CDK2 inhibitors

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

CDK2 Inhibitors CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application Serial No. 63 / 569,055, filed on March 22, 2024, entitled ‘Inhibitors of CDK2.' The disclosure of this provisional application is incorporated herein by reference in its entirety for all purposes.FIELD OF INVENTION

[0002] 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

[0003] 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.

[0004] Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with roles in inactivating phosphorylation of the RB 1 (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.

[0005] 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 andincreased 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.

[0006] 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

[0007] 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

[0008] A first aspect of the invention relates to compounds of Formula (A):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, and -C(O)NR8R9, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R3is selected from C1-C6alkyl, C3-C10cycloalkyl, heterocyclyl, and aryl wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R10;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, - C1-C6alkanediyl-, -C1-C6alkanediyl-O-, - C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3.

[0009] In some embodiments, the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), 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 disease or disorder associated with CDK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with CDK2 an effective amount of a compound of Formula (A), 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 acompound of Formula (A), 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 (A), 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 (A), 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 (A), 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 (A), 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 (A), 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 (A), 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 selectivity 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 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.

[0021] The present invention further provides methods of treating cancer diseases, blood diseases, immune diseases, genetic diseases, respiratory diseases, endocrine diseases, ear diseases, eye diseases, fetal diseases, metabolic diseases, neuronal diseases, skin diseases, gastrointestinal diseases, skin diseases, mental diseases, liver diseases, nephrological diseases, rare diseases, reproductive diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), 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 (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Gastric Cancer (GASC); Hepatocellular Carcinoma (HCC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Ataxia-Telangiectasia (AT); Pheochromocytoma (PCC) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), 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 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 - P1-P159)

[0025] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0026] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0027] 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.

[0028] Other features and advantages of the disclosure will be apparent from the following detailed description and claimsDETAILED DESCRIPTION

[0029] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with CDK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0030] 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. Unlessdefined 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

[0031] 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 examμle, "an element" means one element or more than one element.

[0032] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0033] 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.

[0034] 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 examμle, an aryl substituted witha 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.

[0035] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0036] 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. Exemμlary 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. Exemμlary 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.

[0037] 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 containingone 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. Examμles 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-l-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, lH-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, l,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,l-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.Exemμlary ring systems of these heteroaryl groups include, for examμle, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-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-9 / 7- 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.

[0038] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0039] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examμles of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, neo-pentyl, and iso-hexyl.

[0040] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examμles of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0041] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing2-12 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. Examμles 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.

[0042] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triμle bond in the chain. Examμles of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0043] The terms “alkanediyl”, “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstractionof 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-C4alkylene. 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.

[0044] “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. Examμles of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-lH-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.

[0045] “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. Examμles 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.

[0046] The term “aromatic” means a μlanar 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.

[0047] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examμles of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0048] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examμles of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0049] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triμle bond, i.e., C≡N.

[0050] “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, or identical in size and nature. Examμles 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.

[0051] 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).

[0052] The term "solvate" refers to a comμlex 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. Examμles of suitable solvents include, but are not limited to, water, MeOH, EtOH, 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.

[0053] 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 μlane 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.

[0054] The present disclosure also contemμlates 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 Examμles herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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 fdler, 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.

[0059] 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.

[0060] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0061] 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.

[0062] 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.

[0063] The term “salt’ refers to pharmaceutically acceptable salts.

[0064] 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.

[0065] “ CDK2 inhibitor” as used herein refer to a compound of Formula A and / or compositions comprising a compound of Formula A which inhibits CDK2.

[0066] 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 of Formula A (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 examμle, 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 ormanifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For examμle, 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

[0067] In one aspect, the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereofwherein X, R1, R2, R3, m, and n are as described herein.

[0068] It is understood that, for a compound of Formula (A), X, R1, R2, R3, m and n can each be, where apμlicable, selected from the groups described herein, and any group described herein for any X, R1, R2, R3, m and n can be combined, where apμlicable, with any group described herein for one or more of the remainders of X, R1, R2, R3, m and n.

[0069] In some embodiments, the compound is of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R3is selected from H, halogen, C1-C6alkyl and R6; orR4and R3together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-.;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH,CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.

[0070] In some embodiments, the compound is of Formula (I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0071] In some embodiments, the compound is of Formula (I-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0072] In some embodiments, the compound is of Formula (I-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0073] In some embodiments, the compound is of Formula (I-D):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0074] In some embodiments, the compound is of Formula (I-E):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0075] In some embodiments, the compound is of Formula (I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0076] In some embodiments, the compound is of Formula (I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0077] In some embodiments, the compound is of Formula (I-A-l-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0078] In some embodiments, the compound is of Formula (I-A-l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0079] In some embodiments, the compound is of Formula (I-A-l-a-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0080] In some embodiments, the compound is of Formula (I-A-l-a-I-A-1 -a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0081] In some embodiments, the compound is of Formula (I-B-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0082] In some embodiments, the compound is of Formula (I-B-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0083] In some embodiments, the compound is of Formula (I-B-l-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0084] In some embodiments, the compound is of Formula (I-B-l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0085] In some embodiments, the compound is of Formula (I-B-l-a-I-A-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0086] In some embodiments, the compound is of Formula (I-B-l-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0087] In some embodiments, the compound is of Formula (I-B-l-a-I-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0088] In some embodiments, the compound is of Formula (I-B-l-a-I-B-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0089] In some embodiments, the compound is of Formula (I-B-l-a-I-B-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0090] In some embodiments, the compound is of Formula (I-C-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0091] In some embodiments, the compound is of Formula (I-C-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0092] In some embodiments, the compound is of Formula (I-C-l-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0093] In some embodiments, the compound is of Formula (I-C-l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0094] In some embodiments, the compound is of Formula (I-C-l-a-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0095] In some embodiments, the compound is of Formula (I-C-l-a-I-A-1 -a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0096] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0097] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0098] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-d):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0099] In some embodiments, the compound is of Formula (I-C-l-a-I-A- l-e):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0100] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-f):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0101] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-g):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0102] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-h):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0103] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-i):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0104] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-j):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0105] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-k):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0106] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-k’):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0107] In some embodiments, the compound is of Formula (I-C-l-a-I-A-1-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0108] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-m):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0109] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-n):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0110] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-o):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.[01111 In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-pq):-pq), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5; a is an integer selected from 0, 1, and 2; and b is an integer selected from 1, 2, and 3.

[0112] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-p’):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0113] In some embodiments, the compound is of Formula (I-C-l-a-I-A-l-p”):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0114] In some embodiments, the compound is of Formula (I-C-l-a-I-A-I-q):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0115] In some embodiments, the compound is of Formula (I-C-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0116] In some embodiments, the compound is of Formula (I-C-l-b-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0117] In some embodiments, the compound is of Formula (I-C-l-b-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0118] In some embodiments, the compound is of Formula (I-C-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0119] In some embodiments, the compound is of Formula (I-C-l-c-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0120] In some embodiments, the compound is of Formula (I-C-l-c-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0121] In some embodiments, the compound is of Formula (I-C-l-c-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0122] In some embodiments, the compound is of Formula (I-C-l-c-II):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0123] In some embodiments, the compound is of Formula (I-C-l-c-II-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0124] In some embodiments, the compound is of Formula (I-C-l-c-II-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0125] In some embodiments, the compound is of Formula (I-C-l-c-III):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0126] In some embodiments, the compound is of Formula (I-C-l-c-III-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0127] In some embodiments, the compound is of Formula (I-C-l-c-III-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0128] In some embodiments, the compound is of Formula (I-C-l-c-IV):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0129] In some embodiments, the compound is of Formula (I-C-l-c-IV-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0130] In some embodiments, the compound is of Formula (I-C-l-c-IV-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rais selected from H, C1-C6alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C1-C6alkoxy, aryl, aryloxy.

[0131] In some embodiments, the compound is of Formula (I-C-l-c-V):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0132] In some embodiments, the compound is of Formula (I-C-l-c-V-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0133] In some embodiments, the compound is of Formula (I-C-l-c-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0134] In some embodiments, the compound is of Formula (I-C-l-c-I-A-I-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0135] In some embodiments, the compound is of Formula (I-C-l-d):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0136] In some embodiments, the compound is of Formula (I-C-l-d-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0137] In some embodiments, the compound is of Formula (I-C-l-d-I- A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0138] In some embodiments, the compound is of Formula (I-C-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0139] In some embodiments, the compound is of Formula (I-C-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0140] In some embodiments, the compound is of Formula (l-C-2-a-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rbis selected from H, and R6.

[0141] In some embodiments, the compound is of Formula (I-C-2-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rbis selected from H, and R6.

[0142] In some embodiments, the compound is of Formula (I-C-2-a-I-A- l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Rbis selected from H, and R6.

[0143] In some embodiments, the compound is of Formula (I-C-2-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0144] In some embodiments, the compound is of Formula (I-C-2-a-I-A-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0145] In some embodiments, the compound is of Formula (I-C-2-a-I-A-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0146] In some embodiments, the compound is of Formula (I-C-2-a-I-A-l-c-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0147] In some embodiments, the compound is of Formula (I-C-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0148] In some embodiments, the compound is of Formula (I-C-3-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0149] In some embodiments, the compound is of Formula (I-C-3-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0150] In some embodiments, the compound is of Formula (I-C-3-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0151] In some embodiments, the compound is of Formula (I-C-3-a-I-A-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0152] In some embodiments, the compound is of Formula (I-C-3-a-II):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0153] In some embodiments, the compound is of Formula (I-C-3-a-II-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0154] In some embodiments, the compound is of Formula (I-C-3-a-II-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0155] In some embodiments, the compound is of Formula (I-C-3-a-III):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0156] In some embodiments, the compound is of Formula (I-C-3-a-III-A):-in-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0157] In some embodiments, the compound is of Formula (I-C-3-a-III-A-I):-in-A-l), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0158] In some embodiments, the compound is of Formula (I-C-3-a-IV):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0159] In some embodiments, the compound is of Formula (I-C-3-a-IV-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0160] In some embodiments, the compound is of Formula (I-C-3-a-IV-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0161] In some embodiments, the compound is of Formula (I-C-3-a-V):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0162] In some embodiments, the compound is of Formula (I-C-3-a-V-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0163] In some embodiments, the compound is of Formula (I-C-3-a-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0164] In some embodiments, the compound is of Formula (I-C-3-a-V-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0165] In some embodiments, the compound is of Formula (I-C-3-a-I-B-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0166] In some embodiments, the compound is of Formula (I-C-3-a-V-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0167] In some embodiments, the compound is of Formula (I-C-3-a-I-C-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0168] In some embodiments, the compound is of Formula (I-D-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0169] In some embodiments, the compound is of Formula (I-D-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0170] In some embodiments, the compound is of Formula (I-D-l-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0171] In some embodiments, the compound is of Formula (I-D-l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0172] In some embodiments, the compound is of Formula (I-D-l-a-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0173] In some embodiments, the compound is of Formula (I-D-l-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0174] In some embodiments, the compound is of Formula (I-D-l-a-I-A-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0175] In some embodiments, the compound is of Formula (II):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, and NR6;Y is selected from O, NH, and S; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R’ form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-Cg alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.

[0176] In some embodiments, the compound is of Formula (II-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0177] In some embodiments, the compound is of Formula (II-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0178] In some embodiments, the compound is of Formula (II-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0179] In some embodiments, the compound is of Formula (II-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0180] In some embodiments, the compound is of Formula (II-A-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0181] In some embodiments, the compound is of Formula (II-A-3.1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0182] In some embodiments, the compound is of Formula (II-A-3.1-a):3.1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0183] In some embodiments, the compound is of Formula (II-A-3. I-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0184] In some embodiments, the compound is of Formula (II-A-3.1-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0185] In some embodiments, the compound is of Formula (II-A-3. I-a-I-A-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0186] In some embodiments, the compound is of Formula (II-A-3.1-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0187] In some embodiments, the compound is of Formula (Il-A-3.1-a-I-A-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0188] In some embodiments, the compound is of Formula (II-A-3.1-a-I-A-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0189] In some embodiments, the compound is of Formula (II-A-3.1-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0190] In some embodiments, the compound is of Formula (II-A-3.1 -b-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0191] In some embodiments, the compound is of Formula (II-A-3.1 -b-I- A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0192] In some embodiments, the compound is of Formula (II-A-3.1-b-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0193] In some embodiments, the compound is of Formula (II-A-3. I-b-I-A-I-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0194] In some embodiments, the compound is of Formula (II-A-3.2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0195] In some embodiments, the compound is of Formula (II-A-3.2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0196] In some embodiments, the compound is of Formula (II-A-3.2-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0197] In some embodiments, the compound is of Formula (II-A-3.2-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0198] In some embodiments, the compound is of Formula (II-A-3.2-a-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0199] In some embodiments, the compound is of Formula (II-A-3.2-a-I-A-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0200] In some embodiments, the compound is of Formula (II-B-3.1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0201] In some embodiments, the compound is of Formula (II-B-3.1-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0202] In some embodiments, the compound is of Formula (II-B-3.1-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0203] In some embodiments, the compound is of Formula (II-B-3.1-a-I- A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0204] In some embodiments, the compound is of Formula (II-B-3.1-a-I- A- 1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0205] In some embodiments, the compound is of Formula (II-B-3.1-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0206] In some embodiments, the compound is of Formula (II-B-3.1 -b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0207] In some embodiments, the compound is of Formula (II-B-3.1 -b-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0208] In some embodiments, the compound is of Formula (II-B-3.1-a-I- A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0209] In some embodiments, the compound is of Formula (II-B-3.1-a-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0210] In some embodiments, the compound is of Formula (II-B-3.1-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0211] In some embodiments, the compound is of Formula (II-B-3.2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0212] In some embodiments, the compound is of Formula (II-B-3.2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0213] In some embodiments, the compound is of Formula (II-B-3.2-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0214] In some embodiments, the compound is of Formula (II-B-3.2-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0215] In some embodiments, the compound is of Formula (II-B-3.2-a-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0216] In some embodiments, the compound is of Formula (II-B-3.2-a-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0217] In some embodiments, the compound is of Formula (II-B-3.2-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0218] In some embodiments, the compound is of Formula (II-B-3.2-b-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0219] In some embodiments, the compound is of Formula (ll-B-3.2-b-l-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0220] In some embodiments, the compound is of Formula (II-B-3.2-b-I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0221] In some embodiments, the compound is of Formula (II-B-3.2-b-I-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0222] In some embodiments, the compound is of Formula (III):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9A-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3;r is an integer selected from 0, 1, 2, and 3.

[0223] In some embodiments, the compound is of Formula (III-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0224] In some embodiments, the compound is of Formula (III-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0225] In some embodiments, the compound is of Formula (III-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0226] In some embodiments, the compound is of Formula (III-A- 1-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0227] In some embodiments, the compound is of Formula (III-A-l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0228] In some embodiments, the compound is of Formula (III-A-l-a-I-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0229] In some embodiments, the compound is of Formula (IV):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:Ar is an aryl;X is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN; R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.

[0230] In some embodiments, the compound is of Formula (IV-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0231] In some embodiments, the compound is of Formula (IV-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0232] In some embodiments, the compound is of Formula (IV-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0233] In some embodiments, the compound is of Formula (IV-A-l-a-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0234] In some embodiments, the compound is of Formula (IV-A- l-a-I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0235] In some embodiments, the compound is of Formula (IV-A-l-a-I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0236] In some embodiments, the compound is of Formula (A). In some embodiments, the compound is of Formula (I). In some embodiments, the compound is of Formula (II). In some embodiments, the compound is of Formula (III). In some embodiments, the compound is of Formula (IV).

[0237] In some embodiments, the compound is of Formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0238] In some embodiments, the compound is of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0239] In some embodiments, the compound is of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0240] In some embodiments, the compound is of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0241] In some embodiments, the compound is of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0242] In some embodiments, X is selected from O, CR4R5, S(O)q, NR6.

[0243] In some embodiments, X is O.

[0244] In some embodiments, X is CR4R5.

[0245] In some embodiments, X is CF2.

[0246] In some embodiments, X is S(O)q.

[0247] In some embodiments, X is S.

[0248] In some embodiments, X is S=O.

[0249] In some embodiments, X is SO2.

[0250] In some embodiments, X is -NR6.

[0251] In some embodiments, X is N-L-R7.

[0252] In some embodiments, each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, -C(O)OR8, and -C(O)NR8R9, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl.

[0253] In some embodiments, R1is H.

[0254] In some embodiments, R1is -C(O)OR8.

[0255] In some embodiments, R1is -C(O)OCH3.

[0256] In some embodiments, R1is -C(O)NR8R9.

[0257] In some embodiments, R1is -C(O)NH2.

[0258] In some embodiments, R1is -C(O)N(CH3)2.

[0259] In some embodiments, two R1form a bond.

[0260] In some embodiments, two R1form a single bond.

[0261] In some embodiments, R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy.

[0262] In some embodiments, R2is H.

[0263] In some embodiments, R2is C1-C6alkyl.

[0264] In some embodiments, R2is methyl.

[0265] In some embodiments, R2is ethyl.

[0266] In some embodiments,

[0267] In some embodiments, R2is C1-C6alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy.

[0268] In some embodiments,

[0269] In some embodiments,

[0270] In some embodiments,

[0271] In some embodiments,

[0272] In some embodiments,

[0273] In some embodiments,

[0274] In some embodiments, R2is C3-C10cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy.

[0275] In some embodiments, R2is C3-C10cycloalkyl.

[0276] In some embodiments,

[0277] In some embodiments,

[0278] In some embodiments, R3is selected from C1-C6alkyl, C3-C10cycloalkyl, heterocyclyl, and aryl wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R10.

[0279] In some embodiments, R3is C1-C6alkyl optionally substituted with one or more R10.

[0280] In some embodiments, R3is C1-C6alkyl.

[0281] In some embodiments, R3is propyl.

[0282] In some embodiments, R3is iso-propyl.

[0283] In some embodiments, R3is butyl.

[0284] In some embodiments, R3is tert-butyl.

[0285] In some embodiments, R3is C3-C10cycloalkyl optionally substituted with one or more R10.

[0286] In some embodiments, R3is C3-C10cycloalkyl.

[0287] In some embodiments, R3is C3-C10monocyclic cycloalkyl.

[0288] In some embodiments,

[0289] In some embodiments,

[0290] In some embodiments,

[0291] In some embodiments,

[0292] In some embodiments,

[0293] In some embodiments,

[0294] In some embodiments,

[0295] In some embodiments,

[0296] In some embodiments,

[0297] In some embodiments,

[0298] In some embodiments, R3is heterocyclyl optionally substituted with one or more R10.

[0299] In some embodiments, R3is heterocyclyl.

[0300] In some embodiments, R3is five membered heterocyclyl.

[0301] In some embodiments, R3is six membered heterocyclyl.

[0302] In some embodiments,

[0303] In some embodiments,

[0304] In some embodiments,

[0305] In some embodiments,

[0306] In some embodiments,

[0307] In some embodiments,

[0308] In some embodiments,

[0309] In some embodiments,

[0310] In some embodiments,

[0311] In some embodiments, R3is aryl optionally substituted with one or more R10.

[0312] In some embodiments, R3is aryl.

[0313] In some embodiments,

[0314] In some embodiments, X is selected from O, CR4R5, SO2, NR6.

[0315] In some embodiments, X is O.

[0316] In some embodiments, X is CR4R5.

[0317] In some embodiments, R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN.

[0318] In some embodiments, R4is H.

[0319] In some embodiments, R4is halogen.

[0320] In some embodiments, R4is F.

[0321] In some embodiments, R4is C1-C6alkyl.

[0322] In some embodiments, R4is methyl.

[0323] In some embodiments, R4is tert-butyl.

[0324] In some embodiments, R5is selected from H, halogen, C1-C6alkyl and R6.

[0325] In some embodiments, R5is H.

[0326] In some embodiments, R5is halogen.

[0327] In some embodiments, R5is F.

[0328] In some embodiments, R5is C1-C6alkyl.

[0329] In some embodiments, R5is methyl.

[0330] In some embodiments, R5is R6.

[0331] In some embodiments, R5is -L-R7.

[0332] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionallysubstituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6.

[0333] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0334] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0335] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0336] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0337] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0338] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0339] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0340] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0341] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0342] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0343] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0344] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0345] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0346] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0347] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0348] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0349] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0350] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0351] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0352] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0353] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0354] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0355] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0356] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0357] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0358] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0359] In some embodiments, X is SO2.

[0360] In some embodiments, X is NR6.

[0361] In some embodiments, R6is -L-R7.

[0362] In some embodiments, L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O- CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-.

[0363] In some embodiments, L is a bond.

[0364] In some embodiments, L is a single bond.

[0365] In some embodiments, L is -C(O)-.

[0366] In some embodiments, L is -S(O)2-.

[0367] In some embodiments, L is -O-C(O)-.

[0368] In some embodiments, L is -O-CH2-C(O)-.

[0369] In some embodiments, L is -O-CH2-S(O)2-.

[0370] In some embodiments, L is-CH2-C(O)-.

[0371] In some embodiments, L is-NH-C(O)-.

[0372] In some embodiments, L is -C1-C6alkanediyl-.

[0373] In some embodiments, L is -C1-C6alkanediyl-O-.

[0374] In some embodiments, L is -C1-C6alkanediyl-C(O)-.

[0375] In some embodiments, L is -CH2-C(O)-.

[0376] In some embodiments, L is -C1-C6alkanediyl-NH-C(O)-.

[0377] In some embodiments, L is -CH2-NH-C(O)-.

[0378] In some embodiments, R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-.

[0379] In some embodiments, R7is C1-C6alkyl- optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy.

[0380] In some embodiments, R7is C1-C6alkyl.

[0381] In some embodiments, R7is methyl.

[0382] In some embodiments, R7is ethyl.

[0383] In some embodiments, R7is propyl.

[0384] In some embodiments, R7is n-propyl.

[0385] In some embodiments, R7is / -propyl.

[0386] In some embodiments, R7is butyl.

[0387] In some embodiments, R7is tert-butyl.

[0388] In some embodiments, R7is C1-C6alkyl substituted with one or more halogen.

[0389] In some embodiments, R7is

[0390] In some embodiments, R7is C1-C6alkyl substituted with R8R9N-.

[0391] In some embodiments,

[0392] In some embodiments, R7is cycloalkyl- optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-.

[0393] In some embodiments, R7is cycloalkyl-.

[0394] In some embodiments, R7is C3-C10monocyclic cycloalkyl.

[0395] In some embodiments, R7is cyclopropyl.

[0396] In some embodiments, R7is cyclobutyl.

[0397] In some embodiments, R7is cyclopentyl.

[0398] In some embodiments, R7is cyclohexyl.

[0399] In some embodiments,

[0400] In some embodiments, R7is cycloalkyl- optionally substituted with one or more halogen.

[0401] In some embodiments,

[0402] In some embodiments, R7is aryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-CG alkoxy and R8R9N-.

[0403] In some embodiments, R7is aryl.

[0404] In some embodiments,

[0405] In some embodiments,

[0406] In some embodiments,

[0407] In some embodiments,

[0408] In some embodiments, R7is heterocyclyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-.

[0409] In some embodiments, R7is heterocyclyl.

[0410] In some embodiments,

[0411] In some embodiments,

[0412] In some embodiments, R7is heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-.

[0413] In some embodiments, R7is heteroaryl.

[0414] In some embodiments, R7is 5 membered heteroaryl.

[0415] In some embodiments, R7is 6 membered heteroaryl.

[0416] In some embodiments, R7is 10 membered heteroaryl

[0417] In some embodiments, R7is monocyclic heteroaryl.

[0418] In some embodiments, R7is bicyclic heteroaryl.

[0419] In some embodiments,

[0420] In some embodiments,

[0421] In some embodiments,

[0422] In some embodiments,

[0423] In some embodiments,

[0424] In some embodiments,

[0425] In some embodiments,

[0426] In some embodiments,

[0427] In some embodiments,

[0428] In some embodiments, R8is selected from H, C1-C6alkyl.

[0429] In some embodiments, R8is H.

[0430] In some embodiments, R8is C1-C6alkyl.

[0431] In some embodiments, R8is methyl.

[0432] In some embodiments, R9is selected from H, C1-C6alkyl.

[0433] In some embodiments, R9is H.

[0434] In some embodiments, R9is C1-C6alkyl.

[0435] In some embodiments, R9is methyl.

[0436] In some embodiments, each R10is independently selected from halogen, OH, C1- C6alkyl, C1-C6alkoxy.

[0437] In some embodiments, R10is halogen.

[0438] In some embodiments, R10is F.

[0439] In some embodiments, R10is OH.

[0440] In some embodiments, R10is C1-C6alkyl.

[0441] In some embodiments, R10is methyl.

[0442] In some embodiments, R10is C1-C6alkoxy.

[0443] In some embodiments, R10is methoxy.

[0444] In some embodiments, two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionallysubstituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl.

[0445] In some embodiments, two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl.

[0446] In some embodiments, two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl.

[0447] In some embodiments, two R10together with the atoms to which they are attached and any intervening atoms, form

[0448] In some embodiments, two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl.

[0449] In some embodiments, m is an integer selected from 1 and 2.

[0450] In some embodiments, m is 1.

[0451] In some embodiments, m is 2.

[0452] In some embodiments, n is an integer selected from 1 and 2.

[0453] In some embodiments, n is 1.

[0454] In some embodiments, n is 2.

[0455] 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.

[0456] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0457] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0458] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0459] In some embodiments, the compound is selected from the compounds described inTable 1

[0460] Table 1 certain examμles of the compound of Formula A

[0461] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0462] 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.

[0463] In some embodiments, the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.

[0464] Table 2 Pharmaceutical acceptable acid forming salts with the Compound of Formulas (I)-(IV).

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

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

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

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

[0469] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0470] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0471] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0472] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0473] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0474] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0475] 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.

[0476] 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.

[0477] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0478] 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.

[0479] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0480] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For examμle, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examμlesdescribed herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0481] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0482] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0483] 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 examμle, an isotopic derivative of a compound of Formula (I)-(IV) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I)-(IV). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,180,29Si,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).

[0484] 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.

[0485] 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.

[0486] 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.

[0487] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0488] 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%.

[0489] 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.

[0490] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For examμle, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examμles described herein, by substituting a deuterium labeled reagent for a nondeuterium labeled reagent.

[0491] 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.

[0492] In some embodiments, the compound is a18F labeled compound.

[0493] 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.

[0494] In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a33S labeled compound, a36S labeled compound, or any combination thereof.

[0495] It is understood that the18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For examμle, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examμles described herein, by substituting a18F,123I,124I,125I,129I,131I,1351,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0496] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,1231,1241,123I,129I,1311,1351,3S,34S,35S, and36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,133I,3S,34S,35S, and / or36S) may afford certaintherapeutic advantages resulting from greater metabolic stability, e g., increased in vivo half-life or reduced dosage requirements.

[0497] 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.

[0498] 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 examμle 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 examμle, is 550 Daltons or less, for examμle 500 Daltons or less, for examμle 450 Daltons or less.

[0499] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for examμle, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for examμle, an acid-addition salt with, for examμle, an inorganic or organic acid, for examμle 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 examμle a sodium or potassium salt, an alkaline earth metal salt, for examμle a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for examμle a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0500] 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.

[0501] 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 the arrangement 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. Amixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0502] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0503] 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).

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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 existenceto 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.

[0508] 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.

[0509] 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.

[0510] 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 are termed “enantiomers”. When a compound has an asymmetric centre, for examμle, 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 μlane 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”.

[0511] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (,S')-stereoi somers 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 examμle 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.

[0512] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0513] 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 apμlicable. A salt, for examμle, 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., tri fluoroacetate).

[0514] 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 ionor diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0515] It is to be understood that the compounds of the present disclosure, for examμle, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examμles of hydrates include monohydrates, dihydrates, etc. Nonlimiting examμles of solvates include ethanol solvates, acetone solvates, etc.

[0516] 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.

[0517] 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 reμlacement of one atom by an atom of a different element or in the presence of a particular functional group, or the reμlacement 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.

[0518] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0519] 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 reμlacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric reμlacement may be physicochemically or topologically based. Examμles 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.

[0520] 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 examμle,hydrated forms. A suitable pharmaceutically acceptable solvate is, for examμle, 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.

[0521] 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.

[0522] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of present disclosure 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 (A), (I), (II), (III), or (IV). Examμles of tautomeric forms include keto-, enol-, and enolate-forms, as in, for examμle, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci -nitro.keto enol enolate

[0523] Compounds of any one of the Formulae disclosed herein containing an amine function may also form A-oxides. A reference herein to a compound of Formula (A) 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 A-oxide. Particular examμles 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 thecorresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for examμle 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 (mCPBA), for examμle, in an inert solvent such as dichloromethane.

[0524] 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. Examμles 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.

[0525] 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.

[0526] 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 undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for examμle 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 Apμlication 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.

[0527] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for examμle, 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 examμle, 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-C6alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examμles of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(C1-C4alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0528] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for examμle, an in vivo cleavable amide thereof, for examμle an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4alkyl)2amine such as dimethylamine, N- ethyl- / V-methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2 -methoxy ethylamine, a phenyl-C1-C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0529] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for examμle, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for examμle an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examμles of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-l-ylmethyl and 4-(C1-C4alkyl)piperazin- 1 -ylmethyl .

[0530] 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

[0531] 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.

[0532] The compounds of Formula (A), and Formula (I)-(IV) 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 emμloyed where necessary in accordance with general princiμles 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 (A), and (I)-(IV). Accordingly, the present invention 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 examμle, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0533] 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

[0534] 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 examμle, 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

[0535] In general, the compounds of present invention can be prepared using sequence of reactions presented at the Scheme 1.

[0536] Scheme 1

[0537] It must be understood that any of the compounds at the Schemes 1 any of substituents in these compounds can be further modified at any step of presented sequence to provide modified derivatives of these compounds useful for preparation of compounds of present disclosure.

[0538] 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 multi step synthetic procedures, including but not limited procedures described herein in preparative part.

[0539] It should be obvious for specialist in this field that any of compound of the present invention obtained according to the procedures described above may be a subject for further transformation and modification that will let to obtain other compound of the invention.Biological Assays

[0540] 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 examμle, 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.

[0541] 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 examμle, 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.

[0542] 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

[0543] 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.

[0544] 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.

[0545] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which 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.

[0546] 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 examμle, 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 thickeningagents. 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.

[0547] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for examμle 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 examμle solutions in aqueous polyethylene glycol. Examμles 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, stabilizing and / 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.

[0548] 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.

[0549] 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.

[0550] Any suitable solubility enhancing agent can be used. Examμles of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting ofhydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β- cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β- cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxy ethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated P- cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ- cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0551] Any suitable chelating agent can be used. Examμles of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0552] Any suitable preservative can be used. Examμles 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, 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.

[0553] In some embodiments, examμles 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.

[0554] 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 aspropylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0555] 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.

[0556] 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 about 8.0), 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.

[0557] 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 8-aminocaproic acid, and mixtures thereof.

[0558] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene 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.

[0559] 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 apμlied 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 com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0560] 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.

[0561] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0562] The compositions of the disclosure may be in a form suitable for oral use (for examμle as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for examμle as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for examμle as a finely divided powder or a liquid aerosol), for administration by insufflation (for examμle as a finely divided powder) or for parenteral administration (for examμle as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0563] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositionsintended for oral use may contain, for examμle, one or more coloring, sweetening, flavoring and / or preservative agents.

[0564] 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.

[0565] 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.

[0566] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (A), (I), (II), (III), and / or (IV) 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 princiμles of medicine.Methods of Use

[0567] 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.

[0568] 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.

[0569] 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.

[0570] 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 imμlicated.

[0571] The compounds of the invention are also useful in treating diseases associated with CDK2. For examμle, diseases and conditions treatable according to the methods of theinvention include Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); 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 C6ll Carcinoma; Ataxia-Telangiectasia (AT).

[0572] The method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0573] In some embodiments, 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.

[0574] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0575] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0576] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0578] In some embodiments, the disease or disorder is Colorectal Cancer (CRC).

[0579] In some embodiments, the disease or disorder is Lung Cancer (LNCR).

[0580] In some embodiments, the disease or disorder is Retinoblastoma (RBI).

[0581] In some embodiments, the disease or disorder is Pancreatic Cancer (PNCA).

[0582] In some embodiments, the disease or disorder is Prostate Cancer (PC).

[0583] In some embodiments, the disease or disorder is Ovarian Cancer (OC).

[0584] In some embodiments, the disease or disorder is Hepatocellular Carcinoma (HCC).

[0585] In some embodiments, the disease or disorder is Gastric Cancer (GASC).

[0586] In some embodiments, the disease or disorder is Bladder Cancer (BLC).

[0587] In some embodiments, the disease or disorder is Endometrial Cancer (ENDMC).

[0588] In some embodiments, the disease or disorder is Glioblastoma (GBM).

[0589] In some embodiments, the disease or disorder is Adenocarcinoma.

[0590] In some embodiments, the disease or disorder is Squamous C6ll Carcinoma.

[0591] In some embodiments, the disease or disorder is Ataxia-Telangiectasia (AT).

[0592] 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.

[0593] 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.

[0594] 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).

[0595] 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.

[0596] 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.

[0597] 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.

[0598] 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.

[0599] 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).

[0600] 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.

[0601] 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.

[0602] 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.

[0603] 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.

[0604] 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.

[0605] In some embodiments, the inhibitor of CDK2 is a compound of the present disclosure.

[0606] 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.

[0607] The present disclosure also provides a method of treating a disease or disorder in which CDK2 is imμlicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0608] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.Routes of Administration

[0609] 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).

[0610] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, μlaster, etc.); transmucosal (including, e.g., by a patch, μlaster, 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 examμle, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by imμlant of a depot or reservoir, for examμle, subcutaneously or intramuscularly.EXAMPLESGeneral synthetical procedures and examμles of the compound’s preparation.

[0611] 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 μlates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) 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 is reported as follows: s = singlet, br. = broad, d = doublet, t = triμlet, q = quartet, m = multiμlet, dd = doublet of doublets; couμling constants in Hz; integration.

[0612] Abbreviations used in the following examμles and elsewhere herein are:ACN acetonitrile AcOH acetic acid anh. anhydrous br. broadBSA bovine serum albumin CDI l,l '-Carbonyldiimidazole DIPEA N, N-di i sopropy 1 ethyl amine DMA A,N-dimethylacetamide DMSO dimethyl sulfoxide DTT dithiothreitol eq equivalent FBS fetal bovine serum h hour(s)HPLC high pressure (or performance) liquid chromatographyLCMS liquid chromatography mass spectrometry M molar MHz megahertz min minutes NBS N-bromosuccinimide NMR nuclear magnetic resonance Pdzfdbah tris(dibenzylideneacetone)dipalladium(0) RT retention time rt room temperature s solid t temperature THE tetrahydrofuran TRIS 2-amino-2-(hy droximethyl)propane- 1 , 3 -diolXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneSynthesis of Building BlocksSynthesis of 2-chloro-9-cyclopentyl-7,9-dihydro-8N-purin-8-one (P3)

[0613] Preparation 1. 2-Chloro-N4-cyclopentylpyrimidine-4,5-diamine (Pl).To a mixture of 2,4-dichloropyrimidin-5-amine (1 g, 6 mmol, 1 eq) and DIPEA (2.2 mL, 12 mmol, 2 eq) in dry THF (15 mL) cyclopentanamine (620 mg, 7.2 mmol, 1.2 eq) was added. The mixture was heated to 70 °C under stirring for 48 h. Then the mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (1 : 1 EA / MeOH as an eluent) to afford P1 (1.14 g, yield 88%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 7.37 (d, J= 1.4 Hz, 1H), 6.57 (d, J= 6.7 Hz, 1H), 4.86 (s, 2H), 4.25 (m, 1H), 2.00 - 1.90 (m, 2H), 1.83 - 1.64 (m, 2H), 1.62 - 1.38 (m, 4H).

[0614] Preparation 2. 2-Chloro-9-cyclopentyl-7,9-dihydro-8H-purin-8-one (P2).A solution of Pl (1.14 g, 5.35 mmol, 1 eq) and CDI (950 mg, 5.9 mmol, 1.1 eq) in dry THF (25 mL) was stirred at rt for 16 h. After the comμletion of the reaction all volatiles were removed in vacuo, the residue was dissolved in CHCI3and washed with brine. The organic layer was dried over anh. Na2SO4and filtered, the filtrate was concentrated in vacuo to give P2 (1.25 g, yield 98%), which was used in the next step without further purification. Analytical data1: H NMR (400 MHz, DMSO-d6), δ: 8.11 (s, 1H), 7.64 (s, 1H), 4.69 (m, 1H), 2.20 - 2.03 (m, 2H), 1.98 - 1.82 (m, 4H), 1.69 - 1.56 (m, 2H).

[0615] Preparation 3. 2-Chloro-9-cyclopentyl-7-methyl-7,9-dihydro-8 / f-purin-8-one (P3).To a well stirred solution of P2 (400 mg, 1.67 mmol, 1 eq) and iodomethane (120 μL, 1.84 mmol, 1.1 eq) in dry DMA (5 mL) NaH (75 mg, 1.84 mmol, 1.1 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 3 h and at rt for 12 h. Then water was carefully added, the resulting suspension was extracted with EA and washed with brine. The organic layers were combined, dried over anh. Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1 :2 hexane / EA as an eluent) to give P3 (280 mg, yield 67%).Analytical data: H1NMR (400 MHz, DMSO-d6), δ: 8.31 (s, 1H), 4.73 (m, 1H), 3.35 (s, 3H), 2.10 (m, 2H), 1.94 (m, 4H), 1.64 (m, 2H).Synthesis of 2-chloro-9-cyclopentyl-7-ethyl-7,9-dihydro-8H-purin-8-one (P4)

[0616] Preparation 4. 2-Chloro-9-cyclopentyl-7-ethyl-7,9-dihydro-8H-purin-8-one (P4).To a well stirred solution of P2 (400 mg, 1.67 mmol, 1 eq) and iodoethane (150 μL, 1.84 mmol, 1.1 eq) in dry DMA (5 mL) NaH (75 mg, 1.84 mmol, 1.1 eq) was added portionwise at 10°C. The reaction mixture was stirred at 0°C for 3 h and at rt for 12 h. Then the reaction mixture was carefully diluted with water, the resulting suspension was extracted with EA and washed with brine. The organic layers were combined, dried over anh. Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1 :2 hexane / EA as an eluent) to give P4 (315 mg, yield 71%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 8.38 (s, 1H), 4.73 (m, 1H), 3.88 (q, J = 7.2 Hz, 2H), 2.18 - 2.05 (m, 2H), 2.02 - 1.82 (m, 4H), 1.71 - 1.56 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H).Synthesis of 2-chloro-9-isopropyl-7-methyl-7,9-dihydro-8H-purin-8-one (P7)

[0617] Preparation 5. 2-Chloro-A4-isopropylpyrimidine-4,5-diamine (P5).To a mixture of 2,4-dichloropyrimidin-5-amine (750 mg, 4.57 mmol, 1 eq) and DIPEA (2.4 mL, 13.7 mmol, 3 eq) in n-BuOH (20 mL) isopropylamine (350 mg, 5.94 mmol, 1.3 eq) was added. The reaction mixture was heated to 70°C under stirring for 16 h. After then all volatiles were removed in vacuo, the crude product was purified by silica gel column chromatography (eluent hexane / EA = 1 / 2) to give P5 (810 mg, yield 94%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 7.37 (s, 1H), 6.50 (d, 1H), 4.83 (s, 2H), 4.14 (m, 1H), 1.19 (d, 6H).

[0618] Preparation 6. 2-Chloro-9-isopropyl-7,9-dihydro-8H-purin-8-one (P6).The solution of P5 (800 mg, 4.27 mmol, 1 eq) and CDI (760 mg, 4.7 mmol, 1.1 eq) in dry THF (25 mL) was heated to 50°C under stirring for 16 h. After then all volatiles were removed in vacuo, the residue was dissolved in CHCI3(30 mL) and washed with brine. The organic layers were combined, dried over anh. Na2SO4and evaporated in vacuo to give P6 (520 mg, yield 57%), which was used in the next step without further purification. Analytical data: H1NMR (400 MHz, DMSO-d6), δ: 8.09 (s, 1H), 7.00 (s, 1H), 4.57 (m, 1H), 1.48 (d, 6H).

[0619] Preparation 7. 2-Chloro-9-isopropyl-7-methyl-7,9-dihydro-8H-purin-8-one (P7). To a well stirred solution of P6 (500 mg, 2.35 mmol, 1 eq) and iodomethane (160 μL, 2.59 mmol, 1.1 eq) in dry DMA (12 mL) NaH (105 mg, 2.59 mmol, 1.1 eq) was added at 0°C.The reaction mixture was stirred at 0°C for 3 h and at rt for 12 h. Then water was carefully added, the resulting suspension was extracted with EA and washed with brine. The organic layers were combined, dried over anh. Na2SO4and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent hexane / EA = 1 / 2) to give P7 (401 mg, yield 75%).Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 8.31 (s, 1H), 4.67 - 4.55 (m, 1H), 3.85 (s, 3H), 1.52 - 1.44 (d, 6H).Synthesis of 2-chloro-9-cyclopentyl-7-isopropyl-purin-8-one (P8)

[0620] Preparation 8. 2-Chloro-9-cyclopentyl-7-isopropyl-purin-8-one (P8).To a well stirred solution of P2 (240 mg, 1 mmol, 1 eq) and 2-bromopropane (185 mg, 1.5 mmol, 1.5 eq) in dry DMA (5 mL) CS2CO3(490 mg, 1.5 mmol, 1.5 eq) was added portion wise at rt. The reaction mixture was stirred for 26 h at rt. Then the reaction mixture was carefully diluted with water, the resulting suspension was extracted with EtOAc and washed with brine. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue from evaporation was purified by column chromatography (eluent Hex / EtOAc = 2 / 1) to give 2-chloro-9-cyclopentyl-7-isopropyl-purin-8-one P8 (225 mg, 80%).Analytical data: H1NMR (400 MHz, DMSO-d6), δ: 8.46 (s, 1H), 4.73 (m, 1H), 4.59 (m, 1H), 2.18 - 2.01 (m, 2H), 2.01 - 1.84 (m, 3H), 1.64 (m, 2H), 1.44 (d, 6H). LCMS (APCI) m / z=281 [M+H]+.Synthesis of 2-chloro-9-cyclopentyl-7-cyclopropyl-purin-8-one (P9)

[0621] Preparation 9. 2-Chloro-9-cyclopentyl-7-cyclopropyl-purin-8-one (P9).To a well stirred suspension of P2 (240 mg, 1 mmol, 1 eq), cyclopropylboronic acid (172 mg, 2 mmol, 2 eq) and pyridine (160 mg, 2 mmol, 2eq) in the mixture of DCE / DMF = 3 / 1 (12 mL) CU(OAC)2were added (180 mg, 1 mmol, 1 eq) in one portion at rt. The reaction mixture was stirred for 20 h at 70°C. Then the reaction mixture was cooled to rt, diluted with aqueous saturated NH4CI, extracted with DCM and washed with brine. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue from evaporation was purified by column chromatography (eluent Hex / EtOAc = 7 / 3) to give 2- chloro-9-cyclopentyl-7-cyclopropyl-purin-8-one P9 (182 mg, 54%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 8.26 (s, 1H), 4.70 (m, 1H), 2.96 (m, 1H), 2.09 (m, 2H), 1.91 (m, 4H), 1.63 (m, 2H), 1.06 - 0.88 (m, 4H). LCMS (APCI) m z=280 [M+H]+.Synthesis of terZ-butyl 3-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-8-oxo-purin-9-yl]piperidine-l -carboxylate (PIO)

[0622] Preparation 10. tert-Butyl 3-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-8-oxo-purin-9-yl]piperidine-l -carboxylate (P10).The suspension of tert- butyl 3-(2-chloro-7-methyl-8-oxo-purin-9-yl)piperidine-l- carboxylate (CAS 2711810-60-3, 150 mg, 0.41 mmol, 1 eq), 4-(l-methylpyrazol-4- yl)sulfonylcyclohexanamine hydrochloride (143 mg, 0.41 mmol, 1 eq), CS2CO3(400 mg, 1.23 mmol, 3 eq), Pd2dba3(18 mg, 0.02 mmol, 0.05 eq) and XantPhos (23 mg, 0.041 mmol, 0.1 eq) in dry dioxane (2 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt, diluted by EtOAc and water, and extracted with EtOAc. Organic layer was washed by brine, dried and evaporated. Residue purified by column chromatography using as eluent: EtOAc to obtain tert-butyl 3-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-8-oxo-purin-9-yl]piperidine-l-carboxylat P10 (132 mg, yield 55%).Analytical data:1HNMR (400 MHz, CDCI3), δ: 7.72 (s, 1H), 7.66 (d, J= 5.3 Hz, 2H), 4.91 (d, J= 7.5 Hz, 1H), 4.25 (tt, J= 11.8, 4.3 Hz, 1H), 4.15 - 3.99 (m, 2H), 3.93 (d, J = 1.0 Hz, 3H), 3.73 (ddt, J= 13.5, 9.9, 5.0 Hz, 1H), 3.57 (dt, J= 9.4, 4.7 Hz, 3H), 3.36 - 3.26 (m, 3H), 2.59 (td, J= 12.2, 5.8 Hz, 3H), 2.38 (qd, J= 12.7, 4.2 Hz, 1H), 2.10 (dt, J= 12.9, 4.1 Hz, 2H), 1.89 - 1.71 (m, 2H), 1.69 - 1.49 (m, 3H), 1.41 (s, 9H).Synthesis of 2-(2-azaspiro[3.3]heptan-6-ylamino)-9-cyclopentyl-7-methyl-purin-8-one hydrochloride (P12)

[0623] Preparation 11. tert-Butyl 6-[(9-cyclopentyl-7-methyl-8-oxo-purin-2-yl)amino]-2- azaspiro [3.3 ]heptane-2-carb oxy 1 ate (P 11 ) .The suspension of P3 (300 mg, 1.19 mmol, 1 eq), tert-butyl 6-amino-2- azaspiro[3.3]heptane-2-carboxylate (CAS 1211586-09-2, 760 mg, 3.57 mmol, 3 eq), tert- BuONa (115 mg, 2.38 mmol, 2 eq), Pd2dba3(27 mg, 0.03 mmol, 0.05 eq) and BINAP (37 mg, 0.06 mmol, 0.1 eq) in dry dioxane (4 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled to rt, diluted with EtOAc (4 mL), washed with brine. All volatiles were removed under reduced pressure, the residue was purified by flash chromatography (eluentEtOAc / MeOH= 100 / 0 to 90 / 10) to obtain tert-butyl 6-[(9-cyclopentyl-7-methyl-8-oxo- purin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate Pll (215 mg, 42%), which was used in the next step without further purification.Analytical data: LCMS (APCI) m / z=429 [M+H]+.

[0624] Preparation 12. 2-(2-Azaspiro[3.3]heptan-6-ylamino)-9-cyclopentyl-7-methyl- purin-8-one hydrochloride (P12).Aq. cone. HC1 (100 μL, 1 mmol, 2 eq) was added to a stirred solution of tert-butyl 6-[(9- cyclopentyl-7-methyl-8-oxo-purin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate P11 (215 mg, 0.5 mmol, 1 eq) in 2,2,2-trifluorethanol (5 mL). The resulting solution was left to stand at rt for 1 h, then all volatiles were removed in vacuum, and the residue was triturated with Et2O followed by ACN to give 2-(2-azaspiro[3.3]heptan-6-ylamino)-9-cyclopentyl- 7-methyl-purin-8-one hydrochloride P12 (180 mg, 99%), which was used in the next step without purification.Analytical data: H1NMR (400 MHz, DMSO-d6), δ: 9.05 (br. s, 2H), δ.04 (s, 1H), 4.69 (m, 1H), 4.19 (m, 1H), 4.01 (t, 2H), 3.93 (t, 2H), 3.27 (s, 3H), 2.69 (m, 2H), 2.30 - 2.20 (m, 2H), 2.17 - 2.03 (m, 2H), 2.00 - 1.87 (m, 4H), 1.68 - 1.59 (m, 3H). LCMS (APCI) m / z=329 [M+H]+.Synthesis of 9-cyclopentyl-7-methyl-2-(4-piperidylamino)purin-8-one hydrochloride(P14)

[0625] Preparation 13. tert-Butyl 4-[(9-cyclopentyl-7-methyl-8-oxo-purin-2- yl)amino]piperidine-l -carboxylate (P13).The suspension of 2-chloro-9-cyclopentyl-7-methyl-purin-8-one P3 (300 mg, 1.19 mmol, 1 eq), tert- butyl 4-aminopiperidine-l -carboxylate (CAS 87120-72-7, 270 mg, 1.35 mmol, 2.2 eq), tert-BuONa (170 mg, 1.77 mmol, 3 eq), Pd2dba3(27 mg, 0.03 mmol, 0.05 eq) andBINAP (37 mg, 0.06 mmol, 0.1 eq) in dry dioxane (4 mL) was stirred at 85°C for 1 h. The reaction mixture was cooled to rt, diluted with EtOAc (4 mL), washed with brine. All volatiles were removed under reduced pressure, the residue was purified by column chromatography (eluent EtOAc / MeOH= 100 / 0 to 90 / 10) to obtain tert-butyl 4-[(9- cyclopentyl-7-methyl-8-oxo-purin-2-yl)amino]piperidine-l-carboxylate P13 (475 mg, 64%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 7.91 (s, 1H), 6.55 (d, 1H), 4.66 (m, 1H), 3.90 (m, 2H), 3.80 (m, 1H), 3.24 (s, 3H), 2.85 (m, 2H), 2.25 - 2.07 (m, 2H), 1.88 (m, 6H), 1.67 - 1.54 (m, 2H), 1.40 (s, 9H), 1.38 - 1.28 (m, 2H). LCMS (APCI) m / z=417 [M+H]+.

[0626] Preparation 14. 9-Cyclopentyl-7-methyl-2-(4-piperidylamino)purin-8-one hydrochloride (P14).Aq. cone. HC1 (230 μL, 2.28 mmol, 2 eq) was added to a stirred solution of tert-butyl 4- [(9-cyclopentyl-7-methyl-8-oxo-purin-2-yl)amino]piperidine-l-carboxylate P13 (475 mg, 1.14 mmol, 1 eq) in 2,2,2-trifluorethanol (10 mL). The resulting solution was left to stand at rt for 1 h, then all volatiles were removed in vacuum, ant the residue was triturated with Et2O to give 9-cyclopentyl-7-methyl-2-(4-piperidylamino)purin-8-one hydrochloride P14 (410 mg, 103%), which was used in the next step without purification.Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 9.22 (br. s, 1H), 9.05 (br. s, 1H), δ.11 (s, 1H), 4.71 (m, 1H), 4.07 (br. s, 1H), 3.33 (m, 2H), 3.29 (s, 3H), 3.01 (m, 2H), 2.18 - 2.03 (m, 4H), 2.01 - 1.75 (m, 6H), 1.63 (m, 2H). LCMS (APCI) m / z=3 l7 [M+H]+.Synthesis of tert-butyl 6-[7-methyl-2-[[1-(1-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-8-oxo-purin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate (P18)

[0627] Preparation 15. tert-Butyl 6-[(5-amino-2-chloro-pyrimidin-4-yl)amino]-2- azaspiro [3.3 ] heptane-2-carb oxy 1 ate (P 15) . tert-Butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate CAS 1211586-09-2 (1 g, 4.35 mmol, 1.3 eq) was added to a mixture of 2,4-dichloropyrimidin-5-amine (CAS 5177-27-5, 550 mg, 3.35 mmol, 1 eq) and DIPEA (242 mL, 13.4 mmol, 4 eq) butanol (15 mL). The resulting mixture was stirred for 48 h at 100°C. All volatiles were removed in vacuum. The residue was diluted by EtOAc, washed by water and brine, dried and evaporated. Purifiedby column chromatography (eluent Hex(20%) / EtOAc (80%)) to obtain tert-butyl 6-[(5- amino-2-chloro-pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate P15 (1.07 g, 94%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 7.35 (s, 1H), 6.88 (d, J= 6.5 Hz, 1H), 4.79 (s, 2H), 4.22 (h, J= 7.9 Hz, 1H), 3.88 (s, 2H), 3.76 (s, 2H), 2.59 - 2.47 (m, 2H), 2.14 - 2.04 (m, 2H), 1.33 (s, 9H).

[0628] Preparation 16. tert-Butyl 6-(2-chloro-8-oxo-7H-purin-9-yl)-2- azaspiro [3.3] heptane-2-carb oxy 1 ate (P 16) .The solution of tert-butyl 6-[(5-amino-2-chloro-pyrimidin-4-yl)amino]-2- azaspiro[3.3]heptane-2-carboxylate P15 (1.07 g, 3.14 mmol, 1 eq) and CDI (1 g, 6.29 mmol, 2 eq) was stirred in dry THF (25 mL) at 50°C for 16 h. All volatiles were removed in vacuum, the residue was dissolved in EtOAc and washed with brine. The combined organic phases were dried over Na2SO4and evaporated to give tert-butyl 6-(2-chloro-8- oxo-7H-purin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate P16 (743 mg, 64%), purified by crystallization from EtOH.Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 11.47 (s, 1H), δ.06 (s, 1H), 4.66 (p, J= 8.5 Hz, 1H), 3.92 (s, 2H), 3.87 (s, 2H), 3.02 - 2.92 (m, 2H), 2.61 - 2.54 (m, 2H), 1.34 (s, 9H).

[0629] Preparation 17. tert-Butyl 6-(2-chloro-7-methyl-8-oxo-purin-9-yl)-2- azaspiro[3.3]heptane-2-carboxylate (P17).To a well stirred solution of tert-butyl 6-(2-chloro-8-oxo-7H-purin-9-yl)-2- azaspiro[3.3]heptane-2-carboxylate P16 (743 mg, 2 mmol, 1 eq) and iodomethane (164 μL, 2.64 mmol, 1.3 eq) in dry DMA (5 mL) NaH (105 mg, 2.64 mmol, 1.3 eq) were added at 0°C. The reaction mixture was stirred for 3 hours at 0°C, and 12 h at rt. Then water was carefully added, the resulting suspension was extracted with EtOAc and washed with brine. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue from evaporation was purified by crystallization from EtOH to give tert-butyl 6- (2-chloro-7-methyl-8-oxo-purin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate P17 (738 mg, 96%).Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 8.28 (d, .7= 1.1 Hz, 1H), 4.74 - 4.63 (m, 1H), 3.89 (d, J= 19.5 Hz, 4H), 3.29 (d, J = 1.0 Hz, 3H), 3.03 - 2.92 (m, 2H), 2.64 - 2.53 (m, 2H), 1.34 (d, J = 0.9 Hz, 9H).

[0630] Preparation 18. tert-Butyl 6-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-8-oxo-purin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate (P18).A suspension of tert-butyl 6-(2-chloro-7-methyl-8-oxo-purin-9-yl)-2- azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.5 mmol, 1 eq), 4-(l-methylpyrazol-4- yl)sulfonylcyclohexanamine hydrochloride (184 mg, 0.5 mmol, 1 eq), CS2CO3(513 mg, 1.58 mmol, 3 eq), Pd2dba3(24 mg, 0.025 mmol, 0.05 eq) and XantPhos (30 mg, 0.05 mmol, 0.1 eq) in dry dioxane (4 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt, diluted by EtOAc and water, extracted. Organic layer was washed by brine, dried and evaporated. Residue purified by column chromatography using as eluent: DCM(95%) / MeOH(5%), followed by crystallization from MeOHto obtain tert-butyl 6-[7- methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]-8-oxo-purin-9-yl]-2- azaspiro[3.3]heptane-2-carboxylate P18 (92 mg, yield 30%).Analytical data:1HNMR (400 MHz, CDCI3), δ: 7.80 (s, 1H), 7.75 - 7.65 (m, 2H), 4.82 - 4.68 (m, 2H), 3.99 (d, J= 14.6 Hz, 4H), 3.93 (s, 3H), 3.69 (s, 1H), 3.68 - 3.56 (m, 2H), 3.30 (s, 3H), 3.19 (dd, J = 12.5, 9.3 Hz, 2H), 2.64 - 2.45 (m, 2H), 2.15 (dd, J= 13.0, 3.6 Hz, 2H), 1.72 - 1.58 (m, 4H), 1.43 (s, 9H).Synthesis of 2-chloro-9-cyclopentyl-7-(2 -methoxy ethyl)purin-8-one (P19)

[0631] Preparation 19. 2-Chloro-9-cyclopentyl-7-(2-methoxyethyl)purin-8-one (P19).To a well stirred solution of 2-chloro-9-cyclopentyl-7H-purin-8-one P2 (300 mg, 1,255 mmol, 1 eq) and CS2CO3(530 mg, 1.626 mmol, 1.3 eq) in in dry DMA (5 mL) l-bromo-2-methoxy-ethane (CAS 6482-24-2, 227 mg, 1.626 mmol, 1.3 eq) was added at rt. The reaction mixture was stirred for 3 h at rt, then water was added, the resulting suspension was extracted with EtOAc and washed with brine. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue from evaporation was purified by column chromatography (eluent Hex / EtOAc = 7 / 3) to give 2-chloro-9-cyclopentyl-7-(2- methoxyethyl)purin-8-one P19 (302 mg, 81%).Analytical data: NMR (400 MHz, DMSO-d6), δ: 8.33 (s, 1H), 4.74 (p, 1H), 4.02 (t, 2H), 3.62 (t, 2H), 3.25 (s, 3H), 2.18 - 2.04 (m, 2H), 2.02 - 1.84 (m, 5H), 1.65 (m, 2H). LCMS (APCI) m / z=298 [M+H]+.

[0632] In the Table 3 presented certain non-limiting examμles of the compound of Formula (A).

[0633] Table 3. Selected examμles of the compound of Formula (A) and LCMS (ESI) dataSynthesis of the Representative Examμles of the compound

[0634] Example 1. 9-Cyclopentyl-7-methyl-2-((l-(methylsulfonyl)piperidin-4-yl)amino)- 7,9-dihydro-8H-purin-8-one (Compound 109).The suspension of P3 (100 mg, 0.4 mmol, 1 eq), l-(methylsulfonyl)piperidin-4-amine hydrochloride (85 mg, 0.4 mmol, 1 eq), CS2CO3(390 mg, 1.2 mmol, 3 eq), Pd2dba3(20mg, 0.02 mmol, 0.05 eq) and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in dry dioxane (2 mL) was heated under reflux for 16 h. After the comμletion of the process the mixture was cooled to rt, filtered through a pad of C6lite. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 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, 15-30% ACN at 20 min, RT 16,5 min) to afford 109 (31 mg, yield 20%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 7.93 (s, 1H), 6.62 (d, 1H), 4.67 (m, 1H), 3.79 (m, 1H), 3.60 - 3.50 (m, 2H), 3.25 (s, 3H), 2.93 - 2.81 (m, 5H), 2.13 (m, 2H), 2.03 - 1.82 (m, 6H), 1.59 (m, 4H).

[0635] Example 2. 9-Cyclopentyl-7-ethyl-2-((l-(methylsulfonyl)piperidin-4-yl)amino)- 7,9-dihydro-8H-purin-8-one (Compound 116).The suspension of P4 (105 mg, 0.37 mmol, 1 eq), l-(methylsulfonyl)piperidin-4-amine hydrochloride (85 mg, 0.4 mmol, 1 eq), CS2CO3(385 mg, 1 mmol, 3 eq), Pd2dba3(20 mg, 0.02 mmol, 0.05 eq) and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in dry dioxane (2 mL) was heated under reflux for 16 h. After the comμletion of the process the mixture was cooled to rt and filtered through a pad of C6lite. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 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, 20-35% ACN at 20 min, RT 13 min) to give 116 (8 mg, yield 5%).Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 8.13 - 7.83 (m, 1H), 6.63 (d, 1H), 4.67 (m, 1H), 3.90 - 3.69 (q, 2H), 3.55 (m, 3H), 2.93 - 2.81 (m, 5H), 2.19 - 2.09 (m, 2H), 1.94 (m, 7H), 1.66 - 1.50 (m, 6H), 1.26 - 1.16 (t, 3H).

[0636] Example 3. 9-Cy cl opentyl-7-methyl-2-((l-((l -methyl- 1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 137).The suspension of P3 (100 mg, 0.4 mmol, 1 eq), 1 -((1 -methyl- 1H-pyrazol -4- yl)sulfonyl)piperidin-4-amine hydrochloride (110 mg, 0.4 mmol, 1 eq), CS2CO3(326 mg, 1 mmol, 2.5 eq), Pd2dba3(20 mg, 0.02 mmol, 0.05 eq) and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in dry dioxane (2 mL) was heated under reflux for 16 h. After the comμletion of the process the mixture was cooled to room temperature and filtered through a pad of C6lite. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 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, 20-50% ACN at 20 min, RT 11.5 min) to afford 137 (28 mg, yield 15%). Analytical data:1HNMR (400 MHz, DMSO-d6), δ: 8.29 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 6.60 (d, J = 7.3 Hz, 1H), 4.65 (m, 1H), 3.92 (s, 3H), 3.65 (m, 1H), 3.46 (m, 2H), 3.22 (s, 3H), 2.46 - 2.38 (m, 2H), 2.16 - 2.04 (m, 2H), 2.00 - 1.82 (m, 6H), 1.60 (m, 4H).

[0637] Example 4. 9-Cy cl opentyl-7-ethyl-2-(( 1 -(( 1 -methyl - 1H-py razol -4- yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8 / / -purin-8-one (Compound 151).The suspension of P4 (100 mg, 0.37 mmol, 1 eq), 1-((1 -methyl- 1H-pyrazol-4- yl)sulfonyl)piperidin-4-amine hydrochloride (105 mg, 0.37 mmol, 1 eq), CS2CO3(370 mg, 1 mmol, 3 eq), Pd2dba3(20 mg, 0.02 mmol, 0.05 eq) and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in dry dioxane (2 mL) was heated under reflux for 16 h. After the comμletion of theprocess the mixture was cooled to rt and filtered through a small pad of C6lite. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 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, 20-50% ACN at 20 min, RT 14 min) to give 151 (41 mg, yield 23%).Analytical data: H1NMR (400 MHz, DMSO-d6), 6: 8.29 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 6.61 (d, 1H), 4.65 (m, 1H), 3.92 (s, 3H), 3.76 (q, J = 7.2 Hz, 2H), 3.70 - 3.59 (m, 1H), 3.51 - 3.43 (m, 2H), 2.16 - 2.05 (m, 2H), 2.05 - 1.72 (m, 6H), 1.66 - 1.52 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H).

[0638] Example 5. 9-Isopropyl -7-methyl-2-((l-(( 1 -methyl- 177-pyrazol -4- yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 301).The suspension of P7 (100 mg, 0.44 mmol, 1 eq), 1 -((1 -methyl- l / / -pyrazol -4- yl)sulfonyl)piperidin-4-amine hydrochloride (123 mg, 0.44 mmol, 1 eq), CS2CO3(430 mg, 1.32 mmol, 3 eq), Pd2dba3(20 mg, 0.022 mmol, 0.05 eq) and Xantphos (26 mg, 0.044 mmol, 0.1 eq) in dry dioxane (4 mL) was heated under reflux for 16 h. Then the rection mixture was cooled to rt and filtered through a pad of C6lite. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 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, 10- 30% ACN at 20 min, RT 16 min) to give 301 (55 mg, yield 29%).Analytical data:1H NMR (400 MHz, DMSO-d6), 6: 8.28 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 6.59 (d, 1H), 4.51 (m, 1H), 3.92 (s, 3H), 3.78 - 3.56 (m, 1H), 3.54 - 3.38 (m, 2H), 1.96 (m, 3H), 1.66 - 1.52 (m, 2H), 1.44 (m, 8H).

[0639] Example 6. 9-Cyclopentyl-7-isopropyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one (Compound 160).The suspension of P8 (70 mg, 0.25 mmol, 1 eq), 4-(l-methylpyrazol-4- yl)sulfonylcyclohexanamine hydrochloride (105 mg, 0.375 mmol, 1.5 eq), NaOBuz(72 mg, 0.75 mmol, 3 eq), Pd2dba3(11 mg, 0.0125 mmol, 0.05 eq) and XantPhos (15 mg, 0.025 mmol, 0.1 eq) in dry dioxane (5 mL) was stirred at 90°C for 1 h. The reaction mixture was cooled to rt, diluted with brine, extracted with EtOAc. All volatiles were removed under reduced pressure, the residue was purified by column chromatography on SiO2(EtOAc / MeOH= 100 / 0 to EtOAc / MeOH=10 / l) to obtain 9-cyclopentyl-7-isopropyl-2-[[1- (l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]purin-8-one (160).Analytical data:NMR (400 MHz, DMSO-d6), δ: 8.29 (s, 1H), δ.05 (s, 1H), 7.76 (s, 1H), 6.61 (d, 1H), 4.65 (s, 1H), 4.49 (m, 1H), 3.92 (s, 3H), 3.69 - 3.58 (m, 1H), 3.47 (m, 2H), 2.10 (m, 3H), 1.95 (m, 2H), 1.87 (m, 7H), 1.60 (m, 5H), 1.37 (d, 6H).

[0640] Example 7. 9-Cyclopentyl-7-cyclopropyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one (Compound 163).The suspension of P9 (80 mg, 0.287 mmol, 1 eq), 4-(l-methylpyrazol-4- yl)sulfonylcyclohexanamine hydrochloride (120 mg, 0.43 mmol, 1.5 eq), NaOBu' (83 mg, 0.865 mmol, 3 eq), Pd2dba3(13 mg, 0.0143 mmol, 0.05 eq) and XantPhos (17 mg, 0.0287 mmol, 0.1 eq) in dry dioxane (6 mL) was stirred at 90°C for 1 h. The reaction mixture was cooled to rt, diluted with brine, extracted with EtOAc. All volatiles were removed under reduced pressure, the residue was purified by column chromatography on SiO2(EtOAc / MeOH= 100 / 0 to EtOAc / MeOH=10 / l) followed by preparative HPLC (YMC ODS-A 250 x 20 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, 15-40% ACN at 20 min, RT 17 min) to obtain 9-cyclopentyl-7-cyclopropyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one 163 (43 mg, 31%).Analytical data:1HNMR (400 MHz, CD3OD), δ: 8.10 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 4.73 (m, 1H), 3.96 (s, 3H), 3.73 (m, 1H), 3.60 (m, 2H), 2.87 (m, 1H), 2.58 (m, 3H), 2.19 (m, 2H), 2.08 (m, 2H), 2.00 - 1.87 (m, 3H), 1.74 - 1.59 (m, 5H), 1.08 - 0.88 (m, 4H).

[0641] Example 8. 9-Cyclopentyl-7-methyl-2-(tetrahydropyran-4-ylamino)purin-8-one (Compound 101).The suspension of P3 (100 mg, 0.397 mmol, 1 eq), tetrahydropyran-4-amine hydrochloride (CAS 33024-60-1, 54 mg, 0.397 mmol, 1 eq), Cs2CO3(390 mg, 1.19 mmol, 3 eq), Pd2dba3(18 mg, 0.0198 mmol, 0.05 eq) and XantPhos (23 mg, 0.039 mmol, 0.1 eq) in dry dioxane (2 mL) were stirred at reflux for 16 h. The recti on mixture was cooled to rt, diluted by EtOAc and water, and extracted with EtOAc. Organic layer was washed by brine, dried and evaporated. Residue was purified by column chromatography (eluent: EtOAc / MeOH 10 / 1), followed by preparative HPLC (YMC ODS-A 250 x 20 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, 10-30% ACN at 20 min, RT 15 min) to obtain 9-cyclopentyl-7-methyl-2- (tetrahydropyran-4-ylamino)purin-8-one 101 (12 mg yield 10%).Analytical data:1HNMR (400 MHz, CDCI3), δ: 7.70 (s, 1H), 4.86 - 4.79 (m, 1H), 4.76 (q, J= 8.4 Hz, 1H), 4.00 (t, J= 3.8 Hz, 1H), 3.96 (dt, J= 11.2, 3.7 Hz, 2H), 3.53 (td, J= 11.5, 2.3 Hz, 2H), 3.32 (s, 3H), 2.26 - 2.13 (m, 2H), 2.08 - 1.89 (m, 6H), 1.73 - 1.62 (m, 2H), 1.53 (dtd, J= 12.9, 10.8, 4.3 Hz, 2H).

[0642] Example 9. 7-Methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]-9- phenyl-purin-8-one (Compound 401).The suspension of 2-chloro-7-methyl-9-phenyl-purin-8-one (CAS 89743-87-3, 200 mg, 0.76mmol, 1 eq), 4-(l-methylpyrazol-4-yl)sulfonylcyclohexanamine hydrochloride (270mg, 0.76 mmol, 1 eq), NaOBu' (150 mg, 1.53 mmol, 2 eq), Pd2dba.3 (35mg, 0.038 mmol, 0.05 eq) and XantPhos (44 mg, 0.078 mmol, 0.1 eq) in dry dioxane (4 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt, diluted by EtOAc and water, extracted. Organic layer was washed by brine, dried and evaporated. Residue purified by column chromatography using as eluent: EtOAc / MeOH (20 / 1), followed by followed by preparative HPLC (YMC ODS-A250 x 20 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, 15-40% ACN at 20 min, RT 14 min) to obtain 7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]-9-phenyl-purin-8-one 401 (12 mg, yield 9.5%).Analytical data:1HNMR (400 MHz, CDCI3), δ: 7.79 (s, 1H), 7.72 - 7.58 (m, 4H), 7.47 (t, J= 7.6 Hz, 2H), 7.41 - 7.33 (m, 1H), 4.75 (d, J= 7.6 Hz, 1H), 3.95 (d, J= 1.2 Hz, 3H), 3.76 (d, J= 7.5 Hz, 1H), 3.56 (d, J= 12.3 Hz, 2H), 3.40 (d, J = 1.1 Hz, 3H), 2.72 - 2.52 (m, 2H), 2.10 (d, J= 13.1 Hz, 2H), 1.61 (qd, J= 10.6, 4.0 Hz, 2H).

[0643] Example 10. 7-Methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]- 9-(3-piperidyl)purin-8-one hydrochloride (Compound 207).tert-Butyl 3-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]-8-oxo- purin-9-yl]piperidine-l -carboxylate PIO (132 mg, 0.23 mmol, 1 eq) was dissolved in 2,2,2- trifluoroethanol (5 ml) and HC1 was added dropwise (30 μL, 0.3 mmol, 1.3 eq) and stirred at rt for 2 h. After comμletion of the reaction the solvent was evaporated. Residue was purified by crystallization from EtOH to obtain 56 mg white solid yield 54%.Analytical data: H1NMR (400 MHz, CD3OD), δ: 8.12 (s, 1H), 7.90 (d, J= 0.9 Hz, 1H), 7.74 (d, J= 0.7 Hz, 1H), 4.82 - 4.74 (m, 1H), 3.94 (d, J= 0.8 Hz, 3H), 3.88 (m, 1H), 3.76 - 3.61 (m, 4H), 3.49 (dd, J= 12.4, 4.4 Hz, 1H), 3.40 (d, J= 12.9 Hz, 1H), 3.34 (d, J= 0.9 Hz, 3H), 3.09 - 2.98 (m, 1H), 2.63 (t, J= 11.7 Hz, 2H), 2.51 - 2.36 (m, 1H), 2.16 - 1.99 (m, 4H), 1.99 - 1.83 (m, 1H), 1.76 (q, J = 11.3 Hz, 2H).

[0644] Example 11. 9-Cyclopentyl-7-methyl-2-[[2-(l-methylpyrazol-4-yl)sulfonyl-2- azaspiro[3.3]heptan-6-yl]amino]purin-8-one (Compound 148).l-Methylpyrazole-4-sulfonyl chloride (50 mg, 0.274 mmol, 1 eq) was added in one portion to a stirred solution of 2-(2-azaspiro[3.3]heptan-6-ylamino)-9-cyclopentyl-7-methyl- purin-8-one hydrochloride P12 (100 mg, 0.274 mmol, 1 eq) in dry pyridine (2 mL) at rt. The resulting reaction mixture was stirred at rt for 30 min and purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 μm column, ACN (with 0.05% of TFA ) and water (with 0.05% of TFA) as eluents, flow 17 mL / min, 15-30% ACN at 20 min, RT 19 min) to obtain 9-cyclopentyl-7-methyl-2-[[2-(l-methylpyrazol-4-yl)sulfonyl-2- azaspiro[3.3]heptan-6-yl]amino]purin-8-one 148 (20 mg, 31%).Analytical data:1HNMR (400 MHz, CD3OD), δ: 8.17 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 4.80 (m, 1H), 4.19 (m, 1H), 3.98 (s, 3H), 3.82 (s, 2H), 3.73 (s, 2H), 3.33 (s, 3H), 2.52 (m, 2H), 2.34 - 2.09 (m, 5H), 2.07 - 1.93 (m, 4H), 1.79 - 1.68 (m, 2H).

[0645] Example 12. 9-Cyclopentyl-2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]-4- piperidyl]amino]-7-methyl-purin-8-one (Compound 177).T3P (290 mg, 0.46 mmol, 2 eq) was added in one portion to a stirred solution of 9- cyclopentyl-7-methyl-2-(4-piperidylamino)purin-8-one hydrochloride P14 (80 mg, 0.23 mmol, 1 eq), 2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetic acid (CAS 17253-11 -1, 44 mg, 0.23 mmol, 1 eq) and DIPEA (120 μL, 0.69 mmol, 3 eq) in dry DMA (2 mL) at rt. The resulting mixture was stirred at rt for 16 h, diluted with brine and extracted with EtOAc. All volatiles were removed under reduced pressure, the residue was purified by column chromatography on SiO2(DCM / MeOH=20 / l) to obtain 9-cyclopentyl-2-[[1-[2-(2,3- dihydro-1,4-benzodioxin-6-yl)acetyl]-4-piperidyl]amino]-7-methyl-purin-8-one 177 (22 mg, 20%).Analytical data:1H NMR (400 MHz, DMSO-d6), δ: 7.91 (s, 1H), 6.81 - 6.64 (m, 3H), 6.58 (d, 1H), 4.66 (m, 1H), 4.21 (s, 5H), 3.96 - 3.78 (m, 2H), 3.58 (s, 2H), 3.24 (s, 3H), 3.10 (m, 1H), 2.77 (m, 1H), 2.18 - 2.06 (m, 2H), 1.99 - 1.81 (m, 6H), 1.68 - 1.56 (m, 2H), 1.46 - 1.16 (m, 2H).Example 13. 9-(2-Azaspiro[3.3]heptan-6-yl)-7-methyl-2-[[1-(l-methylpyrazol-4- yl)sulfonyl-4-piperidyl]amino]purin-8-one hydrochloride (Compound 166).tert-Butyl 6-[7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]-8-oxo- purin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate P18 (92 mg, 0.15 mmol, 1 eq) was dissolved in 2,2,2-trifluoroethanol (5 ml) and HC1 was added dropwise (30 μL, 0.3 mmol, 2 eq) and stirred at rt 2 h. After comμletion of the reaction the solvent was evaporated. Residue was purified by crystallization from EtOH to obtain 56 mg 9-(2- Azaspiro[3.3]heptan-6-yl)-7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one hydrochloride 166 as a white solid yield 64%.Analytical data: H1NMR (400 MHz, CD3OD), δ: 8.14 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 4.88 (q, J= 8.4 Hz, 1H), 4.16 (d, J = 17.4 Hz, 4H), 3.95 (s, 3H), 3.82 (s, 1H), 3.63 (d, J = 12.1 Hz, 3H), 3.31 (s, 3H), 3.19 - 3.09 (m, 2H), 2.83 - 2.73 (m, 2H), 2.56 (td, J= 11.6, 2.7 Hz, 2H), 2.08 (dd, J= 13.3, 3.7 Hz, 2H), 1.84 - 1.69 (m, 2H).Example 14. 9-Cyclopentyl-7-(2-methoxyethyl)-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one (Compound 173).The suspension of 2-chloro-9-cyclopentyl-7-(2-methoxyethyl)purin-8-one P19 (150 mg, 0.505 mmol, 1 eq), 4-(l-methylpyrazol-4-yl)sulfonylcyclohexanamine hydrochloride (185 mg, 0.66 mmol, 1.3 eq), tert-BuONa (145 mg, 1.51 mmol, 3 eq), Pd2dba3(23 mg, 0.025 mmol, 0.05 eq) and XantPhos (29 mg, 0.05 mmol, 0.1 eq) in dry dioxane (9 mL) was stirred at 90°C for 1 h. Reaction mixture was cooled to rt, diluted with brine, extracted with EtOAc. All volatiles were removed under reduced pressure, the residue was purified by column chromatography on SiO2(EtOAc / MeOH= 100 / 0 to EtOAc / MeOH=90 / 10) followed by preparative HPLC (YMC ODS-A 250 x 20 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, 15- 45% ACN at 20 min, RT 16 min) to obtain 9-cyclopentyl-7-(2-methoxyethyl)-2-[[1-(l - methylpyrazol-4-yl)sulfonyl-4-piperidyl]amino]purin-8-one 173 (75 mg, 29%).Analytical data:1HNMR (400 MHz, CD3OD), δ: 8.11 (s, 1H), 7.89 (s, 1H), 7.75 (d, 1H), 4.76 (m, 1H), 3.99 - 3.94 (m, 5H), 3.73 (m, 1H), 3.66 - 3.56 (m, 4H), 3.31 (m, 3H), 2.58 (m, 2H), 2.21 (m, 2H), 2.08 (m, 2H), 2.03 - 1.87 (m, 5H), 1.74 - 1.60 (m, 4H).Example 15. 9-Cyclopentyl-7-methyl-2-[(l-pyrimidin-2-yl-4-piperidyl)amino]purin-8- one (Compound 185).The suspension of 2-chloro-9-cyclopentyl-7-methyl-purin-8-one P3 (80 mg, 0.317 mmol, 1 eq), l-pyrimidin-2-ylpiperidin-4-amine hydrochloride (CAS 1179369-48-2, 160 mg, 1.75 mmol, 3 eq), tert-BuONa (120 mg, 1.25 mmol, 4 eq), Pd2dba3(15 mg, 0.016 mmol, 0.05 eq) and XantPhos (18 mg, 0.31 mmol, 0.1 eq) in dry dioxane (6 mL) was stirred at 80°C for 1 h. The reaction mixture was cooled to rt, diluted with EtOAc (4 mL), washed with brine. All volatiles were removed under reduced pressure, the residue was purified by column chromatography on SiO2(EtOAc / MeOH= 100 / 0 to EtOAc / MeOH=90 / 10) followed by preparative HPLC (YMC ODS-A 250 x 20 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, 15-40% MeCN at 20 min, RT 16 min) to obtain 9-cyclopentyl-7-methyl-2-[(l-pyrimidin- 2-yl-4-piperidyl)amino]purin-8-one 185 (25 mg, 20%).Analytical data: H1NMR (400 MHz, CD3OD), δ: 8.30 (d, 2H), 7.86 (s, 1H), 6.55 (t, 1H), 4.78 (m, 1H), 4.01 (m, 1H), 3.34 (s, 3H), 3.13 (m, 3H), 2.33 - 2.19 (m, 3H), 2.14 - 1.92 (m, 7H), 1.77 - 1.64 (m, 2H), 1.58 - 1.44 (m, 2H).

[0646] Example 16.1HNMR spectra of certain compounds of the disclosure.Biological Assays

[0647] Example A. Primary Assay Used to Determine Potency of CDK2 / CyclinA2 enzymatic activity Inhibition.

[0648] Compound activity was determined using recombinant CDK2 / CyclinA2 proteins (SignalChem, Cat# C29-10G), Histone Hl 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-HC1 pH 7.4-7.6, 20 mM MgCh,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 -Hi stone Hl Peptide mix was prepared in assay buffer and 4 μL of mixture per well was added into 384-well white Reaction μlate with NBS (Coming, Cat# 4513). 4 μL of Histone Hl 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 -Hi stone Hl 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 microμlate 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+10A((LogEC50-X)*HillSlope)).

[0649] Example B. Primary Assay Used to Determine Potency of CDKl / CyclinA2 enzymatic activity Inhibition.

[0650] Compound activity was determined using recombinant CDKl / CyclinA2 proteins (SignalChem, Cat# C22-18G), Histone Hl 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-HC1 pH 7.4-7.6, 20 mM MgCL, 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 CDKl / CyclinA2 -Hi stone Hl Peptide mix was prepared in assay buffer and 4 μL of mixture per well was added into 384-well white Reaction μlate with NBS (Coming, Cat# 4513). 4 μL of Histone Hl Peptide w / o CDKl / 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 CDKl / CyclinA2 -Histone Hl 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 microμlate 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+10A((LogEC50-X)*HillSlope)).

[0651] The average IC50values are shown in Table Al, wherein “A” corresponds to IC50: A < 0.05 μM, “B” corresponds to 0.05 μM < IC50< 0.1 μM, “C” 0.1 μM < IC50< O.5 μM, “D” corresponds to 0.5 μM < IC50< 1.0 μM and “E” corresponds to IC50> 1.0 μM.

[0652] Table Al: CDK1 / CDK2*- IC50is the concentration of an inhibitor where the response (or binding) is reduced by half. IC50: A < 0.05 pM; 0.05 pM < B < 0.1 pM; 0.1 pM < C < 0.5 pM; 0.5 pM < D < 1.0 pM; E > 1 0 pM

[0653] Example C. C6llular Growth Inhibition Assay.

[0654] Comμlete culture media for cell cultures: 50:50 of MCDB 105 (C6ll Apμlications, 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:0VCAR- 3, μlus 10 % FBS (Gibco, USA, Cat# 10500-064 or Capricorn, Germany, Cat# HI-11A), lx Antibiotic-antimycotic (Gibco, USA, Cat# 15240-062), 2x Sodium pyruvate (Gibco, USA, Cat# 11360-070), 2x Essential amino acids (Gibco, USA, Cat# 11130-051), lx 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 C6llBIND® 384-well Flat Clear Bottom Black Polystyrene Microμlates (Corning, USA, Cat #3770) in 45 μl total volume of comμlete culture medium apμlying Biomek NX (384). C6lls 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 μlate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S) and DMSO only control was included. 1 μl of 500x compounds (Compounds μlate) was added to 49 μl of comμlete culture medium into Dilution μlate (Diamond Well Plate, Axigen, Cat#P-384- 120SQ-C-S), mixed and then 5 μl of 10x compounds solutions were transferred to cells apμlying 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 μlate) was added to 49 μl of comμlete culture medium into Dilution μlate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S), mixed and then 10 μl of lOx 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% CO2 using Microμlate Reader (CLARIOStar).

[0655] The average CC50values are shown in Table B, wherein “A” corresponds to CC50: A < 0.1 μM, “B” corresponds to 0.1 μM < CC50< 1.0 μM, “C” CC50> 1.0 μM.

[0656] Table B. C6llular Growth Inhibition.Equivalents

[0657] 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

CLAIMSWhat is claimed is:

1. A compound of F ormul a (A) :or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, and -C(O)NR8R9, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R3is selected from C1-C6alkyl, C3-C10cycloalkyl, heterocyclyl, and aryl wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R10;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 memberedheteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3.

2. A compound of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-.;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl;each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.

3. The compound of claim 2, wherein the compound is of Formula (I-A-l-a), Formula (I-B-l-a), Formula (I-C-l-a), Formula (I-C-l-b), Formula (I-C-l-c), Formula (I-C-l-d), Formula (I-C-2-a), Formula (I-C-3-a), or Formula (I-D-l-a):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

4. A compound of Formula (II):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:X is selected from O, CR4R5, SO2, and NR6;Y is selected from O, NH, and S; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.

5. The compound of claim 4, wherein the compound is of Formula (II-A-3.1 -a), Formula (II-A-3.1 -b), Formula (II-A-3.2-a), Formula (II-B-3.1-a), Formula (II-B-3.1-b), Formula (II-B-3.2-a), or Formula (II-B-3.2-b):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

6. A compound of F ormul a (III) :or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, whereinX is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R3together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;R6is R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.

7. The compound of claim 6, wherein the compound is of Formula (III-A-l-a):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

8. A compound of Formula (IV):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, whereinAr is an aryl;X is selected from O, CR4R5, SO2, and NR6; each R1is independently selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C3-C10cycloalkoxy, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, - C(O)OR8, -C(O)NR8R9, and S(O)2R12wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, heterocycle, aryl, and heteroaryl; or two R1form a bond;R2is selected from H, C1-C6alkyl, C3-C10cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6alkoxy;R4is selected from halogen, -CN, -OH, C1-C6alkyl, C3-C10cycloalkyl, C1-C6alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -CN;R5is selected from H, halogen, C1-C6alkyl and R6; orR4and R5together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, R6;Rcis R7-L-;L is selected from a bond, -C(O)-, -S(O)2-, -O-C(O)-, -O-CH2-C(O)-, -O-CH2- S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6alkanediyl-, -C1-C6alkanediyl-O-, -C1-C6alkanediyl-C(O)-, -C1-C6alkanediyl-NH-C(O)-;R7is selected from C1-C6alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl, C1-C6alkoxy and R8R9N-;R8is selected from H, C1-C6alkyl;R9is selected from H, C1-C6alkyl; each R10is independently selected from halogen, OH, C1-C6alkyl, C1-C6alkoxy; or two R10together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.

9. The compound of claim 8, wherein the compound is of Formula (IV-A-l-a-l):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

10. A compound selected from:or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

11. A pharmaceutical composition comprising the compound of any one of claims 1- 10 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, 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 1-10 or a pharmaceutical composition of claim 11 or 12.

14. The method of claim 13, 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 1-10 or a pharmaceutical composition of claim 11 or 12.

16. The method of claim 15, wherein the disease or disorder is selected from the group consisting of Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); 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 C6ll Carcinoma; Ataxia-Telangiectasia (AT).

17. The method of claim 15, wherein the disease or disorder is cancer.

18. The method of any one of claims 13-17, wherein the subject is a mammal.

19. The method of claim 18, wherein the subject is a human.

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