Inhibitors of CDK2

Abstract

The present invention is directed to the compounds of Formula (A) - inhibitors of CDK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with CDK2, such as cancer. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting CDK2, methods of treating diseases or disorders associated with CDK2, and methods of synthesizing these compounds.

Description

Inhibitors of CDK2 FIELD OF INVENTION

[0001] The present invention is directed to inhibitors of CDK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with CDK2, such as autoimmune disease, Alzheimer disease, and coronavirus infection by inducing durable responses. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting CDK2, methods of treating diseases or disorders associated with CDK2, and methods of synthesizing these compounds. BACKGROUND

[0002] Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation.CDK2andits regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.

[0003] Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with roles in inactivating phosphorylation of the RB1 (pRb) tumor suppressor family and in controlling both G1 / S and G2 / M transitions. In addition to promoting cell cycle progression, CDK2 has been described to play a positive role in cell cycle arrest in the DNA damage response (DDR), in particular at the G2 / M checkpoint.

[0004] Over the past decade, the clinical development of CDK4 / 6 inhibitors has led to practice-changing outcomes in breast cancer treatment. This has energized the field and increased interest in therapeutically targeting other members of the CDK family. CDK2 was an early focus for anticancer drug discovery in the 1990s but the initial excitement was dampened owing to off-target effects of the early drugs. Interest in CDK2 inhibition has now reignited with the identification of more functions for CDK2 that impact cancer biology and the possibility of developing inhibitors with greater specificity to CDK2.

[0005] The broad functionality of CDK2 in proliferative and pro-survival pathways highlights it as an ideal target for mechanism-based and low-toxicity therapeutic strategies in cancer treatment. In addition to the roles and potential avenues for intervention discussed above, there is developing evidence that CDK2 activity also impacts cell differentiation and the adaptive immune response. Importantly, CDK2 inhibition appears to have most potential in particular molecular landscapes or cancer subtypes

[0006] All of the CDK2 inhibitors identified to date are nonselective leading to a promiscuous mode of action. In this context, it is important to note that specific cancers can benefit from the selective inhibition of CDK2 in combination with other CDKs, which broadens the spectrum for drug development. For example, endocrine-resistant cancers could benefit from a double blockade of CDK2 / CDK4 action because these cancers are so highly dependent on the G1 / S axis. Cancers that show cyclin E1 amplification and CDK2 dependency could benefit from CDK2 / CDK7 blockade, to directly inhibit CDK2 and then prevent the activation of residual CDK2 via CDK7 inhibition. There is already evidence that this approach will have some success because combination of CDK2 and PI3K inhibitors have demonstrated high in vitro efficacy in colorectal cancer cell lines

[0075] , and the combination of CDK1 / CDK2 inhibitors (e.g., roscovitine) with PI3K was synthetically lethal in human glioma xenograft models

[0076] . Consequently, the availability of a broad spectrum of inhibitors of either high specificity or selective targeting would be a major step forward in the search for new, effective, targeted cancer therapies, especially in those subtypes with CDK2 dependency, such as MYC-amplified cancers. Highly specific CDK2 inhibitors will bring additional benefit in defining further unique roles of CDK2 in cancer development, which will aid the ongoing identification of cancer subtypes that are susceptible to CDK2 inhibition. SUMMARY

[0007] A first aspect of the invention relates to compounds of Formula (A):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: the bonds are selected from single bonds and double bonds; R0is selected from H , and C1-C6 alkyl optionally su A is selected from CR4R5, O, SO2, and NR4; E is selected from C, CH and N, provided that when bonds are single bonds, then E is N or CH, and when bonds are double bonds, then E is C; each G is independently selected from CH and N; X is selected from and R9; Y is selected from CH2, provided that Y is N or CH if the bondsare double bonds and Y is CH2if the bonds are single bonds; Z is selected from a bond, NH, and -CH2-; R1is selected from H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; R2is selected from H, halogen, -CN, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; or R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl, or 3-10 membered heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with one or more substitutients independently selected from halogen, OH, C1-C6alkyl; or R1and R2together form =O; R3is selected from C1-C6 alkyl, -N(R7)2, 3-8 membered cycloalkyl, aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from C1-C6 alkyl, -NH2, -OH, -CN, halogen, oxo; R4is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)-C1-C6 alkyl, - C(O)OC1-C6alkyl, -C(O)NHC1-C6alkyl, -OC(O)NHC1-C6alkyl, -S(O)2-C1-C6alkyl, and aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-C6 alkyl)2, C1- C6alkoxy; or R3and R4together with the atom to which they are attached and any intervening atoms, form a cycle; or R3and R8together with the atoms to which they are attached and any intervening atoms, form a heterocyclyl or heteroaryl; R5is selected from H, halogen, oxo, -OH, -NH2 -CN, C1-C6 alkyl, C1-C6 alkoxy, - OC(O)N(R7)2; each R6is independently selected from halogen, OH, C1-C6alkyl, -N(R7)2, - N(R7)COR4, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, OH, CN; or two R6together with atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6alkyl; or two R6form =O; each R7is independently selected from H, C1-C6 alkyl, -C(O)C1-C6 alkyl, C1-C6 alkyl-OC(O)NH-(C1-C6 alkanediyl)-, C1-C6-alkanediyl-O-C1-C6 alkyl; each R8is independently selected from halogen, OH, CN, C1-C6alkyl, heterocyclyl, heteroaryl; R9is selected from C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH(C1-C6 alkyl), - S(=O)(=NH)(C1-C6alkyl), 5-10 membered monocyclic or bicyclic heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, wherein heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from -OH, - CN, halogen, C1-C6alkyl and C1-C6alkyl-heterocyclyl; orR8and R9together with atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6alkyl, wherein alkyl is optionally substituted with heterocyclyl; n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; k is an integer selected from 0, 1, and 2; r is an integer selected from 0 and 1.

[0008] A more preferred aspect of the invention relates to a compound of Formula (I): , or a pharmaceuticallyor tautomer thereof, wherein: the bonds are selected from single bonds and double bonds; A is selected from CR4R5and NR4; E is selected from C and N, provided that when bonds are single bonds, then E is N, and when bonds are double bonds, then E is C; R1is selected from H, halogen, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; R2is selected from H, halogen, -CN, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; orR1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl; R3is selected from C1-C6 alkyl, -NH2, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from C1-C6 alkyl, -NH2, -OH, -CN, halogen, oxo; R4is selected from H, C1-C6alkyl, C3-C10cycloalkyl, -C(O)OC1-C6alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-C6 alkyl)2, C1-C6 alkoxy; R5is selected from H, halogen, oxo, -OH, -NH2-CN, C1-C6alkyl, C1-C6alkoxy.

[0009] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0010] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0011] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0012] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0013] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers,tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0014] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0015] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0016] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0017] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] The present invention provides inhibitors of CDK2 that are therapeutic agents in the treatment of diseases and disorders.

[0019] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of CDK2. The present disclosure also provides agents with novel mechanisms of action toward CDK2 in the treatment of various types of diseases.

[0020] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0021] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RB1); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).

[0024] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in Synthesis of the Representative Examples of the compound).

[0025] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part).

[0026] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0027] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0029] Other features and advantages of the disclosure will be apparent from the following detailed description and claims DETAILED DESCRIPTION

[0030] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with the CDK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0031] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions

[0032] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0033] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0034] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, – OH, –CN, –COOH, –CH2CN, –O-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, –O-(C2-C6) alkenyl, –O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, –OH, –OP(O)(OH)2, –OC(O)(C1-C6) alkyl, –C(O)(C1-C6) alkyl, – OC(O)O(C1-C6) alkyl, –NH2, –NH((C1-C6) alkyl), –N((C1-C6) alkyl)2, –NHC(O)(C1-C6) alkyl, –C(O)NH(C1-C6) alkyl, –S(O)2(C1-C6) alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0035] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0036] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0037] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, –H, -halogen, –O-(C1-C6)alkyl, (C1-C6)alkyl, – O-(C2-C6)alkenyl, –O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, –OH, – OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6) alkyl, –OC(O)O(C1-C6)alkyl, –NH2, – NH((C1-C6)alkyl), –N((C1-C6)alkyl)2, –S(O)2-(C1-C6) alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0038] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4- b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro- 2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2- a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2- a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H- pyrido[2,3-b]puyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H- spiro[cyclopropane-1,8’-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9’-onyl.

[0039] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0040] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl (iso-propyl), isobutyl (iso-butyl), sec-butyl, tert-butyl, isopentyl (iso-pentyl), neopentyl (neo-pentyl), and isohexyl (iso-hexyl).

[0041] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0042] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso- butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

[0043] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0044] The term “alkylene”, “alkylenyl” or “alkanediyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1- C6 alkylene. An alkylene may further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, - CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0045] “Cycloalkyl” means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0046] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0047] The term “aromatic” means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[0048] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0049] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0050] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

[0051] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, oridentical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0052] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0053] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, DMSO, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0054] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0055] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with2H and14C). Deuterated (i.e.,2H or D) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0056] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0057] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0058] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0059] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0060] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0061] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0062] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0063] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0064] The term “salt’ refers to pharmaceutically acceptable salts.

[0065] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0066] “CDK2 inhibitor” as used herein refer to compounds of Formula A and / or compositions comprising a compound of Formula A which inhibits CDK2.

[0067] “CDK2 inhibitor” as used herein refer to compounds of Formula I and / or compositions comprising a compound of Formula I which inhibits CDK2.

[0068] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions comprising compounds of Formula I (and / or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder ordisease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Present Disclosure

[0069] The compounds of the present invention are represented by general Formula (A): , or a pharmaceuticallyor tautomer thereof, wherein R0, R1, R2, R8, E, X, Y, Z and k are as described herein.

[0070] It is understood that, for a compound of Formula (A), R0, R1, R2, R8, E, X, Y, Z and k can each be, where applicable, selected from the groups described herein, and any group described herein for any R0, R1, R2, R8, E, X, Y, Z and k can be combined, where applicable, with any group described herein for one or more of the remainders of R0, R1, R2, R8, E, X, Y, Z and k.

[0071] In some embodiments, the present invention provides compounds of Formula (A- 0), 0), and salts,tautomers thereof, wherein R0, R1, R2, R3, R8, E, Y, Z and k are as described herein.

[0072] It is understood that, for a compound of Formula (A-0), R0, R1, R2, R3, R8, E, Y, Z and k can each be, where applicable, selected from the groups described herein, and any group described herein for any R0, R1, R2, R3, R8, E, Y, Z and k can be combined, where applicable, with any group described herein for one or more of the remainders of R0, R1, R2, R3, R8, E, Y, Z and k.

[0073] In some embodiments, the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein R1, R2, R3,

[0074] It is understood that, for a compound of Formula (I), R1, R2, R3, A, and E can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, A, and E can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, A, and E.

[0075] In some embodiments, the compound is of Formula (I-A): , or aisotopic derivative, or tautomer thereof.

[0076] In some embodiments, the compound is of Formula (I-B):, or a isotopic derivative,or tautomer thereof.

[0077] In some embodiments, the compound is of Formula (I-A-1): , or aisotopic derivative, or tautomer thereof.

[0078] In some embodiments, the compound is of Formula (I-A-1-a): a), or aisotopic derivative, or tautomer thereof.

[0079] In some embodiments, the compound is of Formula (I-A-1-b):R3O S O Hal , or a isotopic derivative,or tautomer

[0080] In some embodiments, the compound is of Formula (I-A-1-b-I): I), or aisotopic derivative, or tautomer thereof.

[0081] In some embodiments, the compound is of Formula (I-A-1-c): c), or aderivative, or tautomer thereof, wherein u is an integer selected from 0, 1 and 2 and all other variables are as defined herein.

[0082] In some embodiments, the compound is of Formula (I-A-1-c-I):I), or a isotopic derivative,or tautomer

[0083] In some embodiments, the compound is of Formula (I-A-1-c-II): , or aderivative, or tautomer thereof.

[0084] In some embodiments, the compound is of Formula (I-A-1-d): d), or aderivative, or tautomer thereof.

[0085] In some embodiments, the compound is of Formula (I-A-1-d-I):I), or a isotopic derivative,or tautomer

[0086] In some embodiments, the compound is of Formula (I-A-1-d-II): R3O , or aderivative, or tautomer thereof.

[0087] In some embodiments, the compound is of Formula (I-A-1-d-III): , or aderivative, or tautomer thereof.

[0088] In some embodiments, the compound is of Formula (I-A-1-e):e), or a derivative,or tautomer

[0089] In some embodiments, the compound is of Formula (I-A-1-e-I): I), or aisotopic derivative, or tautomer thereof.

[0090] In some embodiments, the compound is of Formula (I-A-1-f): f), or aisotopic derivative, or tautomer thereof.

[0091] In some embodiments, the compound is of Formula (I-A-1-f-I):I), or a isotopic derivative,or tautomer

[0092] In some embodiments, the compound is of Formula (I-A-1-g): , or aisotopic derivative, or tautomer thereof.

[0093] In some embodiments, the compound is of Formula (I-A-1-g-I): I), or aisotopic derivative, or tautomer thereof.

[0094] In some embodiments, the compound is of Formula (I-A-2):, or a isotopic derivative,or tautomer

[0095] In some embodiments, the compound is of Formula (I-A-2-a): a), or aisotopic derivative, or tautomer thereof.

[0096] In some embodiments, the compound is of Formula (I-A-2-e): e), or aderivative, or tautomer thereof.

[0097] In some embodiments, the compound is of Formula (I-A-2-e-I):I), or a isotopic derivative,or tautomer

[0098] In some embodiments, the compound is of Formula (I-B-1): , or aisotopic derivative, or tautomer thereof.

[0099] In some embodiments, the compound is of Formula (I-B-1-a): a), or aisotopic derivative, or tautomer thereof.

[0100] In some embodiments, the compound is of Formula (I-B-1-b):, or a isotopic derivative,or tautomer

[0101] In some embodiments, the compound is of Formula (I-B-1-b-I): I), or aisotopic derivative, or tautomer thereof.

[0102] In some embodiments, the compound is of Formula (I-B-1-c): c), or aisotopic derivative, or tautomer thereof, wherein u is an integer selected from 0, 1 and 2 and all other variables are as defined herein.

[0103] In some embodiments, the compound is of Formula (I-B-1-c-I):I), or a isotopic derivative,or tautomer

[0104] In some embodiments, the compound is of Formula (I-B-1-c-II): , or aderivative, or tautomer thereof.

[0105] In some embodiments, the compound is of Formula (I-B-1-d): d), or aderivative, or tautomer thereof.

[0106] In some embodiments, the compound is of Formula (I-B-1-d-I):I), or a isotopic derivative,or tautomer

[0107] In some embodiments, the compound is of Formula (I-B-1-d-II): , or aisotopic derivative, or tautomer thereof.

[0108] In some embodiments, the compound is of Formula (I-B-1-d-III): , or aderivative, or tautomer thereof.

[0109] In some embodiments, the compound is of Formula (I-B-1-e):e), or a derivative,or tautomer

[0110] In some embodiments, the compound is of Formula (I-B-1-e-I): I), or aisotopic derivative, or tautomer thereof.

[0111] In some embodiments, the compound is of Formula (I-B-1-f): f), or aisotopic derivative, or tautomer thereof.

[0112] In some embodiments, the compound is of Formula (I-B-1-f-I):I), or a isotopic derivative,or tautomer

[0113] In some embodiments, the compound is of Formula (I-B-1-g): , or aisotopic derivative, or tautomer thereof.

[0114] In some embodiments, the compound is of Formula (I-B-1-g-I): I), or aisotopic derivative, or tautomer thereof.

[0115] In some embodiments, the compound is of Formula (I-B-2):, or a isotopic derivative,or tautomer

[0116] In some embodiments, the compound is of Formula (I-a): a), or aisotopic derivative, or tautomer thereof.

[0117] In some embodiments, the compound is of Formula (I-a-1): , or aisotopic derivative, or tautomer thereof.

[0118] In some embodiments, the compound is of Formula (I-a-2):, or a isotopic derivative,or tautomer

[0119] In some embodiments, the compound is of Formula (I-b): , or aisotopic derivative, or tautomer thereof.

[0120] In some embodiments, the compound is of Formula (I-b-1): , or aisotopic derivative, or tautomer thereof.

[0121] In some embodiments, the compound is of Formula (I-b-2):, or a isotopic derivative,or tautomer

[0122] In some embodiments, the compound is of Formula (I-C): , or aisotopic derivative, or tautomer thereof.

[0123] In some embodiments, the compound is of Formula (I-C-1): 1), or aderivative, or tautomer thereof.

[0124] In some embodiments, the compound is of Formula (I-C-1-a):a), or a isotopic derivative,or tautomer

[0125] In some embodiments, the compound is of Formula (I-C-1-b): , or aisotopic derivative, or tautomer thereof.

[0126] In some embodiments, the compound is of Formula (I-C-1-c): c), or aderivative, or tautomer thereof.

[0127] In some embodiments, the compound is of Formula (I-C-2):2), or a derivative,or tautomer

[0128] In some embodiments, the compound is of Formula (I-C-2-a): a), or aisotopic derivative, or tautomer thereof.

[0129] In some embodiments, the compound is of Formula (I-C-2-b): , or aisotopic derivative, or tautomer thereof.

[0130] In some embodiments, the compound is of Formula (I-C-2-c):c), or a isotopic derivative,or tautomer

[0131] In some embodiments, the compound is of Formula (I-C-3): 3), or aderivative, or tautomer thereof.

[0132] In some embodiments, the compound is of Formula (I-C-3-a): a), or aisotopic derivative, or tautomer thereof.

[0133] In some embodiments, the compound is of Formula (I-C-4-a):a), or a isotopic derivative,or tautomer

[0134] In some embodiments, the compound is of Formula (I-C-4-b): , or aisotopic derivative, or tautomer thereof.

[0135] In some embodiments, the compound is of Formula (I-C-4-c): c), or aisotopic derivative, or tautomer thereof.

[0136] In some embodiments, the compound is of Formula (I-C-5-a):a), or a isotopic derivative,or tautomer

[0137] In some embodiments, the compound is of Formula (I-D): , or aisotopic derivative, or tautomer thereof.

[0138] In some embodiments, the compound is of Formula (I-D-1): , or aisotopic derivative, or tautomer thereof.

[0139] In some embodiments, the compound is of Formula (I-D-2):, or a isotopic derivative,or tautomer

[0140] In some embodiments, the compound is of Formula (I-D-3): , or aisotopic derivative, or tautomer thereof.

[0141] In some embodiments, the compound is of Formula (I-D-4): 4), or aderivative, or tautomer thereof.

[0142] In some embodiments, the compound is of Formula (I-D-4-a):a), or a derivative,or tautomer

[0143] In some embodiments, the compound is of Formula (I-D-4-b): b), or aderivative, or tautomer thereof.

[0144] In some embodiments, the compound is of Formula (I-D-4-c): c), or aderivative, or tautomer thereof.

[0145] In some embodiments, the compound is of Formula (I-D-4-d):d), or a derivative,or tautomer

[0146] In some embodiments, the compound is of Formula (I-D-4-e): e), or aderivative, or tautomer thereof.

[0147] In some embodiments, the compound is of Formula (I-D-5): , or aderivative, or tautomer thereof.

[0148] In some embodiments, the compound is of Formula (I-D-6):6), or a derivative,or tautomer

[0149] In some embodiments, the compound is of Formula (I-E-1): , or aisotopic derivative, or tautomer thereof.

[0150] In some embodiments, the compound is of Formula (I-E-2): , or aisotopic derivative, or tautomer thereof.

[0151] In some embodiments, the compound is of Formula (I-F):, or a isotopic derivative,or tautomer

[0152] In some embodiments, the compound is of Formula (A-1): , or a isotopic derivative,or tautomer thereof.

[0153] In some embodiments, R0is selected from H, ,optionally substituted with one or more R6.R0is H.

[0155] In some .

[0156] In some .

[0157] In some .

[0158] In some .

[0159] In some .

[0160] In some .

[0161] In some .

[0162] In some .

[0163] In some .

[0164] In some .

[0165] In some .

[0166] In some ..

[0169] In some .

[0170] In some .

[0171] In some .

[0172] In some .

[0173] In some .

[0174] In some .

[0175] In some .

[0176] In some .

[0177] In some .

[0178] In some .

[0179] In some .

[0180] In some .

[0181] In some .

[0182] In some .

[0183] In some .

[0184] In some .

[0185] In some .

[0186] In some .

[0187] In some .

[0188] In some .

[0189] In some .

[0190] In some .

[0191] In some .

[0192] In some .

[0193] In some .

[0194] In some .

[0195] In some .

[0196] In some .

[0197] In some .

[0198] In somesubstituted with one or more R6.

[0199] In some .

[0200] In some .

[0201] In some CR4R5, O, SO2, and NR4.

[0202] In some

[0203] In some embodiments, A is CH2.

[0204] In some embodiments, A is CH(OH).

[0205] In some embodiments, A is C(CH3)OH.

[0206] In some embodiments, A is CH(OCH3).

[0207] In some embodiments, A is C(CH3)(OCH3).

[0208] In some embodiments, A is O.

[0209] In some embodiments, A is SO2.

[0210] In some embodiments, A is NR4.

[0211] In some embodiments, A is NH.

[0212] In some embodiments, A is N(CH3).

[0213] In some embodiments, A is NC(O)CH3.

[0214] In some embodiments, A is N(C(O)OC(CH3)3).

[0215] In some embodiments, A is NS(=O)2CH3.

[0216] In some embodiments, E is selected from C and N, provided that when bonds are single bonds, then E is N, and when bonds are double bonds, then E is C.

[0217] In some embodiments, E is N and the bonds are single bonds.

[0218] In some embodiments, E is C and the bonds are double bonds.

[0219] In some embodiments, each G is independently selected from CH and N.

[0220] In some embodiments, each G is CH.

[0221] In some embodiments, each G is N.

[0222] In some embodiments, one G is CH, another one is N.

[0223] In some embodiments, X is selected from and R9.

[0224] In some .

[0225] In some .

[0226] In some .

[0227] In some .

[0228] In some .

[0229] In some .

[0230] In some .

[0231] In some .

[0232] In some .

[0233] In some .

[0234] In some .

[0235] In some .CD3

[0236] In some

[0237] In some .

[0238] In some .

[0239] In some .

[0240] In some .

[0241] In some .

[0242] In some .

[0243] In some .

[0244] In some .

[0245] In some .

[0246] In some .

[0247] In some .

[0248] In some .

[0249] In some .

[0250] In some .

[0251] In some .

[0252] In some .

[0253] In some

[0254] In some .

[0255] In some .

[0256] In some .

[0257] In some .

[0258] In some .

[0259] In some .

[0260] In some .

[0261] In some .

[0262] In somewith atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6alkyl.

[0263] In some embodiments, Z is selected from a bond, NH, and -CH2-.

[0264] In some embodiments, Z is a bond.

[0265] In some embodiments, Z is a single bond.

[0266] In some embodiments, Z is NH.

[0267] In some embodiments, Z is -CH2-.

[0268] In some embodiments, R1is selected from H, halogen, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl.

[0269] In some embodiments, R1is H.

[0270] In some embodiments, R1is halogen.

[0271] In some embodiments, R1is F.

[0272] In some embodiments, R1is Cl.

[0273] In some embodiments, R1is Br.

[0274] In some embodiments, R1is C1-C6 alkyl.

[0275] In some embodiments, R1is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl.

[0276] In some embodiments, R1is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0277] In some embodiments, R1is methyl.

[0278] In some embodiments, R1is ethyl.

[0279] In some embodiments, R1is propyl.

[0280] In some embodiments, R1is n-propyl.

[0281] In some embodiments, R1is i-propyl.

[0282] In some .

[0283] In some

[0284] In some embodiments, R1 is -CH2CN.

[0285] In some embodiments, R2is selected from H, halogen, -CN, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl.

[0286] In some embodiments, R2is H.

[0287] In some embodiments, R2is C1-C6 alkyl.

[0288] In some embodiments, R2is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0289] In some embodiments, R2is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0290] In some embodiments, R2is methyl.

[0291] In some embodiments, R2is halogen.

[0292] In some embodiments, R2is F.

[0293] In some embodiments, R2is -CN.

[0294] In some embodiments, R1and R2are each H.

[0295] In some embodiments, R1is F and R2is H.

[0296] In some embodiments, R1is methyl and R2is H.

[0297] In some embodiments, both R1and R2are methyl groups.

[0298] In some embodiments, both R1and R2are -CD3.

[0299] In some embodiments, R1is F and R2is F.

[0300] In some embodiments, R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl, or 3-10 membered heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with one or more substitutients independently selected from halogen, OH, C1-C6 alkyl.

[0301] In some embodiments, R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl.

[0302] In some embodiments, R1and R2together with the atom to which they are attached and any intervening atoms, form 3 membered cycloalkyl.

[0303] In some embodiments, R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered heterocyclyl.

[0304] In some embodiments, R1and R2together with the atom to which they are attached and any intervening atoms, form 6 membered heterocyclyl.

[0305] In some embodiments, R1and R2together form =O.

[0306] In some embodiments, R3is selected from C1-C6 alkyl, -N(R7)2, 3-8 membered cycloalkyl, aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from C1-C6alkyl, -NH2, -OH, -CN, halogen, oxo.

[0307] In some embodiments, R3is C1-C6alkyl optionally substituted with one or more substitutients independently selected from C1-C6 alkyl, -NH2, -OH, -CN, halogen, oxo.

[0308] In some embodiments, R3is C1-C6 alkyl.

[0309] In some embodiments, R3is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0310] In some embodiments, R3is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0311] In some embodiments, R3is methyl.

[0312] In some embodiments, R3is ethyl.

[0313] In some .

[0314] In some .

[0315] In some

[0316] In some embodiments, R3is -N(R7)2.

[0317] In some embodiments, R3is -NH2.

[0318] In some embodiments, R3is -NHCH3.

[0319] In some embodiments, R3is -N(CH3)2.

[0320] In some embodiments, R3is -N(CD3)2.

[0321] In some embodiments, R3 is -NHCH2CH3.

[0322] In some embodiments, R3is -NHC(O)CH3.

[0323] In some embodiments, R3is -NHC(O)CH2CH3.

[0324] In some .

[0325] In some

[0326] In some .

[0327] In some

[0328] In some .

[0329] In some .

[0330] In some .

[0331] In some heterocyclyl optionally substitutedwith one or more substitutients independently selected from C1-C6alkyl, -NH2, -OH, -CN, halogen, oxo.

[0332] In some embodiments, R3is 4-10 membered heterocyclyl.

[0333] In some .

[0334] In some .

[0335] In someheteroaryl optionally substituted with one or more substitutients independently selected from C1-C6alkyl, -NH2, -OH, -CN, halogen, oxo.

[0336] In some embodiments, R3is 5-10 membered heteroaryl.

[0337] In some embodiments, R3is 5 membered heteroaryl.

[0338] In some .

[0339] In some .

[0340] In some .

[0341] In some .. .

[0344] In some .

[0345] In someheteroaryl.

[0346] In some .

[0347] In somewith the atoms to which they are attached and any intervening atoms, form a heterocyclyl or heteroaryl.

[0348] In some embodiments, R4is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)- C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NHC1-C6 alkyl, -OC(O)NHC1-C6 alkyl, -S(O)2-C1- C6alkyl, and aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-C6alkyl)2, C1-C6 alkoxy.

[0349] In some embodiments, R4is H.

[0350] In some embodiments, R4is C1-C6 alkyl.

[0351] In some embodiments, R4is methyl.

[0352] In some embodiments, R4is C(O)-C1-C6alkyl.

[0353] In some embodiments, R4is -C(O)CH3.

[0354] In some embodiments, R4is -C(O)OC1-C6 alkyl.

[0355] In some embodiments, R4is -C(O)OC(CH3)3.

[0356] In some embodiments, R4is -S(O)2-C1-C6 alkyl.

[0357] In some embodiments, R4is -S(O)2CH3.

[0358] In some embodiments, R3and R4together with the atom to which they are attached and any intervening atoms, form a cycle.

[0359] In some embodiments, the compound is of Formula (A-11): , or aisotopic derivative, or tautomer thereof.

[0360] In some embodiments, the compound is of Formula (A-12): ,or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0361] In some embodiments, the compound is of Formula (A-13): , or a isotopic derivative,or tautomer thereof.

[0362] In some embodiments, the compound is of Formula (A-14): , or aisotopic derivative, or tautomer thereof.

[0363] In some embodiments, the compound is of Formula (A-15):, or a isotopic derivative,or tautomer thereof.

[0364] In some embodiments, the compound is of Formula (A-16): 1 O R , or aisotopic derivative, or tautomer thereof.

[0365] In some embodiments, the compound is of Formula (A-17):R1O N R2, or a isotopic derivative,or tautomer thereof, wherein Q is -CH2-O-CH2-CH2-O-CH2- or –(CH2)3-.

[0366] In some embodiments, the compound is of Formula (A-18): , or aisotopic derivative, or tautomer thereof.

[0367] In some embodiments, R5is selected from H, halogen, oxo, -OH, -NH2 -CN, C1-C6 alkyl, C1-C6alkoxy, -OC(O)N(R7)2.

[0368] In some embodiments, R5is H.

[0369] In some embodiments, R5is -OH.

[0370] In some embodiments, R5is C1-C6 alkyl.

[0371] In some embodiments, R5is methyl.

[0372] In some embodiments, R5is C1-C6alkoxy.

[0373] In some embodiments, R5is methoxy.

[0374] In some embodiments, each R6is independently selected from halogen, OH, C1-C6alkyl, -N(R7)2, -N(R7)COR4, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, OH, CN.

[0375] In some embodiments, R6is halogen.

[0376] In some embodiments, R6is F.

[0377] In some embodiments, R6is OH.

[0378] In some embodiments, R6is C1-C6alkyl.

[0379] In some embodiments, R6is methyl.

[0380] In some .

[0381] In somewith atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6alkyl.

[0382] In some embodiments, two R6form =O.

[0383] In some embodiments, each R7is independently selected from H, C1-C6 alkyl, C1- C6alkyl-C(O)-, C1-C6alkyl-OC(O)NH-(C1-C6alkanediyl)-, C1-C6-alkanediyl-O-C1-C6alkyl.

[0384] In some embodiments, R7is H.

[0385] In some embodiments, each R7is H.

[0386] In some embodiments, R7is C1-C6alkyl.

[0387] In some embodiments, at least one R7is C1-C6 alkyl.

[0388] In some embodiments, one R7is C1-C6 alkyl.

[0389] In some embodiments, each R7is C1-C6alkyl.

[0390] In some embodiments, R7is methyl.

[0391] In some embodiments, at least one R7is methyl.

[0392] In some embodiments, one R7is methyl.

[0393] In some embodiments, each R7is methyl.

[0394] In some embodiments, R7is -CD3.

[0395] In some embodiments, at least one R7is -CD3.

[0396] In some embodiments, one R7is -CD3.

[0397] In some embodiments, each R7-CD3.

[0398] In some embodiments, R7is ethyl.

[0399] In some embodiments, at least one R7is ethyl.

[0400] In some embodiments, one R7is ethyl.

[0401] In some embodiments, each R7is ethyl.

[0402] In some embodiments, R7is C1-C6 alkyl-C(O)-.

[0403] In some embodiments, one R7is C1-C6alkyl-C(O)-.

[0404] In some embodiments, R7is -C(O)CH3.

[0405] In some embodiments, one R7is -C(O)CH3.

[0406] In some embodiments, R7is -C(O)CH2CH3.

[0407] In some embodiments, one R7is -C(O)CH2CH3.

[0408] In some embodiments, R7is C1-C6 alkyl-OC(O)NH-(C1-C6 alkanediyl)-.

[0409] In some embodiments, each R8is independently selected from halogen, OH, CN, C1-C6alkyl, heterocyclyl, heteroaryl.

[0410] In some embodiments, R8is halogen.

[0411] In some embodiments, R8is F.

[0412] In some embodiments, R8is OH.

[0413] In some embodiments, R8is C1-C6 alkyl.

[0414] In some embodiments, R8is methyl.

[0415] In some embodiments, R8and R9together with atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6 alkyl, wherein alkyl is optionally substituted with heterocyclyl.

[0416] In some embodiments, R9is selected from -C(O)C1-C6 alkyl, -C(O)NH(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), 5-10 membered monocyclic or bicyclic heterocyclyl, 5—10 membered monocyclic or bicyclic heteroaryl, wherein heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from -OH, - CN, halogen, C1-C6 alkyl and C1-C6 alkyl-heterocyclyl.

[0417] In some embodiments, R9is -C(O)NH(C1-C6alkyl).

[0418] In some embodiments, R9is -C(O)NHCH2CH3.

[0419] In some embodiments,R9is -S(=O)(=NH)(C1-C6alkyl).

[0420] In some .

[0421] In some monocyclic or bicyclic heterocyclyl.

[0422] In some embodiments, is 5 membered monocyclic heterocyclyl.

[0423] In some .

[0424] In some .

[0425] In somemonocyclic heterocyclyl.

[0426] In some .

[0427] In some .

[0428] In some .

[0429] In somefrom 1, 2, and 3.

[0430] In some embodiments, n is 1.

[0431] In some embodiments, n is 2.

[0432] In some embodiments, n is 3.

[0433] In some embodiments, m is an integer selected from 0, 1, 2, and 3;

[0434] In some embodiments, m is 0.

[0435] In some embodiments, m is 1.

[0436] In some embodiments, m is 2.

[0437] In some embodiments, m is 3.

[0438] In some embodiments, p is an integer selected from 0, 1 and 2.

[0439] In some embodiments, p is 0.

[0440] In some embodiments, p is 1.

[0441] In some embodiments, p is 2.

[0442] In some embodiments, k is an integer selected from 0, 1, and 2;

[0443] In some embodiments, k is 0.

[0444] In some embodiments, k is 1.

[0445] In some embodiments, k is 2.

[0446] In some embodiments, r is an integer selected from 0 and 1

[0447] In some embodiments, r is 0.

[0448] In some embodiments, r is 1.

[0449] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0450] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0451] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0452] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0453] In some embodiments, the compound is selected from the compounds described in Table 1.

[0454] Table 1. Certain examples of the compound of Formula I # Structure IUPAC Name# Structure IUPAC Name - e - - e - - e - - - - e# Structure IUPAC Name o- - e '- e - - e# Structure IUPAC Name - - -# Structure IUPAC Name O O l- - - - - - -# Structure IUPAC Name - - e - - )- -# Structure IUPAC Name - - - - -# Structure IUPAC Name - - d - 4- -# Structure IUPAC Name - - - - -# Structure IUPAC Name - - - l- - l- -# Structure IUPAC Name l- - - l- -# Structure IUPAC Name l- - l- - 6- - - )- -# Structure IUPAC Name l- - - 4 - - a# Structure IUPAC Name - a - - - -# Structure IUPAC Name - - - - - - -# Structure IUPAC Name - es l- - - - - - o# Structure IUPAC Name - l- - - - - -# Structure IUPAC Name - n- - n- - - - - -# Structure IUPAC Name H N O - - e - - - - - - - - -# Structure IUPAC Name - - - - o - - -# Structure IUPAC Name - - i# Structure IUPAC Name 1- i -# Structure IUPAC Name - - - - - - 3- -# Structure IUPAC Name - - - - - - -# Structure IUPAC Name n- n- e - - e -# Structure IUPAC Name - - - -# Structure IUPAC Name - e - -# Structure IUPAC Name - - - - 5- -# Structure IUPAC Name - a- ,2o - n# Structure IUPAC Name ,2,1,1n-# Structure IUPAC Name - 6,1l- - - -# Structure IUPAC Name - - 3- - e ]- -# Structure IUPAC Name 2. - r - - - - -# Structure IUPAC Name - ] - n- n-# Structure IUPAC Name - - - - - - - - -# Structure IUPAC Name - l] - ] - o 7- - -# Structure IUPAC Name - - - ,1- ,2- 4,1-# Structure IUPAC Name - l- - 2- - - - -# Structure IUPAC Name ]- - - e -# Structure IUPAC Name ,1, p p y p y one of the compounds described in Table 1.

[0456] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0457] In some embodiments, the compound is a salt of any one of acid described in the Table 2 and any one of the compounds described in Table 1.

[0458] Table 2. Pharmaceutical acceptable acid forming salts with the Compound of Formula (I). 1-hydroxy-2-naphthoic acid ethanesulfonic acid methanesulfonic acid 2,2-dichloroacetic acid formic acid naphthalene-1,5-disulfonic acid

[0459] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0460] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0461] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0462] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0463] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0464] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0465] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0466] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0467] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0468] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0469] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0470] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0471] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0472] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0473] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0474] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0475] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0476] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0477] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I)- (VI). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0478] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0479] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0480] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0481] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0482] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0483] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0484] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non- deuterium labeled reagent.

[0485] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0486] In some embodiments, the compound is a18F labeled compound.

[0487] In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof.

[0488] In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0489] It is understood that the18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0490] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0491] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0492] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less, for example 400 Daltons or less.

[0493] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0494] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0495] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0496] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0497] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0498] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0499] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0500] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0501] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0502] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0503] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0504] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other aretermed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0505] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0506] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0507] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0508] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0509] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0510] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0511] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0512] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0513] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may bephysicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0514] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0515] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0516] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compound of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. H O OH + H - O

[0517] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (m-CPBA), for example, in an inert solvent such as dichloromethane.

[0518] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0519] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.

[0520] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirablepharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0521] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0522] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, aC1-4alkylamine such as methylamine, a (C1-C4alkyl)2amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0523] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0524] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). Method of Synthesizing the Compounds

[0525] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0526] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the presentinvention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0527] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0528] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. GENERAL PROCEDURE

[0529] In general, the compound of the Formula (I) can be prepared using sequence of reactions presented at the Scheme 1.

[0530] Scheme 1

[0531] It must be understood that any of the compounds at the Scheme 1 any of substitutients in these compounds can be further modified at any step of presented sequences to provide modified derivatives of these compounds useful for preparation of compounds of Formula (I).

[0532] All reagents may be commercially available compounds itself or products of synthesis from commercially available reagents. For preparation these reagents may be used one step or multistep synthetic procedures, including but not limited procedures described herein in preparative part.

[0533] It should be obvious for specialist in this field that any of compound of Formula (I) obtained according to the procedures described above may be a subject for further transformation and modification that will lead to other compound of Formula (I).Biological Assays

[0534] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0535] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0536] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions

[0537] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0538] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0539] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substanceswhich may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0540] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0541] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizingand / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0542] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0543] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0544] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β- cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β- cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β- cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ- cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0545] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0546] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkoniumhalides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0547] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0548] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0549] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0550] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0551] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0552] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0553] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0554] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0555] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0556] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0557] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0558] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a CDK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0559] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an CDK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0560] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine.Methods of Use

[0561] In some aspects, the present disclosure provides a method of inhibiting of CDK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0562] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0563] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0564] In some embodiments, the disease or disorder is associated with CDK2. In some embodiments, the disease or disorder is a disease or disorder in which CDK2 is implicated.

[0565] The compounds of the invention are also useful in treating diseases associated with CDK2. For example, diseases and conditions treatable according to the methods of the invention include Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RB1); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT).

[0566] The method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0567] In some embodiments, the disease or disorder is Breast Cancer (BC).

[0568] In some embodiments, the disease or disorder is Colorectal Cancer (CRC).

[0569] In some embodiments, the disease or disorder is Lung Cancer (LNCR).

[0570] In some embodiments, the disease or disorder is Retinoblastoma (RB1).

[0571] In some embodiments, the disease or disorder is Pancreatic Cancer (PNCA).

[0572] In some embodiments, the disease or disorder is Prostate Cancer (PC).

[0573] In some embodiments, the disease or disorder is Ovarian Cancer (OC).

[0574] In some embodiments, the disease or disorder is Hepatocellular Carcinoma (HCC).

[0575] In some embodiments, the disease or disorder is Gastric Cancer (GASC).

[0576] In some embodiments, the disease or disorder is Bladder Cancer (BLC).

[0577] In some embodiments, the disease or disorder is Endometrial Cancer (ENDMC).

[0578] In some embodiments, the disease or disorder is Glioblastoma (GBM).

[0579] In some embodiments, the disease or disorder is Adenocarcinoma.

[0580] In some embodiments, the disease or disorder is Squamous Cell Carcinoma.

[0581] In some embodiments, the disease or disorder is Ataxia-Telangiectasia (AT).

[0582] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0583] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0584] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of CDK2 (e.g., in vitro or in vivo).

[0585] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0586] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0587] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer in a subject in need thereof.

[0588] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.

[0589] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of CDK2 (e.g., in vitro or in vivo).

[0590] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0591] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0592] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0593] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0594] The present disclosure provides compounds that function as inhibitors of CDK2 (e.g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of CDK2 in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0595] In some embodiments, the inhibitor of CDK2 is a compound of the present disclosure.

[0596] Effectiveness of compounds of the disclosure can be determined by industry- accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0597] The present disclosure also provides a method of treating a disease or disorder in which CDK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0598] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Routes of Administration

[0599] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0600] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES General synthetical procedures and examples of the compound’s preparation.

[0601] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC Aluminum sheets silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75^^m) purchased by Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR operating at 400 MHz for1H. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data isreported as follows: s = singlet, br. = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration. The purities were recorded on Waters e2695 separations Module / 2998 PDA Detector HPLC system (Column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L), Eluent: the mixture of mobile phase A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH4OAc, Flow rate: 0.5 mL / min. detection: UV, 254 nm)

[0602] Abbreviations used in the following examples and elsewhere herein are: ACN acetonitrile aq. aqueous anh. anhydrous br. broad BSA bovine serum albumin d duplet DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide EA ethyl acetate eq equivalent ESI Electro spray FA formic acid FBS fetal bovine serum h hour(s) HPLC high pressure (or performance) liquid chromatography LCMS liquid chromatography mass spectrometry m multiplet M molar MHz megahertz min minutes MsCl methanesulfonyl chloride NBS N-bromosuccinimide NMR nuclear magnetic resonance Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) q quadruplet rt room temperature RT retention time s singlet s solidsat. saturated t temperature, triplet TEA triethylamine THF tetrahydrofuran TLC thin layer chromatography XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Synthesis of Building Blocks

[0603] Preparation 1. tert-Butyl N-[1-(1-methylpyrazol-4-yl)sulfonyl-4- piperidyl]carbamate (P1).(2.3 mL, 16.5 mmol, 3 eq) in DCM (20 mL) 1-methylpyrazole-4-sulfonyl chloride (1 g, 5.5 mmol, 1 eq) was added at 0°C. The reaction mixture was stirred at rt overnight. Then the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo to give tert-butyl N-[1-(1-methylpyrazol-4-yl)sulfonyl-4-piperidyl]carbamate P1 (1.78 g, yield 93%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 8.23 (s, 1H), 7.69 (s, 1H), 6.73 (s, 1H), 3.87 (s, 3H), 3.41-3.31 (m, 2H), 3.23 (s, 1H), 2.37 (td, J = 11.6, 2.9 Hz, 2H), 1.75 (dd, J = 13.4, 3.9 Hz, 2H), 1.48-1.35 (m, 2H), 1.33 (s, 9H).

[0604] Preparation 2. tert-Butyl N-(1-methylsulfonyl-4-piperidyl)carbamate (P2).To a mixture of tert-butyl N-(4-piperidyl)carbamate (1.4 g, 7 mmol, 1 eq) and TEA (2.3 mL, 14 mmol, 2 eq) in DCM (20 mL) MsCl (570 µL, 7.34 mmol, 1.1 eq) was added at 0°C. The reaction mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give tert-butyl N-(1-methylsulfonyl- 4-piperidyl)carbamate P2 (1.92 g, yield 100%) which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 6.77 (s, 1H), 3.48-3.38 (m, 2H), 3.38- 3.31 (m, 1H), 2.82-2.71 (m, 5H), 1.77 (dd, J = 13.5, 3.7 Hz, 2H), 1.36 (s, 11H).

[0605] Preparation 3. 1-(1-Methylpyrazol-4-yl)sulfonylpiperidin-4-amine hydrochloride (P3). O O O O(772 µL, 9.28 mmol, 3 eq) was added dropwise. The mixture was stirred at rt for 2 h. After completion of the reaction, the solvent was evaporated in vacuo to provide 1-(1- methylpyrazol-4-yl)sulfonylpiperidin-4-amine hydrochloride P3 (1 g, yield 100%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 12.77 (s, 1H), 6.78 (d, J = 8.8Hz, 1H), 6.74 (s, 1H), 6.68 (d, J = 8Hz, 1H), 4.19 (s, 4H), 3.42 (s, 2H). LCMS (ESI): calc. for C10H10O4194.19; found, 195.6 [M+H]+.

[0606] Preparation 4. 1-Methylsulfonylpiperidin-4-amine hydrochloride (P4).P2 (1.92 g, 0.7 mmol, 1 eq) was dissolved in 2,2,2-trifluoroethanol (20 mL), and HCl (1.14 mL, 1.4 mmol, 2 eq) was added dropwise. The mixture was stirred at rt for 2 h. After completion of the reaction, the solvent was evaporated in vacuo to provide the title compound P4 (1.49 g, yield 100%), which was used in the next step without further purification. Analytical data: Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 8.27 (s, 2H), 3.56 (dd, J = 12.3, 4.4 Hz, 2H), 3.10 (m, 1 H), 2.87-2.73 (m, 5H), 2.02-1.93 (m, 2H), 1.64-1.50 (m, 2H).

[0607] Preparation 5. 2-Chloro-N-cyclopentyl-5-methoxypyrimidin-4-amine (P5). NH O2O To a stirred1 eq) and cyclopentanamine (2.43 mL, 25 mmol, 1.2 eq) in anh. DCM (30 mL) DIPEA (7 mL, 40 mmol, 2 eq) was added. The resulting mixture was stirred at rt for 12 h, then diluted with water and washed with brine. The combined organic phases were dried over Na2SO4and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent hexane / EA = 2 / 1) to give 2-chloro-N-cyclopentyl-5-methoxypyrimidin-4-amine P5 (4.28 g, yield 93%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 7.60 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.28-4.15 (m, 1H), 3.79 (s, 3H), 1.91-1.79 (m, 2H), 1.71-1.58 (m, 2H), 1.58-1.41 (m, 4H).

[0608] Preparation 6. 2-Chloro-4-(cyclopentylamino)pyrimidin-5-ol-4 (P6).To a stirred solution of P5 (1.14 g, 5 mmol, 1 eq) in DCE (15 mL) 1M solution of BBr3in DCM (15 mL, 15 mmol, 3 eq) was carefully added dropwise at rt. The resulting mixture was stirred at reflux for 3 h, then it was cooled to rt, and washed with sat. aq. solution of Na2CO3(gas evaluation). The layers were separated, and the organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo to give 2-chloro-4- (cyclopentylamino)pyrimidin-5-ol P6 (1 g, yield 99%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 10.05-10.00 (m, 1H), 7.43-7.37 (m, 1H), 6.87 (d, J = 7.4 Hz, 1H), 4.19 (s, 1H), 1.86 (s, 2H), 1.64 (s, 2H), 1.54-1.43 (m, 4H).

[0609] Preparation 7. 2-Chloro-8-cyclopentyl-pyrimido[5,4-b][1,4]oxazin-7-one (P7). OH O O N N O2.67 mmol, 2 eq) in anh. DMF (15 mL) ethyl 2-bromoacetate (290 µL, 2.57 mmol, 1.1 eq) was added. The resulting mixture was stirred at room temperature for 1 h, and then heated at 70°C for 3 h. After the completion of the reaction, the mixture was cooled to room temperature, diluted with EA and washed with brine. Organic layers were dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent hexane / EA = 1 / 1) to give P7 (490 mg, yield 80%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 8.24 (s, 1H), 5.17 (ddd, J = 17.0, 9.3, 7.7 Hz, 1H), 4.79 (s, 2H), 2.08-1.73 (m, 6H), 1.55 (d, J = 5.9 Hz, 1H), 1.54-1.49 (m, 1H).

[0610] Preparation 8. 2-Chloro-8-cyclopentyl-6-methyl-pyrimido[5,4-b][1,4]oxazin-7- one (P8).OH O O N K2CO3N O 2.67eq). was added. The resulting mixture was stirred at rt for 1 h, and then heated at 70°C for 6 h. After the completion of the reaction, the mixture was cooled to rt, diluted with EA and washed with brine. Organic layers were dried over Na2SO4and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent hexane / EA = 1 / 1) to give P8 (540 mg, yield 86%), which was used in the next step without further purification. Analytical data:1H NMR (400 MHz, DMSO-d6), ^: 8.08 (d, J = 1.1 Hz, 1H), 5.32 (ttd, J = 9.3, 7.8, 1.1 Hz, 1H), 4.67 (qt, J = 6.8, 1.1 Hz, 1H), 2.19-1.96 (m, 4H), 1.96-1.83 (m, 2H), 1.67-1.47 (m, 5H).

[0611] Preparation 9. N4-cyclopentyl-5-methoxy-N2-(1-methylsulfonyl-4- piperidyl)pyrimidine-2,4-diamine (P9). 5.0 g(dried by boiling in toluene with Dean-Stark apparatus), 390 mg (2.2 mmol) of Pd(OAc)2, 1.37 g (2.20 mmol) BINAP, 2.75 g (28.6 mmol) of tert-BuONa were placed in vial with 80 mL of dioxane, purged with nitrogen, stirred at 90-95°C overnight. The reaction mixture was cooled to rt, diluted with DCM (100 mL), filtered. The solution was diluted with 100 mL of DCM, washed with water (2x75 mL), dried over Na2SO4, evaporated to dryness. Crude product P9 was crystallized from acetone (4.5 mL per 1 g of crude compound, at -18°C). Precipitate was filtered, washed with Et2O. Yield 5.5 g (67%).1H NMR (400 MHz, DMSO-d6), δ: 7.42 (s, 1H), 6.11 (d, J = 7.4 Hz, 1H), 5.88 (d, J = 7.8 Hz, 1H), 4.30-4.23 (m, 1H), 3.74-3.66 (m,4H),3.54-3.49 (m, 2H), 2.87-2.81 (m, 5H), 1.97-1.87 (m, 4H), 1.71-1.65 (m, 2H), 1.57-1.45 (m, 6H).

[0612] Preparation 10. 4-(Cyclopentylamino)-2-[(1-methylsulfonyl-4- piperidyl)amino]pyrimidin-5-ol (P10).1M in DCM) was added dropwise. The DCM was distilled off, the reaction mixture was stirred at 70°C 1 h. Control vial LCMS. Solution was cooled with ice bath, 60 mL of MeOH was added, reaction mixture was concentrated in vacuo, dissolved in DCM (400 mL), washed with NaHCO3solution (400 mL), water, dried over Na2SO4and evaporated. Yield 8.4 g (79%).1H NMR (400 MHz, DMSO-d6), δ: 7.27 (s, 1H), 5.95 (d, J = 7.4 Hz, 1H), 5.75 (d, J = 7.8 Hz, 1H), 4.27-4.20 (m, 1H), 3.74-3.66 (m,1H), 3.53-3.47 (m, 2H), 2.88-2.80 (m, 5H), 1.97-1.87 (m, 4H), 1.71-1.64 (m, 2H), 1.55-1.45 (m, 6H).

[0613] Preparation 11. 2-[4-(Cyclopentylamino)-2-[(1-methylsulfonyl-4- piperidyl)amino]pyrimidin-5-yl]oxy-2-methyl-propanoic acid (P11).in round-bottom flask followed by DSMO (25 mL, 3 mL per 1g of 4). 5.5 g (28.3 mmol) ofethyl bromoisobutirate was dissolved in DMSO (6.0 mL) and added to the mixture of compound P10 and KOH at rt. The reaction mixture was stirred at rt for 2 h, poured into 300 mL of crushed ice. When the ice melted, cloudy solution was washed with DCM (2x 50 mL). Clear water solution was cooled and acidified with 6 M HCl until pH = 6. Precipitate was filtered, washed with cold water (40 mL), dried under vacuum. Yield 8.6 g (87%).

[0614] Preparation 12. 2-Chloro-8-cyclopentyl-6,6-dimethyl-pyrimido[5,4- b][1,4]oxazin-7-one (P12). O O To a wellP6 (400 mg, 1.87 mmol, 1 eq) and K2CO3(516 mg, 3.74 mmol, 2 eq) in a dry DMF (15 mL) ethyl-α- bromisobutyrat (CAS 600-00-0, 300 µL, 2.05 mmol, 1.1 eq) was added. The resulting mixture was stirred at rt for 5 h, and then stirred at 70°C for 16 h. After the completion of the reaction the mixture was cooled to rt, diluted with EtOAc and washed with brine. Organic layers were dried over Na2SO4and evaporated in vacuum. The residue was purified by column chromatography on SiO2 (eluent Hexane / EtOAc = 1 / 1) to obtain 2- chloro-8-cyclopentyl-6,6-dimethyl-pyrimido[5,4-b][1,4]oxazin-7-one P12 (430mg, 82%).1H NMR (400 MHz, DMSO-D6), δ: 8.25 (s, 1H), 5.22 (tt, J = 9.5, 7.4 Hz, 1H), 2.05 – 1.76 (m, 6H), 1.56 (dq, J = 6.7, 4.2 Hz, 2H), 1.45 (s, 6H).

[0615] Preparation 13. 2-Chloro-5-methoxy-pyrimidin-4-amine (P13).16.0 g of 2,4-dichloro-5-methoxypyrimidine was dissolved in 40 mL of dioxane in a pressure tube. 40 mL of NH3 aq was added and reaction mixture was sealed and stirred at 100oC overnight. The reaction mixture was evaporated after cooling to rt, solid was washed with 30 mL of cold water, dried in air to give 12 g of P13 (86%).

[0616] Preparation 14. 4-Amino-2-chloro-pyrimidin-5-ol (P14). O OHTo a stirred suspension of P13 (8.2 g, 51.6 mmol) in 1,2-dichloroethane (400 mL) BBr3 (1M in DCM, 128 mL, 128 mmol, 2.5 eq) was added slowly at rt. DCM was distilled off, the reaction mixture was stirred at 60°C for 12 h. The reaction mixture was cooled with ice bath, quenched with methanol until clear solution. Solvents were removed in vacuo. Product was suspended in 100 mL of water and pH was adjusted to 8 with NaHCO3or K2CO3. Solids were filtered, washed with cold water, and dried under reduced pressure to give 7.15 g (95%) of P14.1H NMR (400 MHz, DMSO-d6), δ: 7.49 (s, 1H), 6.89 (br., 2H).

[0617] Preparation 15. 2-Chloro-6,6-dimethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one (P15). OH O N N O 7.2 g (49.65butyrate and 13.9 g (99.34 mmol, 2 eq) of K2CO3 were stirred in 200 mL of ACN while boiling for 8 h. The reaction mixture was cooled to rt, filtered. Formed solid was washed with ethyl acetate, combined organic solutions were concentrated in vacuo. Residue was washed with Et2O to remove iso-butyrate, dried in vacuum to give 9.4 g (89%) of P15.1H NMR (400 MHz, DMSO-d6), δ: 7.48 (s, 1H), 1.25 (s, 6H).

[0618] Preparation 16. 2-Chloro-6,6-dimethyl-8-(tetrahydropyran-4- ylmethyl)pyrimido[5,4-b][1,4]oxazin-7-one (P16). 488mgeq) of 4- (Bromomethyl)tetrahydro-2H-pyran 702mg (5.078 mmol, 2.0 eq) of potassium carbonate and 4mL of DMA were added into reaction vial. The mixture was stirred at 60°C for 2h. After cooling, water was added followed by extraction with EtOAc. The combined organics were dried over sodium sulphate and concentrated. The residue was purified by column chromatography on silica gel (eluent: EtOAc / Hexane (20% isocratic) to provide compound P16. Yield: 265mg (37%). Examples of the Final Compound

[0619] In the Table 3 presented certain non-limiting examples of the compound of Formula (I).

[0620] Table 3. Selected examples of the compound of Formula (I) and LCMS (ESI) data [MH]+[MH]+# Structure[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. Found[MH]+[MH]+# Structure Calc. FoundSynthesis of the Representative Examples of the compound

[0621] Example 1. 8-Cyclopentyl-2-[(1-methylsulfonyl-4-piperidyl)amino]pyrimido[5,4- b][1,4]oxazin-7-one (Compound 1).The suspension of P7 (50 mg, 0.19 mmol, 1 eq), P4 (49 mg, 0.19 mmol, 1 eq), Cs2CO3(190 mg, 1.77 mmol, 3 eq), Pd2dba3 (9 mg, 0.009 mmol, 0.05 eq) and XantPhos (12 mg, 0.019 mmol, 0.1 eq) in anh. dioxane (2 mL) was stirred at reflux temperature for 16 h. The reaction mixture was cooled to rt, filtered through a small pad of Celite and purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column, ACN (with 0.1% of FA) and water (with 0.1% of formic acid) as eluents, flow 17 mL / min, 40-70% ACN at 20 min, retention time 12 min) to give compound 1 (14 mg, yield 13%).1H NMR (400 MHz, DMSO-d6), δ: 7.88 (s, 1H), 6.81 (d, J = 7.7 Hz, 1H), 5.15 (p, J = 8.8 Hz, 1H), 4.54 (s, 2H), 3.72 (tdd, J = 10.3, 6.3, 3.9 Hz, 1H), 3.51 (d, J = 12.0 Hz, 2H), 2.88-2.75 (m, 5H), 2.17- 2.03 (m, 2H), 1.96-1.69 (m, 6H), 1.52 (tt, J = 10.9, 6.2 Hz, 4H).

[0622] Example 2. 8-Cyclopentyl-2-[[1-(1-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]pyrimido [5,4-b][1,4]oxazin-7-one (Compound 13). O O N O3(576 mg, 1.77 mmol, 3 eq), Pd2dba3 (27 mg, 0.029 mmol, 0.05 eq) and XantPhos (34 mg, 0.059 mmol, 0.1 eq) in anh. dioxane (2 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt, filtered through a small pad of Celite and purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column, ACN (with 0.1% of FA) and water (with 0.1% of FA) as eluents, flow 17 mL / min, 40-70% ACN at 20 min, RT 11 min) to give compound 13 (70 mg, yield 26%).1H NMR (400 MHz, DMSO-d6), δ: 8.26 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 5.12 (p, J = 8.8 Hz, 1H), 4.52 (s, 2H), 3.87(s, 3H), 3.56 (s, 1H), 3.43 (dd, J = 11.6, 4.6 Hz, 2H), 2.39 (td, J = 11.6, 2.9 Hz, 2H), 2.08 (ddd, J = 13.6, 9.8, 6.8 Hz, 2H), 1.89 (dt, J = 13.2, 3.8 Hz, 2H), 1.82 – 1.67 (m, 4H), 1.62- 1.45 (m, 4H).

[0623] Example 3. 8-Cyclopentyl-6-methyl-2-[[1-(1-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]pyrimido[5,4-b][1,4]oxazin-7-one (Compound 16). O O N O S Cs2CO3, xantphos, Pd2dba3(363 mg, 1.1 mmol, 3 eq), Pd2dba3(17 mg, 0.018 mmol, 0.05 eq) and XantPhos (21 mg, 0.037 mmol, 0.1 eq) in anh. dioxane (2 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt, filtered through a small pad of Celite and purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column, ACN (with 0.1% of FA) and water (with 0.1% of FA) as eluents, flow 17 mL / min, 40-70% ACN at 20 min, RT15 min) to give compound 16 (13.6 mg, yield 8%).1H NMR (400 MHz, DMSO-d6), δ: 8.26 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 5.14 (p, J = 8.8 Hz, 1H), 4.59 (q, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.56 (s, 1H), 3.43 (dd, J = 9.9, 5.8 Hz, 2H), 2.45 – 2.34 (m, 2H), 2.10 – 1.96 (m, 2H), 1.89 (dd, J = 13.1, 3.7 Hz, 2H), 1.80 (m, 1H), 1.74-1.67 (m, 3H), 1.53 (dtd, J = 21.2, 10.5, 4.4 Hz, 4H), 1.36 (d, J = 6.6 Hz, 3H).

[0624] Example 4. 8-Cyclopentyl-6,6-dimethyl-2-[(1-methylsulfonyl-4- piperidyl)amino]pyrimido[5,4-b][1,4]oxazin-7-one (Compound 5).of dioxane for 3 h (the solution became clear). The reaction mixture was concentrated, dissolved in 400 mL of DCM, washed with citric acid solution, brine, dried over Na2SO4, solvent was removed in vacuo. Product was purified by column chromatography (110 g SiO2), 200 mL Hexane / 1 L EtOAc. 6.3 g of product after column chromatography was boiled in methanol (180 mL). Solid product was filtered and dried in vacuo to give 5.44 g (66%) of compound 5.1H NMR (400 MHz, DMSO-d6), δ: 7.90 (s, 1H), 6.81 (d, J = 7.3 Hz, 1H), 5.31-5.22 (m, 1H), 3.81-3.72 (m, 1H), 3.58-3.53 (m, 2H), 2.90-2.82 (m, 5H), 2.14- 2.04 (m, 2H), 1.98-1.88 (m, 4H), 1.81-1.74 (m, 2H), 1.62-1.51(m, 4H), 1.39 (s, 6H). MS (ESI) m / z 424.2 [MH]+.

[0625] Example 5. 4-[(8-Cyclopentyl-6,6-dimethyl-7-oxo-pyrimido[5,4-b][1,4]oxazin-2- yl)amino]benzenesulfonamide (Compound 6).0.808 mmol, 1.2 eq) and TsOHxH2O (128 mg, 0.67 mmol, 1 eq) in 4 ml 4-methyl-2- pentanol was stirred at 130°C for 72 h. Reaction mixture was cooled to rt, the resulting precipitate was filtered and recrystallized from isopropanol. The product was purified by preparative HPLC (YMC ODS-A 250x20 mm, 5 µm column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL / min, 50-80% ACN at20 min, RT10 min) to obtain 32 mg of compound 6 (11% yield).1H NMR (400 MHz, METHANOL-D4), δ: 7.99 (d, J = 0.6 Hz, 1H), 7.77 (d, J = 1.0 Hz, 4H), 5.37 (p, J = 8.8 Hz, 1H), 2.17 (ddd, J = 16.0, 12.7, 7.4 Hz, 3H), 2.05 – 1.81 (m, 4H), 1.63 (dtt, J = 7.2, 5.1, 3.1 Hz, 2H), 1.45 (d, J = 0.7 Hz, 6H).

[0626] Example 6. 8-Cyclopentyl-6,6-dimethyl-2-[[1-(1-methylimidazol-4-yl)sulfonyl-4- piperidyl]amino]pyrimido[5,4-b][1,4]oxazin-7-one (Compound 96).4- yl)sulfonylpiperidin-4-amine hydrochloride (180 mg, 0.63 mmol, 1.2 eq), Cs2CO3 (520 mg, 1.6 mmol, 2 eq), Pd2dba3(24 mg, 0.026 mmol, 0.05 eq) and XantPhos (30 mg, 0.053 mmol, 0.1 eq) in dry dioxane (4 mL) was stirred at 80°C for 16 h. The reaction mixture was cooled to rt, filtered thorough celite, washed by EtOAc then diluted and water extracted. Organic layer was washed by brine, dried and evaporated. Residue purified by column chromatography using as eluent mixture EtOAc / MeOH (10%), followed by preparative HPLC (YMC ODS-A 250x20 mm, 5 µm column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL / min, 35-90% ACN at 20 min, RT 15.2 min) to give compound 96 (70 mg, yield 27%).1H NMR (400 MHz, METHANOL-D4), δ: 7.77 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.67 (t, J = 1.7 Hz, 1H), 5.36 – 5.23 (m, 1H), 3.77 (d, J = 2.0 Hz, 3H), 3.73 (dd, J = 9.2, 5.1 Hz, 4H), 2.79 – 2.68 (m, 2H), 2.11 (t, J = 9.6 Hz, 1H), 2.02 (d, J = 13.2 Hz, 2H), 1.98 – 1.77 (m, 2H), 1.71 – 1.56 (m, 4H), 1.45 (d, J = 2.0 Hz, 6H). LCMS (APCI) m / z= 490 [M+H].

[0627] Example 7. 8-cyclopentyl-6,6-dimethyl-2-[4- (methylsulfonylmethyl)anilino]pyrimido[5,4-b][1,4]oxazin-7-one (Compound 147).-were a 2- methyl-pentanol, purged with nitrogen, stirred at 130oC for 10 h. The reaction mixture was diluted with ethyl acetate, washed with NaHCO3solution, dried over Na2SO4, evaporated. The product was purified with prep-HPLC (35% to 75% acetonitrile to give 56 mg (24%) of compound 147.1H NMR (400 MHz, DMSO-d6), δ: 9.39 (s, 1H), 8.09 (s, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.31 (d, J = 7.3 Hz, 2H), 5.31 (p, J = 8.7 Hz, 1H), 4.36 (s, 2H), 2.86 (s, 3H), 2.14-2.07 (m, 2H), 1.94-1.80 (m, 4H), 1.62-1.57 (m, 2H), 1.44 (s, 6H). MS (ESI) m / z 431.2 [MH]+.

[0628] Example 8. 6,6-Dimethyl-2-[(1-methylsulfonyl-4-piperidyl)amino]-8- (tetrahydropyran-4-ylmethyl)pyrimido[5,4-b][1,4]oxazin-7-one (Compound 157).In of 1- methylsulfonylpiperidin-4-amine 7.4 mg (0.0417mmol, 0.1 eq) of palladium(II) acetate, 28mg (0.0417mmol, 0.1 eq) of BINAP, 252mg (1.67mmol, 4 eq) of cesium fluoride and 2mL of 1,4- dioxane were added followed by purging with nitrogen gas. After sealing the reaction was stirred at 110°C for 10-12 h. After cooling, the reaction mass was filteredthrough the celite pad and concentrated. The residue was chromatographed on silica gel 50% EtOAc / Hexane – 100% EtOAc, the residue triturate by diethyl ether to provide pure compound 157. Yield: 49 mg (26%).1H NMR (400 MHz, CHLOROFORM-D), δ: 7.87 (s, 1H), 4.76 (d, J = 7.5 Hz, 1H), 3.99 – 3.94 (m, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.86 (ddt, J = 10.3, 6.7, 3.5 Hz, 1H), 3.77 (dq, J = 12.5, 4.3 Hz, 2H), 3.33 (td, J = 11.6, 2.4 Hz, 2H), 2.93 (ddd, J = 12.6, 10.8, 2.8 Hz, 2H), 2.81 (s, 3H), 2.17 (dd, J = 13.1, 3.8 Hz, 2H), 2.07 (ddt, J = 11.3, 8.0, 4.0 Hz, 1H), 1.65 (dtd, J = 14.3, 10.6, 4.0 Hz, 2H), 1.53 (d, J = 8.2 Hz, 2H), 1.50 (s, 6H), 1.48 – 1.36 (m, 2H). LCMS (APCI) =454.2 [M+H]+.

[0629] Example 9. NMR spectra of certain compounds of the present disclosure. Cmpd # NMR spectra description 1 z, , 7 0 , – 7Cmpd # NMR spectra description 1H) 3.50 (d J = 12.3 Hz 2H) 2.85 – 2.75 (m 5H) 2.06 (d J = 10.1 Hz 4, , – 6 0 – ) 3 ) , 9 ),Cmpd # NMR spectra description 1H NMR (400 MHz DMSO-d6) δ: 8.92 (d J = 2.5 Hz 1H) 8.88 (dd J = 1, , .8 .8 6 - , 6 J 6Cmpd # NMR spectra description 1H NMR (400 MHz DMSO-d6) δ: 8.25 (s 1H) 8.06-8.00(m 2H) 7.36 (dd, ) , J 4 5 - ), ), 6 ,Cmpd # NMR spectra description 1H NMR (400 MHz DMSO-D6) δ: 9.17 (br. 1H) 8.12 (s 1H) 8.10 (t J = 5 3 .8 ), .8 , m, 7 , , ) , - , , )Cmpd # NMR spectra description 1H NMR (400 MHz METHANOL-D4) δ: 7.77 (s 1H) 5.33 (p J = 8.8 Hz, – , ), 3- 9 .9 4 ), - 3 , 4 ) 8 , JCmpd # NMR spectra description 1.89 (m 5H) 1.81 (td J = 13.1 8.4 Hz 2H) 1.69 – 1.51 (m 5H) 1.41 (s , z, , ) , ), , , – – 4 5 6 , 5Cmpd # NMR spectra description Hz 1H) 3.00 – 2.91 (m 2H) 2.30 (s 3H) 2.26 – 1.79 (m 12H) 1.67 – 1.55 ), ), m, , = , , , , ), ),Cmpd # NMR spectra description 2H) 2.72 – 2.57 (m 2H) 2.49 (s 3H) 2.41 (s 0H) 2.16 – 2.07 (m 5H) s, ), , 5 ) 6 m, , ), , – s,Cmpd # NMR spectra description 1H NMR (400 MHz DMSO-d6) δ: 7.95 (s 1H) 7.11 (s 1H) 5.19 (q J = – , , 6 ), , 4 4 4 ,Cmpd # NMR spectra description 1H NMR (400 MHz DMSO-d6) δ: 9.91 (s 1H) 8.21 (s 1H) 7.78 (d J = ), , ) , , .9 6 J = ), 0 ,Cmpd # NMR spectra description 3.69 (m 3H) 2.96 – 2.85 (m 2H) 2.80 (s 4H) 2.14 – 2.06 (m 2H) 1.66 – , , z, ), , , s, 7Biological Assays

[0630] Example A. Primary Assay Used to Determine Potency of CDK2 / CyclinA2 enzymatic activity Inhibition.

[0631] Compound activity was determined using recombinant CDK2 / CyclinA2 proteins (SignalChem, Cat# C29-10G), Histone H1 Peptide (SignalChem, Cat# H10-58) and ATP from ADP-Glo™ Kinase Assay kit (Promega, Cat# V9102) in an in vitro enzymatic reaction. Final concentrations were 0.1 ng / µL, 0.05 µg / µL and 5 µM, respectively. The reaction was carried out in assay buffer: 40 mM TRIS-HCl pH 7.4-7.6, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg / mL BSA. The compounds were dispensed on a 384-well Diamond Well Plate (Axygen, Cat# P-384-120SQ-C-S) at 80x solutions of compounds in DMSO.2x CDK2 / CyclinA2-Histone H1 Peptide mix was prepared in assay buffer and 4 µL of mixture per well was added into 384-well white Reaction plate with NBS (Corning, Cat# 4513). 4 µL of Histone H1 Peptide w / o CDK2 / CyclinA2 was used for negative control. Plates were centrifuged for 1 min at 200 g. Then 80x solutions of compounds in DMSO were diluted down to 2x solutions in 2x ATP and 4 µL of these solutions were added into wells with 4 µL of CDK2 / CyclinA2-Histone H1 Peptide mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then 4 µL of ADP-Glo reagent (Promega, ADP- Glo™ Kinase Assay, Cat# V9102) per well was added. Plates were incubated for 30 min at rt. Then 8 µL of Kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) per well was added and the Luminescence was measured using microplate reader ClarioStarPlus (BMG). The % inhibition was then used to calculate the IC50 values in GraphPad Prism using four-parametric equation: Y=Bottom+(Top- Bottom) / (1+10^((LogEC50-X)*HillSlope)).

[0632] Example B. Primary Assay Used to Determine Potency of CDK1 / CyclinA2 enzymatic activity Inhibition.

[0633] Compound activity was determined using recombinant CDK1 / CyclinA2 proteins (SignalChem, Cat# C22-18G), Histone H1 Peptide (SignalChem, Cat# H10-58) and ATP from ADP-Glo™ Kinase Assay kit (Promega, Cat# V9102) in an in vitro enzymatic reaction. Final concentrations were 0.1 ng / µL, 0.2 µg / µL and 5 µM, respectively. The reaction was carried out in assay buffer: 40 mM TRIS-HCl pH 7.4-7.6, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg / mL BSA. The compounds were dispensed on a 384-well Diamond Well Plate (Axygen, Cat# P-384-120SQ-C-S) at 80x solutions of compounds in DMSO. 2x CDK1 / CyclinA2-Histone H1 Peptide mix was prepared in assay buffer and 4 µL of mixture per well was added into 384-well white Reaction plate with NBS (Corning, Cat# 4513). 4 µL of Histone H1 Peptide w / o CDK1 / CyclinA2 was used for negative control. Plates were centrifuged for 1 min at 200 g. Then 80x solutions of compounds in DMSO were diluted down to 2x solutions in 2x ATP and 4 µL of these solutions were added into wells with 4 µL of CDK1 / CyclinA2-Histone H1 Peptide mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then 4 µL of ADP-Glo reagent (Promega, ADP- Glo™ Kinase Assay, Cat# V9102) per well was added. Plates were incubated for 30 min at rt. Then 8 µL of Kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat#V9102) per well was added and the Luminescence was measured using microplate reader ClarioStarPlus (BMG). The % inhibition was then used to calculate the IC50 values in GraphPad Prism using four-parametric equation: Y=Bottom+(Top- Bottom) / (1+10^((LogEC50-X)*HillSlope)).

[0634] The average IC50 values are shown in Table A, wherein “A” corresponds to IC50: A ≤ 0.001 µM, “B” corresponds to 0.001 µM < IC50 ≤ 0.01 µM, “C” 0.01 µM < IC50 ≤ 0.1 µM, “D” corresponds to 0.1 µM < IC50≤ 1.0 µM and “E” corresponds to IC50> 1.0 µM.

[0635] Table A: CDK2 / CDK1 Compound # CDK2, IC50, µM CDK1, IC50, µM CDK1 / CDK2 1 B C 13.5 .05

[0636] The average Ki values are shown in Table B, wherein “A” corresponds to Ki < 0.001, “B” corresponds to 0.001 ≤ Ki< 0.01, “C” corresponds to 0.01 ≤ Ki< 0.1, “D” corresponds to 0.1 ≤ Ki< 1.0, and “E” corresponds to Ki≥ 1.0.

[0637] Table B: Ki for CDK1 and CDK2 Compound # CDK2 / E1 Ki CDK1 / A2 Ki CDK1 / CDK2Compound # CDK2 / E1 Ki CDK1 / A2 Ki CDK1 / CDK2 54 B D 128.52Compound # CDK2 / E1 Ki CDK1 / A2 Ki CDK1 / CDK2 90 E E 1.35*- Kiis the dissociation constant describing the binding affinity between the inhibitor and the enzyme. Ki: A < 0.001, 0.001 ≤ B < 0.01, 0.01 ≤ C < 0.1, 0.1 ≤ D < 1.0, E ≥ 1.0

[0638] Example C. Cellular Growth Inhibition Assay.

[0639] Complete culture media for cell cultures: 50:50 of MCDB 105 (Cell Applications, USA, Cat# 117-500) and Medium 199 with Earle’s Salts (Capricorn, Germany, Cat# M199-A) for TOV-21G and RPMI-1640 (VWR, USA, Cat# 392-0429) for NIH:OVCAR- 3, plus 10 % FBS (Gibco, USA, Cat# 10500-064 or Capricorn, Germany, Cat# HI-11A), 1x Antibiotic-antimycotic (Gibco, USA, Cat# 15240-062), 2x Sodium pyruvate (Gibco, USA, Cat# 11360-070), 2x Essential amino acids (Gibco, USA, Cat# 11130-051), 1x Non- Essential amino acids (Gibco, USA, Cat# 11140-050). NIH:OVCAR-3 (ATCC, HTB-161) and TOV-21G (ATCC, CRL-11730) were seeded at a density of 500 cells per well in a CellBIND® 384-well Flat Clear Bottom Black Polystyrene Microplates (Corning, USA, Cat #3770) in 45 µl total volume of complete culture medium applying Biomek NX (384). Cells were allowed to adhere overnight at 37°C, 5% CO2. 500x compounds solutions in DMSO (Honeywell International, Inc., USA, Cat# 472301-1L) were prepared in Compounds plate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S) and DMSO only control was included. 1 µl of 500x compounds (Compounds plate) was added to 49 µl of complete culture medium into Dilution plate (Diamond Well Plate, Axigen, Cat#P-384- 120SQ-C-S), mixed and then 5 µl of 10x compounds solutions were transferred to cells applying Biomek NX (384) followed by centrifugation at 100 g for 1 min. Final DMSO concentration was 0.2%. After 3 days of incubation, 1 µl of 500x compounds (Compounds plate) was added to 49 µl of complete culture medium into Dilution plate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S), mixed and then 10 µl of 10x compounds solutions were transferred to cells using Biomek NX (384) followed by centrifugation at 100 g for 1 min. After 7 days of incubation, 15 µl of CyQUANT™ (Invitrogen, USA, CAT# C35011) were added to the cells and the fluorescence signal was measured after 1 h of incubation at 37°C, 5% CO2using Microplate Reader (CLARIOStar).

[0640] The average CC50values are shown in Table B, wherein “A” corresponds to CC50: A ≤ 0.1 µM, “B” corresponds to 0.1 µM < CC50 ≤ 0.5 µM, “C” CC50 > 0.5 µM.

[0641] Table C.OVCAR-3 CyQuant, TOV-21G CyQuant, Compound # CC50 µM CC50 µMOVCAR-3 CyQuant, TOV-21G CyQuant, Compound # CC50 µM CC50 µM M;Equivalents

[0642] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (A): , or a pharmaceutically or tautomer thereof,wherein: the bonds are selected from single bonds and double bonds; R0is selected , and C1-C6 alkylA is selected from CR4R5, O, SO2, and NR4; E is selected from C, CH and N, provided that when bonds are single bonds, then E is N or CH, and when bonds are double bonds, then E is C; each G is independently selected from CH and N; X is selected Y is selected fromthat Y is N or CH if the bonds are double bonds and Y is CH2 if the bonds are single bonds; Z is selected from a bond, NH, and -CH2-; R1is selected from H, halogen, C1-C6alkyl, C3-C7cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl;R2is selected from H, halogen, -CN, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; or R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl, or 3-10 membered heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with one or more substitutients independently selected from halogen, OH, C1-C6alkyl; or R1and R2together form =O; R3is selected from C1-C6 alkyl, -N(R7)2, 3-8 membered cycloalkyl, aryl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from C1-C6 alkyl, -NH2, -OH, -CN, halogen, oxo; R4is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)-C1-C6 alkyl, - C(O)OC1-C6alkyl, -C(O)NHC1-C6alkyl, -OC(O)NHC1-C6alkyl, -S(O)2-C1-C6alkyl, and aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-C6 alkyl)2, C1- C6alkoxy; or R3and R4together with the atoms to which they are attached and any intervening atoms, form a cycle; or R3and R8together with the atoms to which they are attached and any intervening atoms, form a heterocyclyl or heteroaryl; R5is selected from H, halogen, oxo, -OH, -NH2 -CN, C1-C6 alkyl, C1-C6 alkoxy, - OC(O)N(R7)2; each R6is independently selected from halogen, OH, C1-C6alkyl, -N(R7)2, - N(R7)COR4, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, OH, CN; or two R6together with atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6alkyl; or two R6form =O;each R7is independently selected from H, C1-C6alkyl, -C(O)C1-C6alkyl, C1-C6alkyl-OC(O)NH-(C1-C6 alkanediyl)-, C1-C6-alkanediyl-O-C1-C6 alkyl; each R8is independently selected from halogen, OH, CN, C1-C6 alkyl, heterocyclyl, heteroaryl; R9is selected from C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH(C1-C6 alkyl), - S(=O)(=NH)(C1-C6 alkyl), 5-10 membered monocyclic or bicyclic heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, wherein heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from -OH, - CN, halogen, C1-C6 alkyl and C1-C6 alkyl-heterocyclyl; or R8and R9together with atoms to which they are attached and any intervening atoms form a 5-7 membered cycloalkyl, heterocyclyl, or heteroaryl, wherein cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, OH, =O, CN, C1-C6 alkyl, wherein alkyl is optionally substituted with heterocyclyl; n is an integer selected from 1, 2, and 3; m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; k is an integer selected from 0, 1, and 2; r is an integer selected from 0 and 1.

2. The compound of claim 1, wherein the compound has the Formula (A-0): , or aor tautomer thereof.

3. The compound of claim 1, wherein the compound has the Formula (I):, or a pharmaceutically or tautomer thereof,wherein: the bonds are selected from single bonds and double bonds; A is selected from CR4R5and NR4; E is selected from C and N, provided that when bonds are single bonds, then E is N, and when bonds are double bonds, then E is C; R1is selected from H, halogen, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; R2is selected from H, halogen, -CN, C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, heterocycle, aryl, and heteroaryl; or R1and R2together with the atom to which they are attached and any intervening atoms, form 3-10 membered cycloalkyl; R3is selected from C1-C6 alkyl, -NH2, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substitutients independently selected from C1-C6alkyl, -NH2, -OH, -CN, halogen, oxo; R4is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)OC1-C6 alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-C6alkyl)2, C1-C6alkoxy; R5is selected from H, halogen, oxo, -OH, -NH2 -CN, C1-C6 alkyl, C1-C6 alkoxy.

4. The compound of claim 2, wherein the compound is of Formula (I-A):, or a or tautomer thereof.

5. The (I-B): , or aor tautomer thereof.

6. The compound of claim 3, wherein the compound is of Formula (I-A-1): I), or aor tautomer thereof.

7. The compound of claim 3, wherein the compound is of Formula (I-A-2):, or a or tautomer thereof.

8. The (I-B-1): , or aor tautomer thereof.

9. The compound of claim 4, wherein the compound is of Formula (I-B-2): , or aisotopic derivative, or tautomer thereof.

10. A compound selected from:# Structure IUPAC Name - e - - e - - e - - -# Structure IUPAC Name O O - e o- - e '- e - - e# Structure IUPAC Name - -# Structure IUPAC Name OO- l- - - - -# Structure IUPAC Name - - - - e - - )-# Structure IUPAC Name - - - - -# Structure IUPAC Name - - - d -# Structure IUPAC Name N 4- - - - -# Structure IUPAC Name O - - - - - l- -# Structure IUPAC Name l- - l- - -# Structure IUPAC Name l- - l- - l- -# Structure IUPAC Name 6- - - )- - l- - - 4# Structure IUPAC Name - - a - a# Structure IUPAC Name - - - - - -# Structure IUPAC Name - - - - - - es# Structure IUPAC Name l- - - - - - o - l- -# Structure IUPAC Name - - - - - n-# Structure IUPAC Name - n- - - - - - - - e - -# Structure IUPAC Name O - - - - - - - - - -# Structure IUPAC Name N - o - - - -# Structure IUPAC Name - i 1- i# Structure IUPAC Name O N - -# Structure IUPAC Name - - - - - 3- - - -# Structure IUPAC Name - - - - - n- n- e# Structure IUPAC Name - - e - - -# Structure IUPAC Name - - - e# Structure IUPAC Name - - - - - -# Structure IUPAC Name 5- - - a- ,2o# Structure IUPAC Name - n ,2,1# Structure IUPAC Name ,1n- - 6,1# Structure IUPAC Name l- - - - -# Structure IUPAC Name - 3- - e ]- -# Structure IUPAC Name O 2. - r - - - - - - ] -# Structure IUPAC Name n- n- -# Structure IUPAC Name - - - - - - - - - l]# Structure IUPAC Name - ] - o 7- - - - - -# Structure IUPAC Name ,1- ,2- 4,1-# Structure IUPAC Name - l- - 2- - - - -# Structure IUPAC Name ]- - - e -# Structure IUPAC Name ,111. A pharmaceutical composition comprising a compound of any one of claims 1–9 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active agents.

13. A method of inhibiting of CDK2 in a cell, comprising contacting the cell with a compound of any one of claims 1–8 or a pharmaceutical composition of claim 9 or 10.

14. The method of claim 12, wherein the contacting is in vitro or in vivo.

15. A method for the treatment or prevention of a disease or disorder associated with CDK2 comprising administering to a subject in need thereof a compound of any one of claims 1–9 or a pharmaceutical composition of claim10 or 11.

16. The method of claim 14, wherein the disease or disorder is selected from the group consisting of Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RB1); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT).

17. The method of claim 14, wherein the disease or disorder is cancer.

18. The method of any one of claims 12-16, wherein the subject is a mammal.

19. The method of claim 16, wherein the subject is a human.