CDK2 inhibitors

Abstract

This invention relates to the compound represented by formula (A) – a CDK2 inhibitor. The inhibitor described herein can be used to treat CDK2-related diseases or conditions, such as cancer. In particular, this invention relates to compounds and pharmaceutical compositions that inhibit CDK2, methods for treating CDK2-related diseases or conditions, and methods for synthesizing these compounds. (A)

Description

Technical Field

[0001] This invention relates to CDK2 inhibitors. The inhibitors described herein can induce a durable response and be used to treat CDK2-related diseases or conditions, such as autoimmune diseases, Alzheimer's disease, and coronavirus infections. Specifically, this invention relates to compounds and pharmaceutical compositions that inhibit CDK2, methods for treating CDK2-related diseases or conditions, and methods for synthesizing said compounds. Background Technology

[0002] Cyclin-dependent kinase 2 (CDK2) plays a crucial role in cell cycle regulation and participates in a variety 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. CDK2 and its regulatory subunits are dysregulated in many human cancers. Emerging evidence suggests that CDK2 inhibition induces antitumor activity in a subset of tumors with specific genetic characteristics. Previous CDK2 inhibitors lacked specificity and were limited by off-target effects. The development of next-generation CDK2 inhibitors offers therapeutic opportunities for CDK2-dependent cancers.

[0003] Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator whose functions include inactivating phosphorylation of the RB1 (pRb) tumor suppressor protein family and regulating G1 / S and G2 / M transitions. In addition to promoting cell cycle progression, CDK2 has been reported to play an active role in cell cycle arrest during the DNA damage response (DDR), particularly at the G2 / M checkpoint.

[0004] Over the past decade, the clinical development of CDK4 / 6 inhibitors has been a game-changer in breast cancer treatment. This has revitalized the field and increased interest in targeting other members of the CDK family. In the 1990s, CDK2 was an early focus of anticancer drug discovery, but off-target effects of early drugs dampened initial enthusiasm. With the discovery of more CDK2 functions influencing cancer biology and the possibility of developing inhibitors with higher specificity for CDK2, interest in CDK2 inhibition has been rekindled.

[0005] The broad function of CDK2 in proliferation and survival-promoting pathways makes it an ideal target for mechanism-based and low-toxicity therapeutic strategies in cancer treatment. In addition to the roles and potential intervention pathways discussed above, growing evidence suggests that CDK2 activity also influences cell differentiation and adaptive immune responses. Importantly, CDK2 inhibition appears to hold the most potential in specific molecular contexts or cancer subtypes.

[0006] All CDK2 inhibitors discovered to date lack selectivity, resulting in a multi-target mode of action. In this context, it is worth noting that certain cancers can benefit from combining selective inhibition of CDK2 with other CDK inhibitors, which broadens the scope of drug development. For example, endocrine therapy-resistant cancers can benefit from dual blockade of CDK2 / CDK4 action because these cancers are highly dependent on the G1 / S axis. Cancers exhibiting cyclin E1 amplification and CDK2 dependence can benefit from CDK2 / CDK7 blockade to directly inhibit CDK2, and then prevent the activation of residual CDK2 by CDK7 inhibition. There is evidence that this approach will be somewhat successful, as the combination of CDK2 inhibitors and PI3K inhibitors has shown high in vitro potency in colorectal cancer cell lines.

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

[76] Therefore, in the exploration of new and effective targeted cancer therapies, obtaining multiple inhibitors with highly specific or selective targeting effects will be an important step forward, especially for CDK2-dependent subtypes such as MYC-amplified cancers. Highly specific CDK2 inhibitors will help further define the unique role of CDK2 in cancer development, thereby promoting the continued identification of cancer subtypes sensitive to CDK2 inhibition. Summary of the Invention

[0007] The first aspect of the present invention relates to compounds of formula (A):

[0008] (A),

[0009] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:

[0010] X is selected from O, CR 4 R 5 SO2 and NR 6 ;

[0011] Each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR 8 and -C(O)NR 8 R 9 In this embodiment, the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally substituted by one or more substituents, each of which is independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C...10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl;

[0012] Or two R¹ form a bond;

[0013] R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups;

[0014] R³ is selected from C1-C6 alkyl groups, C3-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, heterocyclic, and aryl groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one or more R¹ 0 replace;

[0015] R 4 Selected from halogens, -CN, -OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents, each of which is independently selected from halogen, -OH, -NH2 and -CN;

[0016] R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 ;or

[0017] R 4 and R 5 Together with the atoms it is attached to and any atoms in between, it forms a 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl group, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo-, OH, CN, C1-C6 alkyl, and R. 6 ;

[0018] R 6 For R 7 -L-;

[0019] L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, -C1-C6 alkyldiyl-C(O)- and -C1-C6 alkyldiyl-NH-C(O)-;

[0020] R 7 Selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl-, or R 8 R9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-;

[0021] R 8 Selected from H and C1-C6 alkyl groups;

[0022] R 9 Selected from H and C1-C6 alkyl groups;

[0023] Each R¹ 0 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or

[0024] Two R¹ 0 Together with the atoms to which it is attached and any atoms in between, it forms a 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl, wherein the cycloalkyl, heterocyclic or heteroaryl is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl.

[0025] m is an integer selected from 1, 2, and 3;

[0026] n is an integer selected from 1, 2, and 3.

[0027] In some embodiments, the present invention relates 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 pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0028] Another aspect of the invention relates to a method for treating a CDK2-related disease or condition. The method comprises administering to a patient requiring treatment for a CDK2-related disease or condition an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0029] Another aspect of the invention relates to a method for inhibiting CDK2. The method comprises administering to a patient in need an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0030] Another aspect of the invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the preparation of a medicament for inhibiting CDK2.

[0031] Another aspect of the invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of diseases and conditions associated with CDK2.

[0032] Another aspect of the invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of the diseases or conditions disclosed herein.

[0033] Another aspect of the invention relates to a method for treating or preventing the diseases or conditions disclosed herein in a subject in need of such treatment. The method comprises 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.

[0034] Another aspect of the invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the diseases or conditions disclosed herein.

[0035] The present invention also provides a method for treating a CDK2-related disease or condition, the method comprising administering a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient suffering from at least one of said diseases or conditions.

[0036] Used to treat diseases and conditions related to CDK2.

[0037] This invention also provides compounds and compositions with improved selectivity compared to known CDK2 inhibitors. This disclosure also provides agents with novel mechanisms of action against CDK2 in the treatment of various types of diseases.

[0038] This invention also provides compounds and compositions that have improved efficacy and safety characteristics compared to known CDK2 inhibitors. This disclosure also provides pharmaceutical agents with novel mechanisms of action against CDK2 in the treatment of various types of diseases.

[0039] The present invention also provides methods for treating cancer, blood diseases, immune diseases, genetic diseases, respiratory diseases, endocrine diseases, ear diseases, eye diseases, fetal diseases, metabolic diseases, neuronal diseases, skin diseases, gastrointestinal diseases, mental diseases, liver diseases, nephrological diseases, rare diseases, and reproductive system diseases, said methods comprising administering a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof to a patient suffering from at least one of said diseases or conditions.

[0040] The present invention also provides a method for treating diseases, conditions, or ailments selected from the following: breast cancer (BC); colorectal cancer (CRC); lung cancer (LNCR); retinoblastoma (RB1); 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); and pheochromocytoma (PCC), the method comprising administering a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof to a patient suffering from at least one of the said diseases or ailments.

[0041] In some aspects, this disclosure provides a compound that can be obtained or has been obtained by methods of preparation of compounds described herein (e.g., methods including one or more steps as described in the general procedure).

[0042] In some respects, this disclosure provides intermediates described herein that are suitable for methods of preparing the compounds described herein (e.g., the intermediates are selected from those described in preparation sections—P1-P159).

[0043] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[0044] In some aspects, this disclosure provides a method for preparing the compounds of this disclosure, the method comprising one or more steps described herein.

[0045] 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 pertains. In this specification, the singular form includes the plural form unless the context clearly requires otherwise. Although similar or equivalent methods and materials to those described and materials herein can be used to carry out or test this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure shall prevail.

[0046] Other features and advantages of this disclosure will be apparent from the following detailed description and claims. Detailed Implementation

[0047] This disclosure provides methods for treating, preventing, or improving diseases or conditions related to CDK2, the methods comprising administering a therapeutically effective amount of the compound disclosed herein to a subject in need of such treatment.

[0048] Details of this disclosure are set forth in the following accompanying description. Although similar or equivalent methods and materials may be used to implement or test this disclosure, illustrative methods and materials are described here. Other features, objects, and advantages of this disclosure will be apparent from this specification and the claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly requires otherwise. 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 pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0049] definition:

[0050] The articles “a” and “an” are used in this disclosure to refer to one or more (i.e., at least one) grammatical object modified by the article. For example, “an element” means one element or more elements.

[0051] Unless otherwise stated, the term “and / or” is used in this disclosure to mean either “and” or “or”.

[0052] The term “optional substitution” should be understood to mean that a given chemical moiety (e.g., an alkyl group) may be bonded to other substituents (e.g., heteroatoms) (but is not required to). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have one or more substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point in the chain. Thus, the term “optional substitution” means that a given chemical moiety may contain other functional groups, but is not required to contain any other functional groups. Suitable substituents for optionally substituting the said group include, but are not limited to: 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)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, –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 substituted elements themselves may optionally be substituted. As used herein, “optional substitution” also means “substituted” or “unsubstituted,” as defined below.

[0053] As used herein, the term “substitution” means that a specified group or portion has one or more suitable substituents, wherein the substituents may be attached to the specified group or portion at one or more positions. For example, an aryl group substituted with a cycloalkyl group may mean that the cycloalkyl group is attached to an atom of the aryl group by a single bond, or by being attached by fused with the aryl group and sharing two or more atoms.

[0054] As used in this article, the term "unsubstituted" means that the specified group does not contain substituents.

[0055] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted by one or more substituents (e.g., one to five substituents) at any linking position. Exemplary substituents include, but are not limited to: –H, halogen, –O-(C1-C6)alkyl, (C1-C6)alkyl, –O-(C2-C6)alkenyl, –O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, –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 themselves may optionally be substituted. Furthermore, when containing two fused rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenadrenyl, phenanthrene, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, etc.

[0056] Unless otherwise defined, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic groups include two or more fused rings, and may also include two or more spirocyclic rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise defined, "fused" means that two rings share two ring atoms. Unless otherwise defined, "spirocyclic" means that two rings share one ring atom. As defined herein, a heteroaryl also refers to a bicyclic heteroaryl group in which the heteroatom is selected from N, O, S, P, or B. As defined herein, a heteroaryl also refers to a tricyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. As defined herein, a heteroaryl also refers to a tetracyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. The aromatic group may optionally be independently substituted by one or more substituents described herein.Examples include, but are not limited to: furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazoleyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indoleyl, thiophene-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidozolo[1,2-b]pyrazolyl, furano[2,3-c]pyridyl, imidozolo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl Pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indololinyl, indololinone, dihydrobenzothiazolyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4- [b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzothiophene, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazol[1,5-a]pyridyl Benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazol[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl and their derivatives. Furthermore, when comprising two or more fused rings, a heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings. In heteroaryl ring systems comprising more than two fused rings, the saturated or partially unsaturated rings may also be fused to the saturated or partially unsaturated rings described herein.Furthermore, when comprising three or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused together. Any saturated or partially unsaturated ring described herein may optionally be substituted with one or more oxo groups. Exemplary ring systems of these heteroaryl groups include, for example, indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranone, oxoindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopentano[b]pyrazolo[4,3-e]pyridinyl, 7, 8-Dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-keto, 3,4-dihydropyrazolo[1,2-a]indole-1(2H)-keto, benzo[c][1,2]oxaborphane-1(3H)-ol, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-keto, or 6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-keto.

[0057] Halogens, or "halogenated" halogens, refer to fluorine, chlorine, bromine, or iodine.

[0058] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0059] "Alkoxy" refers to a straight-chain or branched alkyl group containing 1-12 carbon atoms connected by a terminal oxygen atom, i.e., -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0060] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing 2 to 12 carbon atoms. An alkenyl group contains at least one double bond in its chain. The double bond of an alkenyl group may or may not be conjugated with the other unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted. Alkenyl groups as defined herein can be straight-chain or branched.

[0061] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing 2 to 12 carbon atoms. An alkynyl group contains at least one triple bond in its chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups can be unsubstituted or substituted.

[0062] The terms "alkylidene," "alkylene," or "alkylenyl" refer to a divalent alkyl group. Any of the aforementioned monovalent alkyl groups can be made into an alkylene group by removing another hydrogen atom from the alkyl group. Alkylenes as defined herein can also be C1-C6 alkylenes. Alkylenes can also be C1-C4 alkylenes. Typical alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0063] “Cycloalkyl” refers to a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms. A polycyclic cycloalkyl group can be a fused bicyclic cycloalkyl group, a bridged bicyclic cycloalkyl group, or a spirofused bicyclic cycloalkyl group. A polycyclic cycloalkyl group includes at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclic[1.1.1]pentyl, bicyclic[2.2.2]octyl, or bicyclic[2.2.2]octenyl.

[0064] "Heterocyclic group," "heterocycle," or "heterocyclic alkyl" refers to a monocyclic or polycyclic ring containing 3 to 24 ring atoms, wherein the ring atoms include a carbon atom and one or more heteroatoms selected from N, O, S, P, or B, and the ring is a non-aromatic ring. Heterocyclic alkyl ring structures may be substituted by one or more substituents. The substituents themselves may optionally be substituted. Examples of heterocyclic groups include, but are not limited to, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, pyranyl, thiopyranyl, dioxazolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, azathio, oxazolinyl, diazathio, tropane, oxazolidinone, and hotropane.

[0065] The term "aromatic" refers to a planar ring with 4n+2 π electrons in a conjugated system, where n is a non-negative integer. As used herein, "conjugated system" refers to a connected p-orbital system with delocalized electrons, and such systems may include lone pairs.

[0066] As used herein, the term "haloalkyl" refers to an alkyl group that is substituted with one or more halogen atoms, as defined herein. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0067] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0068] As used in this article, the term "cyano" refers to a substituent that has a carbon atom connected to a nitrogen atom via a triple bond, i.e., –C≡N.

[0069] "Spirocycloalkyl" or "spirocycloyl" refers to a carbocyclic bicyclic system in which two rings are linked by a single atom. The two rings can be different in size and properties, or they can be the same. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocyclic ring can be fused with another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spirocyclic ring can be replaced by heteroatoms (e.g., O, N, S, or P). (C3-C) 12 Spirocycloalkyl groups are spirocyclic rings containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced by heteroatoms.

[0070] The terms “spiroheteroalkyl”, “spiroheterocyclic” or “spiroheterocyclic group” should be understood to refer to a spirocycle with at least one heterocyclic ring (e.g., at least one ring is a furan ring, a morpholine ring or a piperidine ring).

[0071] The term "solvate" refers to a complex formed by a solute and a solvent in a variable stoichiometric ratio. For the purposes of this disclosure, such solvents should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), and acetic acid (AcOH). Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0072] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or in their ability to rotate the plane of polarized light (stereoisomers). For stereoisomers, the compound of formula (A) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and either enantiomers or diastereomers.

[0073] This disclosure also covers isotopically labeled compounds of formula (A) (e.g., compounds labeled with ²H and ¹H). 4Compounds labeled with C). Deuterated isotopes (i.e., ²H or D) and carbon-14 isotopes (i.e., ¹⁴H or D). 4 C) is particularly preferred due to its ease of preparation and detection. Furthermore, substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages (e.g., prolonged in vivo half-life or reduced dosage requirements) due to improved metabolic stability, and may therefore be preferred in some cases. Isotope-labeled compounds of formula (A) can generally be prepared by performing a procedure similar to that disclosed in the schemes and / or examples below, and by replacing the non-isotope-labeling reagent with a suitable isotope-labeling reagent.

[0074] This disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, aminosalicylates (4,4′-diaminostilbene-2,2′-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium edetate, camphorsulfonates, carbonates, chlorides, citrates, clavulanates, dihydrochlorides, edetate, ethanedisulfonate, etopolate salts, ethanesulfonate, fumarates, glucono-p-glucose, gluconate, glutamate, glycyrrhetinic acid, hexafluorophosphate, hexylresorcinol salts, hydralamine salts, hydrobromide salts, hydrochloride salts, hydroxyl salts. Naphthyl carboxylates, iodides, hydroxyethanesulfonates, lactates, lactobionates, laurates, magnesium salts, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrate, methyl sulfate, mucilages, naphthalenesulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthyl carboxylates, oleates, oxalates, palmitates, dihydroxynaphthyl salts, pantothenates, phosphates / bisphosphates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, tannates, tartrates, theophylline salts, toluenesulfonates, triiodides, and valerates.

[0075] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0076] When used in combination with a compound, “effective amount” refers to an amount that is sufficient to treat or prevent the disease of the subjects described herein.

[0077] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or medium involved in carrying or transporting a pharmaceutical agent from one organ or body part of a subject to another organ or body part, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0078] For the subject, the term "treatment" means improving at least one symptom of the subject's condition. Treatment includes curing, improving, or at least partially alleviating the condition.

[0079] Unless otherwise stated, the term “symptom” is used in this disclosure to mean disease, condition or illness, and may be used interchangeably with these terms.

[0080] As used in this disclosure, the term "administer" (including administering and administration) means the direct administration to a subject of the disclosed compound, a pharmaceutically acceptable salt of the disclosed compound, or a composition thereof, or the administration to a subject of a prodrug derivative or analogue of the compound, a pharmaceutically acceptable salt of the compound, or the composition thereof, which may form an equivalent amount of the active compound in the subject's body.

[0081] As used in this disclosure, the term "prodrug" means a compound that can be converted into the disclosed compound in vivo through metabolism (e.g., through hydrolysis).

[0082] The term "salt" refers to a pharmaceutically acceptable salt.

[0083] The term "pharmaceutically acceptable salt" also refers to the salt formed by the composition of this disclosure having an acidic functional group (e.g., a carboxylic acid functional group) and a base.

[0084] As used in this article, "CDK2 inhibitor" refers to a compound of formula (A) that inhibits CDK2 and / or a composition containing a compound of formula (A).

[0085] The amount of the compound or composition described herein required to achieve a therapeutic effect may be determined empirically according to routine procedures for a particular purpose. Generally, when a therapeutic agent (e.g., a compound or composition of formula (A) and / or other pharmaceutical agent described herein) is administered for a therapeutic purpose, it is given at a pharmacologically effective dose. "Pharmacologically effective dose," "therapeuticly effective dose," or "effective dose" means an amount sufficient to produce the desired physiological effect or to achieve the desired result, particularly for the treatment of the condition or disease. Effective doses as used herein include, for example, amounts sufficient to delay the onset of symptoms of the condition or disease, alter the symptom progression of the condition or disease (e.g., slow the progression of symptoms), alleviate or eliminate one or more symptoms or manifestations of the condition or disease, and reverse the symptoms of the condition or disease. For example, when a therapeutic agent is administered to a subject with cancer, therapeutic benefits may be provided not only when the underlying condition is eliminated or improved, but also when the subject exhibits a reduction in the severity or duration of symptoms associated with the disease, such as reduced tumor burden, reduced circulating tumor cells, or prolonged progression-free survival. Treatment benefits also include stopping or slowing the progression of the underlying disease or condition, regardless of whether improvement is achieved.

[0086] The compounds disclosed herein:

[0087] In one aspect, this disclosure provides compounds of formula (A) and their salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers:

[0088] (A),

[0089] Wherein, X, R¹, R², R³, m, and n are as described in this article.

[0090] It should be understood that, for compounds of formula (A), where applicable, X, R¹, R², R³, m and n may each be selected from the group described herein, and where applicable, any group described herein for any of X, R¹, R², R³, m and n may be combined with any group described herein for one or more of the other X, R¹, R², R³, m and n.

[0091] In some embodiments, the compound is a compound of formula (I):

[0092] (I),

[0093] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:

[0094] X is selected from O, CR 4 R 5 SO2 and NR6 ;

[0095] Each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, –C(O)OR 8 –C(O)NR 8 R 9 and –S(O)2R¹², wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl;

[0096] Or two R¹ form a bond;

[0097] R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups;

[0098] R 4 Selected from halogens, –CN, –OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents, each of which is independently selected from halogen, –OH, –NH2 and –CN;

[0099] R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 ;or

[0100] R 4 and R 5 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, and R. 6 ;

[0101] R 6 For R 7 -L-;

[0102] L is selected from the following: –C(O)–, –S(O)2–, –O–C(O)–, –O–CH2–C(O)–, –O–CH2–S(O)2–, –CH2–C(O)–, –NH–C(O)–, –C1-C6 alkyldiyl–, –C1-C6 alkyldiyl–O–, –C1-C6 alkyldiyl–C(O)– and –C1-C6 alkyldiyl–NH–C(O)–;

[0103] R 7 Selected from C1-C6 alkyl–, cycloalkyl–, aryl–, heterocyclic–, heteroaryl–, or R 8 R 9 N–, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N–;

[0104] R 8 Selected from H and C1-C6 alkyl groups;

[0105] R 9 Selected from H and C1-C6 alkyl groups;

[0106] Each R¹ 0 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or

[0107] Two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups;

[0108] m is an integer selected from 1, 2, and 3;

[0109] n is an integer selected from 1, 2, and 3;

[0110] p is an integer selected from 1, 2, 3, 4, and 5;

[0111] r is an integer selected from 0, 1, 2, and 3.

[0112] In some embodiments, the compound is a compound of formula (IA):

[0113] (IA),

[0114] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0115] In some embodiments, the compound is a compound of formula (IB):

[0116] (IB),

[0117] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0118] In some embodiments, the compound is a compound of formula (IC):

[0119] (IC),

[0120] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0121] In some embodiments, the compound is a compound of formula (ID):

[0122] (ID),

[0123] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0124] In some embodiments, the compound is a compound of formula (IE):

[0125] (IE),

[0126] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0127] In some embodiments, the compound is a compound of formula (IA-1):

[0128] (IA-1),

[0129] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0130] In some embodiments, the compound is a compound of formula (IA-1-a):

[0131] (IA-1-a),

[0132] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0133] In some embodiments, the compound is a compound of formula (IA-1-aI):

[0134] (IA-1-aI),

[0135] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0136] In some embodiments, the compound is a compound of formula (IA-1-aIA):

[0137] (IA-1-aIA),

[0138] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0139] In some embodiments, the compound is a compound of formula (IA-1-aIA-1):

[0140] (IA-1-aIA-1),

[0141] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0142] In some embodiments, the compound is a compound of formula (IA-1-aIA-1-a):

[0143] (IA-1-aIA-1-a),

[0144] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0145] In some embodiments, the compound is a compound of formula (IB-1):

[0146] (IB-1),

[0147] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0148] In some embodiments, the compound is a compound of formula (IB-1-a):

[0149] (IB-1-a),

[0150] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0151] In some embodiments, the compound is a compound of formula (IB-1-aI):

[0152] (IB-1-aI),

[0153] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0154] In some embodiments, the compound is a compound of formula (IB-1-aIA):

[0155] (IB-1-aIA),

[0156] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0157] In some embodiments, the compound is a compound of formula (IB-1-aIA-1):

[0158] (IB-1-aIA-1),

[0159] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0160] In some embodiments, the compound is a compound of formula (IB-1-aIA-1-a):

[0161] (IB-1-aIA-1-a),

[0162] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0163] In some embodiments, the compound is a compound of formula (IB-1-aIB):

[0164] (IB-1-aIB),

[0165] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0166] In some embodiments, the compound is of formula (IB-1-aIB-1).

[0167] (IB-1-aIB-1),

[0168] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0169] In some embodiments, the compound is a compound of formula (IB-1-aIB-1-a):

[0170] (IB-1-aIB-1-a),

[0171] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0172] In some embodiments, the compound is a compound of formula (IC-1):

[0173] (IC-1),

[0174] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0175] In some embodiments, the compound is a compound of formula (IC-1-a):

[0176] (IC-1-a),

[0177] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0178] In some embodiments, the compound is a compound of formula (IC-1-aI):

[0179] (IC-1-aI),

[0180] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0181] In some embodiments, the compound is a compound of formula (IC-1-aIA):

[0182] (IC-1-aIA),

[0183] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0184] In some embodiments, the compound is of formula (IC-1-aIA-1).

[0185] (IC-1-aIA-1),

[0186] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0187] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-a):

[0188] (IC-1-aIA-1-a),

[0189] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0190] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-b):

[0191] (IC-1-aIA-1-b),

[0192] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0193] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-c):

[0194] (IC-1-aIA-1-c),

[0195] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0196] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-d):

[0197] (IC-1-aIA-1-d),

[0198] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0199] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-e):

[0200] (IC-1-aIA-1-e),

[0201] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0202] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-f):

[0203] (IC-1-aIA-1-f),

[0204] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0205] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-g):

[0206] (IC-1-aIA-1-g),

[0207] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0208] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-h):

[0209] (IC-1-aIA-1-h),

[0210] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0211] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-i):

[0212] (IC-1-aIA-1-i),

[0213] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0214] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-j):

[0215] (IC-1-aIA-1-j),

[0216] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0217] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-k):

[0218] (IC-1-aIA-1-k),

[0219] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0220] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-k'):

[0221] (IC-1-aIA-1-k'),

[0222] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0223] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-l):

[0224] (IC-1-aIA-1-l),

[0225] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0226] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-m):

[0227] (IC-1-aIA-1-m),

[0228] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0229] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-n):

[0230] (IC-1-aIA-1-n),

[0231] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0232] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-o):

[0233] (IC-1-aIA-1-o),

[0234] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0235] In some embodiments, the compound is of formula (IC-1-aIA-1-pq).

[0236] (IC-1-aIA-1-pq),

[0237] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope 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.

[0238] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-p').

[0239] (IC-1-aIA-1-p'),

[0240] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0241] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-p”):

[0242] (IC-1-aIA-1-p”),

[0243] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0244] In some embodiments, the compound is a compound of formula (IC-1-aIA-1-q):

[0245] (IC-1-aIA-1-q),

[0246] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0247] In some embodiments, the compound is a compound of formula (IC-1-b):

[0248] (IC-1-b),

[0249] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0250] In some embodiments, the compound is a compound of formula (IC-1-bI):

[0251] (IC-1-bI),

[0252] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0253] In some embodiments, the compound is a compound of formula (IC-1-bIA):

[0254] (IC-1-bIA),

[0255] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0256] In some embodiments, the compound is a compound of formula (IC-1-c):

[0257] (IC-1-c),

[0258] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0259] In some embodiments, the compound is a compound of formula (IC-1-cI):

[0260] (IC-1-cI),

[0261] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0262] In some embodiments, the compound is a compound of formula (IC-1-cIA):

[0263] (IC-1-cIA),

[0264] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0265] In some embodiments, the compound is of formula (IC-1-cIA-1).

[0266] (IC-1-cIA-1),

[0267] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0268] In some embodiments, the compound is a compound of formula (IC-1-c-II):

[0269] (IC-1-c-II),

[0270] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0271] In some embodiments, the compound is a compound of formula (IC-1-c-II-A):

[0272] (IC-1-c-II-A),

[0273] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0274] In some embodiments, the compound is a compound of formula (IC-1-c-II-A-1):

[0275] (IC-1-c-II-A-1),

[0276] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein Ra The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0277] In some embodiments, the compound is a compound of formula (IC-1-c-III):

[0278] (IC-1-c-III),

[0279] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0280] In some embodiments, the compound is a compound of formula (IC-1-c-III-A):

[0281] (IC-1-c-III-A),

[0282] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0283] In some embodiments, the compound is a compound of formula (IC-1-c-III-A-1):

[0284] (IC-1-c-III-A-1),

[0285] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0286] In some embodiments, the compound is a compound of formula (IC-1-c-IV):

[0287] (IC-1-c-IV),

[0288] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0289] In some embodiments, the compound is a compound of formula (IC-1-c-IV-A):

[0290] (IC-1-c-IV-A),

[0291] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0292] In some embodiments, the compound is a compound of formula (IC-1-c-IV-A-1):

[0293] (IC-1-c-IV-A-1),

[0294] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein R a The alkyl or aryl group is selected from H, C1-C6 alkyl, and aryl, wherein the alkyl or aryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, CN, OH, C1-C6 alkoxy, aryl, and aryloxy groups.

[0295] In some embodiments, the compound is a compound of formula (IC-1-cV):

[0296] (IC-1-cV),

[0297] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0298] In some embodiments, the compound is a compound of formula (IC-1-cVA):

[0299] (IC-1-cVA),

[0300] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0301] In some embodiments, the compound is of formula (IC-1-cIA-1).

[0302] (IC-1-cIA-1),

[0303] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0304] In some embodiments, the compound is a compound of formula (IC-1-cIA-1-a):

[0305] (IC-1-cIA-1-a),

[0306] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0307] In some embodiments, the compound is a compound of formula (IC-1-d):

[0308] (IC-1-d),

[0309] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0310] In some embodiments, the compound is a compound of formula (IC-1-dI):

[0311] (IC-1-dI),

[0312] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0313] In some embodiments, the compound is a compound of formula (IC-1-dIA):

[0314] (IC-1-dIA),

[0315] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0316] In some embodiments, the compound is a compound of formula (IC-2):

[0317] (IC-2),

[0318] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0319] In some embodiments, the compound is a compound of formula (IC-2-a):

[0320] (IC-2-a),

[0321] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0322] In some embodiments, the compound is a compound of formula (IC-2-aI):

[0323] (IC-2-aI),

[0324] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein Rᵇ is selected from H and R 6 .

[0325] In some embodiments, the compound is a compound of formula (IC-2-aIA):

[0326] (IC-2-aIA),

[0327] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein Rᵇ is selected from H and R 6 .

[0328] In some embodiments, the compound is of formula (IC-2-aIA-1).

[0329] (IC-2-aIA-1),

[0330] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein Rᵇ is selected from H and R 6 .

[0331] In some embodiments, the compound is a compound of formula (IC-2-aIA-1-a):

[0332] (IC-2-aIA-1-a),

[0333] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0334] In some embodiments, the compound is a compound of formula (IC-2-aIA-1-b):

[0335] (IC-2-aIA-1-b),

[0336] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0337] In some embodiments, the compound is a compound of formula (IC-2-aIA-1-c):

[0338] (IC-2-aIA-1-c),

[0339] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0340] In some embodiments, the compound is of formula (IC-2-aIA-1-CI).

[0341] (IC-2-aIA-1-cI),

[0342] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0343] In some embodiments, the compound is a compound of formula (IC-3):

[0344] (IC-3),

[0345] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0346] In some embodiments, the compound is a compound of formula (IC-3-a):

[0347] (IC-3-a),

[0348] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0349] In some embodiments, the compound is a compound of formula (IC-3-aI):

[0350] (IC-3-aI),

[0351] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0352] In some embodiments, the compound is a compound of formula (IC-3-aIA):

[0353] (IC-3-aIA),

[0354] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0355] In some embodiments, the compound is of formula (IC-3-aIA-1).

[0356] (IC-3-aIA-1),

[0357] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0358] In some embodiments, the compound is a compound of formula (IC-3-a-II):

[0359] (IC-3-a-II),

[0360] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0361] In some embodiments, the compound is a compound of formula (IC-3-a-II-A):

[0362] (IC-3-a-II-A),

[0363] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0364] In some embodiments, the compound is a compound of formula (IC-3-a-II-A-1):

[0365] (IC-3-a-II-A-1),

[0366] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0367] In some embodiments, the compound is a compound of formula (IC-3-a-III):

[0368] (IC-3-a-III),

[0369] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0370] In some embodiments, the compound is a compound of formula (IC-3-a-III-A):

[0371] (IC-3-a-III-A),

[0372] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0373] In some embodiments, the compound is a compound of formula (IC-3-a-III-A-1):

[0374] (IC-3-a-III-A-1),

[0375] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0376] In some embodiments, the compound is a compound of formula (IC-3-a-IV):

[0377] (IC-3-a-IV),

[0378] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0379] In some embodiments, the compound is a compound of formula (IC-3-a-IV-A):

[0380] (IC-3-a-IV-A),

[0381] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0382] In some embodiments, the compound is of formula (IC-3-a-IV-A-1).

[0383] (IC-3-a-IV-A-1),

[0384] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0385] In some embodiments, the compound is a compound of formula (IC-3-aV):

[0386] (IC-3-aV),

[0387] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0388] In some embodiments, the compound is a compound of formula (IC-3-aVA):

[0389] (IC-3-aVA),

[0390] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0391] In some embodiments, the compound is of formula (IC-3-aIA-1).

[0392] (IC-3-aIA-1),

[0393] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0394] In some embodiments, the compound is a compound of formula (IC-3-aVB):

[0395] (IC-3-aVB),

[0396] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0397] In some embodiments, the compound is of formula (IC-3-aIB-1).

[0398] (IC-3-aIB-1),

[0399] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0400] In some embodiments, the compound is a compound of formula (IC-3-aVC):

[0401] (IC-3-aVC),

[0402] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0403] In some embodiments, the compound is of formula (IC-3-aIC-1).

[0404] (IC-3-aIC-1),

[0405] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0406] In some embodiments, the compound is a compound of formula (ID-1):

[0407] (ID-1),

[0408] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0409] In some embodiments, the compound is a compound of formula (ID-1-a):

[0410] (ID-1-a),

[0411] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0412] In some embodiments, the compound is a compound of formula (ID-1-aI):

[0413] (ID-1-aI),

[0414] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0415] In some embodiments, the compound is a compound of formula (ID-1-aIA):

[0416] (ID-1-aIA),

[0417] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0418] In some embodiments, the compound is a compound of formula (ID-1-aIA-1):

[0419] (ID-1-aIA-1),

[0420] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0421] In some embodiments, the compound is a compound of formula (ID-1-aIA-1-a):

[0422] (ID-1-aIA-1-a),

[0423] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0424] In some embodiments, the compound is a compound of formula (ID-1-aIA-1-b):

[0425] (ID-1-aIA-1-b),

[0426] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0427] In some embodiments, the compound is a compound of formula (II):

[0428] (II),

[0429] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:

[0430] X is selected from O, CR 4 R 5 SO2 and NR6 ;

[0431] Y is selected from O, NH, and S;

[0432] Each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, –C(O)OR 8 –C(O)NR 8 R 9 and –S(O)2R¹², wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl;

[0433] Or two R¹ form a bond;

[0434] R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups;

[0435] R 4 Selected from halogens, –CN, –OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents, each of which is independently selected from halogen, –OH, –NH2 and –CN;

[0436] R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 ;or

[0437] R 4 and R 5 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, and R. 6 ;

[0438] R 6 For R 7 -L-;

[0439] L is selected from the following: –C(O)–, –S(O)2–, –O–C(O)–, –O–CH2–C(O)–, –O–CH2–S(O)2–, –CH2–C(O)–, –NH–C(O)–, –C1-C6 alkyldiyl–, –C1-C6 alkyldiyl–O–, –C1-C6 alkyldiyl–C(O)– and –C1-C6 alkyldiyl–NH–C(O)–;

[0440] R 7 Selected from C1-C6 alkyl–, cycloalkyl–, aryl–, heterocyclic–, heteroaryl–, or R 8 R 9 N–, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N–;

[0441] R 8 Selected from H and C1-C6 alkyl groups;

[0442] R 9 Selected from H and C1-C6 alkyl groups;

[0443] Each R¹ 0 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or

[0444] Two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups;

[0445] m is an integer selected from 1, 2, and 3;

[0446] n is an integer selected from 1, 2, and 3;

[0447] Each b is an independent integer selected from 1, 2, and 3;

[0448] r is an integer selected from 0, 1, 2, and 3.

[0449] In some embodiments, the compound is a compound of formula (II-A):

[0450] (II-A),

[0451] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0452] In some embodiments, the compound is a compound of formula (II-B):

[0453] (II-B),

[0454] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0455] In some embodiments, the compound is a compound of formula (II-C):

[0456] (II-C),

[0457] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0458] In some embodiments, the compound is a compound of formula (II-A-1):

[0459] (II-A-1),

[0460] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0461] In some embodiments, the compound is a compound of formula (II-A-2):

[0462] (II-A-2),

[0463] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0464] In some embodiments, the compound is a compound of formula (II-A-3.1):

[0465] (II-A-3.1),

[0466] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0467] In some embodiments, the compound is a compound of formula (II-A-3.1-a):

[0468] (II-A-3.1-a),

[0469] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0470] In some embodiments, the compound is a compound of formula (II-A-3.1-aI):

[0471] (II-A-3.1-aI),

[0472] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0473] In some embodiments, the compound is a compound of formula (II-A-3.1-aIA):

[0474] (II-A-3.1-aIA),

[0475] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0476] In some embodiments, the compound is a compound of formula (II-A-3.1-aIA-1):

[0477] (II-A-3.1-aIA-1),

[0478] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0479] In some embodiments, the compound is a compound of formula (II-A-3.1-aIA-1-a):

[0480] (II-A-3.1-aIA-1-a),

[0481] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0482] In some embodiments, the compound is a compound of formula (II-A-3.1-aIA-1-b):

[0483] (II-A-3.1-aIA-1-b),

[0484] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0485] In some embodiments, the compound is a compound of formula (II-A-3.1-aIA-1-c):

[0486] (II-A-3.1-aIA-1-c),

[0487] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0488] In some embodiments, the compound is a compound of formula (II-A-3.1-b):

[0489] (II-A-3.1-b),

[0490] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0491] In some embodiments, the compound is a compound of formula (II-A-3.1-bI):

[0492] (II-A-3.1-bI),

[0493] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0494] In some embodiments, the compound is a compound of formula (II-A-3.1-bIA):

[0495] (II-A-3.1-bIA),

[0496] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0497] In some embodiments, the compound is a compound of formula (II-A-3.1-bIA-1):

[0498] (II-A-3.1-bIA-1),

[0499] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0500] In some embodiments, the compound is a compound of formula (II-A-3.1-bIA-1-a):

[0501] (II-A-3.1-bIA-1-a),

[0502] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0503] In some embodiments, the compound is a compound of formula (II-A-3.2):

[0504] (II-A-3.2),

[0505] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0506] In some embodiments, the compound is a compound of formula (II-A-3.2-a):

[0507] (II-A-3.2-a),

[0508] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0509] In some embodiments, the compound is a compound of formula (II-A-3.2-aI):

[0510] (II-A-3.2-aI),

[0511] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0512] In some embodiments, the compound is a compound of formula (II-A-3.2-aIA):

[0513] (II-A-3.2-aIA),

[0514] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0515] In some embodiments, the compound is a compound of formula (II-A-3.2-aIA-1):

[0516] (II-A-3.2-aIA-1),

[0517] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0518] In some embodiments, the compound is a compound of formula (II-A-3.2-aIA-1-c):

[0519] (II-A-3.2-aIA-1-c),

[0520] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0521] In some embodiments, the compound is a compound of formula (II-B-3.1):

[0522] (II-B-3.1),

[0523] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0524] In some embodiments, the compound is a compound of formula (II-B-3.1-a):

[0525] (II-B-3.1-a),

[0526] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0527] In some embodiments, the compound is a compound of formula (II-B-3.1-aI):

[0528] (II-B-3.1-aI),

[0529] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0530] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA):

[0531] (II-B-3.1-aIA),

[0532] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0533] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA-1):

[0534] (II-B-3.1-aIA-1),

[0535] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0536] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA-1-a):

[0537] (II-B-3.1-aIA-1-a),

[0538] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0539] In some embodiments, the compound is a compound of formula (II-B-3.1-b):

[0540] (II-B-3.1-b),

[0541] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0542] In some embodiments, the compound is a compound of formula (II-B-3.1-bI):

[0543] (II-B-3.1-bI),

[0544] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0545] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA):

[0546] (II-B-3.1-aIA),

[0547] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0548] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA-1):

[0549] (II-B-3.1-aIA-1),

[0550] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0551] In some embodiments, the compound is a compound of formula (II-B-3.1-aIA-1-a):

[0552] (II-B-3.1-aIA-1-a),

[0553] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0554] In some embodiments, the compound is a compound of formula (II-B-3.2):

[0555] (II-B-3.2),

[0556] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0557] In some embodiments, the compound is a compound of formula (II-B-3.2-a):

[0558] (II-B-3.2-a),

[0559] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0560] In some embodiments, the compound is a compound of formula (II-B-3.2-aI):

[0561] (II-B-3.2-aI),

[0562] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0563] In some embodiments, the compound is a compound of formula (II-B-3.2-aIA):

[0564] (II-B-3.2-aIA),

[0565] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0566] In some embodiments, the compound is a compound of formula (II-B-3.2-aIA-1):

[0567] (II-B-3.2-aIA-1),

[0568] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0569] In some embodiments, the compound is a compound of formula (II-B-3.2-aIA-1-a):

[0570] (II-B-3.2-aIA-1-a),

[0571] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0572] In some embodiments, the compound is a compound of formula (II-B-3.2-b):

[0573] (II-B-3.2-b),

[0574] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0575] In some embodiments, the compound is a compound of formula (II-B-3.2-bI):

[0576] (II-B-3.2-bI),

[0577] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0578] In some embodiments, the compound is a compound of formula (II-B-3.2-bIA):

[0579] (II-B-3.2-bIA),

[0580] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0581] In some embodiments, the compound is a compound of formula (II-B-3.2-bIA-1):

[0582] (II-B-3.2-bIA-1),

[0583] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0584] In some embodiments, the compound is a compound of formula (II-B-3.2-bIA-1-a):

[0585] (II-B-3.2-bIA-1-a),

[0586] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0587] In some embodiments, the compound is a compound of formula (III):

[0588] (III),

[0589] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:

[0590] X is selected from O, CR 4 R 5 SO2 and NR 6 ;

[0591] Each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, –C(O)OR 8 –C(O)NR 8 R 9 and –S(O)2R¹², wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl;

[0592] Or two R¹ form a bond;

[0593] R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups;

[0594] R 4 Selected from halogens, –CN, –OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents, each of which is independently selected from halogen, –OH, –NH2 and –CN;

[0595] R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 ;or

[0596] R 4 and R 5 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, and R. 6 ;

[0597] R 6 For R 7 -L-;

[0598] L is selected from the following: –C(O)–, –S(O)2–, –O–C(O)–, –O–CH2–C(O)–, –O–CH2–S(O)2–, –CH2–C(O)–, –NH–C(O)–, –C1-C6 alkyldiyl–, –C1-C6 alkyldiyl–O– and –C1-C6 alkyldiyl–C(O)–;

[0599] R 7 Selected from C1-C6 alkyl–, cycloalkyl–, aryl–, heterocyclic–, heteroaryl–, or R 8 R 9 N–, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N–;

[0600] R 8 Selected from H and C1-C6 alkyl groups;

[0601] R 9 Selected from H and C1-C6 alkyl groups;

[0602] Each R¹ 0 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or

[0603] Two R¹0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups;

[0604] m is an integer selected from 1, 2, and 3;

[0605] n is an integer selected from 1, 2, and 3;

[0606] Each b is an independent integer selected from 1, 2, and 3;

[0607] r is an integer selected from 0, 1, 2, and 3.

[0608] In some embodiments, the compound is a compound of formula (III-A):

[0609] (III-A),

[0610] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0611] In some embodiments, the compound is a compound of formula (III-A-1):

[0612] (III-A-1),

[0613] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0614] In some embodiments, the compound is a compound of formula (III-A-1-a):

[0615] (III-A-1-a),

[0616] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0617] In some embodiments, the compound is a compound of formula (III-A-1-aI):

[0618] (III-A-1-aI),

[0619] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0620] In some embodiments, the compound is a compound of formula (III-A-1-aIA):

[0621] (III-A-1-aIA),

[0622] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0623] In some embodiments, the compound is a compound of formula (III-A-1-aIB):

[0624] (III-A-1-aIB),

[0625] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0626] In some embodiments, the compound is a compound of formula (IV):

[0627] (IV),

[0628] Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:

[0629] Ar is an aryl group;

[0630] X is selected from O, CR 4 R 5 SO2 and NR 6 ;

[0631] Each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, –C(O)OR 8 –C(O)NR 8 R 9 and –S(O)2R¹², wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl;

[0632] Or two R¹ form a bond;

[0633] R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups;

[0634] R 4 Selected from halogens, –CN, –OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents, each of which is independently selected from halogen, –OH, –NH2 and –CN;

[0635] R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 ;or

[0636] R 4 and R 5 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, and R. 6 ;

[0637] R 6 For R 7 -L-;

[0638] L is selected from the following: –C(O)–, –S(O)2–, –O–C(O)–, –O–CH2–C(O)–, –O–CH2–S(O)2–, –CH2–C(O)–, –NH–C(O)–, –C1-C6 alkyldiyl–, –C1-C6 alkyldiyl–O–, –C1-C6 alkyldiyl–C(O)– and –C1-C6 alkyldiyl–NH–C(O)–;

[0639] R 7 Selected from C1-C6 alkyl–, cycloalkyl–, aryl–, heterocyclic–, heteroaryl–, or R 8 R 9 N–, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N–;

[0640] R 8 Selected from H and C1-C6 alkyl groups;

[0641] R9 Selected from H and C1-C6 alkyl groups;

[0642] Each R¹ 0 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or

[0643] Two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups;

[0644] m is an integer selected from 1, 2, and 3;

[0645] n is an integer selected from 1, 2, and 3;

[0646] p is an integer selected from 1, 2, 3, 4, and 5;

[0647] r is an integer selected from 0, 1, 2, and 3.

[0648] In some embodiments, the compound is a compound of formula (IV-A):

[0649] (IV-A),

[0650] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0651] In some embodiments, the compound is a compound of formula (IV-A-1):

[0652] (IV-A-1),

[0653] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0654] In some embodiments, the compound is a compound of formula (IV-A-1-a):

[0655] (IV-A-1-a),

[0656] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0657] In some embodiments, the compound is a compound of formula (IV-A-1-aI):

[0658] (IV-A-1-aI),

[0659] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0660] In some embodiments, the compound is a compound of formula (IV-A-1-aIA):

[0661] (IV-A-1-aIA),

[0662] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0663] In some embodiments, the compound is a compound of formula (IV-A-1-aIA-1):

[0664] (IV-A-1-aIA-1),

[0665] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof.

[0666] 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).

[0667] In some embodiments, the compound is of formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof.

[0668] In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof.

[0669] In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof.

[0670] In some embodiments, the compound is of formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof.

[0671] In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof.

[0672] In some implementation schemes, X is selected from O, CR 4 R 5 S(O) q NR 6 .

[0673] In some implementations, X is O.

[0674] In some implementations, X is CR 4 R 5 .

[0675] In some implementations, X is CF2.

[0676] In some implementations, X is S(O). q .

[0677] In some implementations, X is S.

[0678] In some implementations, X is S=O.

[0679] In some implementations, X is SO2.

[0680] In some implementations, X is –NR 6 .

[0681] In some implementations, X is NLR 7 .

[0682] In some embodiments, each R¹ is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, –C(O)OR 8 and –C(O)NR 8 R 9 In this embodiment, the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally substituted by one or more substituents, each of which is independently selected from halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C... 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl.

[0683] In some implementations, R¹ is H.

[0684] In some implementations, R¹ is –C(O)OR 8 .

[0685] In some implementations, R¹ is –C(O)OCH3.

[0686] In some implementations, R¹ is –C(O)NR 8 R 9 .

[0687] In some implementations, R¹ is –C(O)NH2.

[0688] In some implementations, R¹ is –C(O)N(CH3)2.

[0689] In some implementations, two R¹ form a bond.

[0690] In some implementations, two R¹ form a single bond.

[0691] In some embodiments, R² is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN, and C1-C6 alkoxy groups.

[0692] In some implementations, R² is H.

[0693] In some implementations, R² is a C1-C6 alkyl group.

[0694] In some implementations, R² is methyl.

[0695] In some implementations, R² is ethyl.

[0696] In some implementations, R² is .

[0697] In some embodiments, R² is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN, and C1-C6 alkoxy groups.

[0698] In some implementations, R² is .

[0699] In some implementations, R² is .

[0700] In some implementations, R² is .

[0701] In some implementations, R² is .

[0702] In some implementations, R² is .

[0703] In some implementations, R² is .

[0704] In some implementations, R² is C3-C 10 Cycloalkyl, wherein the cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogens, OH, CN and C1-C6 alkoxy groups.

[0705] In some implementations, R² is C3-C 10 Cycloalkyl.

[0706] In some implementations, R² is .

[0707] In some implementations, R² is .

[0708] In some embodiments, R³ is selected from C1-C6 alkyl, C3 ... 10 Cycloalkyl, heterocyclic, and aryl groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one or more R¹ 0 replace.

[0709] In some implementations, R³ is optionally controlled by one or more R¹ 0 Substituted C1-C6 alkyl groups.

[0710] In some implementations, R³ is a C1-C6 alkyl group.

[0711] In some implementations, R³ is propyl.

[0712] In some implementations, R³ is isopropyl.

[0713] In some implementations, R³ is butyl.

[0714] In some implementations, R³ is tert-butyl.

[0715] In some implementations, R³ is optionally controlled by one or more R¹ 0 Replacement C3-C 10 Cycloalkyl.

[0716] In some implementations, R³ is C3-C 10 Cycloalkyl.

[0717] In some implementations, R³ is C3-C 10 Monocyclic cycloalkyl.

[0718] In some implementations, R³ is .

[0719] In some implementations, R³ is .

[0720] In some implementations, R³ is .

[0721] In some implementations, R³ is .

[0722] In some implementations, R³ is .

[0723] In some implementations, R³ is .

[0724] In some implementations, R³ is .

[0725] In some implementations, R³ is .

[0726] In some implementations, R³ is .

[0727] In some implementations, R³ is .

[0728] In some implementations, R³ is optionally controlled by one or more R¹ 0 Substituted heterocyclic groups.

[0729] In some implementations, R³ is a heterocyclic group.

[0730] In some implementations, R³ is a 5-membered heterocyclic group.

[0731] In some implementations, R³ is a 6-membered heterocyclic group.

[0732] In some implementations, R³ is .

[0733] In some implementations, R³ is .

[0734] In some implementations, R³ is .

[0735] In some implementations, R³ is .

[0736] In some implementations, R³ is .

[0737] In some implementations, R³ is .

[0738] In some implementations, R³ is .

[0739] In some implementations, R³ is .

[0740] In some implementations, R³ is .

[0741] In some implementations, R³ is optionally controlled by one or more R¹ 0 Substituted aryl groups.

[0742] In some implementations, R³ is aryl.

[0743] In some implementations, R³ is .

[0744] In some implementation schemes, X is selected from O, CR 4 R 5 SO2 and NR 6 .

[0745] In some implementations, X is O.

[0746] In some implementations, X is CR 4 R 5 .

[0747] In some implementation schemes, R 4 Selected from halogens, –CN, –OH, C1-C6 alkyl, C3-C 10 Cycloalkyl and C1-C6 alkoxy groups, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted with one or more substituents, each substituent being independently selected from halogens, –OH, –NH2 and –CN.

[0748] In some implementation schemes, R 4 For H.

[0749] In some implementation schemes, R 4 It is a halogen.

[0750] In some implementation schemes, R 4 It is F.

[0751] In some implementation schemes, R 4 It is a C1-C6 alkyl group.

[0752] In some implementation schemes, R 4 It is a methyl group.

[0753] In some implementation schemes, R 4It is tert-butyl.

[0754] In some implementation schemes, R 5 Selected from H, halogens, C1-C6 alkyl groups and R 6 .

[0755] In some implementation schemes, R 5 For H.

[0756] In some implementation schemes, R 5 It is a halogen.

[0757] In some implementation schemes, R 5 It is F.

[0758] In some implementation schemes, R 5 It is a C1-C6 alkyl group.

[0759] In some implementation schemes, R 5 It is a methyl group.

[0760] In some implementation schemes, R 5 For R 6 .

[0761] In some implementation schemes, R 5 For –LR 7 .

[0762] In some implementation schemes, R 4 and R 5 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic, or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, and R. 6 .

[0763] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0764] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0765] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0766] In some implementation schemes, R4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0767] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0768] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0769] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0770] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0771] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0772] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0773] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0774] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0775] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0776] In some implementation schemes, R 4 and R5 Together with the atoms they are connected to and any spacer atoms, they form .

[0777] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0778] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0779] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0780] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0781] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0782] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0783] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0784] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0785] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0786] In some implementation schemes, R 4 and R 5Together with the atoms they are connected to and any spacer atoms, they form .

[0787] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0788] In some implementation schemes, R 4 and R 5 Together with the atoms they are connected to and any spacer atoms, they form .

[0789] In some implementations, X is SO2.

[0790] In some implementations, X is NR 6 .

[0791] In some implementation schemes, R 6 For –LR 7 .

[0792] In some embodiments, L is selected from 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-C6 alkyldiyl–, –C1-C6 alkyldiyl–O–, –C1-C6 alkyldiyl–C(O)– and –C1-C6 alkyldiyl–NH–C(O)–.

[0793] In some implementations, L stands for key.

[0794] In some implementations, L stands for a single bond.

[0795] In some implementations, L is –C(O)–.

[0796] In some implementations, L is –S(O)2–.

[0797] In some implementations, L stands for -OC(O)-.

[0798] In some implementations, L is -O-CH2-C(O)-.

[0799] In some implementations, L is -O-CH2-S(O)2-.

[0800] In some implementations, L is -CH2-C(O)-.

[0801] In some implementations, L is -NH-C(O)-.

[0802] In some implementations, L is -C1-C6 alkyldiyl-.

[0803] In some implementations, L is -C1-C6 alkyldiyl-O-.

[0804] In some implementations, L is -C1-C6 alkyldiyl-C(O)-.

[0805] In some implementations, L is -C1-C6 alkyldiyl-NH-C(O)-.

[0806] In some implementations, L is -CH2-NH-C(O)-.

[0807] In some implementation schemes, R 7 Selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-.

[0808] In some implementation schemes, R 7 The C1-C6 alkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy groups.

[0809] In some implementation schemes, R 7 It is a C1-C6 alkyl group.

[0810] In some implementation schemes, R 7 It is a methyl group.

[0811] In some implementation schemes, R 7 It is an ethyl group.

[0812] In some implementation schemes, R 7 It is propyl.

[0813] In some implementation schemes, R 7 It is n-propyl.

[0814] In some implementation schemes, R 7 It is isopropyl.

[0815] In some implementation schemes, R 7 It is butyl.

[0816] In some implementation schemes, R 7 It is tert-butyl.

[0817] In some implementation schemes, R 7 It is a C1-C6 alkyl group substituted with one or more halogens.

[0818] In some implementation schemes, R 7 for .

[0819] In some implementation schemes, R 7 For R 8 R 9 N-substituted C1-C6 alkyl groups.

[0820] In some implementation schemes, R 7 for .

[0821] In some implementation schemes, R 7 The cycloalkyl group is optionally substituted with one or more substituents, each of which is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-.

[0822] In some implementation schemes, R 7 It is a cycloalkyl group.

[0823] In some implementation schemes, R 7 For C3-C 10 Monocyclic cycloalkyl.

[0824] In some implementation schemes, R 7 It is cyclopropyl.

[0825] In some implementation schemes, R 7 It is cyclobutyl.

[0826] In some implementation schemes, R 7 It is cyclopentyl.

[0827] In some implementation schemes, R 7 It is a cyclohexyl group.

[0828] In some implementation schemes, R 7 for .

[0829] In some implementation schemes, R 7 It is a cycloalkyl group that is optionally substituted with one or more halogens.

[0830] In some implementation schemes, R 7 for .

[0831] In some implementation schemes, R 7 The aryl group is optionally substituted with one or more substituents, each independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-.

[0832] In some implementation schemes, R 7 It is an aryl group.

[0833] In some implementation schemes, R 7 for .

[0834] In some implementation schemes, R 7 for .

[0835] In some implementation schemes, R 7 for .

[0836] In some implementation schemes, R 7 for .

[0837] In some implementation schemes, R 7 A heterocyclic group optionally substituted with one or more substituents, each independently selected from halogens, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-.

[0838] In some implementation schemes, R 7 It is a heterocyclic group.

[0839] In some implementation schemes, R 7 for .

[0840] In some implementation schemes, R 7 for .

[0841] In some implementation schemes, R 7 The heteroaryl group is optionally substituted with one or more substituents, each of which is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and R. 8 R 9 N-.

[0842] In some implementation schemes, R 7 It is a heteroaryl group.

[0843] In some implementation schemes, R 7 It is a 5-membered heteroaryl group.

[0844] In some implementation schemes, R 7 It is a 6-membered heteroaryl group.

[0845] In some implementation schemes, R 7 It is a 10-membered heteroaryl group.

[0846] In some implementation schemes, R 7 It is a monocyclic heteroaryl group.

[0847] In some implementation schemes, R 7 It is a bicyclic heteroaryl group.

[0848] In some implementation schemes, R 7 for .

[0849] In some implementation schemes, R 7 for .

[0850] In some implementation schemes, R 7 for .

[0851] In some implementation schemes, R 7 for .

[0852] In some implementation schemes, R 7 for .

[0853] In some implementation schemes, R 7 for .

[0854] In some implementation schemes, R 7 for .

[0855] In some implementation schemes, R 7 for .

[0856] In some implementation schemes, R 7 for .

[0857] In some implementation schemes, R 8 Selected from H and C1-C6 alkyl groups.

[0858] In some implementation schemes, R 8 For H.

[0859] In some implementation schemes, R 8 It is a C1-C6 alkyl group.

[0860] In some implementation schemes, R 8 It is a methyl group.

[0861] In some implementation schemes, R 9 Selected from H and C1-C6 alkyl groups.

[0862] In some implementation schemes, R 9 For H.

[0863] In some implementation schemes, R 9 It is a C1-C6 alkyl group.

[0864] In some implementation schemes, R 9 It is a methyl group.

[0865] In some implementations, each R¹ 0 It is independently selected from halogens, OH, C1-C6 alkyl and C1-C6 alkoxy groups.

[0866] In some implementations, R¹ 0 It is a halogen.

[0867] In some implementations, R¹ 0 It is F.

[0868] In some implementations, R¹ 0 It is OH.

[0869] In some implementations, R¹ 0 It is a C1-C6 alkyl group.

[0870] In some implementations, R¹ 0 It is a methyl group.

[0871] In some implementations, R¹ 0 It is a C1-C6 alkoxy group.

[0872] In some implementations, R¹ 0 It is a methoxy group.

[0873] In some implementations, two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl, 4-9 membered heterocyclic or 4-9 membered heteroaryl groups, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents, each of which is independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups.

[0874] In some implementations, two R¹ 0Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered cycloalkyl groups, wherein the cycloalkyl groups are optionally substituted by one or more substituents, each of which is independently selected from halogens, oxo-, OH, CN and C1-C6 alkyl groups.

[0875] In some implementations, two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered heterocycles that may be optionally substituted with one or more substituents, each of which is independently selected from halogens, oxo, OH, CN, and C1-C6 alkyl groups.

[0876] In some implementations, two R¹ 0 Together with the atoms they are connected to and any spacer atoms, they form .

[0877] In some implementations, two R¹ 0 Together with the atoms they are attached to and any spacer atoms, they form 4-9 membered heteroaryl groups that are optionally substituted with one or more substituents, each of which is independently selected from halogens, oxo-, OH, CN, and C1-C6 alkyl groups.

[0878] In some implementations, m is an integer selected from 1 and 2.

[0879] In some implementations, m is 1.

[0880] In some implementations, m is 2.

[0881] In some implementations, n is an integer selected from 1 and 2.

[0882] In some implementations, n is 1.

[0883] In some implementations, n is 2.

[0884] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, or tautomers.

[0885] In some embodiments, the compound is selected from the compounds described in Table 1, their prodrugs, and pharmaceutically acceptable salts.

[0886] In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0887] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0888] In some embodiments, the compound is selected from the compounds described in Table 1.

[0889] Table 1. Some examples of compounds of formula (A)

[0890]

[0891] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 1.

[0892] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any of the compounds listed in Table 1.

[0893] In some embodiments, the compound is a salt formed by any of the acids described in Table 2 and any of the compounds described in Table 1.

[0894] Table 2. Pharmaceutically acceptable acids that can form salts with compounds of formulas (I)-(IV).

[0895]

[0896] In some embodiments, the compound is an acetate of any of the compounds listed in Table 1.

[0897] In some embodiments, the compound is an adipate of any of the compounds listed in Table 1.

[0898] In some embodiments, the compound is an L-ascorbate of any of the compounds listed in Table 1.

[0899] In some embodiments, the compound is a hydrobromide of any of the compounds listed in Table 1.

[0900] In some embodiments, the compound is a hydrochloride salt of any of the compounds listed in Table 1.

[0901] In some embodiments, the compound is a citrate of any of the compounds listed in Table 1.

[0902] In some embodiments, the compound is a glutamate salt of any of the compounds listed in Table 1.

[0903] In some embodiments, the compound is an oxalate of any of the compounds listed in Table 1.

[0904] In some embodiments, the compound is a formate salt of any of the compounds listed in Table 1.

[0905] In some embodiments, the compound is a sulfate of any of the compounds listed in Table 1.

[0906] In some aspects, this disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds disclosed herein.

[0907] In some embodiments, the compound is any of the compounds listed in Table 1, its prodrug, or an isotopic derivative of a pharmaceutically acceptable salt thereof.

[0908] In some embodiments, the compound is any of the compounds listed in Table 1 or isotopic derivatives of a pharmaceutically acceptable salt thereof.

[0909] In some embodiments, the compound is any prodrug of the compounds listed in Table 1 or an isotopic derivative of a pharmaceutically acceptable salt thereof.

[0910] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1.

[0911] It should be understood that the isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, the isotope derivatives can typically be prepared by implementing the reaction schemes described herein and / or the procedures disclosed in the examples, using isotope-labeled reagents instead of non-isotope-labeled reagents.

[0912] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0913] In some embodiments, the isotope derivative is a deuterated compound of any of the compounds disclosed herein.

[0914] As used herein, the term "isotope derivative" refers to a compound derivative in which one or more atoms are isotopically enriched or labeled. For example, isotope derivatives of formulas (I)-(IV) are enriched or labeled with one or more isotopes compared to the corresponding formulas (I)-(IV). In some embodiments, the isotope derivative is enriched or labeled with one or more isotopes selected from ²H, ¹³C ... 4 C、¹ 5 N、¹ 8 O、² 9 Si, ³¹P and ³ 4 Isotopes of S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., one or more atomic positions of which are enriched with ²H).

[0915] In some embodiments, the compound is any of the compounds listed in Table 1, its prodrug, or a deuterated compound of a pharmaceutically acceptable salt thereof.

[0916] In some embodiments, the compound is any of the compounds listed in Table 1 or a deuterated compound of a pharmaceutically acceptable salt thereof.

[0917] In some embodiments, the compound is a prodrug of any of the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof, and is a deuterated compound thereof.

[0918] In some embodiments, the compound is a deuterated compound of any of the compounds described in Table 1.

[0919] It should be understood that the deuterium-labeled compound contains deuterium atoms with a deuterium abundance significantly higher than the natural abundance of deuterium, which is 0.015%.

[0920] In some embodiments, the deuterium enrichment factor for each deuterium-labeled site of the deuterium-labeled compound is at least 3500 (52.5% deuterium incorporation per deuterium-labeled site), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), 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" refers to the ratio of deuterium abundance to the natural abundance of deuterium.

[0921] It should be understood that the deuterium-labeled compound can be prepared using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compound can typically be prepared by implementing the reaction schemes described herein and / or the procedures disclosed in the examples, using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent.

[0922] All compounds of this disclosure containing one or more of the aforementioned deuterium atoms, or their pharmaceutically acceptable salts or solvates, fall within the scope of this disclosure. Furthermore, substitution with deuterium (i.e., ²H) can provide certain therapeutic advantages due to improved metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements.

[0923] In some embodiments, the compound is¹ 8 F-labeled compounds.

[0924] In some embodiments, the compound is ¹²³I, ¹² 4 I、¹² 5 I、¹² 9 I, ¹³¹I or ¹³ 5 Compounds labeled with one or any combination of the terms I.

[0925] In some embodiments, the compound is ³³S, ³ 4 S、³ 5 S or ³ 6 A compound labeled with one or any combination of S.

[0926] It should be understood that,¹ 8 F、¹²³I、¹² 4 I、¹² 5 I、¹² 9 I、¹³¹I、¹³ 5 I、³³S、³ 4 S、³ 5 S and / or ³ 6 S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, the isotope-labeled compounds can typically be prepared by implementing the reaction schemes described herein and / or the procedures disclosed in the examples, and using ¹ 8 F、¹²³I、¹² 4 I、¹² 5 I、¹² 9 I、¹³¹I、¹³ 5 I、³³S、³ 4 S、³ 5 S and / or ³ 6 The preparation is carried out by replacing the non-isotope labeled reagent with an S-labeled reagent.

[0927] Contains one or more of the above¹ 8 F、¹²³I、¹²4 I、¹² 5 I、¹² 9 I、¹³¹I、¹³ 5 I、³³S、³ 4 S、³ 5 S or ³ 6 Compounds containing the S atom of this disclosure, or their pharmaceutically acceptable salts or solvates, fall within the scope of this disclosure. Furthermore, isotopes (e.g.,¹) are also permitted. 8 F、¹²³I、¹² 4 I、¹² 5 I、¹² 9 I、¹³¹I、¹³ 5 I、³³S、³ 4 S、³ 5 S and / or ³ 6 Substitution of S) can provide certain therapeutic advantages by improving metabolic stability, such as extending the in vivo half-life or reducing the required dosage.

[0928] For the avoidance of doubt, it should be understood that when the term "described herein" is used to modify a group, the group includes both the broadest definition given for the first time and every specific definition given for that group.

[0929] The various functional groups and substituents of compounds of formula (I) are generally selected such that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound is less than 900 Daltons, for example less than 800 Daltons, 750 Daltons, 700 Daltons, or 650 Daltons. More preferably, the molecular weight is less than 600 Daltons, for example not exceeding 550 Daltons, 500 Daltons, or 450 Daltons.

[0930] Suitable pharmaceutically acceptable salts of the sufficiently basic compounds of this disclosure are, for example, their acid addition salts, such as acid addition salts formed with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the sufficiently acidic compounds of this disclosure are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts formed with organic bases capable of providing pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0931] It should be understood that any compound disclosed herein and any pharmaceutically acceptable salt thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomer forms.

[0932] As used in this article, "isomer" refers to compounds with the same molecular formula but different atomic sequences or spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers," sometimes also referred to as optical isomers. A mixture containing equal amounts of two opposite chiral enantiomers is called a "racemic mixture."

[0933] As used in this article, the term "chiral center" refers to a carbon atom bonded to four distinct substituents.

[0934] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers, referred to as a "diastereomer mixture." When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ordered according to the sequence rules proposed by Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; corrigendum 511; Cahnet 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).

[0935] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation of the double bond or cycloalkyl linker (e.g., 1,3-disubstituted cyclobutane). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E. cis and trans indicate that the relevant groups are located on the same or opposite sides of the double bond or ring; Z and E, according to the Cahn-Ingold-Prelog rule, indicate that the higher priority groups at both ends of the double bond are located on the same or opposite sides.

[0936] It should be understood that the compounds of this disclosure may be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer; however, not all isomers have the same level of activity.

[0937] It should be understood that the structures and other compounds discussed in this disclosure include all their transisomers. It should also be understood that not all transisomers possess the same level of activity.

[0938] As used in this article, "restricted transisomers" refers to a class of stereoisomers in which the atoms of the two isomers are arranged in different spatial arrangements. The existence of restricted transisomers stems from the steric hindrance that restricts the rotation of the bulky groups around the central bond. These restricted transisomers typically exist as mixtures; however, with the development of chromatographic techniques in recent years, it has become possible to separate mixtures of two restricted transisomers in certain situations.

[0939] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and can readily transform from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. In solution, tautomers exist as a mixture of tautomers. In solutions where tautomerism is possible, chemical equilibrium is reached between the tautomers. The exact proportions of the tautomers depend on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called tautomerism. Among the various types of tautomerism that can exist, two are more common. In keto-enol tautomerism, electrons and hydrogen atoms migrate simultaneously. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with a hydroxyl group (-OH) in the same molecule, forming a ring structure; glucose is an example of this.

[0940] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer. It should be understood that some tautomers may have higher activity levels than others.

[0941] Compounds with the same molecular formula but different atomic bonding properties, connection order, or spatial arrangement are called "isomers." Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, when this asymmetry center is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized according to the Cahn-Ingold-Prelog sequence rule by the absolute configuration of their asymmetry center, or by the direction in which they rotate the plane of polarization, and are designated as dextrorotatory or levorotatory isomers (i.e., (+)- isomers or (-)- isomers, respectively). Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0942] The compounds disclosed herein may have one or more asymmetric centers; therefore, such compounds can be prepared as single (R) or (S) stereoisomers, or mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in this specification and claims is intended to include its single enantiomer as well as its racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolving racemates (see Chapter 4 of *Advanced Organic Chemistry*, 4th edition, John Wiley and Sons, New York, 2001). Some compounds of this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure covers all optical isomers, diastereomers, and geometric isomers, as well as mixtures thereof.

[0943] This disclosure also covers compounds of this disclosure that contain one or more isotope substitutions as defined herein.

[0944] It should be understood that compounds of any formula described herein include the compound itself and its salts, and, where applicable, its solvates. For example, salts may be formed between an anion and a positively charged group (e.g., an amino group) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, p-toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate.

[0945] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed from cations and negatively charged groups (e.g., carboxyl groups) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, and calcium ions, as well as ammonium cations such as tetramethylammonium or diethylammonium ions. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0946] It should be understood that the compounds disclosed herein (e.g., salts of the compounds) may exist in hydrated or non-hydrated (anhydrous) forms, and may also form solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0947] As used herein, the term "solvate" refers to a solvation compound containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to incorporate a fixed molar ratio of solvent molecules in a crystalline solid state, thereby forming a sovate. If the solvent is water, the resulting sovate is a hydrate; if the solvent is an alcohol, the resulting sovate is an alcohol. Hydrates are formed by the combination of one molecule of a substance with one or more water molecules, wherein the water retains its molecular state as H₂O.

[0948] As used herein, the term "analog" refers to a compound that is similar to, but not identical to, another compound in terms of function and structure (e.g., by substitution of an atom with an atom of a different element, the presence of a specific functional group, or the substitution of one functional group for another). Therefore, an analog is a compound that is similar or comparable to, but not identical to, a reference compound in structure and / or function.

[0949] As used herein, the term "derivative" refers to compounds that share a common core structure and are substituted by the various groups described herein.

[0950] As used herein, the term "bioisostere" refers to a compound obtained by replacing one atom or group of atoms with another, which is generally similar. The aim of bioisostere substitution is to produce new compounds with similar biological properties to the parent compound. Bioisostere substitution can be based on physicochemical properties or topological structure. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0951] It should also be understood that certain compounds of any of the formulas disclosed herein may exist in solvated and non-solvated forms, such as in a hydrated form. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having CDK2 inhibitory activity.

[0952] It should also be understood that some compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure covers all such forms or mixtures thereof with CDK2 inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques, such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance Fourier transform infrared (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0953] Compounds of any formula disclosed herein may exist in a variety of different tautomeric forms, and all such forms are included in reference to compounds of this disclosure. For the avoidance of doubt, when a compound may exist in several tautomeric forms, and only one form is specifically described or shown, all other forms are still covered within the scope of formulas (A), (I), (II), (III), or (IV). Examples of tautomeric forms include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (as shown below), imine / enamine, amide / imineol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0954]

[0955] Compounds containing amine functional groups of any of the formulas disclosed herein can also form N-oxides. When referring to compounds of formula (A) containing amine functional groups, this also includes their N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The respective amines can be treated with oxidizing agents (e.g., hydrogen peroxide or peracids, such as peroxycarboxylic acids) to form N-oxides; see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience. More specifically, N-oxides can be prepared according to the procedure described by LW Deady (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0956] Compounds of any of the formulas disclosed herein can be administered as prodrugs, which decompose in the human or animal body to release the disclosed compounds. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the disclosed compounds. Prodrugs can be formed when the disclosed compounds contain suitable groups or substituents that can be attached to property-modifying groups. Examples of prodrugs include derivatives of any of the formulas disclosed herein containing alkyl or acyl substituents that can be cleaved in vivo at the ester or amide group.

[0957] Therefore, this disclosure includes compounds of any of the formulas disclosed herein as defined above, whether obtained by organic synthesis or by cleavage of their prodrugs in humans or animals. Thus, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis, as well as such compounds produced by the metabolism of prodrugs in humans or animals; that is, compounds of any of the formulas disclosed herein can be compounds produced by synthesis or compounds produced by metabolism.

[0958] A suitable pharmaceutically acceptable prodrug of any of the compounds disclosed herein is a prodrug that, based on reasonable medical judgment, is suitable for administration to humans or animals without producing undesirable pharmacological activity and excessive toxicity. Existing literature describes various forms of prodrugs, such as: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard, pp. 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”, ACS Symposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0959] Suitable pharmaceutically acceptable prodrugs of any of the hydroxyl-containing compounds disclosed herein are, for example, cleavable esters or ethers thereof. Cleavable esters or ethers of any of the hydroxyl-containing compounds disclosed herein are, for example, pharmaceutically acceptable esters or ethers that can be cleaved in the human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable esterifying groups for the hydroxyl group include inorganic esters, such as phosphate esters (including cyclic aminophosphate esters). Other suitable pharmaceutically acceptable esterifying groups for the hydroxyl group include C1-C1 esters. 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; C1-C 10Alkoxycarbonyl groups, such as ethoxycarbonyl; N,N-di(C1-C6 alkyl)carbamoyl; 2-dialkylaminoacetyl; and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholino-4-ylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable etherifying groups for the hydroxyl group include α-acyloxyalkyl, such as acetoxymethyl and neopentyloxymethyl.

[0960] Suitable pharmaceutically acceptable prodrugs of any carboxyl-containing compound disclosed herein are, for example, cleavable amides in vivo, such as amides formed with amines, such as ammonia, C1-C4 alkylamines (e.g., methylamine), di(C1-C4 alkyl)amines (e.g., dimethylamine, ethylmethylamine, or diethylamine), C1-C4 alkoxy-C2-C4 alkylamines (e.g., 2-methoxyethylamine), phenyl-C1-C4 alkylamines (e.g., benzylamine), and amino acids (e.g., glycine) or esters thereof.

[0961] Suitable pharmaceutically acceptable prodrugs of any of the amino groups disclosed herein are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides for the amino group include, for example, those composed of C1-C... 10 Amides formed from alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholino-4-ylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0962] The in vivo effects of any of the compounds disclosed herein may be partly produced by one or more metabolites formed in the human or animal body after administration of the compound. As mentioned above, the in vivo effects of any of the compounds disclosed herein may also be produced by the metabolism of a prodrug.

[0963] Synthetic methods of compounds:

[0964] The compounds of this invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are shown in the following reaction schemes.

[0965] Compounds of formula (A) and (I)-(IV) can be prepared by methods known in the field of organic synthesis, some of which are described in the following synthetic schemes. In the reaction schemes described below, it should be fully understood that protecting groups are used on sensitive or reactive groups as necessary, in accordance with general principles of chemistry. Protecting groups are treated according to standard methods of organic synthesis (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley, New York, 1999). At appropriate stages of compound synthesis, these groups are removed using methods readily determined by those skilled in the art. The choice of process, as well as the reaction conditions and sequence of execution, will be apparent to those skilled in the art. Those skilled in the art will also recognize that stereocenters may be present in compounds of formula (A) and (I)-(IV). Therefore, the present invention includes two possible stereoisomers (unless otherwise stated in the synthetic process), and includes not only racemic compounds, but also individual enantiomers and / or diastereomers. When a single enantiomer or diastereomer of a compound is required, it can be obtained through stereospecific synthesis or by resolving the end product or any suitable intermediate. The resolving of the end product, intermediate, or starting material can be achieved using any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by El. E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0966] The compounds described herein can be obtained from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods.

[0967] Preparation of compounds:

[0968] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, in combination with synthetic methods known in the field of organic synthetic chemistry or variations thereof that can be understood by those skilled in the art. Suitable methods include, but are not limited to, the methods described below. The compounds of the present invention can be synthesized according to the steps listed in a general procedure, which includes different sequences of assembling intermediates or compounds. Starting materials are commercially available or prepared using known procedures in reported literature or procedures shown below.

[0969] General procedures:

[0970] Typically, the compounds of the present invention can be prepared using the reaction sequence shown in reaction scheme 1.

[0971] Option 1:

[0972]

[0973] It should be understood that any compound in reaction scheme 1 and any substituents in these compounds may be further modified at any step of the indicated reaction sequence to provide modified derivatives that can be used to prepare compounds of this disclosure.

[0974] All reagents may be commercially available compounds or products synthesized from commercially available reagents. These reagents may be prepared using one-step or multi-step synthetic procedures, including but not limited to the procedures described in the preparation section herein.

[0975] It will be apparent to those skilled in the art that any compound of the present invention obtained according to the above procedure can be further transformed and modified to obtain other compounds of the present invention.

[0976] Biological assay:

[0977] After the compounds designed, selected, and / or optimized using the above methods are obtained, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, conventional assays (including but not limited to the assays described below) can be used to characterize the molecules to determine whether they possess the expected activity, binding activity, and / or binding specificity.

[0978] Furthermore, high-throughput screening can be used to accelerate analyses performed using such assays. Therefore, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998), High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can employ one or more different assay techniques, including but not limited to those described below.

[0979] A variety of in vitro or in vivo biological assays can be used to detect the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift analysis, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0980] Pharmaceutical composition:

[0981] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from any of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0982] As used herein, the term "composition" is intended to cover products containing specified amounts of specified ingredients, and any products directly or indirectly produced by a combination of specified amounts of specified ingredients.

[0983] Solid dosage forms include powders, tablets, pills, capsules, suppositories, and dispersible granules. Solid carriers can be one or more substances that can also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is typically a finely powdered solid mixed with the finely powdered active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the desired binding ability in an appropriate proportion and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. In addition to the active ingredient, solid dosage forms may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0984] Liquid formulations suitable for oral administration include emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These formulations also include solid formulations intended to be converted into a liquid form immediately before use. Emulsions can be prepared in solutions (e.g., aqueous solutions of propylene glycol) or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing a finely powdered active ingredient in water containing a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0985] The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus or continuous infusion) and can be in unit dose form in ampoules, pre-filled syringes, or small-volume infusion formulations, or in multi-dose containers with added preservatives. The compositions can be in the form of suspensions, solutions, or emulsions in oily or aqueous carriers, such as aqueous polyethylene glycol solutions. Examples of oily or non-aqueous carriers, diluents, solvents, or media include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulation adjuvants such as preservatives, wetting agents, emulsifiers, suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic separation of a sterile solid or by lyophilizing a solution and reconstituted with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0986] The compounds disclosed herein can be formulated into forms for oral administration, such as tablets, capsules (both including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds disclosed herein can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal administration (e.g., patches), all using dosage forms well known to those skilled in the pharmaceutical art.

[0987] The formulation disclosed herein may be in the form of an aqueous solution comprising an aqueous carrier. The aqueous carrier component may comprise water and at least one pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include those selected from solubilizers, chelating agents, preservatives, isotonic modifiers, thickeners / suspending agents, buffers, pH adjusters, and mixtures thereof.

[0988] Any suitable solubilizer may be used. Examples of solubilizers include cyclodextrins, such as those selected from hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-chain-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0989] Any suitable chelating agent may be used. Examples of suitable chelating agents include chelating agents selected from ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate, and mixtures thereof.

[0990] Any suitable preservative may be used. Examples of preservatives include preservatives selected from the following substances and mixtures thereof: quaternary ammonium salts, such as benzalkonium chloride halides (preferably benzalkonium chloride); chlorhexidine gluconate; benzyl chloride; cetylpyridinium chloride; benzyl bromide; phenylmercuric nitrate; phenylmercuric acetate; phenylmercuric neodecanoate; thimerosal; methylparaben; propylparaben; sorbic acid; potassium sorbate; sodium benzoate; sodium propionate; ethylparaben; propylaminopropyl biguanide; butylparaben.

[0991] In some embodiments, examples of preservatives include preservatives selected from substances such as quaternary ammonium salts, such as benzalkonium chloride (preferably benzalkonium chloride); chlorhexidine gluconate; benzyl chloride; cetylpyridinium chloride; benzyl bromide; phenylmercuric nitrate; thimerosal; methylparaben; propylparaben; sorbic acid; potassium sorbate; sodium benzoate; sodium propionate; ethylparaben; propylaminopropyl biguanide; butylparaben.

[0992] The aqueous carrier may also contain an isotonic regulator for adjusting isotonicity (osmotic pressure). The isotonic regulator may be selected from glycols (e.g., propylene glycol, diethylene glycol, and triethylene glycol), glycerol, glucose, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonic regulator is selected from glycols (e.g., propylene glycol and triethylene glycol), glycerol, glucose, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0993] Aqueous carriers may also contain thickeners / suspending agents. Suitable thickeners / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropyl methylcellulose; polyethylene glycols such as polyethylene glycol 300 and polyethylene glycol 400; and crosslinked acrylic polymers (carbopols), such as acrylic polymers crosslinked with polyolefin ethers or divinyl glycol [Carbopol class, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P], and mixtures thereof.

[0994] 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, especially 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 adjuster. The pH adjuster is typically an inorganic acid or a metal hydroxide base selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, depending on the specific formulation, it may not be necessary to use both an acid and a base simultaneously; adding only one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0995] The aqueous carrier may also contain a buffer for stabilizing pH. When used, the buffer is selected from phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[0996] The formulation may also contain wetting agents. Suitable classes of wetting agents include polyoxypropylene-polyoxyethylene block copolymers (poloxam), polyethoxylated castor oil ether, polyoxyethyleneized dehydrated sorbitan esters (polysorbates), oxyethyleneized octylphenol polymers (teroxam), polyoxyethylene (40) stearate, fatty acid diol esters, fatty acid glycerides, sucrose fatty acid esters and polyoxyethylene fatty acid esters, and mixtures thereof.

[0997] Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be mixed with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be formulated as mouthwashes using fluid carriers, wherein the compound in the fluid carrier is administered orally, gargled, and then spat out or swallowed. Compositions may also contain pharmaceutically compatible binders and / or excipients. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel (sodium carboxymethyl starch), or corn starch; lubricants, such as magnesium stearate or Sterotex (hydrogenated vegetable oil); flow aids, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0998] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0999] In some embodiments, the pharmaceutical compositions described herein may also contain one or more other pharmaceutically active agents.

[1000] The compositions disclosed herein can be in forms suitable for the following uses: oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs); topical administration (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions); inhalation administration (e.g., fine powders or liquid aerosols); inhalation administration (e.g., fine powders); parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration); or rectal administration (e.g., suppositories).

[1001] The compositions disclosed herein can be obtained using conventional pharmaceutical excipients well known in the art and by conventional methods. Therefore, compositions intended for oral administration may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1002] Therapeutic effective amount of the compounds disclosed herein for treatment means an amount sufficient to treat or prevent the CDK2-related conditions described herein, slow their progression, and / or alleviate symptoms associated with the condition.

[1003] Therapeutic effective amount of the compounds disclosed herein for treatment means an amount sufficient to treat the CDK2-related conditions described herein, slow their progression, and / or alleviate symptoms associated with the conditions.

[1004] Based on well-known medical principles, the dosage of compounds of formulas (A), (I), (II), (III) and / or (IV) used for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration.

[1005] How to use:

[1006] In some aspects, this disclosure provides a method for inhibiting CDK2 (e.g., in vitro or in vivo), which includes contacting cells with a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[1007] In some aspects, this disclosure provides a method for treating or preventing a disease or condition disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[1008] In some aspects, this disclosure provides a method of treating a disease or condition disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[1009] In some implementations, the disease or condition is associated with CDK2. In some implementations, the disease or condition is one in which CDK2 is involved in its occurrence or development.

[1010] The compounds of this invention can also be used to treat CDK2-related diseases. For example, diseases and conditions treatable according to the methods of this invention include: breast cancer (BC); colorectal cancer (CRC); lung cancer (LNCR); retinoblastoma (RB); pancreatic cancer (PNCA); prostate cancer (PC); ovarian cancer (OC); hepatocellular carcinoma (HCC); gastric cancer (GASC); bladder cancer (BLC); endometrial cancer (ENDMC); glioblastoma (GBM); adenocarcinoma; squamous cell carcinoma; and ataxia-telangiectasia (AT).

[1011] The treatment methods include administering a compound of formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said diseases or conditions.

[1012] In some embodiments, the treatment method includes administering a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said diseases or conditions.

[1013] In some embodiments, the treatment method includes administering a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said diseases or conditions.

[1014] In some embodiments, the treatment method includes administering a compound of formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said diseases or conditions.

[1015] In some embodiments, the treatment method includes administering a formula (IV) compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said diseases or conditions.

[1016] In some implementations, the disease or condition is breast cancer (BC).

[1017] In some implementations, the disease or condition is colorectal cancer (CRC).

[1018] In some implementations, the disease or condition is lung cancer (LNCR).

[1019] In some implementations, the disease or condition is retinoblastoma (RB).

[1020] In some implementations, the disease or condition is pancreatic cancer (PNCA).

[1021] In some implementations, the disease or condition is prostate cancer (PC).

[1022] In some implementations, the disease or condition is ovarian cancer (OC).

[1023] In some implementations, the disease or condition is hepatocellular carcinoma (HCC).

[1024] In some implementations, the disease or condition is gastric cancer (GASC).

[1025] In some implementations, the disease or condition is bladder cancer (BLC).

[1026] In some implementations, the disease or condition is endometrial cancer (ENDMC).

[1027] In some implementations, the disease or condition is glioblastoma (GBM).

[1028] In some implementations, the disease or condition is adenocarcinoma.

[1029] In some implementations, the disease or condition is squamous cell carcinoma.

[1030] In some implementations, the disease or condition is ataxia-telangiectasia (AT).

[1031] In some aspects, this disclosure provides a method of treating or preventing cancer in a subject in need, 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.

[1032] In some aspects, this disclosure provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[1033] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for inhibiting CDK2 (e.g., in vitro or in vivo).

[1034] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of the diseases or conditions disclosed herein.

[1035] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for treating the diseases or conditions disclosed herein.

[1036] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of cancer in subjects in need.

[1037] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment of cancer in subjects in need.

[1038] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting CDK2 (e.g., in vitro or in vivo).

[1039] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[1040] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating the diseases or conditions disclosed herein.

[1041] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment or prevention of cancer in subjects in need.

[1042] In some respects, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating cancer in subjects in need.

[1043] This disclosure provides compounds that act as CDK2 inhibitors (e.g., in vitro or in vivo). Therefore, this disclosure provides a method for inhibiting CDK2 in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1044] In some embodiments, the CDK2 inhibitor is a compound disclosed herein.

[1045] The effectiveness of the disclosed compounds can be determined using industry-recognized assays / disease models, in accordance with standard methods described in the art and which are common knowledge in the art for demonstrating said effectiveness.

[1046] This disclosure also provides a method for treating a disease or condition in which CDK2 is involved in its occurrence or development in a subject with such treatment needs, the method comprising administering to the subject a therapeutically effective amount of a compound as defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[1047] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[1048] Route of administration:

[1049] The compounds disclosed herein or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[1050] Routes of administration include, but are not limited to: oral administration (e.g., by swallowing); buccal administration; sublingual administration; transdermal administration (including, for example, by patches, ointments, etc.); transmucosal administration (including, for example, by patches, ointments, etc.); intranasal administration (e.g., by nasal sprays); ocular administration (e.g., by eye drops); pulmonary administration (e.g., by inhalation or blowing therapy, such as using aerosols administered orally or nasally); rectal administration (e.g., by suppositories or enemas); vaginal administration (e.g., by vaginal suppositories); parenteral administration, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal injections; and administration by implanting a drug reservoir or reservoir device, such as subcutaneous or intramuscular implantation.

[1051] Example:

[1052] General synthetic methods and compound preparation examples:

[1053] All reagents were commercially available and used without further purification. Yields are based on purified compounds of spectral purity. Thin-layer chromatography (TLC) was performed using Merck TLC silica gel 60F. 254Aluminum plates were used for chromatography, and detection was performed under UV irradiation with fluorescence quenching. Rapid chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) purchased from Fuji Silysia Chemicals. Nuclear magnetic resonance (NMR) spectra were recorded using a Varian-400MR NMR spectrometer with a working frequency of 400 MHz for ¹H. Chemical shifts are expressed in ppm, and the resonance signal of the solvent was used as an internal standard. The spectral data are reported as follows: s = singlet, br. = broad peak, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet; coupling constants are in Hz; integral values.

[1054] The following abbreviations are used in the following examples and other parts of this document:

[1055]

[1056] Composition of building blocks:

[1057] Synthesis of 2-chloro-9-cyclopentyl-7,9-dihydro-8H-purine-8-one (P3)

[1058]

[1059] Preparation Example 1: 2-Chloro-N 4 -Cyclopentylpyrimidine-4,5-diamine (P1).

[1060] Cyclopentanylamine (620 mg, 7.2 mmol, 1.2 eq) was added 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 anhydrous THF (15 mL). The mixture was heated to 70 °C with stirring and maintained for 48 hours. The mixture was then concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (using EA / MeOH as eluent in a 1:1 ratio) to give P1 (1.14 g, 88% yield).

[1061] Analysis data: ¹H NMR (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).

[1062] Preparation Example 2: 2-chloro-9-cyclopentyl-7,9-dihydro-8H-purine-8-one (P2).

[1063] A solution of P1 (1.14 g, 5.35 mmol, 1 eq) and CDI (950 mg, 5.9 mmol, 1.1 eq) in anhydrous THF (25 mL) was stirred at room temperature for 16 hours. After the reaction was complete, all volatile substances were removed under reduced pressure. The residue was dissolved in CHCl3 and washed with saturated brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give P2 (1.25 g, 98% yield), which was used directly in the next step without further purification.

[1064] Analysis data: ¹H 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).

[1065] Preparation Example 3: 2-chloro-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purine-8-one (P3).

[1066] At 0 °C, NaH (75 mg, 1.84 mmol, 1.1 eq) was added 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 anhydrous DMA (5 mL). The reaction mixture was stirred at 0 °C for 3 h, then at room temperature for 12 h. Water was then carefully added, and the resulting suspension was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (using 1:2 hexane / EA as eluent) to give P3 (280 mg, 67% yield).

[1067] Analysis data: ¹H NMR (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).

[1068] Synthesis of 2-chloro-9-cyclopentyl-7-ethyl-7,9-dihydro-8H-purine-8-one (P4)

[1069]

[1070] Preparation Example 4: 2-Chloro-9-cyclopentyl-7-ethyl-7,9-dihydro-8H-purine-8-one (P4).

[1071] At 10 °C, NaH (75 mg, 1.84 mmol, 1.1 eq) was added fractionally 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 anhydrous DMA (5 mL). The reaction mixture was stirred at 0 °C for 3 h, then at room temperature for 12 h. The reaction mixture was then carefully diluted with water, and the resulting suspension was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (using 1:2 hexane / EA as eluent) to give P4 (315 mg, 71% yield).

[1072] Analysis data: ¹H NMR (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).

[1073] Synthesis of 2-chloro-9-isopropyl-7-methyl-7,9-dihydro-8H-purin-8-one (P7)

[1074]

[1075] Preparation Example 5: 2-Chloro-N 4 -Isopropylpyrimidine-4,5-diamine (P5).

[1076] Isopropylamine (350 mg, 5.94 mmol, 1.3 eq) was added 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-butanol (n-BuOH, 20 mL). The reaction mixture was heated to 70 °C with stirring and maintained for 16 hours. All volatiles were then removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: hexane / EA = 1:2) to give P5 (810 mg, 94% yield).

[1077] Analysis data: ¹H NMR (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).

[1078] Preparation Example 6: 2-chloro-9-isopropyl-7,9-dihydro-8H-purine-8-one (P6).

[1079] A solution of P5 (800 mg, 4.27 mmol, 1 eq) and CDI (760 mg, 4.7 mmol, 1.1 eq) in anhydrous THF (25 mL) was heated to 50 °C with stirring and maintained for 16 hours. All volatile substances were then removed under reduced pressure. The residue was dissolved in CHCl3 (30 mL) and washed with saturated brine. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give P6 (520 mg, 57% yield), which was used directly in the next step without further purification.

[1080] Analysis data: ¹H NMR (400 MHz, DMSO-d6), δ: 8.09 (s, 1H), 7.00 (s, 1H), 4.57 (m, 1H), 1.48 (d, 6H).

[1081] Preparation Example 7: 2-Chloro-9-isopropyl-7-methyl-7,9-dihydro-8H-purine-8-one (P7).

[1082] At 0 °C, NaH (105 mg, 2.59 mmol, 1.1 eq) was added 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 12 mL of anhydrous DMA. The reaction mixture was stirred at 0 °C for 3 h, then at room temperature for 12 h. Water was then carefully added, and the resulting suspension was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: hexane / EA = 1:2) to give P7 (401 mg, 75% yield).

[1083] Analysis 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).

[1084] Synthesis of 2-chloro-9-cyclopentyl-7-isopropyl-7,9-dihydro-8H-purine-8-one (P8)

[1085]

[1086] Preparation Example 8: 2-Chloro-9-cyclopentyl-7-isopropyl-7,9-dihydro-8H-purine-8-one (P8)

[1087] At room temperature, Cs₂CO₃ (490 mg, 1.5 mmol, 1.5 eq) was added fractionally to an anhydrous DMA (5 mL) solution of P₂ (240 mg, 1 mmol, 1 eq) and 2-bromopropane (185 mg, 1.5 mmol, 1.5 eq) with well-stirred mixture. The reaction mixture was stirred at room temperature for 26 hours. The reaction mixture was then carefully diluted with water, and the resulting suspension was extracted with EA. The organic phases were combined, washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue obtained by evaporation was purified by column chromatography (eluent: hexane / EA = 2:1) to give 2-chloro-9-cyclopentyl-7-isopropyl-7,9-dihydro-8H-purin-8-one P₈ (225 mg, 80% yield).

[1088] Analysis data: ¹H NMR (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]⁺.

[1089] Synthesis of 2-chloro-9-cyclopentyl-7-cyclopropyl-7,9-dihydro-8H-purine-8-one (P9)

[1090]

[1091] Preparation Example 9: 2-chloro-9-cyclopentyl-7-cyclopropyl-7,9-dihydro-8H-purine-8-one (P9).

[1092] At room temperature, Cu(OAc)₂ (180 mg, 1 mmol, 1 eq) was added in a single batch 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, 2 eq) in a mixed solvent (12 mL) of DCE / DMF = 3 / 1. The reaction mixture was stirred at 70 °C for 20 hours. The reaction mixture was then cooled to room temperature, diluted with saturated aqueous NH₄Cl solution, and extracted with DCM. The organic phases were combined, washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue obtained by evaporation was purified by column chromatography (eluent: Hex / EtOAc = 7 / 3) to give 2-chloro-9-cyclopentyl-7-cyclopropyl-7,9-dihydro-8H-purin-8-one P₉ (182 mg, 54% yield).

[1093] Analysis data: ¹H NMR (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]⁺.

[1094] Synthesis of tert-butyl piperidine-1-carboxylate (P10)

[1095]

[1096] Preparation Example 10. 3-[7-methyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]-8-oxopurin-9-yl]piperidin-1-carboxylic acid tert-butyl ester (P10).

[1097] A suspension of tert-butyl 3-(2-chloro-7-methyl-8-oxopurin-9-yl)piperidin-1-carboxylate (CAS 2711810-60-3, 150 mg, 0.41 mmol, 1 eq), 4-(1-methyl-1H-pyrazole-4-yl)sulfonylcyclohexaneamine 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 anhydrous dioxane (2 mL) was heated under reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, and extracted with EtOAc. The organic layer was washed with saturated brine, dried, and the solvent was evaporated to remove the solvent. The residue was purified by column chromatography (eluent: EtOAc) to give tert-butyl 3-[7-methyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]-8-oxopurin-9-yl]piperidin-1-carboxylic acid P10 (132 mg, yield 55%).

[1098] Analysis data: ¹H NMR (400 MHz, CDCl₃), 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, 3H). 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).

[1099] Synthesis of 2-[(2-azaspiro[3.3]heptane-6-yl)amino]-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purine-8-one hydrochloride (P12)

[1100]

[1101] Preparation Example 11: 6-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (P11).

[1102] A suspension of P3 (300 mg, 1.19 mmol, 1 eq), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (CAS1211586-09-2, 760 mg, 3.57 mmol, 3 eq), sodium tert-butoxide (tert-BuONa, 115 mg, 2.38 mmol, 2 eq), Pd2(dba)3 (27 mg, 0.03 mmol, 0.05 eq), and BINAP (37 mg, 0.06 mmol, 0.1 eq) in anhydrous dioxane (4 mL) was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (4 mL), and washed with saturated saline. All volatile substances were removed under reduced pressure, and the residue was purified by rapid chromatography (eluent: EtOAc / MeOH = 100 / 0 to 90 / 10) to give 6-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester P11 (215 mg, yield 42%), which was used directly in the next step without further purification.

[1103] Analysis data: LCMS (APCI), m / z=429 [M+H]⁺.

[1104] Preparation Example 12: 2-[(2-azaspiro[3.3]heptane-6-yl)amino]-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purine-8-one hydrochloride (P12).

[1105] Concentrated hydrochloric acid (100 µL, 1 mmol, 2 eq) was added to a 2,2,2-trifluoroethanol (5 mL) solution of 2-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester P11 (215 mg, 0.5 mmol, 1 eq) in 2,2,2-trifluoroethanol. The resulting solution was allowed to stand at room temperature for 1 hour, followed by removal of all volatiles under reduced pressure. The residue was then ground successively with Et2O and ACN to give 2-[(2-azaspiro[3.3]heptane-6-yl)amino]-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purin-8-one hydrochloride P12 (180 mg, 99% yield), which was used directly in the next step without purification.

[1106] Analysis data: ¹H NMR (400 MHz, DMSO-d6), δ: 9.05 (br. s, 2H), 8.04 (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]⁺.

[1107] Synthesis of 9-cyclopentyl-7-methyl-2-[(piperidin-4-yl)amino]-7,9-dihydro-8H-purine-8-one hydrochloride (P14)

[1108]

[1109] Preparation Example 13: 4-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (P13).

[1110] A suspension of 2-chloro-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purin-8-one P3 (300 mg, 1.19 mmol, 1 eq), tert-butyl 4-aminopiperidin-1-carboxylate (CAS 87120-72-7, 270 mg, 1.35 mmol, 2.2 eq), sodium tert-butoxide (tert-BuONa, 170 mg, 1.77 mmol, 3 eq), Pd2(dba)3 (27 mg, 0.03 mmol, 0.05 eq), and BINAP (37 mg, 0.06 mmol, 0.1 eq) in anhydrous dioxane (4 mL) was stirred at 85 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (4 mL), and washed with saturated saline. All volatile substances were removed under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc / MeOH = 100 / 0 to 90 / 10) to give 4-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester P13 (475 mg, yield 64%).

[1111] Analysis data: ¹H NMR (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]⁺.

[1112] Preparation Example 14: 9-Cyclopentyl-7-methyl-2-[(piperidin-4-yl)amino]-7,9-dihydro-8H-purine-8-one hydrochloride (P14).

[1113] Concentrated hydrochloric acid (230 µL, 2.28 mmol, 2 eq) was added to a 10 mL solution of 4-[(9-cyclopentyl-7-methyl-8-oxopurin-2-yl)amino]piperidine-1-carboxylic acid tert-butyl ester P13 (475 mg, 1.14 mmol, 1 eq) in 2,2,2-trifluoroethanol. The resulting solution was allowed to stand at room temperature for 1 hour, followed by removal of all volatiles under reduced pressure. The residue was then ground with Et2O to give 9-cyclopentyl-7-methyl-2-[(piperidine-4-yl)amino]-7,9-dihydro-8H-purine-8-one hydrochloride P14 (410 mg, 103% yield), which was used directly in the next step without purification.

[1114] Analysis data: ¹H NMR (400 MHz, DMSO-d6), δ: 9.22 (br. s, 1H), 9.05 (br. s, 1H), 8.11 (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 = 317 [M+H]⁺.

[1115] Synthesis of 6-[7-methyl-2-[[1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl]amino]-8-oxopurin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (P18)

[1116]

[1117] Preparation Example 15: 6-[(5-amino-2-chloropyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (P15).

[1118] 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) in butanol (15 mL), 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. The resulting mixture was stirred at 100 °C for 48 hours. All volatile substances were removed under reduced pressure. The residue was diluted with EtOAc, washed successively with water and saturated brine, dried, and concentrated by evaporation. The residue was purified by column chromatography (eluent: Hex (20%) / EtOAc (80%)) to give tert-butyl 6-[(5-amino-2-chloropyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxylate P15 (1.07 g, yield 94%).

[1119] Analysis data: ¹H NMR (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).

[1120] Preparation Example 16: tert-butyl 6-(2-chloro-8-oxo-7H-purin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate (P16).

[1121] A solution of tert-butyl 6-[(5-amino-2-chloropyrimidin-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) in anhydrous THF (25 mL) was stirred at 50 °C for 16 hours. All volatiles were removed under reduced pressure, and the residue was dissolved in EtOAc and washed with saturated brine. The organic layer was separated, dried over Na2SO4, and concentrated by evaporation to give tert-butyl 6-(2-chloro-8-oxo-7H-purin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate P16 (743 mg, 64% yield), which was then purified by crystallization from EtOH.

[1122] Analysis data: ¹H NMR (400 MHz, DMSO-d6), δ: 11.47 (s, 1H), 8.06 (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).

[1123] Preparation Example 17: tert-butyl 6-(2-chloro-7-methyl-8-oxopurin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate (P17).

[1124] At 0 °C, NaH (105 mg, 2.64 mmol, 1.3 eq) was added 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 anhydrous DMA (5 mL). The reaction mixture was stirred at 0 °C for 3 h, then at room temperature for 12 h. Water was then carefully added, and the resulting suspension was extracted with EtOAc. The organic phases were combined, washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue obtained from evaporation was purified by crystallization from EtOH to give tert-butyl 6-(2-chloro-7-methyl-8-oxopurin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate P17 (738 mg, 96% yield).

[1125] Analysis data: ¹H NMR (400 MHz, DMSO-d6), δ: 8.28 (d, J=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).

[1126] Preparation Example 18. 6-[7-methyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]-8-oxopurin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (P18).

[1127] A suspension of tert-butyl 6-(2-chloro-7-methyl-8-oxopurin-9-yl)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.5 mmol, 1 eq), 4-(1-methyl-1H-pyrazol-4-yl)sulfonylcyclohexaneamine 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 anhydrous dioxane (4 mL) was heated under reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, and extracted. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM (95%) / MeOH (5%)), followed by crystallization from MeOH to give tert-butyl 6-[7-methyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]-8-oxopurin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylate P18 (92 mg, yield 30%).

[1128] Analysis data:¹H NMR (400 MHz, CDCl₃), 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).

[1129] Synthesis of 2-chloro-9-cyclopentyl-7-(2-methoxyethyl)-7,9-dihydro-8H-purine-8-one (P19)

[1130]

[1131] Preparation Example 19: 2-chloro-9-cyclopentyl-7-(2-methoxyethyl)-7,9-dihydro-8H-purine-8-one (P19).

[1132] At room temperature, 1-bromo-2-methoxyethane (CAS 6482-24-2, 227 mg, 1.626 mmol, 1 eq) was added to a well-stirred mixture of anhydrous DMA (5 mL) of 2-chloro-9-cyclopentyl-7,9-dihydro-8H-purin-8-one P2 (300 mg, 1,255 mmol, 1 eq) and Cs₂CO₃ (530 mg, 1.626 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 3 hours, followed by the addition of water. The resulting suspension was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue obtained by evaporation was purified by column chromatography (eluent: Hex / EtOAc=7 / 3) to give 2-chloro-9-cyclopentyl-7-(2-methoxyethyl)-7,9-dihydro-8H-purine-8-one P19 (302 mg, yield 81%).

[1133] Analysis data: ¹H 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]⁺.

[1134] Table 3 lists some non-limiting examples of compounds of formula (A).

[1135] Table 3: Selected Examples and LCMS (ESI) Data of Compounds of Formula (A)

[1136]

[1137] Synthesis of representative compounds:

[1138] Preparation Example 1. 9-Cyclopentyl-7-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 109).

[1139]

[1140] A suspension of P3 (100 mg, 0.4 mmol, 1 eq), 1-(methanesulfonyl)piperidine-4-amine hydrochloride (85 mg, 0.4 mmol, 1 eq), Cs2CO3 (390 mg, 1.2 mmol, 3 eq), Pd2(dba)3 (20 mg, 0.02 mmol, 0.05 eq), and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in anhydrous dioxane (2 mL) was heated under reflux for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The crude product was purified by preparative HPLC (YMCODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluent; flow rate 17 mL / min; ACN concentration 15-30% within 20 min; RT 16.5 min) to obtain 109 (31 mg, yield 20%).

[1141] Analysis data:¹H NMR (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).

[1142] Example 2. 9-Cyclopentyl-7-ethyl-2-((1-(methanesulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 116).

[1143]

[1144] A suspension of P4 (105 mg, 0.37 mmol, 1 eq), 1-(methylsulfonyl)piperidine-4-amine hydrochloride (85 mg, 0.4 mmol, 1 eq), Cs₂CO₃ (385 mg, 1 mmol, 3 eq), Pd₂(dba)₃ (20 mg, 0.02 mmol, 0.05 eq), and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in anhydrous dioxane (2 mL) was heated under reflux for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The crude product was purified by preparative HPLC (YMCODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluent; flow rate 17 mL / min; ACN concentration 20-35% within 20 min; RT 13 min) to obtain 116 (8 mg, yield 5%).

[1145] Analysis data:¹H NMR (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).

[1146] Example 3. 9-Cyclopentyl-7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 137).

[1147]

[1148] A suspension of P3 (100 mg, 0.4 mmol, 1 eq), 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-amine hydrochloride (110 mg, 0.4 mmol, 1 eq), Cs2CO3 (326 mg, 1 mmol, 2.5 eq), Pd2(dba)3 (20 mg, 0.02 mmol, 0.05 eq), and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in anhydrous dioxane (2 mL) was heated under reflux for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluent; flow rate 17 mL / min; ACN concentration 20-50% within 20 min; RT 11.5 min) to obtain 137 (28 mg, yield 15%).

[1149] Analysis data:¹H NMR (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).

[1150] Example 4. 9-Cyclopentyl-7-ethyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 151).

[1151]

[1152] A suspension of P4 (100 mg, 0.37 mmol, 1 eq), 1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidine-4-amine hydrochloride (105 mg, 0.37 mmol, 1 eq), Cs₂CO₃ (370 mg, 1 mmol, 3 eq), Pd₂(dba)₃ (20 mg, 0.02 mmol, 0.05 eq), and Xantphos (23 mg, 0.04 mmol, 0.1 eq) in anhydrous dioxane (2 mL) was heated under reflux for 16 h. After the reaction was complete, the mixture was cooled to room temperature and filtered through a thin layer of diatomaceous earth. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluent; flow rate 17 mL / min; ACN concentration 20-50% within 20 min; RT 14 min) to obtain 151 (41 mg, yield 23%).

[1153] Analysis data:¹H NMR (400 MHz, DMSO-d6), δ: 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).

[1154] Example 5. 9-Isopropyl-7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 301).

[1155]

[1156] A suspension of P7 (100 mg, 0.44 mmol, 1 eq), 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-amine hydrochloride (123 mg, 0.44 mmol, 1 eq), Cs₂CO₃ (430 mg, 1.32 mmol, 3 eq), Pd₂(dba)₃ (20 mg, 0.022 mmol, 0.05 eq), and Xantphos (26 mg, 0.044 mmol, 0.1 eq) in anhydrous dioxane (4 mL) was heated under reflux for 16 h. The reaction mixture was then cooled to room temperature and filtered through a diatomaceous earth mat. The crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluent; flow rate 17 mL / min; ACN concentration 10-30% within 20 min; RT 16 min) to obtain 301 (55 mg, yield 29%).

[1157] Analysis data:¹H NMR (400 MHz, DMSO-d6), δ: 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).

[1158] Example 6. 9-Cyclopentyl-7-isopropyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 160).

[1159]

[1160] A suspension of P8 (70 mg, 0.25 mmol, 1 eq), 4-(1-methyl-1H-pyrazole-4-yl)sulfonylcyclohexaneamine hydrochloride (105 mg, 0.375 mmol, 1.5 eq), NaOBut (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 anhydrous dioxane (5 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with saturated brine, and extracted with EtOAc. All volatiles were removed under reduced pressure, and the residue was purified by SiO2 column chromatography (EtOAc / MeOH=100 / 0 to EtOAc / MeOH=10 / 1) to give 9-cyclopentyl-7-isopropyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]purine-8-one (160).

[1161] Analysis data:¹H NMR (400 MHz, DMSO-d6), δ: 8.29 (s, 1H), 8.05 (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).

[1162] Example 7. 9-Cyclopentyl-7-cyclopropyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 163).

[1163]

[1164] A suspension of P9 (80 mg, 0.287 mmol, 1 eq), 4-(1-methyl-1H-pyrazole-4-yl)sulfonylcyclohexaneamine hydrochloride (120 mg, 0.43 mmol, 1.5 eq), NaOBut (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 anhydrous dioxane (6 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with saturated brine, and extracted with EtOAc. All volatiles were removed under reduced pressure, and the residue was purified by SiO2 column chromatography (EtOAc / MeOH=100 / 0 to EtOAc / MeOH=10 / 1), followed by preparative HPLC purification (YMC ODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluents; flow rate 17 mL / min; ACN 15-40% within 20 min; RT 17 min) to obtain 9-cyclopentyl-7-cyclopropyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]purine-8-one 163 (43 mg, 31%).

[1165] Analysis data:¹H NMR (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).

[1166] Example 8. 9-Cyclopentyl-7-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 101).

[1167]

[1168] A suspension of P3 (100 mg, 0.397 mmol, 1 eq), tetrahydro-2H-pyran-4-amine hydrochloride (CAS 33024-60-1, 54 mg, 0.397 mmol, 1 eq), Cs2CO3 (390 mg, 1.19 mmol, 3 eq), Pd2(dba)3 (18 mg, 0.0198 mmol, 0.05 eq), and XantPhos (23 mg, 0.039 mmol, 0.1 eq) in anhydrous dioxane (2 mL) was heated under reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, and extracted with EtOAc. The organic layer was washed with saturated brine, dried, and the solvent was evaporated to remove it. The residue was purified by column chromatography (eluent: EtOAc / MeOH10 / 1), followed by preparative HPLC purification (YMC ODS-A 250 x 20 mm, 5 µm column; eluent: ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid); flow rate: 17 mL / min; ACN concentration: 10-30% within 20 min; RT: 15 min) to obtain 9-cyclopentyl-7-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-7,9-dihydro-8H-purin-8-one 101 (12 mg, yield 10%).

[1169] Analysis data: ¹H NMR (400 MHz, CDCl3), 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).

[1170] Example 9. 7-Methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8-one (compound 401).

[1171]

[1172] A suspension of 2-chloro-7-methyl-9-phenylpurin-8-one (CAS 89743-87-3, 200 mg, 0.76 mmol, 1 eq), 4-(1-methyl-1H-pyrazol-4-yl)sulfonylcyclohexaneamine hydrochloride (270 mg, 0.76 mmol, 1 eq), NaOBut (150 mg, 1.53 mmol, 2 eq), Pd2dba3 (35 mg, 0.038 mmol, 0.05 eq), and XantPhos (44 mg, 0.078 mmol, 0.1 eq) in anhydrous dioxane (4 mL) was heated under reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water, and extracted. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue was purified by column chromatography (eluent: EtOAc / MeOH (20 / 1)), followed by preparative HPLC (YMC ODS-A250 x 20 mm, 5 µm column; eluent: ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid); flow rate: 17 mL / min; ACN concentration: 15-40% within 20 min; RT: 14 min) to obtain 7-methyl-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]-9-phenylpurine-8-one 401 (12 mg, yield 9.5%).

[1173] Analysis data:¹H NMR (400 MHz, CDCl₃), 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).

[1174] Example 10. 7-Methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-9-(piperidin-3-yl)-7,9-dihydro-8H-purine-8-one hydrochloride (compound 207).

[1175]

[1176] 3-[7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-8-oxopurin-9-yl]piperidin-1-carboxylic acid tert-butyl ester P10 (132 mg, 0.23 mmol, 1 eq) was dissolved in 2,2,2-trifluoroethanol (5 mL), and HCl (30 µL, 0.3 mmol, 1.3 eq) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed by evaporation. The residue was purified by recrystallization from EtOH to give 56 mg of white solid, yield 54%.

[1177] Analysis data: ¹H NMR (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).

[1178] Example 11. 9-Cyclopentyl-7-methyl-2-[[2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2-azaspiro[3.3]heptane-6-yl]amino]-7,9-dihydro-8H-purine-8-one (compound 148).

[1179]

[1180] At room temperature, 1-methyl-1H-pyrazole-4-sulfonyl chloride (50 mg, 0.274 mmol, 1 eq) was added in a single batch to an anhydrous pyridine (2 mL) stirred solution of 2-((2-azaspiro[3.3]heptane-6-yl)amino)-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purine-8-one hydrochloride P12 (100 mg, 0.274 mmol, 1 eq). The resulting reaction mixture was stirred at room temperature for 30 min and purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 µm column; using ACN (containing 0.05% TFA) and water (containing 0.05% TFA) as eluents; flow rate 17 mL / min; ACN 15-30% within 20 min; RT 19 min) to obtain 9-cyclopentyl-7-methyl-2-[[2-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2-azaspiro[3.3]heptane-6-yl]amino]-7,9-dihydro-8H-purin-8-one 148 (20 mg, 31%).

[1181] Analysis data:¹H NMR (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).

[1182] Example 12. 9-Cyclopentyl-2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]piperidin-4-yl]amino]-7-methyl-7,9-dihydro-8H-purine-8-one (compound 177).

[1183]

[1184] At room temperature, T3P (290 mg, 0.46 mmol, 2 eq) was added in a single batch to a stirred solution of 9-cyclopentyl-7-methyl-2-((piperidin-4-yl)amino)-7,9-dihydro-8H-purine-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 anhydrous DMA (2 mL). The resulting mixture was stirred at room temperature for 16 h, diluted with saturated saline, and extracted with EtOAc. All volatiles were removed under reduced pressure, and the residue was purified by SiO2 column chromatography (DCM / MeOH=20 / 1) to give 9-cyclopentyl-2-[[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]piperidin-4-yl]amino]-7-methyl-7,9-dihydro-8H-purine-8-one 177 (22 mg, 20%).

[1185] Analysis 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).

[1186] Example 13. 9-(2-azaspiro[3.3]heptane-6-yl)-7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one hydrochloride (compound 166).

[1187]

[1188] 6-[7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-8-oxopurin-9-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester P18 (92 mg, 0.15 mmol, 1 eq) was dissolved in 2,2,2-trifluoroethanol (5 mL), and HCl (30 µL, 0.3 mmol, 2 eq) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated to remove it. The residue was purified by recrystallization from EtOH to give 56 mg of 9-(2-azaspiro[3.3]heptane-6-yl)-7-methyl-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one hydrochloride 166 as a white solid, in 64% yield.

[1189] Analysis data:¹H NMR (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).

[1190] Example 14. 9-Cyclopentyl-7-(2-methoxyethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 173).

[1191]

[1192] A suspension of 2-chloro-9-cyclopentyl-7-(2-methoxyethyl)purin-8-one P19 (150 mg, 0.505 mmol, 1 eq), 4-(1-methyl-1H-pyrazol-4-yl)sulfonylcyclohexaneamine 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 anhydrous dioxane (9 mL) was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with saturated brine, and extracted with EtOAc. All volatiles were removed under reduced pressure, and the residue was purified by SiO2 column chromatography (EtOAc / MeOH=100 / 0 to EtOAc / MeOH=90 / 10), followed by preparative HPLC purification (YMC ODS-A250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluents; flow rate 17 mL / min; ACN 15-45% within 20 min; RT 16 min) to obtain 9-cyclopentyl-7-(2-methoxyethyl)-2-[[1-(1-methyl-1H-pyrazol-4-yl)sulfonyl-4-piperidinyl]amino]purine-8-one 173 (75 mg, 29%).

[1193] Analysis data:¹H NMR (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).

[1194] Example 15. 9-Cyclopentyl-7-methyl-2-((1-(pyrimidin-2-yl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one (compound 185).

[1195]

[1196] Suspensions of 2-chloro-9-cyclopentyl-7-methyl-7,9-dihydro-8H-purin-8-one P3 (80 mg, 0.317 mmol, 1 eq), 1-(pyrimidin-2-yl)piperidin-4-amine hydrochloride (CAS 1179369-48-2, 160 mg, 1.75 mmol, 3 eq), tert-BuONa (120 mg, 1.25 mmol, 4 eq), Pd2(dba)3 (15 mg, 0.016 mmol, 0.05 eq), and XantPhos (18 mg, 0.31 mmol, 0.1 eq) in anhydrous dioxane (6 mL) were stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (4 mL), and washed with saturated saline. All volatiles were removed under reduced pressure, and the residue was purified by SiO2 column chromatography (EtOAc / MeOH=100 / 0 to EtOAc / MeOH=90 / 10), followed by preparative HPLC purification (YMC ODS-A 250 x 20 mm, 5 µm column; ACN (containing 0.1% formic acid) and water (containing 0.1% formic acid) as eluents; flow rate 17 mL / min; ACN 15-40% within 20 min; RT 16 min) to obtain 9-cyclopentyl-7-methyl-2-((1-(pyrimidin-2-yl)piperidin-4-yl)amino)-7,9-dihydro-8H-purine-8-one 185 (25 mg, 20%).

[1197] Analysis data:¹H NMR (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).

[1198] Example 16. ¹H NMR spectra of certain compounds disclosed herein.

[1199]

[1200] Biological assay:

[1201] Example A. A preliminary assay for determining the inhibitory efficacy of CDK2 / CyclinA2 enzyme activity.

[1202] In vitro enzymatic reactions were performed using recombinant CDK2 / CyclinA2 protein (SignalChem, catalog number C29-10G), histone H1 peptide (SignalChem, catalog number H10-58), and ATP from the ADP-Glo™ kinase assay kit (Promega, catalog number V9102) to determine the activity of the compounds. The final concentrations of these components were 0.1 ng / µL, 0.05 µg / µL, and 5 µM, respectively. Reactions were performed in assay buffer: 40 mM Tris-HCl, pH 7.4–7.6; 20 mM MgCl2; 0.05 mM DTT; 0.1 mg / mL BSA. DMSO 80× concentration solutions of the compounds were spotted into 384-well Diamond Well plates (Axygen, catalog number P-384-120SQ-CS). Prepare a 2× CDK2 / CyclinA2-histone H1 peptide mixture in assay buffer, and add 4 µL of this mixture to each well of a 384-well white reaction plate (Corning, catalog number 4513) equipped with NBS. Use 4 µL of CDK2 / CyclinA2-free histone H1 peptide per well as a negative control. Centrifuge the plate at 200 g for 1 min. Then, dilute the compound in DMSO 80× solution to a 2× concentration with 2× ATP, and add 4 µL of this solution to each well containing 4 µL of the CDK2 / CyclinA2-histone H1 peptide mixture. Centrifuge the plate at 200 g for 1 min and incubate at room temperature for 1 h. Then, add 4 µL of ADP-Glo ​​reagent (Promega, ADP-Glo™ kinase assay, catalog number V9102) to each well and incubate the plate at room temperature for 30 min. Then, 8 µL of kinase assay reagent (Promega, ADP-Glo™ kinase assay, catalog number V9102) was added to each well, and the luminescence signal was measured using a ClarioStarPlus (BMG) microplate reader. Subsequently, the IC50 was calculated in GraphPad Prism based on the inhibition rate and using a four-parameter equation. 50 Value: Y = Bottom + (Top - Bottom) / (1 + 10^(LogEC)) 50 -X)*HillSlope))

[1203] Example B. A preliminary assay for determining the inhibitory efficacy of CDK1 / CyclinA2 enzyme activity.

[1204] In vitro enzymatic reactions were performed using recombinant CDK1 / CyclinA2 protein (SignalChem, catalog number C22-18G), histone H1 peptide (SignalChem, catalog number H10-58), and ATP from the ADP-Glo™ kinase assay kit (Promega, catalog number V9102) to determine the activity of the compounds. The final concentrations of these components were 0.1 ng / µL, 0.2 µg / µL, and 5 µM, respectively. Reactions were performed in assay buffer: 40 mM Tris-HCl, pH 7.4–7.6; 20 mM MgCl2; 0.05 mM MTT; 0.1 mg / mL BSA. DMSO 80× concentration solutions of the compounds were spotted into 384-well Diamond Well plates (Axygen, catalog number P-384-120SQ-CS). Prepare a 2× CDK1 / CyclinA2-histone H1 peptide mixture in assay buffer, and add 4 µL of this mixture to each well of a 384-well white reaction plate (Corning, catalog number 4513) equipped with NBS. Use 4 µL of CDK1 / CyclinA2-free histone H1 peptide per well as a negative control. Centrifuge the plate at 200 g for 1 min. Then, dilute the compound in DMSO 80× solution to a 2× concentration with 2× ATP, and add 4 µL of this solution to each well containing 4 µL of the CDK1 / CyclinA2-histone H1 peptide mixture. Centrifuge the plate at 200 g for 1 min and incubate at room temperature for 1 h. Then, add 4 µL of ADP-Glo ​​reagent (Promega, ADP-Glo™ kinase assay, catalog number V9102) to each well and incubate the plate at room temperature for 30 min. Then, 8 µL of kinase assay reagent (Promega, ADP-Glo™ kinase assay, catalog number V9102) was added to each well, and the luminescence signal was measured using a ClarioStarPlus (BMG) microplate reader. Subsequently, the IC50 was calculated in GraphPad Prism based on the inhibition rate and using a four-parameter equation. 50 Value: Y = Bottom + (Top - Bottom) / (1 + 10^(LogEC)) 50 -X)*HillSlope))

[1205] Average IC 50 The values ​​are shown in Table A1, where "A" corresponds to IC. 50 IC 50 ≤ 0.05 µM; "B" corresponds to 0.05 µM < IC 50 ≤ 0.1 µM; “C” corresponds to 0.1 µM < IC 50≤ 0.5 µM; “D” corresponds to 0.5 µM < IC 50 ≤ 1.0 µM; “E” corresponds to IC 50 > 1.0 µM.

[1206] Table A1: CDK1 / CDK2

[1207]

[1208] *-IC 50 IC50 refers to the inhibitor concentration that reduces the reaction (or binding) by half. 50 : A ≤ 0.05 µM; 0.05µM < B ≤ 0.1 µM; 0.1 µM < C ≤ 0.5 µM; 0.5 µM < D ≤ 1.0 µM; E > 1.0 µM.

[1209] Example C. Cell growth inhibition assay.

[1210] The complete culture media used for cell culture are as follows: For TOV-21G, MCDB 105 (Cell Applications, USA, catalog number 117-500) and Earle salt-containing medium 199 (Capricorn, Germany, catalog number M199-A) are prepared at a ratio of 50:50; for NIH, RPMI-1640 (VWR, USA, catalog number 392-0429) is used. All the above culture media were supplemented with 10% FBS (Gibco, USA, catalog number 10500-064, or Capricorn, Germany, catalog number HI-11A), 1× antibiotic-antifungal agent (Gibco, USA, catalog number 15240-062), 2× sodium pyruvate (Gibco, USA, catalog number 11360-070), 2× essential amino acids (Gibco, USA, catalog number 11130-051), and 1× non-essential amino acids (Gibco, USA, catalog number 11140-050). Using Biomek NX (384), NIH (ATCC, HTB-161) and TOV-21G (ATCC, CRL-11730) were seeded at a density of 500 cells per well in CellBIND® 384-well flat-bottomed transparent black polystyrene microplates (Corning, USA, catalog number 3770), with a total culture medium volume of 45 µL per well. Cells were incubated overnight at 37 °C with 5% CO2. A 500× compound DMSO solution (DMSO: Honeywell International, Inc., USA, catalog number 472301-1L) was prepared in a compound plate (Diamond Well plate, Axigen, catalog number P-384-120SQ-CS), and a DMSO-only control was set up. 1 µL of the 500× compound solution from the compound plate was added to 49 µL of complete culture medium in a dilution plate (Diamond Well plate, Axigen, catalog number P-384-120SQ-CS) and mixed well. Subsequently, 5 µL of a 10× compound solution was transferred to the cells using a Biomek NX (384) and centrifuged at 100 g for 1 min. The final DMSO concentration was 0.2%. After 3 days of incubation, 1 µL of 500× compound solution from the compound plate was added to 49 µL of complete culture medium in the dilution plate (Diamond Well plate, Axigen, catalog number P-384-120SQ-CS) and mixed well. Subsequently, 10 µL of 10× compound solution was transferred to the cells using Biomek NX (384) and centrifuged at 100 g for 1 min.After 7 days of incubation, 15 µL of CyQUANT™ (Invitrogen, USA, catalog number C35011) was added to the cells, and after incubation at 37 °C and 5% CO2 for 1 h, the fluorescence signal was measured using a microplate reader (CLARIOStar).

[1211] Average CC 50 The values ​​are shown in Table B, where "A" corresponds to CC. 50 :CC 50 ≤ 0.1 µM; "B" corresponds to 0.1 µM < CC 50 ≤1.0 µM; “C” corresponds to CC 50 > 1.0 µM.

[1212] Table B. Cell growth inhibition.

[1213]

[1214] *-CC 50 This refers to the concentration of the test compound required to reduce cell viability by 50%. CC 50 :A ≤ 0.1 µM; 0.1 µM < B ≤ 1 µM; C > 1.0 µM.

[1215] Equivalent solution:

[1216] Those skilled in the art will recognize, or be able to determine, through routine experiments alone, that the embodiments specifically described herein have numerous equivalents. Such equivalents are intended to be covered within the scope of the following claims.

Claims

1. A compound represented by formula (A): (A), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: X is selected from O, CR4R5, SO2, and NR6; Each R1 is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR8 and -C(O)NR8R9, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl or heteroaryl group is optionally selected independently by one or more halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Substitution with cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl groups; Or two R1s form a bond; R2 is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from halogens, OH, CN and C1-C6 alkoxy groups; R3 is selected from C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl, heterocyclic, and aryl groups, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one or more R groups. 10 replace; R4 is selected from halogens, -CN, -OH, C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents independently selected from halogen, -OH, -NH2 and -CN; R5 is selected from H, halogens, C1-C6 alkyl groups, and R6; or R4 and R5 together with the atoms they are attached to and any intermediate atoms form a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl and R6. R6 is R7-L-; L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, -C1-C6 alkyldiyl-C(O)- and -C1-C6 alkyldiyl-NH-C(O)-; R7 is selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl- or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy and R8R9N-; R8 is selected from H and C1-C6 alkyl groups; R9 is selected from H and C1-C6 alkyl groups; Each R 10 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or Two Rs 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3.

2. A compound represented by formula (I): (I), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: X is selected from O, CR4R5, SO2, and NR6; Each R1 is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR8, -C(O)NR8R9 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally selected independently from one or more halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Substitution with cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl groups; Or two R1s form a bond; R2 is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from halogens, OH, CN and C1-C6 alkoxy groups; R4 is selected from halogens, -CN, -OH, C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents independently selected from halogen, -OH, -NH2 and -CN; R5 is selected from H, halogens, C1-C6 alkyl groups, and R6; or R4 and R5 together with the atoms they are attached to and any intermediate atoms form a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl and R6. R6 is R7-L-; L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, -C1-C6 alkyldiyl-C(O)- and -C1-C6 alkyldiyl-NH-C(O)-; R7 is selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl- or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy and R8R9N-; R8 is selected from H and C1-C6 alkyl groups; R9 is selected from H and C1-C6 alkyl groups; Each R 10 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or Two Rs 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups; 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 according to claim 2, wherein, The compound is a compound of formula (IA-1-a), (IB-1-a), (IC-1-a), (IC-1-b), (IC-1-c), (IC-1-d), (IC-2-a), (IC-3-a), or (ID-1-a): (I-A-1-a), (I-B-1-a), (I-C-1-a), (I-C-1-b), (I-C-1-c), (I-C-1-d), (I-C-2-a), (I-C-3-a), (I-D-1-a), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

4. A compound represented by formula (II): (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 R1 is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR8, -C(O)NR8R9 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally selected independently from one or more halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Substitution with cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl groups; Or two R1s form a bond; R2 is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from halogens, OH, CN and C1-C6 alkoxy groups; R4 is selected from halogens, -CN, -OH, C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents independently selected from halogen, -OH, -NH2 and -CN; R5 is selected from H, halogens, C1-C6 alkyl groups, and R6; or R4 and R5 together with the atoms they are attached to and any intermediate atoms form a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl and R6. R6 is R7-L-; L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, -C1-C6 alkyldiyl-C(O)- and -C1-C6 alkyldiyl-NH-C(O)-; R7 is selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl- or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy and R8R9N-; R8 is selected from H and C1-C6 alkyl groups; R9 is selected from H and C1-C6 alkyl groups; Each R 10 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or Two Rs 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; Each b is an independent integer selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.

5. The compound according to claim 4, wherein, The compound is one of the compounds represented by formula (II-A-3.1-a), (II-A-3.1-b), (II-A-3.2-a), (II-B-3.1-a), (II-B-3.1-b), (II-B-3.2-a), or (II-B-3.2-b). (II-A-3.1-a), (II-A-3.1-b), (II-A-3.2-a), (II-B-3.1-a), (II-B-3.1-b), (II-B-3.2-a), (II-B-3.2-b), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

6. A compound represented by formula (III): (III), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: X is selected from O, CR4R5, SO2, and NR6; Each R1 is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR8, -C(O)NR8R9 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally selected independently from one or more halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Substitution with cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl groups; Or two R1s form a bond; R2 is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from halogens, OH, CN and C1-C6 alkoxy groups; R4 is selected from halogens, -CN, -OH, C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents independently selected from halogen, -OH, -NH2 and -CN; R5 is selected from H, halogens, C1-C6 alkyl groups, and R6; or R4 and R5 together with the atoms they are attached to and any intermediate atoms form a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl and R6. R6 is R7-L-; L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, and -C1-C6 alkyldiyl-C(O)-. R7 is selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl- or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy and R8R9N-; R8 is selected from H and C1-C6 alkyl groups; R9 is selected from H and C1-C6 alkyl groups; Each R 10 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or Two Rs 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; Each b is an independent integer selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.

7. The compound according to claim 6, wherein, The compound is the compound represented by formula (III-A-1-a): (III-A-1-a), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

8. A compound represented by formula (IV): (IV), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: Ar is an aryl group; X is selected from O, CR4R5, SO2, and NR6; Each R1 is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, -C(O)OR8, -C(O)NR8R9 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl groups are optionally selected independently from one or more halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Substitution with cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl groups; Or two R1s form a bond; R2 is selected from H, C1-C6 alkyl groups, and C3-C6 alkyl groups. 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from halogens, OH, CN and C1-C6 alkoxy groups; R4 is selected from halogens, -CN, -OH, C1-C6 alkyl groups, C3-C6 alkyl groups, and C4-C6 alkyl groups. 10 Cycloalkyl and C1-C6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy group is optionally substituted by one or more substituents independently selected from halogen, -OH, -NH2 and -CN; R5 is selected from H, halogens, C1-C6 alkyl groups, and R6; or R4 and R5 together with the atoms they are attached to and any intermediate atoms form a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl and R6. R6 is R7-L-; L is selected from the following: -C(O)-, -S(O)2-, -OC(O)-, -O-CH2-C(O)-, -O-CH2-S(O)2-, -CH2-C(O)-, -NH-C(O)-, -C1-C6 alkyldiyl-, -C1-C6 alkyldiyl-O-, -C1-C6 alkyldiyl-C(O)- and -C1-C6 alkyldiyl-NH-C(O)-; R7 is selected from C1-C6 alkyl-, cycloalkyl-, aryl-, heterocyclic-, heteroaryl- or R8R9N-, wherein the alkyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy and R8R9N-; R8 is selected from H and C1-C6 alkyl groups; R9 is selected from H and C1-C6 alkyl groups; Each R 10 Independently selected from halogens, OH, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or Two Rs 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a 4- to 9-membered cycloalkyl, a 4- to 9-membered heterocyclic or a 4- to 9-membered heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, oxo, OH, CN and C1-C6 alkyl groups; 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 according to claim 8, wherein, The compound is the compound represented by formula (IV-A-1-aI): (IV-A-1-aI), Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

10. A compound selected from the following: 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 according to claim 11, further comprising one or more other pharmaceutically active agents.

13. A method for inhibiting CDK2 in cells, comprising contacting the cells with a compound according to any one of claims 1-10, or a pharmaceutical composition according to claim 11 or 12.

14. The method of claim 13, wherein the contact is performed in vitro or in vivo.

15. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 11 or 12 in the manufacture of a medicament for treating or preventing a CDK2-related disease or condition in a subject in need.

16. The use according to claim 15, wherein the disease or condition is selected from: breast cancer (BC), colorectal cancer (CRC), lung cancer (LNCR), retinoblastoma (RB1), pancreatic cancer (PNCA), prostate cancer (PC), ovarian cancer (OC), hepatocellular carcinoma (HCC), gastric cancer (GASC), bladder cancer (BLC), endometrial cancer (ENDMC), glioblastoma (GBM), adenocarcinoma, squamous cell carcinoma, and ataxia-telangiectasia (AT).

17. The use according to claim 15, wherein the disease or condition is cancer.

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

19. The use according to claim 18, wherein the subject is a human.

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