N to which they are connected, are taken together to form an unsubstituted or substituted C3-C8 heterocyclyl. In various embodiments, R⁴ is CN, N,N- dimethylamido, N,N-diethylamido,

[0079] Each R^5a, R^5b, and R⁶ in Formula (I) can independently be hydrogen, alkyl, haloalkyl, or cycloalkyl. In an embodiment, at least one of R^5a, R^5b, and R⁶ is hydrogen. In an embodiment, at least one of R^5a, R^5b, and R⁶ is alkyl, e.g., C1-3 alkyl. In an embodiment, at least one of R^5a, R^5b, and R⁶ is haloalkyl, e.g., C1-3 haloalkyl. In an embodiment, at least one of R^5a, R^5b, and R⁶ is cycloalkyl, e.g., C_3-6 cycloalkyl. [0080] R⁷ and R⁸ in Formula (I) can each independently be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. In various embodiments, the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR⁶, CN, alkyl, NHR^5a, or NR^5aR^5b. In alternative embodiments, R⁷ and R⁸ in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted or substituted C₃-C₈ heterocyclyl. In an embodiment, the substituted C₃-C₈ heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl (e.g., C1-3 alkyl), alkoxy (e.g., C1-3 alkoxy), haloalkyl (e.g., C1-3 haloalkyl), cycloalkyl (e.g., C3-6 cycloalkyl), heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶. In an embodiment, at least one of R⁷ and R⁸ is independently hydrogen, substituted or unsubstituted alkyl (e.g., C_1-3 alkyl), or substituted or unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl). In an embodiment, at least one of R⁷ and R⁸ is hydrogen. In an embodiment, at least one of R⁷ and R⁸ is substituted alkyl. In an embodiment, at least one of R⁷ and R⁸ is unsubstituted alkyl (e.g., C_1-3 alkyl). In an embodiment, at least one of R⁷ and R⁸ is substituted cycloalkyl (e.g., substituted C3-6 cycloalkyl). In an embodiment, at least one of R⁷ and R⁸ is unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl). In an embodiment, R⁷ and R⁸ in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted C3-C8 heterocyclyl. In an embodiment, R⁷ and R⁸ in Formula (I), along with the N to which they are connected, are taken together to form a substituted C₃-C₈ heterocyclyl. [0081] X in Formula (I) can be N or CR⁹; Q1 can be C or N; Q2 can be CH or N; and Q3 can be CH, N, or NH. In an embodiment, when Q1 is N, then Q3 is N. In an embodiment, X is N. In another embodiment, X is CR⁹. In an embodiment, Q₁ is C. In another embodiment, Q1 is N and Q3 is N. In an embodiment, Q2 is CH. In another embodiment, Q2 is N. In an embodiment, Q3 is CH. In another embodiment, Q3 is N. In another embodiment, Q3 is NH. [0082] R⁹ in Formula (I) can be hydrogen

, , or . In an embodiment, R⁹ is hydrogen. In an embodiment, R⁹ is . I ⁹

n an embodiment, R is In an embodim ^{9 9}

ent, R is

. In an embodiment, R is

Each n in Formula (I) can independently be 0, 1, 2, 3, or 4. In an embodiment, n in R⁹ is 1. In another embodiment, n in R⁹ is 2. [0083] Each R¹⁰ in Formula (I) can independently be hydrogen, alkyl (e.g., C1-3 alkyl), haloalkyl (e.g., C_1-3 haloalkyl), or cycloalkyl (e.g., C_3-6 cycloalkyl). In an embodiment,

each R¹⁰ is C_1-3 alkyl. In various embodiments of Formula (I), when each R¹⁰ is independently methyl or ethyl, Formula (I) is not

. [0084] Y and Z in Formula (I) can each independently be N or CH. In an embodiment, at least one of Y and Z is N. In an embodiment, at least one of Y and Z is CH. [0085] In various embodiments, the compound of Formula (I) has a chemical structure as described in any one of Tables 2-6 and/or the examples below. Synthesis [0086] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein, including the Examples provided below. For example, in an embodiment, compounds of the Formula (I) are prepared in accordance with the general scheme illustrated in FIG 1. Compounds of the Formulae A and B can undergo an AlCl3 induced heteroarylation reaction or metal-catalyzed coupling reaction followed by installation of R⁹ on X or full decoration of R⁴. In FIG. 1, L represents a suitable leaving group which is replaced by R³ amine via aromatic nucleophilic substitution or Buchwald amination. Removal of the protecting group via a hydrogenolysis reaction or acidic hydrolysis provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Any preliminary reaction steps required to form starting compounds or other precursors, can be carried out by those skilled in the art. In FIG. 1 and the illustrated formulae, the variables R¹, R², R³ R⁴, R^5a, R^5b, R⁶ R⁷, R⁸, R⁹, R¹⁰, X^, Y, Z, Q_1, Q₂, Q₃ and n can be as described elsewhere herein, taking into consideration the synthetic conversions involved as understood by those of skill in the art. Pharmaceutical Compositions [0087] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0088] The term “pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. [0089] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended. [0090] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. [0091] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood. [0092] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and/or a metal- chelating agent. A “diluent” is a type of excipient. [0093] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. [0094] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. [0095] Multiple techniques of administering a compound, salt and/or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally. [0096] One may also administer the compound, salt and/or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable. [0097] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for treatment of an indicated condition. Uses and Methods of Treatment [0098] Some embodiments described herein relate to a method for treating a cancer or a tumor described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or a tumor described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer or a tumor described herein. [0099] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor described herein that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor described herein. In some embodiments, the use can include contacting the growth or the tumor with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor described herein. [0100] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. In some embodiments, the use can include contacting the malignant growth or a tumor described herein with the medicament. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth or a tumor described herein, wherein the malignant growth or tumor is due to a cancer described herein. [0101] Examples of suitable malignant growths, cancers and tumors include, but are not limited to: urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas. [0102] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult. [0103] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance. [0104] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0105] For example, an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non- small cell lung cancer), a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount, or a therapeutically effective amount of a CDK7 inhibitor is the amount which results in the reduction in CDK7 protein activity. Methods for measuring reductions in CDK7 activity are known to those skilled in the art and can be determined by the analysis of CDK7 binding, e.g., as illustrated in the Examples below. [0106] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions. [0107] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form. [0108] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. [0109] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine) [0110] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [0111] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine. [0112] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime. EXAMPLES [0113] FIG. 1 illustrates a synthetic scheme for making compounds of the Formula (I). Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. Intermediate 1 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile

1 [0114] Intermediate 1 was synthesized according to a published procedure (WO 2020/093006). Intermediate 2 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6- carbonitrile (FIG. 2)

7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H-indole-6-carbonitrile [0115] In a sealed tube, to a stirred solution of 2,4-dichloro-5-nitropyrimidine ( 2.56 g, 13.6 mmol) in 1,2-DCE (15 mL) was added AlCl3 (1.81 g, 20.3 mmol) at RT and stirred at 80 °C for 30 min. Then was added 7-bromo-1H-indole-6-carbonitrile (1.000 g, 4.524 mmol) portion wise at 80 °C and stirred at 80 °C for 12 h. After completion of reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 10% tetrahydrofuran in ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered and evaporated to get crude compound. The crude compound was triturated with ethyl acetate (100 mL) and dried under vacuum to afford 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H-indole-6- carbonitrile (1.100 g, 2.906 mmol, 64% yield). MS-(LCMS) m/z: calcd for C13H5BrClN5O2 [M+H]⁺ = 377.93/379.93, observed = 378.07/380.08. LCMS purity: 94%; ¹H NMR (400 MHz, DMSO-d6) 13.13 (s, 1H), 9.32 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H). 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole- 6-carbonitrile [0116] To a stirred solution of 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1H- indole-6-carbonitrile (2.80 g, 7.40 mmol) in DMF (30 mL) was added NaH (60% in mineral oil, 355 mg, 8.88 mmol) at 0 °C , stirred for 10 min and added SEM-Cl (1.48 g, 8.88 mmol) at 0 °C . The reaction mixture was stirred at 0 °C for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na₂SO₄ and evaporated. The crude material was purified by silica-gel (100-200) column chromatography using 30-40% EtOAc in pet-ether as an eluent to afford 7-bromo-3-(2-chloro-5-nitropyrimidin- 4-yl)-1-((2 (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.50 g, 4.91 mmol, 66% yield). MS-(LCMS) m/z: calcd for C19H19BrClN5O3Si [M+H]⁺ = 508.01/510.01, observed = 508.23/510.25. LCMS purity: 93.28%; ¹H NMR (400 MHz, CDCl3) 8.99 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.99 (t, J =8.0 Hz, 2H), 0.002 (s, 9H). 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indole-6-carbonitrile [0117] To a stirred solution of 7-bromo-3-(2-chloro-5-nitropyrimidin-4-yl)-1-((2 (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.00 g, 3.93 mmol) in THF (20 mL) and AcOH (5 mL) was added Fe powder (2.195 g, 39.31 mmol) and stirred at rt for 16 h. After consumption of starting material by TLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate (50 mL), evaporated under reduced pressure obtained crude was diluted with water (30 mL) and extracted with ethyl acetate (2 x 750 mL). Organic layer was separated, dried over Na₂SO₄, filtered and evaporated. Crude was triturated with diethyl ether (25 mL) to afford 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (1.69 g, 3.54 mmol, 90% yield). MS- (LCMS) m/z: calcd for C19H21BrClN5OSi [M+H]⁺ = 478.04/480.04, observed = 478.25/480.22. LCMS purity: 92.79%; ¹H NMR (400 MHz, CDCl3) 8.38 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 5.97 (s, 2H), 3.88 (s, 2H, NH₂), 3.61 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8 Hz, 2H), 0.02 (s, 9H). 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- -indole-6-

carbonitrile [0118] To a stirred solution of 3-(5-amino-2-chloropyrimidin-4-yl)-7-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (three batches, 3 x 1.00 g, 3 x 2.09 mmol) in ACN (20 mL) were added isoamyl nitrite (3 x 489 mg, 3 x 4.18 mmol) and Cu(I)Cl (414 mg, 4.18 mmol) at rt and stirred at rt for 30 min. After consumption of starting material by TLC, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (2 x 70 mL). The combined organic layer was separated, dried over Na2SO4 and evaporated. The crude material was purified by silica-gel (100-200) column chromatography using 20-30% EtOAc in pet-ether as a eluent to afford 7-bromo-3-(2,5-dichloropyrimidin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile, Intermediate 2 (1.40 g, 2.82 mmol, 45% yield). MS-(LCMS) m/z: calcd for C₁₉H₁₉BrCl₂N₄OSi [M+H]⁺ = 496.99/498.99/500.98 (60%/100%/47%), observed = 497.21/499.23/501.20 (60%/100%/47%). LCMS purity: 96.23%; ¹H NMR (400 MHz, CDCl3) 8.76 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 5.99 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.95 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H). Intermediate 3 7-bromo-3-(6-halo-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6- carbonitrile

[0119] Intermediate 3 was synthesized similarly to Intermediate 1 with starting pyrimidine analogs as (3,5-dichloro-4-(trifluoromethyl)phenyl)(methyl)sulfane and (3-chloro- 5-fluoro-4-(trifluoromethyl)phenyl)(methyl)sulfane (see WO 2005/047279, CN 112739689 and J Fluorine Chemistry, 1987, 35, 275-285) followed by oxidation to sulfone. Intermediate 4 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic

[0120] To a stirred solution of 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4- yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Reference: WO 2019/143719) ( 0.900 g, 1.89 mmol) in EtOH (15 mL) were added 5 M aq. NaOH (10 mL) at 0 °C and stirred at 70°C for 16 h. After completion of the reaction, the solvent was evaporated and slowly acidified with 2N HCl to PH = ~4 and the precipitate was filtered and dried under vacuum to afford 3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3- b]pyridine-6-carboxylic acid, Intermediate 4 (0.800 g, crude used for next step without purification). MS-(LCMS) m/z: calcd for C₁₄H₉F₃N₄O₂S [M+H]⁺ = 355.04, observed = 355.14. Intermediate 5 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole- 6-carbonitrile (FIG. 3)

7-amino-1H-indole-6-carbonitrile [0121] In sealed tube, to a stirred solution of 7-bromo-1H-indole-6-carbonitrile (Reference WO 2018/013867, three batches, 3 x 3.000 g, 3 x 13.57 mmol) in NMP (30 mL) and water (10 mL) were added NaN₃ (3 x 3.529 g, 3 x 54.28 mmol), sodium ascorbate (5.377 g, 27.14 mmol,) and degassed with Argon for 10 min. Then was added CuI (3 x 517 mg, 3 x 2.71 mmol) and (S,S’)-N,N’-dimethyl-1,2-cyclohexanediamine (3 x 642 µL,3 x 4.07 mmol,) degassed again for 10 min. The reaction mixture was heated at 100 °C for 2 h. After completion of the reaction, the reaction was cooled to room temperature and solvent was evaporated under reduced pressure. The brown residue diluted with EtOAc (100 mL), passed through Celite pad and washed with EtOAc (100 mL). The filtrate was evaporated under reduced pressure and the crude was purified by silica gel column chromatography using 20-30% EtOAc and Pet. ether to afford 7-amino-1H-indole-6-carbonitrile (3.62 g , 23.0 mmol, 57%). MS-(LCMS) m/z: calcd for C9H7N3 [M+H]⁺ = 158.06, observed = 158.26.¹H NMR (400 MHz, CDCl3) δ 8.43 (br s, 1H, NH), 7.32 (dd, J = 3.0, 3.0 Hz, 1H), 7.11 (s, 2H), 6.57 (dd, J = 2.2, 3.0 Hz, 1H), 4.45 (br s, 2H, NH₂). 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1-sulfonamide [0122] To a stirred solution of 7-amino-1H-indole-6-carbonitrile (2.80 g, 17.8 mmol) in DCM (20 mL) were added pyridine (2.87 mL, 35.6 mmol), DMAP (1.74 g, 14.3 mmol) and 3-chloropropane-1-sulfonyl chloride (10.8 mL, 89.1 mmol) (portion wise) at 0°C and stirred at rt for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold-water (50 mL), extracted with DCM (2 x 75 mL). The combined organic layer was separated, dried over Na₂SO₄ and evaporated. The resultant crude material was purified by silica gel (100-200) column chromatography using 20% - 30% EtOAc in pet ether to afford 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1-sulfonamide (3.51 g, 11.8 mmol, 66% yield). MS-(LCMS) m/z: calcd for C₁₂H₁₂ClN₃O₂S [M+H]⁺ = 298.03, observed = 298.24. 7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile [0123] To a stirred solution of 3-chloro-N-(6-cyano-1H-indol-7-yl)propane-1- sulfonamide (3.50 g, 11.8 mmol) in DMF (35 mL) was added DBU (5.27 mL, 35.3 mmol) at 0°C stirred at rt for 16h. After consumption of starting material by TLC, the reaction mixture was quenched with cold-water (100 mL), extracted with ethyl acetate (2 x 150 mL). The combined organic layer was separated, dried over Na2SO4 and evaporated. The resultant crude material was purified by silica gel (100-200) column chromatography using 20% - 30% EtOAc in pet ether to afford 7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (2.61 g, 9.962 mmol, 85% yield). MS-(LCMS) m/z: calcd for C₁₁H₁₁N₃O₂S [M+H]⁺ = 262.06, observed = 262.30. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (br s, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 2.8, 2.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 2.0, 2.8 Hz, 1H), 3.86 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.63-2.56 (m, 2H). 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole- 6-carbonitrile [0124] In a sealed tube, to a stirred solution of 2,4-dichloro-5- (trifluoromethyl)pyrimidine (3.737 g, 17.22 mmol) in 1,2-DCE (15 mL) was added AlCl3 (1.378 g, 10.33 mmol) at RT and stirred at 80 °C for 30 min. Then was added 7-(1,1- dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (900 mg, 3.44 mmol) at 80°C and stirred at 80 °C for 16 h. After completion of reaction by TLC, the reaction mixture was cooled to 0 °C and quenched with ice water (30 mL), extracted with 2-Methyl tetrahydrofuran (2 x 150 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to get crude compound. The crude compound was purified by silica gel column chromatography using 20%-30% EtOAc in pet-ether as a mobile phase to afford partially pure compound of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2- yl)-1H-indole-6-carbonitrile, Intermediate 5, which was purified by prep-HPLC to afford Intermediate 5 (590 mg, 1.34 mmol, 39% yield). MS-(LCMS) m/z: calcd for C17H11ClF3N5O2S [M+H]⁺ = 442.03, observed = 442.35.¹H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H, NH), 9.16 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.67-2.60 (m, 2H). Intermediate 6 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxido-1,2-thiazinan-2-yl)-1H-indole- 6-carbonitrile

[0125] Intermediate 6 was synthesized similarly to Intermediate 5. MS-(LCMS) m/z: calcd for C18H13ClF3N5O2S [M+H]⁺ = 456.04, observed = 456.37. ¹H NMR and 19F- HOESY]⁺.¹H NMR (400 MHz, DMSO-d6) δ 12.44 (brs, 1H, NH), 9.14 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.76 – 3.73 (m, 1H), 3.48 – 3.32 (m, 1H), 2.40 – 2.23 (m, 2H), 2.01 – 1.83 (m, 2H). Intermediate 7

[0126] A solution of 1,4-dibromobutane (2.000 g, 9.263 mmol) in THF (5 mL) was added to activated magnesium (0.474 g, 19.5 mmol) in THF (5 mL) at 0°C and stirred at 0°C for 1.5 h. Then a solution of diethylphosphite (0.61 mL, 4.8 mmol) in THF (2 mL) was added to the reaction mixture at 0°C and stirred at RT for 16 h. After consumption of the starting material by monitoring TLC, the reaction mixture was quenched with aq. NH4Cl solution (20 mL) and filtered through a celite bed, washed with DCM (10 mL). The separated organic layer was dried over Na₂SO₄, filtered and evaporated at 35°C to afford phospholane 1-oxide, Intermediate 1 (0.300 g, 2.88 mmol, crude) as a pale-yellow gummy liquid and which was used as such for next step without further purification and analysis. (Reference: J. Molecular Catalysis A: Chemical, 2000, 160 (2), 249) Intermediate 8 Phosphinane 1-oxide

[0127] Intermediate 8 was synthesized similarly to Intermediate 7. Example 1 3-(2-(((3S,6S)-6-Methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile (FIG. 4)

[0128] To a stirred solution of 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-indole-6-carbonitrile (Intermediate 1, WO 2020/093006) (590 mg, 1.47 mmol) in NMP (6 mL) were added DIPEA (1.28 mL, 7.35 mmol) and benzyl (2S,5S)-5-amino-2- methylpiperidine-1-carboxylate HCl salt (420 mg, 1.47 mmol) and stirred at 140 °C for 16 h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)- 5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- methylpiperidine-1-carboxylate (750 mg, 1.22 mmol, 83% yield). MS-(LCMS) m/z: calcd for C28H24BrF3N6O2 [M+H]⁺ = 613.11/615.11, observed = 613.16/615.14. [0129] In a microwave vial, to an argon degassed solution of Benzyl (2S,5S)-5-((4- (7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- methylpiperidine-1-carboxylate (three batches, 3 x 100 mg, 0.163 mmol) in DMF (1 mL) were added phospholane 1-oxide, Intermediate 7 (3 x 339 mg, 3 x 3.26 mmol), K3PO4 (3 x 38 mg, 3 x 0.18 mmol), xanthphos (3 x 9.3 mg, 3 x 0.016 mmol) and Pd(OAc)₂ (3 x 3.6 mg, 3 x 0.016 mmol). The reaction mixture was heated at 150 °C in a microwave for 1h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The crude compound was purified by silica gel (100-200) column chromatography using 50-60% EtOAc as a mobile phase in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxidophospholan-1-yl)-1H-indol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-methyl-piperidine-1-carboxylate (85 mg, for 3 batches, 0.13 mmol, 27% yield) as a pale-yellow sticky liquid. MS (LCMS) m/z: calcd for C32H32F3N6O3P [M+H]⁺ = 637.22, observed = 637.42. [0130] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-cyano-7-(1- oxidophospholan-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methyl- piperidine-1-carboxylate (150 mg, 0.236 mmol) in ethyl acetate (2 mL) was added 10% palladium on carbon (50% moisture) (70 mg) and stirred under hydrogen balloon atmosphere at room temperature for 3 days. After completion of reaction by monitoring TLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was concentrated to get crude material, which was purified by prep HPLC to afford3-(2-(((3S,6S)- 6-Methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1-oxidophospholan-1- yl)-1H-indole-6-carbonitrile, Example 1 (36.8 mg, 0.0732 mmol, 31%). [0131] Prep. HPLC method: Column/dimensions: X–bridge PHENYL (19*250*5µm); Mobile phase A: 10mm Ammonium bicarbonate in water; Mobile phase B: Acetonitrile Gradient (Time/%B): 0.01/30, 1/30, 10/55, 14/59, 14.1/100, 17/100, 20/30, 20.1/30. Flow rate: 18 ml/min solubility: Acetonitrile + THF+WATER. [0132] MS-(LCMS) m/z: calcd for C24H26F3N6OP [M+H]⁺ = 503.19, observed = 503.52. ¹H NMR (400 MHz, , 90 °C VT, DMSO-d6) δ 8.57 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.61 (dd, J = 3.0, 8.4 Hz 1H), 7.43 (d, J = 8.4 Hz, 1H, NH), 3.92 – 3.78 (m, 1H), 3.20 – 3.13 (m, 1H), 2.50 – 2.58 (m, 1H), 2.45 – 2.35 (m, 3H), 2.30 – 2.07 (m, 6H), 2.07 – 1.95 (m, 1H), 1.71 – 1.64 (m, 1H), 1.55 – 1.39 (m, 1H), 1.18 – 1.06 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H). LCMS purity: 98.47%; HPLC purity: 99.36%. [0133] The examples in Table 2 were prepared using methods similar to those described for the synthesis of Example 1. Table 2

Example 8 3-(5-Chloro-2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile (FIG. 5)

[0134] To a stirred solution of benzyl (2S,5S)-5-amino-2-methylpiperidine-1- carboxylate HCl salt (0.689 g, 2.42 mmol) in 1,4-dioxane (12 mL) was added DIPEA (2.10 mL, 12.1 mmol), followed by adding Intermediate 2 (1.21 g, 2.42 mmol) and stirred at 120 °C for 16 h. After consumption of starting material, the reaction mixture was evaporated under reduced pressure to obtain crude compound. Crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(7-bromo- 6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-chloropyrimidin-2-yl)amino)- 2-methyl-piperidine-1-carboxylate (0.8 g, 1.13 mmol, 47% yield). MS (LCMS) m/z: calcd for C₃₃H₃₈BrClN₆O₃Si [M+H]⁺ = 709.16/711.16/712.17 (75%/100%/36%), observed = 709.53/711.54/712.56 (71%/100%/36%). LCMS purity: 93.35%; ¹H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 – 7.25 (bs, 5H), 5.99 (s, 2H), 5.54 (d, J = 7.6 Hz, 1H), 5.18-5.09 (m, 2H), 4.64 – 4.54 (m, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.25-4.13 (m, 1H), 3.63 (t, J = 8.0 Hz, 2H), 3.26 (dd, J = 2.4, 14 Hz, 1H), 2.10 – 1.90 (m, 2H), 1.53 – 1.44 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 0.98 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). [0135] To a stirred solution of Benzyl (2S,5S)-5-((4-(7-bromo-6-cyano-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-5-chloropyrimidin-2-yl)amino)-2-methyl- piperidine-1-carboxylate (two batches, 2 x 0.400 g, 0.563 mmol) in THF (4 mL) was added ethylene diamine (2 x 0.11 mL, 2 x 1.69 mmol) and TBAF (2 x 3.38 mL, 2 x 3.38 mmol). The reaction mixture was stirred at 70 °C for 1 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was separated, dried over Na₂SO₄, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 40-50% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-chloropyrimidin- 2-yl)amino)-2-methylpiperidine-1-carboxylate (0.570 g, 0.983 mmol, 87% yield). MS- (LCMS) m/z: calcd for C27H24BrClN6O2 [M+H]⁺ = 579.08/581.08/582.08 (77%/100%/31%), observed = 579.19/581.21/583.20 (77%/100%/30%). LCMS purity: 98.85%; ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H, NH), 8.49 (d, J =8.4 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.34 – 7.20 (bs, 5H), 5.48 (d, J = 7.2 Hz, 1H, NH), 5.15 – 5.07 (m, 2H), 4.62 – 4.56 (m, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.23 – 4.14 (m, 1H), 3.24 (dd, J = 2.4, 14.0 Hz, 1H), 2.06 – 1.91 (m, 2H), 1.50 – 1.42 (m, 1H), 1.24 (d, J =6.8 Hz, 3H). [0136] In a microwave vial, to an argon degassed solution of Benzyl (2S,5S)-5-((4- (7-bromo-6-cyano-1H-indol-3-yl)-5-chloropyrimidin-2-yl)amino)-2-methylpiperidine-1- carboxylate (five batches, 5 x 100 mg, 5 x 0.172 mmol) in DMF (1 mL) were added phospholane 1-oxide, Intermediate 7 (5 x 359 mg, 5 x 3.45 mmol), K₃PO₄ (5 x 40 mg, 5 x 0.19 mmol), xantphos (5 x 10 mg, 5 x 0.017 mmol) and Pd(OAc)2 (3.9 mg, 5 x 0.017 mmol), stirred at 150 °C in a microwave reactor for 1 h. After consumption of starting material, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was dried over Na₂SO₄ and evaporated to get crude material. The crude compound was purified by silica gel column chromatography using 90-100% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((5-chloro-4-(6-cyano-7-(1-oxidophospholan-1-yl)- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate, Intermediate 9 (180 mg, 0.298 mmol, 35% yield). MS-(LCMS) m/z: calcd for C₃₁H₃₂ClN₆O₃P [M+H]⁺ = 603.20, observed = 603.55. LCMS purity: 94.25%; ¹H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H, NH), 8.74 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 7.58 (dd, J =3.2, 8.0 Hz, 1H), 7.34 –7.20 (bs, 5H), 5.47 (d, J = 7.2 Hz, 1H), 5.16 – 5.05 (m, 2H), 4.62 – 4.52 (m, 1H), 4.31 (d, J = 14.0 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.23 (dd, J = 2.4, 14.0 Hz, 1H), 2.50 – 2.17 (m, 8H), 2.10 – 1.87 (m, 2H), 1.50 – 1.40 (m, 1H), 1.24 (d, J =6.8 Hz, 3H). [0137] To a stirred degassed solution of Intermediate 9 (two batches, 2 x 40 mg, 0.066 mmol) in DCM (0.4 mL), Et₃N (2 x 4 µL, 2 x 0.03 mmol), Et₃SiH (2 x 53 µL, 2 x 39 mg, 2 x 0.33 mmol), Pd(OAc)₂ (2 x 3.0 mg, 2 x 0.013 mmol) was added and stirred at RT for 1.5 h. After consumption of starting material, reaction mixture was evaporated under reduced pressure. The crude compound was purified by prep-HPLC to afford 3-(5-Chloro-2-(((3S,6S)- 6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophospholan-1-yl)-1H-indole-6- carbonitrile, Example 8 (18 mg, 0.038 mmol, 29% yield). [0138] Prep. HPLC purification conditions: Column/dimensions: YMC C18(19*250*5µm); Mobile Phase A :10 mM ABC in water; Mobile phase B: Acetonitrile Gradient (Time/%B): 0.01/15, 1/15, 10/45, 14.5/45, 14.6/100, 18/100, 18.1/15, 21/15. Flow rate: 18 ml/min. Solubility: THF+ACN. [0139] MS-(LCMS) m/z: calcd for C₂₃H₂₆ClN₆OP [M-H]- = 467.16, observed = 467.38. LCMS purity: 98.87%; HPLC purity: 97.05%; ¹H NMR (400 MHz, DMSO-d₆) (D₂O Exchange-VT at 90 °C) δ 8.88 (dd, J = 1.6, 8.4 Hz, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J = 3.2, 8.4 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.34 – 3.16 (m, 1H), 2.61 – 2.52 (m, 1H), 2.44 – 2.34 (m, 3H), 2.30 – 2.21 (m, 6H), 2.10 – 2.03 (m, 1H), 1.75 – 1.66 (m, 1H), 1.48 – 1.37 (m, 1H), 1.26 – 1.16 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). Example 13 3-(5-Methyl-2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile

[0140] In a microwave vial, to an argon degassed solution of Intermediate 9 (two batches, 2 x 40 mg, 2 x 0.066 mmol) in 1,4-dioxane/H2O (1.0 mL) were added methylboronic acid (2 x 40 mg, 2 x 0.33 mmol), Cs2CO3 (2 x 65 mg, 2 x 0.20 mmol), Catacxium (2 x 24 mg, 2 x 0.066 mmol) and Pd(OAc)₂ (2 x 7.4 mg, 2 x 0.033 mmol) at rt. The reaction mixture was stirred at 100 °C in a microwave reactor for 2 h. After consumption of starting material, the reaction mixture was diluted with ethyl acetate (10 mL), filtered through celite pad, filtrate concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography using 2-3% methanol in DCM to afford Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxidophospholan-1-yl)-1H-indol-3-yl)-5-methylpyrimidin-2- yl)amino)-2-methylpiperidine-1-carboxylate (60 mg, 0.10 mmol, 78% yield). MS-(LCMS) m/z: calcd for C₃₂H₃₅N₆O₃P [M+H]⁺ = 583.25, observed = 583.55. LCMS purity: 88.50%. [0141] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-cyano-7-(1- oxidophospholan-1-yl)-1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-methylpiperidine- 1-carboxylate (two batches, 2 x 30 mg, 2 x 0.051 mmol) in DCM (0.4 mL) were added Et₃N (2 x 2.9 µL, 2 x 0.021 mmol), Et3SiH (2 x 41 µL, 2 x 30 mg, 2 x 0.26 mmol) and Pd(OAc)2 (2 x 2.3 mg, 2 x 0.010 mmol) at rt. The reaction mixture was stirred at 45 °C for 1.5 h. After consumption of starting material by TLC, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by prep-HPLC to afford3-(5-Methyl-2-(((3S,6S)- 6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophospholan-1-yl)-1H-indole-6- carbonitrile, Example 13 (7.0 mg, 0.015 mmol, 15% yield). [0142] MS-(LCMS) m/z: calcd for C₂₄H₂₉N₆OP [M+H]⁺ = 449.21, observed = 449.57. LCMS purity: 97.42%; HPLC purity: 98.66%; Chiral purity: 98.84; ¹H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H, NH), 8.91 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.53 (br s, 1H, NH), 3.81 – 3.69 (m, 1H), 3.20 – 3.11 (m, 1H), 2.50 – 2.30 (m, 4H), 2.28 (s, 3H), 2.30 – 1.96 (m, 7H), 1.70 – 1.60 (m, 1H), 1.43 – 1.30 (m, 1H), 1.19 – 1.06 (m, 1H), 1.04 (d, J = 6.2 Hz, 3H). [0143] The examples in Table 3 were prepared using methods similar to those described for the syntheses of Examples 8 and 13. Table 3

Example 18 N-(3,5-dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide (FIG. 6)

[0144] To a stirred solution of Intermediate 4 (800 mg, crude) in DMF (10 mL) were added DIPEA (2.21 mL, 12.7 mmol), HOBt (512 mg, 3.79 mmol) and EDC-HCl (720 mg, 3.76 mmol) at 0 °C. The reaction mixture was stirred for 10 min and then was added 3,5- dimethylisoxazol-4-amine (420 mg, 3.75 mmol) at room temperature. The reaction mixture was stirred for 16h at room temperature. After consumption of starting materials by TLC, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4 and evaporated to get crude compound. The crude compound was purified by silica gel (100-200) column chromatography using 70-80% EtOAc in pet-ether as an eluent to afford N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide (300 mg , 0.669 mmol, 35% over 2 steps). MS-(LCMS) m/z: calcd for C₁₉H₁₅F₃N₆O₂S [M+H]⁺ = 449.09, observed = 449.24. ¹H NMR (400 MHz, DMSO-d₆) δ 12.72 (br s, 1H, NH), 9.98 (s, 1H), 8.99 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 2.67 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H). [0145] To a stirred solution of N-(3,5-dimethylisoxazol-4-yl)-3-(2-(methylthio)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide (300 mg, 0.669 mmol) in 1,2-DME (8 mL) was added m-CPBA (~70%, 412 mg, 1.67 mmol) at- 40 °C and stirred at -40 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na2SO4 and evaporated to afford N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6- carboxamide (400 mg, crude used for next step without purification). MS-(LCMS) m/z: calcd for C19H15F3N6O4S [M+H]⁺ = 481.08, observed = 481.26. [0146] To a stirred solution of N-(3,5-dimethylisoxazol-4-yl)-3-(2- (methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6- carboxamide (400 mg, crude) in THF (5 mL) were added DIPEA (0.76 mL, 4.4 mmol), benzyl (2S,5S)-5-amino-2-methylpiperidine-1-carboxylate HCl salt (191 mg, 0.669 mmol) and stirred at rt for 1h. After consumption of starting material by TLC, the reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 50 mL). The organic layer was separated, dried over Na₂SO₄, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 40-50% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-((3,5- dimethylisoxazol-4-yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate (60 mg, 0.092 mmol, 14% yield over two steps). MS-(LCMS) m/z: calcd for C₃₂H₃₁F₃N₈O₄ [M+H]⁺ = 649.24, observed = 649.57. [0147] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-((3,5-dimethylisoxazol-4- yl)carbamoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2- methylpiperidine-1-carboxylate (60 mg, 0.092 mmol) in DCM (1 mL) was added BBr3 (1M in DCM (0.5 mL) at 0 °C and stirred at 0 °C for 30 min. The reaction mixture was quenched with ice water (1 mL) and evaporated. Crude was purified by prep HPLC to afford N-(3,5- dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, Example 18 (7.0 mg, 0.014 mmol, 15% yield). [0148] Prep-HPLC method: Column/dimensions: X BRIDGE PHENYL (19*250*5um); Mobile phase A: 10 MM ABC in water (aq); Mobile phase B: Acetonitrile (org); Gradient (Time/%B): 0/25,1/25,09/55,11.8. /55,11.9/100,14.8/100,14.9/25,17/25. Flow rate: 19 mL/min; Solubility: Acetonitrile+ THF+WATER. [0149] MS-(LCMS) m/z: calcd for C₂₄H₂₅F₃N₈O₂ [M-H]- = 513.21, observed = 513.32. ¹H NMR (400 MHz, DMSO-d6) VT at 90 °C δ 12.72 (br s, 1H, NH), 9.61 (s, 1H, NH), 8.81 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H, NH), 3.92 – 3.83 (m, 1H), 3.22 – 3.15 (m, 1H), 2.60 – 2.47 (m, 2H), 2.33 (s, 3H), 2.16 (s, 3H), 2.07 – 2.00 (m, 1H), 1.72 – 1.64 (m, 1H), 1.55 – 1.41 (m, 1H), 1.20 – 1.10 (m, 1H), 1.00 (d, J = 6.0 Hz, 3H). LCMS purity: 98.68%, UPLC purity 97.62%. [0150] The examples in Table 4 were prepared using methods similar to those described for the synthesis of Example 18. Table 4

Example 28 N-(3,5-dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxamide (FIG. 7)

[0151] To a stirred solution of 1H-indole-6-carboxylic acid (two batches, 2 x 5.00 g, 2 x 31.0 mmol) in DMF (60 mL) were added DIPEA (2 x 16.2 mL, 93.0 mmol) and HATU (2 x 14.1 g, 37.2 mmol). The reaction mixture was stirred for 10 min, then added 3,5- dimethylisoxazol-4-amine (2 x 3.48 g, 31.0 mmol). The reaction mixture was stirred at rt for 16 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (250 mL) and extracted with ethyl acetate (2x 100 mL), solvent was evaporated to get crude compound. The combined crude compound was purified by silica gel (100-200) column chromatography using 70-80% EtOAc in pet-ether to afford N-(3,5-dimethylisoxazol- 4-yl)-1H-indole-6-carboxamide (10.0 g, 39.2 mmol, 63% yield). MS-(LCMS) m/z: calcd for C14H13N3O2 [M+H]⁺ = 256.10, observed = 256.22. [0152] In a sealed tube, to a stirred solution of 2,4-dichloro-5- (trifluoromethyl)pyrimidine (15.176 g, 69.95 mmol) in DCE (60 mL) was added AlCl₃ (4.694 g, 35.21 mmol) at room temperature and stirred at 80 °C for 30 min. Then was added N-(3,5- dimethylisoxazol-4-yl)-1H-indole-6-carboxamide (6.000 g, 23.50 mmol) to the above reaction mixture at 80 °C and stirred for 16 h. After completion of reaction by TLC, the reaction mixture was quenched with ice cold water (60 mL), extracted with 10% THF in ethyl acetate (2 x 300 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and evaporated to get semi pure compound. The crude compound was purified by silica gel column chromatography using 30% EtOAc in pet-ether to afford partially pure 3-(2-chloro-5- (trifluoromethyl) pyrimidin-4-yl)-N-(3,5-dimethylisoxazol-4-yl)-1H-indole-6-carboxamide which was purified by prep-HPLC to afford pure desired product (700 mg, 1.61 mmol, 7% yield). Structure was further confirmed by ¹⁹F HOESY. MS-(LCMS) m/z: calcd for C₁₉H₁₃ClF₃N₅O₂ [M+H]⁺ = 436.06, observed = 436.34. ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 9.83 (s, 1H), 9.08 (s, 1H), 8.43 (d, J = 8.80 Hz, 1H)), 8.25 (s, 1H)), 8.20 (s, 1H), 7.88 (d, J = 8.80 Hz, 1H)), 2.34 (s, 3H), 2.16 (s, 3H). [0153] Prep-HPLC method: Column/dimensions: X-BRIDGE-C18 (19*250*5um); Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: CAN; Gradient (Time/%B): 0/35, 3/35, 15/75, 18/75, 18.1/100, 20/100, 20.1/35, 22/35; Flow rate: 17ml/min. Solubility: WATER+THF+ACN. [0154] To a stirred solution of 3-(2-chloro-5-(trifluoromethyl) pyrimidin-4-yl)-N- (3,5-dimethylisoxazol-4-yl)-1H-indole-6-carboxamide (700 mg, 1.61 mmol) in NMP (10 mL) were added DIPEA (1.40 mL, 8.05 mmol), benzyl (2S,5S)-5-amino-2-methylpiperidine-1- carboxylate hydrochloride (458 mg, 1.61 mmol) and stirred at 120 °C for 16h. After consumption of starting material, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 20-30% EtOAc in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-((3,5- dimethylisoxazol-4-yl)carbamoyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 2-methylpiperidine-1-carboxylate (500 mg, 0.772 mmol, 48% yield). MS-(LCMS) m/z: calcd for C₃₃H₃₂F₃N₇O₄ [M+H]⁺ = 648.25, observed = 648.54. [0155] To a stirred solution of Benzyl (2S,5S)-5-((4-(6-((3,5-dimethylisoxazol-4- yl)carbamoyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylpiperidine- 1-carboxylate (500 mg, 0.772 mmol) in DCM (5 mL) was added BBr₃ (1M in DCM, 3.9 mL, 3.9 mmol) and stirred at room temperature for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated to get crude material, which was purified by prep-HPLC to afford N-(3,5- dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxamide, Example 28 (200 mg, 0.389 mmol, 50%). [0156] Prep-HPLC Method: Column/dimensions: X –bridge PHENYL ((19*250*5µm); Mobile phase A: 10mM ABC in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0.01/20, 1/20, 10/40, 17/40, 17.1/100, 21/100, 21.1/20, 23/20; Flow rate: 18 ml/min; Solubility: Acetonitrile + THF+WATER. [0157] MS-(LCMS) m/z: calcd for C25H26F3N7O2 [M+H]⁺ = 514.21, observed = 514.29. ¹H NMR (400 MHz, DMSO-d6) VT at 90 °C; δ 11.81 (br s, 1H, NH), 9.47 (s, 1H, NH), 8.53 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H, NH), 3.96 – 3.83 (m, 1H), 3.21 – 3.15 (m, 1H), 2.60 – 2.48 (m, 2H), 2.13 (s, 3H), 2.15 (s, 3H), 2.10 – 2.00 (m, 1H), 1.72 – 1.66 (m, 1H), 1.52 – 1.42 (m, 1H), 1.20 – 1.07 (m, 1H), 1.00 (d, J = 6.00 Hz, 3H). LC-MS purity: 97.11%; HPLC purity: 98.63%. [0158] The examples in Table 5 were prepared using methods similar to those described for the synthesis of Example 28. Table 5

Example 32 (S)-7-(1,1-dioxidoisothiazolidin-2-yl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) pyrimidin-4-yl)-1H-indole-6-carbonitrile

[0159] To a stirred solution of Intermediate 5 (120 mg, 0.272 mmol) in NMP (1.21 mL) were added DIPEA (237 µL, 1.36 mmol), tert-butyl (S)-3-aminopiperidine-1-carboxylate (54.4 mg, 0.272 mmol) and stirred at 140 °C for 16 h. After consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 15 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 50-70% EtOAc in pet-ether to afford tert-butyl (S)-3-((4-(6-cyano-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (113 mg, 0.186 mmol, 69% yield). MS-(LC-MS) m/z: calcd for C27H30F7N7O4S [M+H]⁺ = 606.20, observed = 606.58. [0160] To a stirred solution of tert-butyl (S)-3-((4-(6-cyano-7-(1,1- dioxidoisothiazolidin-2-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (120 mg, 0.198 mmol) in DCM (3 mL) was added TFA (76 µL, 0.99 mmol) at 0 °C and stirred at 0 °C for 30 min. After consumption of starting material by TLC, the reaction mixture was concentrated under vac. The obtained crude material was purified by combi-flash (C-18) using 0.1% ABC buffer to afford (S)-7-(1,1- dioxidoisothiazolidin-2-yl)-3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) pyrimidin-4-yl)- 1H-indole-6-carbonitrile, Example 32 ( 22 mg , 0.044 mmol, 22% yield). [0161] MS-(LCMS) m/z: calcd for C₂₂H₂₂F₃N₇O₂S [M-H]- = 504.15, observed = 504.25. LCMS purity: 98.78%; UPLC purity: 98.60%; ¹H NMR (400 MHz, DMSO-d6, D2O Exchange-VT at 90 °C) δ 8.58 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 3.95 (d, J = 6.6 Hz, 2H), 3.98 – 3.89 (m, 1H), 3.56 (d, J = 7.4 Hz, 2H), 3.10 (dd, J = 3.2, 12.0 Hz, 1H), 2.86 – 2.77 (m, 1H), 2.74 – 2.63 (m, 2H), 2.60 – 2.50 (m, 2H), 2.02 – 1.94 (m, 1H), 1.74 – 1.64 (m, 1H), 1.62 – 1.42 (m, 2H). [0162] The examples in Table 6 were prepared using methods similar to those described for the synthesis of Example 32. Table 6

Example A [0163] CDK7 enzymatic inhibition activity was evaluated at Reaction Biology Corporation using the “HotSpot” assay platform as published in the literature (Anastassiadis T. et al., Nat Biotechnol. 2011, 29(11):1039-45). The data is provided in Table 7. [0164] The effect of the CDK7 inhibitor to inhibit the growth of MCF7 and OVCAR3 cells was evaluated through the 6 day-time period of viability assay (Table 7). Briefly, the candidate cell lines were plated in 96 well plate at the following density of cells respectively, 3000-3500 cells/well for MCF7, 3000 cells/well for OVCAR-3. After 24 hours, the cells were treated with various concentrations of the compound (diluting the compound 1:3 in DMSO for 10 points). DMSO solvent without compound served as a control. After 6 days of incubation at 37 °C, 5% CO2 incubator, cells were analyzed for the viability using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat# G7570). All viability assays were performed in duplicate, and Luminescence was read using an Envision (Perkin Elmer, USA). Nonliner regression and sigmoidal dose-response curves are used to calculate EC50 with Graphpad Prism software. [0165] The results of these assays are shown in Table 7 where “A” represents a measured CDK7/cyclin H IC50 of less than 10 nM or OVCAR3 CGT EC50 of less than 100 nM or MCF7 CGT EC₅₀ of less than 100 nM; “B” represents a measured CDK7/cyclin H IC₅₀ of between 10 nM and less than 100 nM or OVCAR3 CGT EC50 of between 100 nM and less than 1 μΜ or MCF7 CGT EC50 of between 100 nM and less than 1 μΜ; “C” represents a measured CDK7/cyclin H IC₅₀ of greater than or equal to 100 nM or OVCAR3 CGT EC₅₀ of greater than or equal to 1 μΜ or MCF CGT EC₅₀ of greater than or equal to 1 μΜ, and “NT” represents that the specified compound was not tested in the specified assay. Table 7

[0166] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR^5a, or NR^5aR^5b; R³ is substituted or unsubstituted C3-C8 cycloalkyl or C3-C8 heterocyclyl, wherein the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶; R⁴ is halogen, CN, alkyl, cycloalkyl, -NR⁷R⁸, OR⁶, -CO2R⁶, or -C(O)-NR⁷R⁸; each R^5a, R^5b, and R⁶ is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; R⁷ and R⁸ are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; wherein the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR⁶, CN, alkyl, NHR^5a, or NR^5aR^5b; or R⁷ and R⁸, along with the N to which they are connected, are taken together to form an unsubstituted or substituted C3-C8 heterocyclyl wherein the substituted C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR^5a, NR^5aR^5b, or OR⁶; X is N or CR⁹; Q₁ is C or N; Q₂ is CH or N; Q3 is CH, N, or NH; provided that when Q1 is N, then Q3 is N; R⁹ is hydrogen,

each R¹⁰ is independently hydrogen, alkyl, haloalkyl, or cycloalkyl; Y and Z are independently N or CH, and each n is independently 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is hydrogen.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is halogen.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is CN.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is alkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is alkoxy.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is haloalkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is cycloalkyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is NHR^5a.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is NR^5aR^5b.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein at least one of R¹ and R² is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R³ is substituted C₃-C₈ cycloalkyl.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R³ is unsubstituted C3-C8 cycloalkyl.

14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R³ is substituted C3-C8 heterocyclyl.

15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R³ is unsubstituted C₃-C₈ heterocyclyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R³ is piperidinyl, methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxaazaspirodecyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is halogen.

18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is CN.

19. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is alkyl.

20. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is cycloalkyl.

21. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is -NR⁷R⁸.

22. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is OR⁶.

23. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is -CO2R⁶.

24. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R⁴ is -C(O)-NR⁷R⁸.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R⁴ is CN, N,N-dimethylamido, N,N-diethylamido,

,

.

26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R^5a, R^5b, and R⁶ is hydrogen.

27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R^5a, R^5b, and R⁶ is alkyl.

28. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R^5a, R^5b, and R⁶ is haloalkyl.

29. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one of R^5a, R^5b, and R⁶ is cycloalkyl.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

31. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is hydrogen.

32. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is substituted alkyl.

33. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is unsubstituted alkyl.

34. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is substituted cycloalkyl.

35. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein at least one of R⁷ and R⁸ is unsubstituted cycloalkyl.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is N.

37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X is CR⁹.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q₁ is C.

39. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Q1 is N and Q3 is N.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q₂ is CH.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein Q2 is N.

42. The compound of any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q₃ is CH.

43. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Q3 is N.

44. The compound of any one of claims 1 to 38, 40 or 40, or a pharmaceutically acceptable salt thereof, wherein Q3 is NH.

45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R⁹ is hydrogen.

46. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein

47. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein

48. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein

49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein

.

50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is N.

51. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein at least one of Y and Z is CH.

52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, with the proviso that, when each R¹⁰ is independently methyl or ethyl, Formula (I) i

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected is selected from ,

,

,

, , ,

54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

55. A method for treating a cancer or a tumor comprising administering an effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 54, to a subject having the cancer or the tumor.

56. The method of claim 55, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas.

57. Use of an effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically active salt thereof, or a pharmaceutical composition of claim 54, in the manufacture of a medicament for treating a cancer or a tumor.

58. The use of claim 57, wherein the cancer or the tumor is selected from urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas.