Protein kinase inhibitor

Abstract

The present invention provides a compound of general formula (I) for treating diseases. The compound is an effective cyclin-dependent kinase 2 (CDK2) inhibitor.

Description

protein kinase inhibitors

[0001] This invention claims priority to Chinese invention patent application CN202411098517.9, filed on August 12, 2024, the entire contents of which are incorporated herein by reference as a part of this disclosure. Invention Field

[0002] This invention provides a class of compounds as cyclin-dependent kinase (CDK) inhibitors, exhibiting broad-spectrum and potent inhibitory activity against CDKs. The compounds of this invention are effective in treating diseases such as cancer and inflammation. Background Technology

[0003] Cyclin-dependent kinases (CDKs) and cyclins are important factors in cell cycle regulation. CDKs can bind to cyclins to form heterodimers, where CDK is the catalytic subunit and cyclin is the regulatory subunit, forming various cyclin-CDK complexes that phosphorylate different substrates, thus promoting and transitioning between different phases of the cell cycle.

[0004] Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, as dysregulation of CDK2 activity frequently occurs in various human cancers. CDK2 plays a crucial role in promoting the G1 / S transition and S phase progression. In its complex with cyclin E (CCNE), CDK2 phosphorylates members of the retinoblastoma pocket protein family (p107, p130, pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and the transition from G1 to S phase (Henley, SA, and FADick, Cell Div, 2012, 7(1): p. 10). This, in turn, activates CDK2 / cyclin A, resulting in phosphorylation of endogenous substrates that allow DNA synthesis, replication, and centrosome replication (Ekholm, SV, and SIReed, Curr Opin Cell Biol, 2000, 12(6): 676-84). It has been reported that the CDK2 pathway mainly affects tumorigenesis through the amplification and / or overexpression of CCNE1 and mutations that inactivate endogenous CDK2 inhibitors.

[0005] Amplification and / or overexpression of CCNE1 has been identified in a variety of cancers (e.g., ovarian cancer, gastric cancer, endometrial cancer, breast cancer, etc.) (Keyomarsi, K. et al., N Engl J Med, 2002. 347(20): 1566-75; Nakayama, N. et al., Cancer, 2010. 116(11): 2621-34; Au-Yeung, G. et al., Clin Cancer Res, 2017. 23(7): 1862-1874; Rosen, D.G. et al., Cancer, 2006. 106(9): 1925-32). Amplification and / or overexpression of CCNE1 has also been reported to cause trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M. et al., Proc Natl Acad Sci U S A, 2011. 108(9): 3761-6; Herrera-Abreu, M.T. et al., Cancer Res, 2016. 76(8): 2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, Y.N. et al., Proc Natl Acad Sci U S A, 1999. 96(8): 4325-9; Mendoza, N. et al., Cancer Res, 2003. 63(5): 1020-4). Inhibition of CDK2 was reported to restore the sensitivity of resistant HER2+ breast tumors to trastuzumab treatment in preclinical models (Scaltriti, supra).

[0006] While a number of CDK inhibitor compounds have been disclosed, there remains a need for additional CDK inhibitors, particularly CDK2 selective inhibitors, for the treatment of CDK-related diseases. SUMMARY

[0007] The present invention provides a new class of compounds as cyclin-dependent kinase inhibitors, particularly inhibitors targeting CDK2, with potent inhibitory activity and selectivity. Specifically, the compounds of the present invention are effective in inhibiting CDK2 and are useful in the treatment of a variety of cancers. Importantly, the disclosed compounds are selective CDK2 inhibitors, i.e., the compounds of the present invention have no or low activity against other kinases of the CDK family, particularly CDK1. Advantages associated with this selectivity can include facilitating effective dosing and reducing CDK1 -mediated off-target toxicity.

[0008] In one aspect, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:

[0009] wherein,

[0010] L1is selected from -O-C 0-6 alkyl- or -NH-C 0-6 alkyl-;

[0011] L2is selected from a bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl-, -S(O) m -C 0-6 alkyl-, -C 1-6 alkylene-, -C 2-6 alkylene- or -C 2-6 alkynylene-;

[0012] Ring A is selected from C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0013] said Ring A is optionally substituted with 1, 2, 3, 4, or 5 R#;

[0014] R1and R2are independently selected from H, D, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0015] or, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein said C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene and 5-10 membered heteroarylene is optionally substituted with oxo or thioxo;

[0016] R3is selected from -OR, -SR, -NR’R”, -C 1-6 alkylene-R5, -O-C 1-6 alkylene-R5, -NH-C1-6 Alkylene-R5, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the group is optionally substituted by one, two, three, four or five R5 groups;

[0017] Alternatively, R3 forms a ring loop with ring A, for example, selected from C. 5-12 Cycloalkyl, 5-12 membered heterocyclic, C 6-12 Aryl or 5-12 heteroaryl groups, wherein the cyclic ring is optionally substituted by 1, 2, 3, 4 or 5 R5 groups;

[0018] R4 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the R4 is optionally substituted by one, two, three, four or five R6 groups;

[0019] Each R5 is independently selected from H, D, halogen, -C 0-6 Alkylene-OR a -C 0-6 Alkylene-NR b R c CN, C 1-6 Alkyl or C 1-6 Haloalkyl; or two R5 atoms on the same atom together form an oxo or thio group;

[0020] Each R6 is independently selected from H, D, halogen, -C 0-6 Alkylene-OR a -C 0-6 Alkylene-NR b R c CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0021] m is selected from 0, 1, or 2;

[0022] R, R', and R" are independently selected from H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 0-6 Alkylene-OR a or -C 0-6 Alkylene-NR a R b ;

[0023] each R#is independently selected from H, D, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl;

[0024] R a , R b , and R c are independently selected from H, halogen, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH2, -C 0-6 alkylene-CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C 0-6 alkylene-C 3-7 cycloalkyl, -C 0-6 alkylene-3-7 membered heterocyclyl, -C 0-6 alkylene-C 6-10 aryl, or -C 0-6 alkylene-5-10 membered heteroaryl; or, R b , R c together with the N atom form a 3-7 membered heterocyclyl;

[0025] each of the above groups can be optionally substituted with 1 or more deuterium atoms, up to per-deuteration.

[0026] In another aspect, the present application provides a pharmaceutical composition containing a compound of the present application, and optionally a pharmaceutically acceptable excipient.

[0027] In another aspect, the present application provides a pharmaceutical composition containing a compound of the present application and a pharmaceutically acceptable excipient, further containing another therapeutic agent.

[0028] In another aspect, the present application provides a kit comprising a compound of the present application, and another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0029] In another aspect, the present application provides use of a compound of the present application in the manufacture of a medicament for the treatment and / or prevention of a disease.

[0030] In another aspect, the present application provides a method of treating and / or preventing a disease in a subject, comprising administering to the subject a compound of the present application or a composition of the present application.

[0031] In another aspect, the present application provides a compound of the present application or a composition of the present application for use in the treatment and / or prevention of a CDK2 mediated disease.

[0032] In another aspect, the present application provides the use of a compound of the present application in the manufacture of a medicament for the treatment and / or prevention of a CDK2 mediated disease.

[0033] In another aspect, the present application provides a method of treating and / or preventing a CDK2 mediated disease in a subject comprising administering to said subject a compound of the present application or a composition of the present application.

[0034] In another aspect, the present application provides a compound of the present application or a composition of the present application for use in the treatment and / or prevention of a CDK2 mediated disease.

[0035] Other objects and advantages of the present application will be readily appreciated, as the same becomes better understood by reference to the following detailed description, when considered in connection with the accompanying drawings wherein:

[0036] Definitions

[0037] Chemical Definitions

[0038] The definitions of specific functional groups and chemical terms are described in more detail below.

[0039] When a range is listed, it is intended to include every value and sub-range within the range. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0040] It should be understood that when described herein any of the moieties defined forth below can be substituted on any atom as allowed by the stable formation of the compound by those skilled in the art. As used herein, the term "substituted" means that any of the moieties defined forth below can be substituted on any atom as allowed by stable formation of the compound by those skilled in the art. Unless otherwise indicated, the term "substituted" shall include all permissible substituents

[0041] "C 1-6 alkyl" means a straight or branched chain saturated hydrocarbon radical of from 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. C 1-6Examples of alkyl groups include: methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). The term "C 1-6 Alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0042] "C 2-6 Alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. C 2-6 Examples of alkenyl groups include: ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "C 2-6 Alkynyl" refers to a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6alkynyl" also includes heteroalkynyl groups wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, e.g., with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-" refers to divalent groups of the above-defined "C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl".

[0045] "C 1-6 alkylene" refers to a divalent group formed by removing an additional hydrogen from a C 1-6 alkyl group, and can be substituted or unsubstituted alkylene. In some embodiments, the C 1-4 alkylene is particularly preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- 2), and the like.

[0046] "C 0-6 alkylene" represents a chemical bond and a "C 1-6 alkylene" as defined above.

[0047] "C 2-6 alkenylene" refers to a divalent group formed by removing an additional hydrogen from a C 2-6 alkenyl group, and can be substituted or unsubstituted alkenylene. In some embodiments, the C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylenes include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylenes, e.g., alkenylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylenes (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0048] "C 2-6 Alkynylene refers to a divalent radical formed by the removal of two hydrogens from a C 2-6 Alkynylene refers to a divalent radical formed by the removal of two hydrogens from a C 2-4 Alkynylene is particularly preferred. Exemplary alkylenes include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like.

[0049] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0050] "C 1-6 Haloalkyl refers to "C 1-6 Alkyl" groups substituted with one or more halogen groups. Examples include monohalo, dihalo, and polyhaloalkyl groups, including perhalo. A single halogen substituent can be an iodine, bromine, chlorine, or fluorine atom in the group; two or more halogen substituents can be two or more of the same halogen atoms or a combination of different halogens. Preferred haloalkyl examples include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The haloalkyl group can be substituted at any available attachment point, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] "C 3-10 Cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having from three to ten ring carbon atoms and zero heteroatoms. "C 3-7 Cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having from three to seven ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl and C 3-6Cycloalkyl is particularly preferred, more preferably C 4-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl is particularly preferred, more preferably C

[0052] "3-12 membered heterocyclyl" refers to a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-12 membered heterocyclyl is preferred, which is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms; in some embodiments, 3-9 membered heterocyclyl is preferred, which is a 3- to 9-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 3-6 membered heterocyclyl is preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 4-7 membered heterocyclyl is preferred, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 4-6 membered heterocyclyl is preferred, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 5-6 membered heterocyclyl is more preferred, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl rings, wherein the point of attachment is on the cycloalkyl ring, or with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, dioxanyl.Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. 3-12-membered heterocyclic groups also include cases where the ring carbon atom is oxidized or thiolated (e.g., forming a -C(O)- or -C(S)- structure), and cases where the ring sulfur atom is oxidized (e.g., forming a -S(O)2- structure).

[0053] 3-12 membered heterocyclic groups also include spiroheterocyclic groups, i.e., groups in which two rings (e.g., heterocycles and carboalkyl groups) share a carbon atom, wherein at least one ring is a heterocyclic group as defined above. More specifically, the spiroheterocyclic group is a spirocycle formed by two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, wherein at least one ring is a 4-6 membered heterocyclic group as defined above, preferably a 4-6 membered heterocyclic group containing one, two, or three O, N, or S heteroatoms, more preferably a 4-6 membered heterocyclic group containing one N heteroatom. Specific spiroheterocyclic groups include, but are not limited to:

[0054] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

[0055] "5-12 membered heteroaryl" refers to a radical of a 5-12 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 p-electrons shared in a cyclic arrangement) having ring carbon atoms and 1-5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or a nitrogen atom, as valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein an above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl rings, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms indicates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is particularly preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0056] "Carbonyl," whether used alone or as part of a larger moiety, e.g., aminocarbonyl, oxycarbonyl, or thiocarbonyl, represents a -C(O)- group.

[0057] "Oxy" represents =O.

[0058] "Thio" represents =S.

[0059] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted groups. In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen present on a group, e.g., a carbon or nitrogen atom, by a permissible substituent, for example, a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each substitutable position. The term "substituted" includes substitution with all permissible substituents of organic compounds (any of the substituents described herein that result in the formation of a stable compound). For the present application, a heteroatom such as nitrogen can have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0060] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NRbb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(ORcc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0061] or two geminal hydrogens on a carbon atom are replaced with a group =0, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc ;

[0062] each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0063] each R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(Rcc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0064] R cc each occurrence is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are joined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0065] R dd each occurrence is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff)2, -OC(=NR ff )2, -NR ff )2, -NR ff )2, -NR ff )2, -NR ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0066] each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0067] each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0068] each R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C1-6 alkyl, -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1- 6alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 aryl, C3-C7 heterocyclyl, C5-C 10 heteroaryl; or two geminal R gg substituents can combine to form =O or =S; wherein X - is a counterion.

[0069] Exemplary substituents on a nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd , R aa , R bb , R cc , and R dd are as described above.

[0070] Other Definitions

[0071] As used herein, "cancer" refers to any disease caused or contributed to by an inappropriately high level of cell division, an inappropriately low level of apoptosis, or both. Examples of cancer include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors.

[0072] As used herein, the term "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the act of treating as the term is defined above.

[0073] As used herein, the term "pharmaceutically acceptable" means that the substance is suitable for use with tissue of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, effective for their intended application, including (where possible) two-ionic forms of the compounds of the application.

[0074] The term "salt" refers to relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present application. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.

[0075] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals, and organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0076] Salts can be prepared from inorganic acids such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include the following: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, among others. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, phenyl- benzoate, phenylsulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and aluminum, and nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, galacturonate, and the like (see, e.g., Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0077] A "subject" for administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0078] "Disease," "disorder," and "condition" are used interchangeably herein.

[0079] Unless otherwise indicated, the term "treatment" as used herein includes the intended action occurring when a subject has a particular disease, disorder, or condition, and it reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also includes the action occurring before a subject has developed a particular disease, disorder, or condition ("prophylactic treatment").

[0080] "Compound," "compound of Formula (I)," as described herein refers to a compound of Formula (I) and its sub-formulae, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof. The sub-formulae of Formula (I) refer to other formulae mentioned herein other than Formula (I), including but not limited to Formula (I-l), Formula (II), Formula (II-l), Formula (II-2), Formula (III), Formula (III-l), Formula (III-2), Formula (IV), Formula (IV-l), Formula (IV-2), Formula (V), Formula (V-l), Formula (V-2), Formula (VI), Formula (VI-l), Formula (VI-2), Formula (VI-3), Formula (VII), Formula (VII-l), Formula (VII-2), and Formula (VII-3), etc.

[0081] Generally, an "effective amount" of a compound refers to a quantity sufficient to effect a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the application can vary depending on such factors as the biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0082] Unless otherwise indicated, a "therapeutically effective amount" of a compound, as used herein, is an amount that is sufficient, in the course of treating a disease, disorder, or condition, to provide a therapeutic benefit, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the course of treating a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic effects of another therapeutic agent.

[0083] As used herein, unless otherwise noted, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with the disease, disorder or condition, or to prevent the recurrence of the disease, disorder or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the process of preventing the disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or enhances the prophylactic effect of other prophylactic agents.

[0084] "Combination" and related terms mean simultaneous or sequential administration of a compound of the present application and another therapeutic agent. For example, a compound of the present application can be administered simultaneously or sequentially in separate unit dosage forms or concurrently in a single unit dosage form with another therapeutic agent. Specific embodiments

[0085] As used herein, a "compound of the present application" refers to a compound of Formula (I) (including sub-formulae of Formula (I), e.g., Formula (I-l), Formula (II), Formula (II-l), Formula (II-2), Formula (III), Formula (III-l), Formula (III-2), Formula (IV), Formula (IV-l), Formula (IV-2), Formula (V), Formula (V-l), Formula (V-2), Formula (VI), Formula (VI-l), Formula (VI-2), Formula (VI-3), Formula (VII), Formula (VII-l), Formula (VII-2), or Formula (VII-3)), a pharmaceutically acceptable salt, enantiomeric, diastereomeric, racemic, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

[0086] Compounds are generally described herein using standard nomenclature. Compounds with asymmetric centers should be understood to include all optical isomers and mixtures thereof unless otherwise indicated. In addition, unless otherwise indicated, all isomeric forms of a compound of the application are embraced by the application including Z and E isomers of carbon-carbon double bonds. Where a compound exists in different tautomeric forms, a compound described herein is not limited to any particular tautomer, but rather is intended to embrace all tautomeric forms.

[0087] In one embodiment, the present application relates to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomeric, diastereomeric, racemic, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof:

[0088] wherein,

[0089] L1is selected from -O-C 0-6 alkyl- or -NH-C 0-6alkyl-, -NH-C

[0090] L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl-, -S(O) m -C 0-6 alkyl-, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;

[0091] ring A is selected from C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0092] said ring A is optionally substituted with 1, 2, 3, 4 or 5 R#;

[0093] R1and R2are independently selected from H, D, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0094] or, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein said C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene and 5-10 membered heteroarylene is optionally substituted with oxo or thioxo;

[0095] R3is selected from -OR, -SR, -NR’R”, -C 1-6 alkylene-R5, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said group is optionally substituted with 1, 2, 3, 4 or 5 R5groups;

[0096] or, R3forms a fused ring with ring A, for example is selected from C5-12 cycloalkyl, 5-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, which fused ring is optionally substituted with 1, 2, 3, 4, or 5 R5groups;

[0097] R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which R4is optionally substituted with 1, 2, 3, 4, or 5 R6groups;

[0098] each R5is independently selected from H, D, halogen, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo;

[0099] each R6is independently selected from H, D, halogen, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0100] m is selected from 0, 1, or 2;

[0101] R, R’ and R” are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, -C 0-6 alkylene-OR a or -C 0-6 alkylene-NR a R b ;

[0102] each R# is independently selected from H, D, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl;

[0103] R a , R b and R cindependently selected from H, halogen, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH2, -C 0-6 alkylene-CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C 0-6 alkylene-C 3-7 cycloalkyl, -C 0-6 alkylene-3-7 membered heterocyclyl, -C 0-6 alkylene-C 6-10 aryl or -C 0-6 alkylene-5-10 membered heteroaryl; or, R b , R c together with the N atom form a 3-7 membered heterocyclyl;

[0104] each of the above groups can be optionally substituted with one or more deuterium atoms, up to per-deuteration.

[0105] In one embodiment, the present application relates to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein the compound has the structure of Formula (I-1), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), Formula (VI), Formula (VI-1), Formula (VI-2), Formula (VI-3), Formula (VII), Formula (VII-1), Formula (VII-2), or Formula (VII-3):

[0106] wherein,

[0107] X1is selected from CR X1 or N, preferably N, CH, or CF;

[0108] X2is selected from CR X2 or N, preferably CR X2 , for example CH;

[0109] X3is selected from CR X3 or N, preferably CR X3 , for example CH;

[0110] X4is selected from CR X1 or N, preferably N, CH, or CF;

[0111] C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0112] C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said ring C being optionally substituted with 1, 2, 3, 4 or 5 R5groups;

[0113] L2, R1, R2, R3, R4, R5are as defined herein;

[0114] Preferably,

[0115] C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0116] C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3 or 4 R5groups;

[0117] More preferably,

[0118] C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0119] ring C together with the ring in which X1, X4are located forms the following structure:

[0120] L1

[0121] In one particular embodiment, L1is -O-C 0-6 alkyl-, for example -O-; in another particular embodiment, L1is -NH-C 0-6 alkyl-, for example -NH- or -NHCH2-.

[0122] L2

[0123] In one particular embodiment, L2is a chemical bond; in another particular embodiment, L2is -O-C 0-6 alkyl-, for example -O-; in another particular embodiment, L2is -NH-C 0-6 alkyl-, for example -NH-; in another particular embodiment, L2is -C(O)-C 0- 6alkyl-, for example -C(O)-; in another particular embodiment, L2is -S(O) m -C 0-6 alkyl-, for example -S(O)2-; in another particular embodiment, L2is -C1-6 Alkylene; in another specific embodiment, L2 is -C 2-6 Idemenyl-; in another specific embodiment, L2 is -C 2-6 Ethyne-.

[0124] In one specific implementation, L2 is selected from chemical bonds, -OC 0-6 Alkyl-, -NH-C 0-6 Alkyl-, -C(O)-C 0-6 Alkyl- or -S(O) m -C 0-6 alkyl-.

[0125] In one specific implementation, L2 is selected from chemical bonds, -O-, -NH-, -C(O)-, or -S(O)2-.

[0126] Ring A

[0127] In one specific implementation, ring A is C. 3-10 Cycloalkylene; in another specific embodiment, ring A is C 3-7 Cycloalkylene, such as C 5-6 Cycloalkylene; in another embodiment, ring A is a 3-10 membered heterocyclic group; in another embodiment, ring A is a 3-7 membered heterocyclic group, such as a 5-6 membered heterocyclic group; in another embodiment, ring A is a C 6-10 The arylene group, such as phenylene; in another specific embodiment, ring A is a 5-10 member heteroarylene, such as a 5-6 member heteroarylene.

[0128] In one specific implementation, ring A is C. 3-7 Cycloalkylene, 3-7 membered heterocyclic alkylene, C 6-10 arylene or 5-7 quinone heteroarylene, preferably C 5-6 Cycloalkylene, 5-6 membered heterocyclic alkylene, phenylene or 5-6 membered heteroaryl alkylene.

[0129] In one specific implementation, R3 forms a parallel loop with ring A, for example, C. 5-12 Cycloalkyl, 5-12 membered heterocyclic, C 6-12 Aryl or 5-12 heteroaryl, preferably C 6-12 The aryl or 5-12 heteroaryl group, wherein the cyclic ring is optionally substituted with 1, 2, 3, 4 or 5 R5 groups.

[0130] In one specific implementation, ring A is selected from...

[0131] In one specific implementation, ring A is selected from...

[0132] In one embodiment, the ring A is unsubstituted; in another embodiment, the ring A is substituted with 1, 2, 3, 4, or 5 R#.

[0133] Ring B

[0134] In one embodiment, the ring B is C 3-7 cycloalkylene; in another embodiment, the ring B is C 3-5 cycloalkylene; in another embodiment, the ring B is 3-7 membered heterocyclylene; in another embodiment, the ring B is 3-5 membered heterocyclylene; in another embodiment, the ring B is C 6-10 arylene; in another embodiment, the ring B is 5-10 membered heteroarylene.

[0135] In one embodiment, the ring B is cyclopropylene; in another embodiment, the ring B is cyclobutylene; in another embodiment, the ring B is cyclopentylene.

[0136] Ring C

[0137] In one embodiment, the ring C is C 3-10 cycloalkyl; in another embodiment, the ring C is 3-10 membered heterocyclyl; in another embodiment, the ring C is C 6-10 aryl; in another embodiment, the ring C is 5-10 membered heteroaryl. In one embodiment, the ring C is C 3-7 cycloalkyl or 4-7 membered heterocyclyl, the ring C being optionally substituted with 1, 2, 3, or 4 R5groups.

[0138] In one embodiment, the ring C is unsubstituted; in another embodiment, the ring C is substituted with 1, 2, 3, 4, or 5 R5groups.

[0139] In one embodiment, the ring C forms a fused ring with the ring in which X1, X4is located, as follows:

[0140] X1, X2, X3, and X4

[0141] In one embodiment, X1is CR X1 , for example CH or CF; in another embodiment, X1is N.

[0142] In one embodiment, X2is CR X2 or N, preferably CR X2 , for example CH.

[0143] In one embodiment, X3is CR X3 , for example CH; in another embodiment, X3is N.

[0144] In one embodiment, X4is CR X1 , for example CH or CF; in another embodiment, X4is N.

[0145] R X1 , R X2 , R X3 , and R X4

[0146] In one embodiment, R X1 is H; in another embodiment, R X1 is halogen, for example F; in another embodiment, R X1 is -CN; in another embodiment, R X1 is -OR a , for example -OH; in another embodiment, R X1 is -NR b R c , for example -NH2; in another embodiment, R X1 is C 1-6 alkyl; in another embodiment, R X1 is C 1-6 haloalkyl.

[0147] In one embodiment, R X2 is H; in another embodiment, R X2 is halogen, for example F; in another embodiment, R X2 is -CN; in another embodiment, R X2 is -OR a , for example -OH; in another embodiment, R X2 is -NR b R c , for example -NH2; in another embodiment, R X2 is C 1-6 alkyl; in another embodiment, R X2 is C 1-6 haloalkyl.

[0148] In one embodiment, R X3 is H; in another embodiment, R X3 is halogen, for example F; in another embodiment, RX3 -CN; in another specific embodiment, R X3 -OR a , for example -OH; in another specific embodiment, R X3 -NR b R c , for example -NH2; in another specific embodiment, R X3 C 1-6 alkyl; in another specific embodiment, R X3 C 1-6 haloalkyl.

[0149] In one specific embodiment, R X4 is H; in another specific embodiment, R X4 is halogen, for example F; in another specific embodiment, R X4 -CN; in another specific embodiment, R X4 -OR a , for example -OH; in another specific embodiment, R X4 -NR b R c , for example -NH2; in another specific embodiment, R X4 C 1-6 alkyl; in another specific embodiment, R X4 C 1-6 haloalkyl.

[0150] R1and R2

[0151] In one specific embodiment, R1is H; in another specific embodiment, R1is D; in another specific embodiment, R1is halogen; in another specific embodiment, R1is -CN; in another specific embodiment, R1is -OR a , for example -OH; in another specific embodiment, R1is -NR b R c , for example -NH2; in another specific embodiment, R1is C 1-6 alkyl; in another specific embodiment, R1is C 1-6 haloalkyl; in another specific embodiment, R1is C 3-7 cycloalkyl; in another specific embodiment, R1is 3-7 membered heterocyclyl; in another specific embodiment, R1is C 6-10 aryl; in another specific embodiment, R1is 5-10 membered heteroaryl.

[0152] In one embodiment, R2is H; in another embodiment, R2is D; in another embodiment, R2is halogen; in another embodiment, R2is -CN; in another embodiment, R2is -OR a , for example -OH; in another embodiment, R2is -NR b R c , for example -NH2; in another embodiment, R2is C 1-6 alkyl; in another embodiment, R2is C 1-6 haloalkyl; in another embodiment, R2is C 3-7 cycloalkyl; in another embodiment, R2is 3-7 membered heterocyclyl; in another embodiment, R2is C 6-10 aryl; in another embodiment, R2is 5-10 membered heteroaryl.

[0153] In one embodiment, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-10 cycloalkylidene; in another embodiment, R1and R2are joined together with the carbon atom to which they are attached to form a 3-10 membered heterocyclylidene; in another embodiment, R1and R2are joined together with the carbon atom to which they are attached to form a C 6-10 arylidene; in another embodiment, R1and R2are joined together with the carbon atom to which they are attached to form a 5-10 membered heteroarylidene; in another embodiment, the foregoing C 3- 10 cycloalkylidene, 3-10 membered heterocyclylidene, C 6-10 arylidene and 5-10 membered heteroarylidene is optionally substituted with oxo or thioxo.

[0154] In one embodiment, R1and R2are independently H, halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl.

[0155] In one embodiment, R1and R2are independently H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

[0156] In one embodiment, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylidene, or 3-7 membered heterocyclylidene, preferably C 3-5 cycloalkylidene, or 3-5 membered heterocyclylidene.

[0157] R3

[0158] In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is -OR, e.g., -OH; in another embodiment, R3 is -SR, e.g., -SH; in another embodiment, R3 is -NR'R", e.g., -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, or -N(C 1-6 alkyl)2; in another embodiment, R3 is -C 1-6 alkylene-R5; in another embodiment, R3 is -O-C 1-6 alkylene-R5; in another embodiment, R3 is -NH-C 1-6 alkylene-R5; in another embodiment, R3 is C 1-6 alkyl; in another embodiment, R3 is C 2-6 alkenyl; in another embodiment, R3 is C 1-6 haloalkyl; in another embodiment, R3 is C 3- 10 cycloalkyl; in another embodiment, R3 is 3-10 membered heterocyclyl; in another embodiment, R3 is C 6-10 aryl; in another embodiment, R3 is 5-10 membered heteroaryl.

[0159] In one embodiment, R3 forms a fused ring with ring A; in another embodiment, R3 forms a C 5-12 cycloalkyl; in another embodiment, R3 forms a 5-12 membered heterocyclyl with ring A; in another embodiment, R3 forms a C 6-12 aryl; in another embodiment, R3 forms a 5-12 membered heteroaryl with ring A; in another embodiment, the foregoing fused ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 R5 groups.

[0160] In one embodiment, R3 is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 2- 6alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups;

[0161] R3is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1- 6deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups.

[0162] In one embodiment, R3is -NH2, -NH(C 1-6 alkyl), -NH(C 1-6 haloalkyl), N(C 1-6 alkyl)2, -NH-C 1- 4alkylene-R5, C 1-4 alkyl, C 2-4 alkenyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl; in another embodiment, R3is selected from -NH2, -NH(C 1-6 alkyl), -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1- 6deuteroalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; in another specific embodiment, R3 is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3 being optionally substituted with 1, 2, or 3 R5 groups; in another specific embodiment, R3 is C 3-7 cycloalkyl or 4-7 membered heterocyclyl.

[0163] In one specific embodiment, the R3 is unsubstituted; in another specific embodiment, the R3 is substituted with 1, 2, 3, 4, or 5 R5 groups.

[0164] In a more specific embodiment, R3 is H, CH3, -CH=CH2, -NH2, -NHCH3, -NHCH2CH3, -NHCF3, -NH-(CH2)2-OH, -(CH2)2-OH,

[0165] In a more specific embodiment, R3 is selected from CH3, -CH=CH2, -NH2, -NHCH3, -NHCD3, -NHCH2CH3, -NHCF3, -NH-(CH2)2-OH, -(CH2)2-OH,

[0166] In one specific embodiment, R3 and Ring A are joined to form a fused ring, for example

[0167] R4

[0168] In one specific embodiment, R4 is H; in another specific embodiment, R4 is C 1-6 alkyl; in another specific embodiment, R4 is C 1-6 haloalkyl; in another specific embodiment, R4 is C 3-7 cycloalkyl, for example C 5-6 cycloalkyl; in another specific embodiment, R4 is 4-7 membered heterocyclyl, for example 5-6 membered heterocyclyl; in another specific embodiment, R4 is C 6-10 aryl; in another specific embodiment, R4 is 5-10 membered heteroaryl.

[0169] In a more specific embodiment, R4is selected from preferably

[0170] In a specific embodiment, R4is unsubstituted; in another specific embodiment, R4is substituted with 1, 2, 3, 4, or 5 R6groups.

[0171] R5

[0172] In a specific embodiment, R5is H; in another specific embodiment, R5is D; in another specific embodiment, R5is halo; in another specific embodiment, R5is -C 0-6 alkylene-OR a , for example -OR a , and also -OH; in another specific embodiment, R5is -C 0-6 alkylene-NR b R c , for example -NR b R c , and also -NH2; in another specific embodiment, R5is CN; in another specific embodiment, R5is C 1-6 alkyl; in another specific embodiment, R5is C 1-6 haloalkyl; in another specific embodiment, two R5on the same atom together form an oxo or thioxo.

[0173] In a specific embodiment, R5is selected from H, halo, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, or C 1-6 haloalkyl, or two R5on the same atom together form an oxo or thioxo; in another specific embodiment, R5is selected from H, -NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, or C 1-4 alkyl, or two R5on the same atom together form an oxo or thioxo; in another specific embodiment, R5is selected from H, halo, OH, C 1-6 alkyl, or C 1-6 haloalkyl.

[0174] In a more particular embodiment, R5is H; in another more particular embodiment, R5is NH2; in another more particular embodiment, R5is NHCH3; in another more particular embodiment, R5is N(CH3)2; in another more particular embodiment, R5is CH3; in another more particular embodiment, two R5on the same sulfur atom form a -S(O)2- structure; in another more particular embodiment, two R5on the same carbon atom form a -C(O)- structure.

[0175] R6

[0176] In a particular embodiment, R6is H; in another more particular embodiment, R6is D; in another more particular embodiment, R6is halogen; in another particular embodiment, R6is -C 0-6 alkylene-OR a , for example -OR a , and also -OH; in another particular embodiment, R6is -C 0-6 alkylene-NR b R c , for example -NR b R c , and also -NH2; in another particular embodiment, R6is CN; in another particular embodiment, R6is C 1-6 alkyl; in another particular embodiment, R6is C 1-6 haloalkyl.

[0177] In a particular embodiment, R6is H; in another particular embodiment, R6is OH; in another particular embodiment, R6is NH2; in another particular embodiment, R6is CN; in another particular embodiment, R6is C 1-6 alkyl, for example CH3; in another particular embodiment, R6is C 1-6 haloalkyl.

[0178] m

[0179] In a particular embodiment, m is 0, 1 or 2.

[0180] R, R' and R"

[0181] In a particular embodiment, R is H; in another particular embodiment, R is D; in another particular embodiment, R is halogen; in another particular embodiment, R is CN; in another particular embodiment, R is C 1-6 alkyl; in another particular embodiment, R is C 1-6 haloalkyl; in another particular embodiment, R is C1-6 deuteroalkyl, e.g., CD3; in another specific embodiment, R is -C 0-6 alkylene-OR a , e.g., -OR a , e.g., -OH; in another specific embodiment, R is -C 0-6 alkylene-NR a R b , e.g., -NR b R c , e.g., -NH2.

[0182] In one specific embodiment, R' is H; in another specific embodiment, R' is D; in another specific embodiment, R' is halogen; in another specific embodiment, R' is CN; in another specific embodiment, R' is C 1-6 alkyl; in another specific embodiment, R' is C 1-6 haloalkyl; in another specific embodiment, R' is C 1-6 deuteroalkyl, e.g., CD3; in another specific embodiment, R' is -C 0-6 alkylene-OR a , e.g., -OR a , e.g., -OH; in another specific embodiment, R' is -C 0-6 alkylene-NR a R b , e.g., -NR b R c , e.g., -NH2.

[0183] In one specific embodiment, R" is H; in another specific embodiment, R" is D; in another specific embodiment, R" is halogen; in another specific embodiment, R" is CN; in another specific embodiment, R" is C 1-6 alkyl; in another specific embodiment, R" is C 1-6 haloalkyl; in another specific embodiment, R" is C 1-6 deuteroalkyl, e.g., CD3; in another specific embodiment, R" is -C 0-6 alkylene-OR a , e.g., -OR a , e.g., -OH; in another specific embodiment, R" is -C 0-6 alkylene-NR a R b , e.g., -NR b R c , e.g., -NH2.

[0184] In one embodiment, R, R' and R" are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl, for example H, CH3, CF3or -CH2CH3.

[0185] R

[0186] In one embodiment, R# is H; in another embodiment, R# is D; in another embodiment, R# is halogen; in another embodiment, R# is OH; in another embodiment, R# is NH2; in another embodiment, R# is CN; in another embodiment, R# is C 1-6 alkyl; in another embodiment, R# is C 2-6 alkenyl; in another embodiment, R# is C 2-6 alkynyl; in another embodiment, R# is C 1-6 haloalkyl.

[0187] In one embodiment, R# is selected from H, halogen, OH or C 1-6 alkyl, for example F, OH or CH3.

[0188] R a , R b and R c

[0189] In one embodiment, R a is H; in another embodiment, R a is halogen; in another embodiment, R a is -C 0-6 alkylene-OH, for example -OH; in another embodiment, R a is -C 0-6 alkylene-NH2, for example -NH2; in another embodiment, R a is -C 0-6 alkylene-CN, for example -CN; in another embodiment, R a is C 1-6 alkyl; in another embodiment, R a is C 2-6 alkenyl; in another embodiment, R a is C 2-6 alkynyl; in another embodiment, R a is C 1-6 haloalkyl; in another embodiment, R a is -C 0-6 alkylene-C3-7 cycloalkyl, for example C 3-7 cycloalkyl; in another specific embodiment, R a is -C 0-6 alkylene-3-7 membered heterocyclyl, for example 3-7 membered heterocyclyl; in another specific embodiment, R a is -C 0-6 alkylene-C 6-10 aryl, for example C 6-10 aryl; in another specific embodiment, R a is -C 0-6 alkylene-5-10 membered heteroaryl, for example 5-10 membered heteroaryl; in another specific embodiment, R b , R c together with the N atom form a 3-7 membered heterocyclyl.

[0190] each of the above groups can be optionally substituted with one or more deuterium atoms, up to per-deuteration.

[0191] Any of the technical solutions in any of the above specific embodiments or any combination thereof can be combined with any of the technical solutions in other specific embodiments or any combination thereof. For example, any of the technical solutions of ring A or any combination thereof can be combined with any of the technical solutions of L1, L2, ring B, ring C, X1-X4, R1-R6, R, R’, R”, R a , R b , R c , R#and m or any combination thereof. The present application is intended to include all combinations of these technical solutions, which are not listed one by one due to the length.

[0192] In more specific embodiments, the present application provides the above-mentioned compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein L1is -NH-C 0-6 alkyl-, for example -NH- or -NHCH2-, preferably -NH-.

[0193] In more specific embodiments, the present application provides the above-mentioned compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-, preferably a chemical bond, -C(O)- or -S(O)m m is selected from 0, 1 or 2.

[0194] In more particular embodiments, the present application provides the above-mentioned compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, wherein R1and R2are independently selected from H, halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;

[0195] or R1and R2are linked together with the carbon atom to which they are attached to form a C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0196] Preferably,

[0197] R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0198] or R1and R2are linked together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene or 3-7 membered heterocyclylene, preferably C 3-5 cycloalkylene or 3-5 membered heterocyclylene.

[0199] In more particular embodiments, the present application provides the above-mentioned compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, wherein R4is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted by 1, 2 or 3 R6groups;

[0200] Preferably, R4is selected from C 1-6 alkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups;

[0201] More preferably, R4is selected from preferably

[0202] In more particular embodiments, the present application provides a compound of Formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein,

[0203] L1is selected from -O-C 0-6 alkyl- or -NH-C 0-6 alkyl-;

[0204] L2is selected from a bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-;

[0205] Ring A is selected from C 3-10 cycloalkylene, 3-10 membered heterocyclyl ene, C 6-10 arylene or 5-10 membered heteroarylene;

[0206] said Ring A is optionally substituted with 1, 2, 3, 4, or 5 R#;

[0207] R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0208] or, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene, 3-7 membered heterocyclyl ene, C 6-10 arylene or 5-10 membered heteroarylene, wherein said C 3-7 cycloalkylene, 3-7 membered heterocyclyl ene, C 6-10 arylene and 5-10 membered heteroarylene is optionally substituted with oxo or thioxo;

[0209] R3is selected from -OR, -NR’R”, -C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said group is optionally substituted with 1, 2, 3, 4, or 5 R5groups;

[0210] or R3and ring A form a fused ring, for example selected from C 5-12 cycloalkyl, 5-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said fused ring optionally substituted with 1, 2, or 3 R5groups;

[0211] R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally substituted with 1, 2, 3, 4, or 5 R6groups;

[0212] each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo;

[0213] each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0214] m is selected from 0, 1, or 2;

[0215] R, R’ and R” are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, -C 0-6 alkylene-OR a , or -C 0-6 alkylene-NR a R b , preferably from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , or -C 0-6 alkylene-NR a R b ;

[0216] each R# is independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl;

[0217] R a , R b and R c are independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl.

[0218] In more specific embodiments, the present application provides a compound of Formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein,

[0219] L1is selected from -NH- or -NH-C 1-6 alkyl-;

[0220] L2is selected from a bond, -O-, -NH-, -C(O)-, or -S(O)2-;

[0221] Ring A is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylidenyl, C 6-10 arylenyl, or 5-7 membered heteroarylenyl, preferably C 5-6 cycloalkylene, 5-6 membered heterocyclylenyl, phenylenyl, or 5-6 membered heteroarylenyl;

[0222] said Ring A is optionally substituted with 1, 2, or 3 R#;

[0223] R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0224] or, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene, 3-7 membered heterocyclylenyl, C 6-10 arylenyl, or 5-10 membered heteroarylenyl;

[0225] R3is selected from -NR’R”, -C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, 3-7 membered heterocyclyl, or 5-10 membered heteroaryl, said R3is optionally substituted with 1, 2, 3, or 4 R5groups;

[0226] or R3and ring A are connected to form a fused ring, for example selected from C 6-12 aryl or 5-12 membered heteroaryl, said fused ring optionally substituted with 1, 2, or 3 R5groups;

[0227] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4optionally substituted with 1, 2, or 3 R6groups;

[0228] each R5is independently selected from H, halo, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo;

[0229] each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH, or C 1-6 alkyl, for example OH or CH3;

[0230] each R# is independently selected from H, halo, OH, or C 1-6 alkyl, for example F, OH, or CH3;

[0231] R, R’ and R” are independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl, preferably selected from H, halo, C 1-6 alkyl or C 1-6 haloalkyl, for example H, CH3, CF3, CD3, or -CH2CH3, further for example H, CH3, CF3, or -CH2CH3.

[0232] In more specific embodiments, the present application provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein,

[0233] L1is selected from -NH- or -NH-CH2-;

[0234] L2is selected from a bond, -C(O)-, or -S(O)2-;

[0235] ring A is selected from preferably selected from

[0236] R1and R2are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0237] or R1and R2are joined together with the carbon atom to which they are attached to form a C 3-5 cycloalkylene or 3-5 membered heterocyclyl ene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0238] R3is selected from CH3, -CH=CH2, -NH2, -NHCH3, -NHCD3, -NHCH2CH3, -NHCF3, -NH-(CH2)2-OH, -(CH2)2-OH, preferably selected from CH3, -CH=CH2, -NH2, -NHCH3, -NHCH2CH3, -NHCF3, -NH-(CH2)2-OH, -(CH2)2-OH,

[0239] or R3and ring A are joined to form a fused ring, for example

[0240] R4is selected from preferably

[0241] In more specific embodiments, the present application provides the above-mentioned compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (II):

[0242] wherein,

[0243] X1is selected from CR X1 or N;

[0244] R X1 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0245] R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C1-6 alkyl or C 1-6 haloalkyl;

[0246] or R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0247] R3is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3being optionally substituted with 1, 2, 3, 4 or 5 R5groups;

[0248] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted with 1, 2, 3, 4 or 5 R6groups;

[0249] each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo;

[0250] each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0251] R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0252] Preferably,

[0253] X1is selected from CR X1 or N;

[0254] R X1 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0255] R1and R2are independently selected from H, halo, C 1-6 alkyl or C 1-6 haloalkyl;

[0256] Alternatively, R1and R2are joined together to form, together with the carbon atom to which they are attached, a C 3-7 cycloalkylene or 3-7 membered heterocyclyl ene;

[0257] R3is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3being optionally substituted by 1, 2 or 3 R5groups;

[0258] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted by 1, 2 or 3 R6groups;

[0259] each R5is independently selected from H, halo, OH, CN, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo;

[0260] each R6is independently selected from H, halo, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl;

[0261] More preferably;

[0262] X1is selected from CR X1 or N, preferably CH or N;

[0263] R X1 is selected from H, halo or C 1-4 alkyl, preferably H;

[0264] R1and R2are independently selected from H or C 1-4 alkyl;

[0265] Alternatively, R1and R2are joined together to form, together with the carbon atom to which they are attached, a C 3-5 cycloalkylene or 3-5 membered heterocyclyl ene, for example, cyclopropyl ene, cyclobutyl ene or cyclopentyl ene;

[0266] R3is selected from C 3-7cycloalkyl or 4-7 membered heterocyclyl, said R3being optionally substituted with 1, 2, or 3 R5groups;

[0267] For example, R3is selected from

[0268] R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4being optionally substituted with 1, 2, or 3 R6groups;

[0269] For example, R4is selected from Preferably,

[0270] each R5is independently selected from H, -NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2or C 1-4 alkyl; or two R5on the same carbon atom together form oxo or thioxo;

[0271] each R6is independently selected from H, OH or C 1-4 alkyl, preferably H, OH or CH3.

[0272] In more specific embodiments, the present application provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (II-1) or (II-2):

[0273] wherein,

[0274] R1, R2, R3, R4and X1are as defined herein;

[0275] Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0276] Preferably,

[0277] Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0278] More preferably,

[0279] Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

[0280] In more particular embodiments, the present application provides a compound of the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (III), (III-1) or (III-2):

[0281] wherein,

[0282] X1is selected from CR X1 or N;

[0283] X2is selected from CR X2 or N;

[0284] X3is selected from CR X3 or N;

[0285] R X1 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0286] R X2 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0287] R X3 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0288] L2is selected from a bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-, m is selected from 0, 1 or 2, preferably L2is not a bond;

[0289] R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0290] or R1and R2are linked, together with the carbon atom to which they are attached, to form a C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0291] R3is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1- 6deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups;

[0292] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4is optionally substituted with 1, 2, or 3 R6groups;

[0293] each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo;

[0294] each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0295] R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0296] Preferably,

[0297] X1is selected from CR X1 or N, preferably N, CF or CH;

[0298] X2is selected from CR X2 or N, preferably CR X2 ;

[0299] X3is selected from CR X3 or N, preferably CR X3 ;

[0300] R X1 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0301] R X2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0302] R X3 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0303] L2is selected from a bond, -O-, -NH-, -C(O)- or -S(O)2-, preferably L2is not a bond;

[0304] R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0305] or R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0306] R3is selected from -NH2, -NH(C 1-6 alkyl), -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from -NH2, -NH(C 1-6 alkyl), -NHC 1-6 haloalkyl, N(C 1-6 alkyl)2, -N(C 1- 6haloalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, -NH-C 1-4 alkylene-OH, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups;

[0307] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4is optionally substituted with 1, 2, or 3 R6groups;

[0308] each R5is independently selected from H, halogen, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo;

[0309] each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH, or C 1-6 alkyl;

[0310] More preferably,

[0311] X1is selected from CR X1 or N, preferably N, CH or CF, more preferably CH or CF;

[0312] X2is selected from CR X2 or N, preferably CR X2 , for example CH;

[0313] X3is selected from CR X3 or N, preferably CR X3 , for example CH;

[0314] R X1 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F;

[0315] R X2 is selected from H, halogen or C 1-4 alkyl, preferably H;

[0316] R X3 is selected from H, halogen or C 1-4 alkyl, preferably H;

[0317] L2is selected from a bond, -C(O)- or -S(O)2-, preferably -C(O)- or -S(O)2-;

[0318] R1and R2are independently selected from H or C 1-4 alkyl;

[0319] Alternatively, R1and R2are linked together with the carbon atom to which they are attached to form a C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0320] R3is selected from -NH2, -NH(C 1-6 alkyl), -NH(C 1-4 haloalkyl), N(C 1-4 alkyl)2, -NHC 1-4 deuteroalkyl, -N(C 1-4 deuteroalkyl)2, -NH-C 1-4 alkylene-R5, C 1-4 alkyl, C 2-4 alkenyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably selected from -NH2, -NH(C 1-4 alkyl), -NH(C 1-4 haloalkyl), N(C 1-4alkyl)2, -NH-C 1-4 alkylene-R5, C 1-4 alkyl, C 2-4 alkenyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl; said R3is optionally substituted with 1, 2, or 3 R5groups;

[0321] R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably C 3-7 cycloalkyl, said R4is optionally substituted with 1, 2, or 3 R6groups;

[0322] each R5is independently selected from H, halogen, OH, -NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2or C 1-4 alkyl; or two R5on the same atom together form an oxo or thioxo;

[0323] each R6is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3;

[0324] More preferably,

[0325] R3is selected from -NH2, -NHCH3, -NH-CF3, -NHCD3, -CH=CH2, -NH-CH2CH2OH, preferably selected from -NH2, -NHCH3, NH-CF3, -CH=CH2, -NH-CH2CH2OH,

[0326] R4is selected from preferably is

[0327] In more specific embodiments, the present application provides the above-mentioned compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (IV), (IV-1), or (IV-2):

[0328] wherein,

[0329] X1is selected from CR X1 or N, preferably N, CH, or CF;

[0330] R X1 is selected from H, halogen, C 1-4alkyl or C 1-4 haloalkyl, preferably H or F;

[0331] ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0332] R3is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2 or 3 R5groups;

[0333] each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo;

[0334] R1, R2, R4, R a , R b and R c are as defined herein;

[0335] Preferably,

[0336] X1is selected from CR X1 or N, preferably N or CH, more preferably CH;

[0337] R X1 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F;

[0338] ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0339] R3is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2 or 3 R5groups;

[0340] each R5is independently selected from H, halogen, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl;

[0341] R1, R2and R4are as defined herein;

[0342] More preferably,

[0343] X1is N or CH, more preferably CH;

[0344] Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0345] R3is selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl (preferably 5-7 membered heterocyclyl, more preferably 5 membered heterocyclyl or 7 membered heterocyclyl); said R3is optionally substituted with 1, 2 or 3 R5groups;

[0346] each R5is independently selected from H, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl, for example, H, NH2, NHCH3, N(CH3)2or CH3;

[0347] for example, R3is selected from

[0348] R1, R2and R4are as defined herein.

[0349] In more particular embodiments, the present application provides a compound of the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (V), (V-1) or (V-2):

[0350] wherein,

[0351] X1is selected from CR X1 or N, preferably N or CH, more preferably CH;

[0352] R X1 is selected from H, halo, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F;

[0353] Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0354] R3is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C1-6 haloalkyl)2, -NHC 1- 6deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1- alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; said R3is optionally substituted with 1, 2 or 3 R5groups;

[0355] each R5is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl;

[0356] R1, R2and R4are as defined herein;

[0357] preferably,

[0358] X1is selected from CR X1 or N, preferably N, CH or CF;

[0359] R X1 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F;

[0360] Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0361] R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C1-6 alkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 alkyl)2, -NHC 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl, preferably selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl; said R3is optionally substituted with 1, 2 or 3 R5groups;

[0362] each R5is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl;

[0363] R1, R2and R4are as defined herein;

[0364] more preferably,

[0365] X1is N, CH or CF, more preferably CH or CF;

[0366] ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0367] R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 alkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl, preferably selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl, more preferably -NH2, -NHC 1-6 alkyl, -NH-C 1-6 alkylene-OH or 5-7 membered heterocyclyl; said R3is optionally substituted with 1, 2 or 3 R5groups;

[0368] For example, R3is selected from -CH=CH2, -NH2, -NHCH3, NH-CF3, -NHCD3, -NH-CH2CH2OH or More preferably, R3is -CH=CH2, NH2, -NHCH3, -NH-CH2CH2OH or

[0369] each R5is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl;

[0370] R1, R2and R4are as defined herein.

[0371] In more specific embodiments, the present application provides a compound of the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of the formula (VI):

[0372] wherein,

[0373] X1is selected from CR X1 or N;

[0374] X4is selected from CR X4 or N;

[0375] R X1 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0376] R X4 is selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0377] Ring C is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said Ring C being optionally substituted with 1, 2, 3, 4 or 5 R5groups;

[0378] R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c, C 1-6 alkyl or C 1-6 haloalkyl;

[0379] or, R1and R2are joined, together with the carbon atom to which they are attached, to form a C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0380] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted with 1, 2, or 3 R6groups;

[0381] each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo;

[0382] each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0383] R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0384] Preferably,

[0385] X1is selected from CR X1 or N;

[0386] X4is selected from CR X4 or N;

[0387] R X1 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0388] R X4 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0389] ring C is selected from C3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3 or 4 R5groups;

[0390] R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0391] or R1and R2are linked together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3 or 4 R5groups;

[0392] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted with 1, 2 or 3 R6groups;

[0393] each R5is independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo (e.g. -S(O)2- structure on the same sulfur atom);

[0394] each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl;

[0395] more preferably,

[0396] X1is selected from CR X1 or N, preferably N, CH or CF;

[0397] X4is selected from CR X4 or N, preferably N, CH or CF;

[0398] R X1 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F;

[0399] R X4 is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F, more preferably H;

[0400] ring C is selected from C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3 or 4 R5groups;

[0401] R1and R2are independently selected from H or C 1-4 alkyl;

[0402] or, R1and R2are joined together with the carbon atom to which they are attached to form a C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0403] R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4being optionally substituted with 1, 2 or 3 R6groups;

[0404] for example, R4is selected from preferably

[0405] each R5is independently selected from H, halogen, OH or C 1-4 alkyl; or two R5on the same atom together form an oxo or thio (e.g., -S(O)2- structure on the same sulfur atom);

[0406] each R6is independently selected from H, OH or C 1-4 alkyl, preferably H, OH or CH3;

[0407] more preferably,

[0408] ring C together with the ring on which X1, X4is located forms the following structure: preferably the following structure: more preferably the following structure:

[0409] In more specific embodiments, the present application provides the above-mentioned compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (VI-1), (VI-2) or (VI-3):

[0410] wherein,

[0411] X1, X4, ring C, R1, R2and R4are as defined herein;

[0412] ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0413] Preferably,

[0414] Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0415] More preferably,

[0416] Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

[0417] In more specific embodiments, the present application provides a compound of the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of the formula (VII):

[0418] wherein,

[0419] Ring A is selected from C 3-7 cycloalkylene, 4-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, said Ring A being optionally substituted with 1, 2 or 3 R#;

[0420] each R# is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl;

[0421] L2 is selected from a bond, -O-, -C(O)- or -S(O) m m is selected from 0, 1 or 2;

[0422] R1 and R2 are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

[0423] or, R1 and R2 are linked together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0424] R3 is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -C 1-6 alkylene-R5, C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3is optionally substituted with 1, 2, 3, 4, or 5 R5groups;

[0425] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4is optionally substituted with 1, 2, 3, 4, or 5 R6groups;

[0426] each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0427] each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0428] R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0429] m is selected from 0, 1, or 2;

[0430] Preferably,

[0431] Ring A is selected from C 3-7 cycloalkylene or 4-7 membered heterocyclylene, said Ring A is optionally substituted with 1, 2, or 3 R#;

[0432] each R#is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl;

[0433] L2is selected from a bond, -C(O)-, or -S(O)2-;

[0434] R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0435] or R1and R2are linked together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene or 3-7 membered heterocyclylene;

[0436] R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from -C 1-6 alkylene-R5, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5;

[0437] R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4is optionally substituted with 1, 2, or 3 R6groups;

[0438] each R5is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl;

[0439] each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH, or C 1-6 alkyl;

[0440] More preferably,

[0441] Ring A is selected from C 5-6 cycloalkylene or 5-6 membered heterocyclylene, said Ring A is optionally substituted with 1, 2, or 3 R#;

[0442] each R#is independently selected from H, OH, or C 1-4 alkyl, for example H, OH, or CH3, preferably H;

[0443] L2is selected from a bond or -S(O)2-;

[0444] R1and R2are independently selected from H or C 1-4 alkyl;

[0445] or R1and R2are linked together with the carbon atom to which they are attached to form a C 3-5cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene;

[0446] R3is selected from -NH2, -NHC 1-4 alkyl, -C 1-4 alkylene-R5, C 1-4 alkyl or 5-6 membered heteroaryl, preferably selected from -C 1-4 alkylene-R5or 5-6 membered heteroaryl, said R3being optionally substituted with 1 or 2 R5;

[0447] R4is selected from C 1-4 alkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, said R4being optionally substituted with 1, 2 or 3 R6groups;

[0448] each R5is independently selected from H, OH or C 1-4 alkyl, preferably H, OH or CH3;

[0449] each R6is independently selected from H, OH or C 1-4 alkyl, preferably H, OH or CH3;

[0450] More preferably,

[0451] is selected from is preferably More preferably,

[0452] R4is selected from is preferably

[0453] In more specific embodiments, the present application provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein the compound is of formula (VII-1), (VII-2) or (VII-3):

[0454] wherein,

[0455] Ring A, L2, R3and R4are as defined herein;

[0456] Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene;

[0457] Preferably,

[0458] Ring B is selected from C 3-7cycloalkylene or 3-7 membered heterocyclylidene;

[0459] More preferably,

[0460] Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylidene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

[0461] The compounds of the present application can include one or more asymmetric centers and can thus occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present application can be individual enantiomers, diastereomers or geometric isomers (such as cis- and trans-isomers), or can be mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0462] Those skilled in the art will appreciate that organic compounds can form complexes with solvents, often in the form of a hydrate, in which the solvent or water is incorporated in the crystalline solvent as a structural component of the compound. These complexes are in essence true solvates and are obtained when required amounts of solvent (e.g. water) are crystallized with the compound. The present application encompasses all solvates of the compounds of the present application.

[0463] The term "solvate" refers to a form of a compound or salt thereof in combination with a solvent, usually formed by solvolysis. This physical association can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include chemical in stoichiometric and non-stoichiometric solvates. In some cases the solvate will be capable of isolation, for example, where a covalent bond is formed between the solvent and the compound as occurs, for example, in a hemiketal or a hemiacetal. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0464] The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules to the number of molecules of the compound in a hydrate of the compound is defined. Thus, a hydrate of a compound can be represented, for example, by the general formula R-x H2O, where R is the compound, and x is a number greater than 0. A given compound can form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0465] The compounds of the present application can be in the form of an amorphous or crystalline form (polymorph). Furthermore, the compounds of the present application can exist in one or more crystalline forms. Accordingly, the present application includes within its scope all amorphous or crystalline forms of the compounds of the present application. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, the rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate over another. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0466] The present application also includes isotopically-labeled compounds (isotopic variants) which are identical to those recited by Formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be suitably substituted into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application includes within its scope prodrugs of the compounds of the present application, as well as the pharmaceutically acceptable salts of said compounds or of said prodrugs. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are incorporated can be used in the preparation of pharmaceuticals and / or in assays. Tritiated, i.e., 3 H, and carbon-14, i.e.,14 C isotopes are particularly preferred because of ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e. 2 H, can afford greater metabolic stability, often desirably leading to improved pharmacological properties such as increased half-life or reduced dosage requirements. Isotopically labeled compounds of formula (I) of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and

[0467] In addition, prodrugs are also encompassed by the present application. The term "prodrug" as used herein denotes a compound which is converted into its active form, the compound having the medical effects, by the action of the enzyme's in the body, for example hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each incorporated herein by reference.

[0468] The present application also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient therefor. All such forms are within the scope of the present application.

[0469] Preferred compounds of the present application include, but are not limited to, the compounds listed below, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:

[0470] Pharmaceutical compositions and kits

[0471] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0472] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0473] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0474] Treatment methods and uses

[0475] The compounds of the present invention can inhibit CDK2 and are therefore used to treat diseases in which the underlying pathology is wholly or partially mediated by CDK2. Compounds of formula (I) or any of the formulas described herein, or compounds as described in any of the claims and herein, or salts thereof, can be used to inhibit the growth of abnormal cancerous tumors having activated CDK2 kinase activity. These cancerous tumors include, but are not limited to, diseases (e.g., cancers) characterized by amplification or overexpression of CCNE1, such as ovarian cancer, uterine sarcoma, and breast cancer, and diseases characterized by p27 inactivation, such as breast cancer and melanoma. Therefore, in some embodiments of these methods, the patient has previously been identified as having amplification of the cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than the control CCNE1 expression level in biological samples obtained from human subjects.

[0476] The present application provides a method for treating a disease in a subject comprising administering to the subject an effective amount of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein.

[0477] The present application also provides the use of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a disease in a subject.

[0478] The present application also provides a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein for use in treating a disease in a subject.

[0479] In one embodiment, the disease is a CDK2-mediated disease. In one embodiment, the disease is cancer.

[0480] The present application provides a method for inhibiting CDK2 in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein.

[0481] The present application also provides the use of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a CDK2-mediated disease in a subject.

[0482] The present application also provides a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein for use in treating a CDK2-mediated disease in a subject.

[0483] In one embodiment, the CDK2-mediated disease is cancer.

[0484] The present application provides a method for treating cancer in a subject comprising administering to the subject an effective amount of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein.

[0485] The present application also provides the use of a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating cancer in a subject.

[0486] The present application also provides a compound of Formula (I) disclosed herein or a pharmaceutical composition disclosed herein for use in treating cancer in a subject.

[0487] A subject in need of inhibiting CDK2 is a subject having a disease for which a beneficial therapeutic effect can be achieved by inhibiting CDK2, such as slowing progression of the disease, alleviating one or more symptoms associated with the disease, or extending the life of the subject according to the disease.

[0488] In some embodiments, the present application provides a method of treating a disease associated with or modulated by CDK2, wherein inhibition of CDK2 has a therapeutic benefit, including but not limited to treating cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0489] In one embodiment, the foregoing disease, CDK2-mediated disease, or cancer is selected from a cancer associated with myc amplification and / or overexpression.

[0490] In one embodiment, the foregoing disease, CDK2-mediated disease, or cancer is selected from a cancer associated with amplification of the cyclin El (CCNE1) gene and / or overexpression of CCNE1.

[0491] CCNE1 is a cell cycle factor essential for controlling the cell cycle at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 functions as a regulatory subunit of CDK2, interacting with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity to the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin El (“CCNE1”) gene (GenBank Accession No. NM_001238). The amino acid sequence of human CCNE1 is found at GenBank Accession No. NP_001229 / UniProtKB Accession No. P24864).

[0492] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar et al., Proc Natl Acad Sci USA 106(31): 12968-12973), K-Ras mutant lung cancer (see Hu, S. et al., Mol Cancer Ther, 2015. 14(11):2576-85, and cancers with FBW7 mutations and CCNE1 overexpression (see Takada et al., Cancer Res, 2017. 77(18):4881-4893).

[0493] The myc genes belong to the oncogenes that encode nuclear proteins. The three genes encode a nuclear DNA-binding protein that is involved in cell cycle regulation. The myc gene family and its products can promote cell proliferation, immortalization, dedifferentiation and transformation, and play an important role in the formation of various tumors. The myc genes include C-myc, N-myc, and L-myc, which are located on chromosome 8, chromosome 2, and chromosome 1, respectively.

[0494] In one embodiment, the cancer is selected from uterine cancer (including uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including invasive breast carcinoma (BRCA), TNBC (triple negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), ER+ HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2 low breast cancer (human epidermal growth factor 2 low breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV)), gastric cancer (including stomach adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), biliary tract cancer, adrenocortical carcinoma (ACC), or mesothelioma. In some embodiments, the cancer is breast cancer. In one embodiment, the subject has a CCNE1 -amplified advanced / recurrent tumor.

[0495] In one embodiment, the cancer is breast cancer, e.g., HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), or ER+ HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer).

[0496] In one embodiment, the cancer is HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer).

[0497] In one embodiment, the cancer is responsive to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.). The term "responsive" in this context means that the disease, e.g., the progression of the disease, or one or more symptoms of the disease, is either reversed, alleviated, inhibited, or prevented, or that the disease is stabilized, i.e., not further progressed.

[0498] In one embodiment, the cancer (e.g., breast cancer) is resistant to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.).

[0499] In one embodiment, the subject has a cancer (e.g., breast cancer, endometrial cancer, or gastric cancer, etc.) that has progressed after 2 or more lines of therapy, including platinum therapy (using prior platinum therapy, e.g., where the patient has been previously treated with platinum therapy). In one embodiment, the subject has a CCNE1 amplified cancer (e.g., breast cancer, endometrial cancer) that has failed 2 or more lines of therapy, which can include prior platinum therapy.

[0500] In one embodiment, the cancer is selected from a cancer that has progressed after 2 or more lines of therapy, including platinum therapy (using prior platinum therapy, e.g., where the patient has been previously treated with platinum therapy; e.g., breast cancer, endometrial cancer, or gastric cancer, etc.). In one embodiment, the cancer is selected from a CCNE1 amplified cancer (e.g., breast cancer, endometrial cancer) that has failed 2 or more lines of therapy, which can include prior platinum therapy.

[0501] In some embodiments, the cancer is an advanced or metastatic cancer.

[0502] In some embodiments, the breast cancer is a chemotherapy- or radiotherapy- resistant breast cancer, an endocrine-resistant breast cancer, a trastuzumab-resistant breast cancer, or a breast cancer that exhibits primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is an advanced or metastatic breast cancer.

[0503] Primary resistance, also known as de novo resistance, refers to a cancer that has never responded to the therapy and thus progresses. Acquired resistance, also known as secondary resistance, refers to a cancer that eventually progresses despite initially responding to the therapy.

[0504] In one embodiment, the subject has a cancer (e.g., breast cancer) that has progressed despite treatment with a CDK4 / 6 inhibitor, or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.).

[0505] In one embodiment, the subject has ER+HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

[0506] In one embodiment, the subject has cancer (e.g., breast cancer) that has progressed despite treatment with platinum.

[0507] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein has CCNE1 amplification and / or overexpression.

[0508] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein does not have CCNE1 amplification and / or overexpression.

[0509] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein has myc amplification and / or overexpression.

[0510] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein does not have myc amplification and / or overexpression.

[0511] In one embodiment, the cancer to be treated described herein is a CCNE1 or myc amplification and / or overexpression associated cancer, e.g., a refractory or recurrent solid tumor, such as, e.g., hormone refractory prostate cancer, relapsed or refractory non-Hodgkin's lymphoma, relapsed follicular lymphoma, etc.

[0512] In one embodiment, the subject has CCNE1 amplified platinum-resistant or platinum-refractory ovarian cancer.

[0513] The term "platinum-resistant" includes primary platinum-resistant or acquired platinum-resistant, and refers to a patient who has not responded to platinum-based chemotherapy, or if the cancer initially responded to platinum-based chemotherapy, but relapsed some time after the initial treatment.

[0514] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein has CCNE1 amplification and / or overexpression.

[0515] In one embodiment, the cancer (e.g., breast cancer) to be treated described herein does not have CCNE1 amplification and / or overexpression.

[0516] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian or breast cancer characterized by amplification or overexpression of CCNE1.

[0517] In some embodiments, the compounds of the present application can be used to prevent or reduce the risk of developing any of the diseases mentioned herein; for example, to prevent or reduce the risk of developing a disease, condition or disorder in an individual who can be predisposed to the disease, condition or disorder but has not yet experienced or displayed the pathology or symptoms of the disease.

[0518] In some embodiments, the dose administered to a subject can vary depending on the embodiment, the drug used, the method of administration, and the site and subject to be treated. However, the dose should be sufficient to provide a therapeutic response. A clinician can determine the effective amount for administration to a human or other subject to treat a medical condition. The precise amount required can depend on many factors such as the activity of the drug conjugate and the route of administration.

[0519] A compound of Formula (I) or composition described herein can be administered to a mammal in a suitable period of time, either as a single dose or in a series of sub-doses, for example, as needed, daily, semi-weekly, weekly, bi-weekly, semi-monthly, bi-monthly, semi-annually, or annually. Dose units comprising an effective amount of a compound of Formula (I) or composition can be administered as a single daily dose, or the total daily dose can be administered in two, three, four or more divided doses administered daily as needed.

[0520] The appropriate mode of administration can be chosen by a physician. The route of administration can be parenteral administration, for example, administration by injection, nasal administration, pulmonary administration, or transdermal administration. Systemic or local administration can be performed by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection. In some embodiments, a compound of Formula (I) or composition is selected for parenteral delivery, for inhalation, or for delivery through the digestive tract, for example, orally. The dose and method of administration can vary depending on the weight, age, condition, etc. of the subject, and can be appropriately selected.

[0521] In some embodiments, the method further comprises administering a second therapeutic agent to the subject. In some embodiments, a compound of Formula (I) or pharmaceutical composition disclosed herein is used in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, and a small molecule drug. In certain embodiments, a compound of Formula (I) or composition disclosed herein is administered prior to, substantially simultaneously with, or following administration of the second therapeutic agent.

[0522] Examples

[0523] The following examples are provided in order to give a full and enabling disclosure of how the methods and compounds claimed herein are made, prepared, and evaluated, and are intended to merely illustrate the application and not to limit the scope of the application.

[0524] When ring A is selected from C 6-10arylene or 5-10 membered heteroarylene; or, when R3and ring A are joined to form a fused ring, the compounds of the application can be prepared according to the reaction scheme shown in Scheme 1.

[0525] Scheme 1:

[0526] Compounds of Formula I can be prepared according to the general reaction scheme above. First, alcohol (1) undergoes an Appel reaction in the presence of triphenylphosphine, imidazole and iodine to give iodo product (2); then (2) undergoes a cyano substitution reaction in the presence of potassium fluoride and trimethylsilyl cyanide to give intermediate (3); (3) undergoes alcoholysis in the presence of concentrated sulfuric acid to give carboxylic acid dimethyl ester (4); (4) undergoes an Acyloin condensation reaction in the presence of finely dispersed sodium and trimethylsilyl chloride to give (5); (5) undergoes a catalytic reaction in the presence of p-toluenesulfonic acid to give enone intermediate (6); (6) undergoes ring closure with 1-azido-4-nitrobenzene and amine (7) to give triazole intermediate (8); (8) undergoes hydrolysis under acidic conditions to give ketone (9); (9) is reacted with N,N-dimethylformamide dimethyl acetal to give an enamine intermediate, which is then reacted with guanidine hydrochloride to close the pyrimidine ring to give pyrimidine amine compound (10); finally, compound (10) is coupled with side chain (11) (when there is a Boc protecting group in the molecule, the protecting group must be further removed) to give a compound of Formula (I).

[0527] when ring A is C 3-10 when ring A is C

[0528] Scheme 2:

[0529] wherein compound (10) (prepared according to Scheme 1) undergoes a Sandmeyer reaction in the presence of antimony tribromide and tert-butyl nitrite to give bromide (14); compound (14) undergoes a Suzuki coupling reaction with side chain (11) (when there is a Boc protecting group in the molecule, the protecting group must be further removed) to give a compound of Formula (I). N when ring A is C

[0530] Example I-1

[0531] 1): 1,1-bis(iodomethyl)cyclopropane (2)

[0532] To a solution of 1,1-cyclopropanedimethanol 1 (50.0 g, 489.72 mmol) in dichloromethane (500 mL) was added imidazole (80.0 g, 1.17 mol), triphenylphosphine (295.1 g, 1.12 mol) successively at 0 °C. After stirring to dissolve, iodine (298.5 g, 1.17 mol) was added in three portions. After the addition was completed, the reaction was stirred at room temperature for 2 hours. TLC was used to monitor the completion of the reaction. After the reaction was quenched with saturated sodium thiosulfate solution (200 mL), the aqueous phase was extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The obtained residue was purified by flash silica gel column chromatography (petroleum ether) to give the title compound 2 (137.1 g, 425.9 mmol, 87%) as a colorless oily liquid. 1 H NMR (400 MHz, Chloroform-d) δ 3.32 (s, 4H), 1.01 (s, 4H).

[0533] 2) 2,2'-(cyclopropane-1,1-diyl)diacetonitrile (3)

[0534] To a solution of 1,1-bis(iodomethyl)cyclopropane 2 (137.1 g, 425.9 mmol) in N,N-dimethylformamide (500 mL) was added potassium fluoride (123.5 g, 2.13 mol), trimethylsilyl cyanide (126.8 g, 1.28 mol) successively at 0 °C. After the addition was completed, the reaction was stirred at room temperature for 1 hour. The temperature was then increased to 65 °C and the reaction was stirred overnight. TLC was used to monitor the completion of the reaction. After the pH of the aqueous phase was adjusted to >9 by adding saturated sodium bicarbonate solution (500 mL) dropwise, the reaction was stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed successively with saturated brine (200 mL), H2O (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The obtained residue was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound 3 (40.4 g, 336.2 mmol, 79%) as a colorless oily liquid. 1 H NMR (400 MHz, Chloroform-d) δ 2.56 (s, 4H), 0.79 (s, 4H)

[0535] 3) dimethyl 2,2'-(cyclopropane-1,1-diyl)diacetate (4)

[0536] To a solution of 1,1-cyclopropyldicyanide 3 (40.4 g, 336.2 mmol) in methanol (100 mL) was added dropwise a solution of methanol-concentrated sulfuric acid (2.3:1) (600 mL) at 0 °C. After the addition was completed, the reaction was warmed to 65 °C and stirred overnight. The reaction was monitored by TLC. Most of the methanol was removed by concentration under reduced pressure. To the residue was added water (100 mL) dropwise with stirring. After the aqueous phase was adjusted to pH > 9 with aqueous NaOH (4 N), the aqueous phase was extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1) to give the title compound 4 (35.2 g, 189.2 mmol, 56%) as a colorless oily liquid. 1 H NMR (400 MHz, Chloroform-d) δ 3.67 (s, 6H), 2.40 (s, 4H), 0.54 (s, 4H).

[0537] 4): 6-hydroxyspiro[2.4]heptan-5-one (5)

[0538] Sodium sand was prepared by placing sodium (14.8 g, 645.2 mmol) in a reaction flask, adding toluene (140 mL), and replacing with nitrogen three times. The reaction was warmed to 115 °C and stirred vigorously until the reaction liquid became fine sand. Then a solution of dimethyl 2,2'-(cyclopropane-1,1-diyl)diacetate 4 (30.0 g, 161 mmol) in toluene (90 mL) and a solution of trimethylsilyl chloride (70.1 g, 645.2 mmol) in toluene (90 mL) were added successively. After the addition was completed, the reaction was stirred for 2 h. The reaction was monitored by TLC. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure to give a crude product. The crude product was dissolved in dichloromethane (30 mL) and a solution of bromine (20.6 g, 129.0 mmol) in dichloromethane (30 mL) was added dropwise at -78 °C. After the addition was completed, the reaction was stirred for 30 min. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1) to give the title compound 5 (6.0 g, 48.4 mmol, 30%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 6.11 (s, 1H), 5.64 (s, 1H), 2.50 (s, 2H), 0.99-0.95 (m, 2H), 0.94-0.90 (m, 2H).

[0539] 5): 6-ethoxyspiro[2.4]heptan-5-one (6)

[0540] Compound 5 (6.0 g, 48.4 mmol) was dissolved in absolute ethanol (60 mL) at room temperature, and then triethyl orthoformate (10.8 g, 72.6 mmol) and p-toluenesulfonic acid (416.6 mg, 2.41 mmol) were added successively. The reaction was carried out for 30 min, and TLC detection showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the ethanol was removed by concentration. The aqueous phase was extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to obtain compound 6 (6.0 g, 39.5 mmol, 81%) in the form of a brown oily liquid. 1 H NMR (400 MHz, Chloroform-d) δ 5.89 (s, 1H), 3.88 (q, J = 7.0 Hz, 2H), 2.48 (s, 2H), 1.38 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 2.8 Hz, 2H), 0.92 - 0.86 (m, 2H).

[0541] 6) : (1R, 2R)-2-(6-ethoxy-1H-spiro[cyclopenta[d][1,2,3]triazol-4,1'-cyclopropan]-1-yl)-1- methylcyclopentan-1-ol (8a)

[0542] Compound 6 (6.0 g, 39.5 mmol) was dissolved in toluene (90 mL) at room temperature, and then p-nitroazide (9.71 g, 59.2 mmol), (1R, 2R)-2-amino-1-methylcyclopentan-1-ol 7a (4.99 g, 43.4 mmol), 4A molecular sieves (6.0 g), and acetic acid (236.8 mg, 3.94 mmol) were added successively. The reaction was heated to 100°C, and the reaction was carried out for 2 hours. TLC detection showed that the reaction was complete. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to obtain compound 8a (8.52 g, 30.75 mmol, 78%) in the form of a brown oily liquid. 1 H NMR (400 MHz, Chloroform-d) δ 5.03 (s, 1H), 4.84 (t, J = 8.5 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 2.60 (tt, J = 14.1, 6.0 Hz, 1H), 2.50 - 2.38 (m, 1H), 1.94 (dddd, J = 11.6, 9.2, 6.8, 4.0 Hz, 4H), 1.77 (q, J = 4.2 Hz, 2H), 1.48 - 1.38 (m, 5H), 1.00 (s, 3H).

[0543] 7) 1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1H-spiro[cyclopentyl[d][1,2,3]triazole-4,1'- cyclopropan]-6(5H)-one (9a)

[0544] Compound 8a (8.52 g, 30.75 mmol) was dissolved in ethyl acetate (90 mL) at room temperature, 4N HC1 solution (15.4 mL, 61.5 mmol) was added, the reaction was carried out for 2 hours, TLC detection reaction was complete; add sodium carbonate solid to adjust pH to 7-8, and extract the aqueous phase with ethyl acetate (150 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid, which was compound 9a (7.06 g, 28.6 mmol, 93%). 1 H NMR (400 MHz, Chloroform-d) δ 4.85 (t, J = 8.6 Hz, 1H), 3.20 (d, J = 0.9 Hz, 2H), 2.64 - 2.53 (m, 1H), 2.51 - 2.41 (m, 1H), 2.02 - 1.87 (m, 4H), 1.51 - 1.46 (m, 2H), 1.19 - 1.15 (m, 2H), 1.00 (s, 3H).

[0545] 8) (1R,2R)-2-(5'-amino-3'H-spiro[cyclopropane-8'-[1,2,3]triazole[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-3'-yl)-1- methylcyclopentan-1-ol (10a)

[0546] A solution of compound 9a (7.06 g, 28.58 mmol) and N,N-dimethylformamide dimethyl acetal (8.51 g, 71.45 mmol) in N,N-dimethylformamide (50 mL) was reacted at 100 °C for 2 hours, TLC monitoring reaction was complete, the resulting brown oil was concentrated under reduced pressure to obtain the enamine intermediate, which was used directly in the next step without purification.

[0547] The crude product obtained in the previous step was dissolved in anhydrous ethanol (50 mL), guanidine hydrochloride (6.83 g, 71.45 mmol), potassium tert-butoxide (8.01 g, 71.45 mmol) were added in turn, the temperature was raised to 60 °C and reacted for 2 h, TLC monitoring reaction was complete, the reaction was concentrated to remove most of the ethanol, extracted with ethyl acetate (150 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 1:2) to obtain a yellow solid, which was compound 10a (6.39 g, 21.43 mmol, 75%). 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 6.69 (s, 2H), 5.03 (s, 1H), 4.97 (dd, J = 8.6, 6.8 Hz, 1H), 2.63 - 2.55 (m, 1H), 2.42 (dd, J = 8.9, 4.3 Hz, 1H), 2.06 - 1.98 (m, 1H), 1.90 (tt, J = 8.0, 4.2 Hz, 2H), 1.78 (h, J = 2.8, 2.4 Hz, 3H), 1.71 (q, J = 5.2, 4.2 Hz, 2H), 0.87 (s, 3H).

[0548] 9) 4-(4-bromobenzoyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (11a)

[0549] To a suspension of 1,4-diazepane-1-carboxylic acid tert-butyl ester 13a (0.48 g, 2.42 mmol, 1.0 eq) in MeCN (2.5 mL) was added 4-bromobenzoic acid 12a (0.53 g, 2.66 mmol, 1.1 eq), EDCI (0.5 g, 2.66 mmol, 1.1 eq) and HOBt (0.32 g, 0.24 mmol, 0.1 eq) at room temperature, then DIPEA (0.79 mL, 4.84 mmol, 2.0 eq) was added dropwise. After the addition was completed, the reaction mixture was warmed to 50 °C for 4 h. Water (9 mL) was added dropwise at room temperature and stirred for 1 h. The mixture was filtered and the filter cake was washed with water (2 mL). The wet product was dried under reduced pressure for 2 h to give the title compound 11a (0.9 g, 2.35 mmol, 95%) as a yellow solid. LC-MS (ESI), C 17 H 24 BrN2O3[M+H] + : m / z = 383.1.

[0550] 10) 4-(4-((3'-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-3'H-spiro[cyclopropane-8'- [1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)amino)benzoyl)-1,4- diazepane-1-carboxylic acid tert-butyl ester (I-1a)

[0551] To a solution of side chain 11a (191 mg, 0.50 mmol) and 10a (100 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.033 mmol) and potassium carbonate (68 mg, 0.50 mmol) at room temperature. After the addition, the reaction vessel was purged with argon twice and then heated to 100 °C for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (20 mL) and half-saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL) three times. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol = 98:2) to give the title compound 1-1a (132 mg, 0.22 mmol, 68%) as a white solid. 32 H 41 N8O4[M+H] + : m / z = 601.3

[0552] 11): (1,4-diazepan-1-yl)(4-((3'-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-3'H-spiro[cyclopropane-1,8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)amino)phenyl)methanone (1-1)

[0553] To a solution of 1-1a (132 mg, 0.22 mmol) in dichloromethane / methanol (10:1, 4 mL) was added HCl (4 M in EA, 0.55 mL, 2.2 mmol, 10 eq) dropwise at room temperature. After the addition, the reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The aqueous phase was adjusted to pH > 10 with NaOH aqueous solution (4 N), and then extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), H2O (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting yellow solid was the title compound 1-1 (100 mg, 0.20 mmol, 93%). 1H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.38 (s, 1H), 5.04 (t, J = 8.9 Hz, 1H), 3.78 (s, 2H), 3.55 (s, 2H), 3.10 (s, 1H), 3.00 - 2.87 (m, 4H), 2.68 - 2.56 (m, 1H), 2.03 (tt, J = 7.8, 3.7 Hz, 8H), 1.79 (d, J = 3.1 Hz, 2H), 1.06 (d, J = 2.8 Hz, 3H).

[0554] Table 1 Examples I-2 to I-9 and I-16 to I-21

[0555] Preparation of Example I-2:

[0556] To a solution of 11a (1.0 g, 3.91 mmol) in dichloromethane (20 mL) was added 4-bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) at room temperature, followed by the dropwise addition of triethylamine (0.79 g, 7.82 mmol), ethanolamine (0.25 g, 4.10 mmol). The reaction was stirred for 2 h, quenched with saturated ammonium chloride solution and extracted with dichloromethane (50 mL) for 3 times. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title compound 11b (0.95 g, 3.41 mmol, 87%) as a white solid. LC-MS (ESI), C8H 11 NO3SBr [M+H] + : m / z = 280.0.

[0557] Reference Example 1 was prepared according to the synthetic method of I-la using 10a (100 mg, 0.33 mmol) and 11b (140 mg, 0.50 mmol) to give compound I-2 (103 mg, 208 pmol, 63%). 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.51 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 6.1 Hz, 1H), 5.09 (d, J = 8.6 Hz, 2H), 4.66 (d, J = 5.9 Hz, 1H), 3.37 (d, J = 6.2 Hz, 2H), 2.77 (q, J = 6.2 Hz, 3H), 2.05 - 1.75 (m, 9H), 0.92 (s, 3H).

[0558] Procedure for preparation of Example I-3:

[0559] Referring to the synthesis of 11a, compound (S)-(4-bromophenyl)(3- dimethylaminopyrrolidin-l-yl)methanone 11c (0.68 g, 2.3 mmol, 95%) was prepared from 12a (0.53 g, 2.66 mmol, 1.1 eq) and (S)-N,N-dimethylpyrrolidin-3-amine 13c (0.28 g, 2.42 mmol, 1.0 eq). LC-MS (ESI), C 13 H 18 N2OBr[M+H] + : m / z = 297.1.

[0560] Referring to the synthesis of I-la in Example 1, compound I-3 (115 mg, 224 pmol, 68%) was prepared from 10a (100 mg, 0.33 mol) and 11c (148 mg, 0.50 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.48 (s, 1H), 7.90 - 7.81 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.13 - 5.05 (m, 2H), 4.11 (s, 1H), 3.76 - 3.61 (m, 1H), 3.61 - 3.53 (m, 2H), 2.80 (s, 2H), 2.43 (dt, J = 7.8, 4.0 Hz, 1H), 2.30 - 2.13 (m, 6H), 1.99 (s, 1H), 1.94 (d, J = 3.1 Hz, 2H), 1.91 (s, 2H), 1.88 (d, J = 6.6 Hz, 2H), 1.84 (q, J = 4.9, 4.3 Hz, 2H), 1.78 - 1.74 (m, 1H), 0.93 (s, 3H).

[0561] Procedure for preparation of Example I-4:

[0562] Referring to the synthesis of 11a, compound (4-bromophenyl)(4-methyl- 1,4-azepan-l-yl)methanone 11d (0.68 g, 2.3 mmol, 91%) was prepared from 12a (0.53 g, 2.66 mmol, 1.1 eq) and N-methylhomopiperazine 13g (0.28 g, 2.42 mmol, 1.0 eq). LC-MS (ESI), C 13 H 18 N2OBr[M+H] + : m / z = 297.1.

[0563] Compound I-4 (105 mg, 204 pmol, 62%) was prepared from 10a (100 mg, 0.33 mmol) and lid (148 mg, 0.50 mmol) following the synthetic procedure of I-la in Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.47 (s, 1H), 7.90 - 7.82 (m, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.13 - 5.04 (m, 2H), 3.56 (d, J = 39.0 Hz, 5H), 2.86 - 2.72 (m, 3H), 2.42 (qd, J = 8.6, 4.4 Hz, 2H), 1.97 - 1.80 (m, 10H), 0.93 (s, 3H).

[0564] Preparation of Example I-5:

[0565] Compound I-5 (79 mg, 175 pmol, 53%) was prepared from 10a (100 mg, 0.33 mmol) and p-bromobenzenesulfonamide lie (118 mg, 0.50 mmol) following the synthetic procedure of I-la in Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.51 (s, 1H), 7.97 (dd, J = 8.4, 6.5 Hz, 2H), 7.76 - 7.72 (m, 2H), 7.21 (s, 2H), 5.11 (d, J = 5.8 Hz, 2H), 2.89 (s, 1H), 2.81 - 2.75 (m, 1H), 2.73 (s, 1H), 2.45 (d, J = 8.6 Hz, 1H), 1.95 (t, J = 3.5 Hz, 2H), 1.92 - 1.86 (m, 2H), 1.85 (t, J = 3.5 Hz, 2H), 0.92 (s, 3H).

[0566] Preparation of Example I-6:

[0567] Compound I-6 (74 mg, 158 pmol, 48%) was prepared from 10a (100 mg, 0.33 mmol) and 4-bromo-N-methylbenzenesulfonamide 1 If (125 mg, 0.50 mmol) following the synthetic procedure of I-la in Reference Example 1. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.52 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.34 (q, J = 5.0 Hz, 1H), 5.18 - 5.05 (m, 2H), 2.74 (dt, J = 13.3, 8.2 Hz, 1H), 2.44 (t, J = 4.3 Hz, 1H), 2.39 (d, J = 5.0 Hz, 3H), 1.96 (h, J = 6.8, 6.3 Hz, 4H), 1.89 (d, J = 6.2 Hz, 2H), 1.84 (q, J = 4.7, 4.2 Hz, 2H), 0.91 (s, 3H).

[0568] Process for the preparation of example I-7:

[0569] Referring to the synthesis of 11a, compound 11g (0.84 g, 2.2 mmol, 92%) was prepared from 12a (0.53 g, 2.66 mmol, 1.1 eq) and (S)-3-N-Boc-N-methylaminopyrrolidine 13g (0.48 g, 2.42 mmol, 1.0 eq). LC-MS (ESI), C 17 H 24 N2O3Br[M+H] + : m / z = 383.1.

[0570] Referring to the synthesis of I-1 in example 1, compound I-7 (99 mg, 198 pmol, 60%) was prepared from 10a (100 mg, 0.33 mol) and 11g (203 mg, 0.50 mmol). 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.56 (s, 2H), 7.46 (s, 1H), 5.05 (t, J = 8.8 Hz, 1H), 3.79 (dt, J = 13.3, 7.3 Hz, 2H), 3.57 (s, 2H), 3.42 (s, 1H), 2.90 (dd, J = 14.0, 8.2 Hz, 1H), 2.66 - 2.56 (m, 1H), 2.48 (d, J = 42.0 Hz, 3H), 2.04 (q, J = 4.8 Hz, 8H), 1.79 - 1.75 (m, 2H), 1.06 (s, 3H).

[0571] Process for the preparation of example I-8:

[0572] Compound 11h (0.68 g, 2.3 mmol, 95%) was prepared from 12a (0.53 g, 2.66 mmol, 1.1 eq) and (S)-3-tert-butoxycarbonylaminopyrrolidine 13h (0.27 g, 2.42 mmol, 1.0 eq) according to the synthetic method of 11a. LC-MS (ESI), C 16 H 22 N2O3Br[M+H] + : m / z = 369.1.

[0573] Compound I-8 (96 mg, 198 µmol, 60%) was prepared from 10a (100 mg, 0.33 mol) and 11h (200 mg, 0.50 mmol) according to the synthetic method of I-1a in Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.47 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.49 (t, J = 6.9 Hz, 2H), 5.09 (t, J = 8.4 Hz, 2H), 3.69 – 3.41 (m, 6H), 2.79 (dt, J = 16.7, 8.2 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.01 – 1.78 (m, 10H), 1.64 (dt, J = 12.6, 6.5 Hz, 1H), 0.92 (s, 3H).

[0574] Preparation of Example I-9:

[0575] Compound I-9 (109 mg, 208 µmol, 63%) was prepared from 10a (100 mg, 0.33 mol) and 1-tert-butoxycarbonyl-4-[(4-bromophenyl)sulfonyl]piperazine 11i (203 mg, 0.50 mmol) according to the synthetic method of I-1 in Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.53 (s, 1H), 8.07 (dd, J = 8.9, 2.2 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 5.14 – 5.06 (m, 2H), 3.17 (d, J = 4.7 Hz, 1H), 2.88 (s, 8H), 2.79 – 2.64 (m, 1H), 2.04 – 1.93 (m, 4H), 1.93 – 1.82 (m, 4H), 0.92 (s, 3H).

[0576] Preparation of Example I-16:

[0577] Compound I-16 (150 mg, 0.32 mmol, 48%) was prepared from 10a (200.0 mg, 0.67 mmol) and 5-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dioxide 11j (200.0 mg, 0.8 mmol) following the synthetic procedure of Reference Example 1 for I-1a. 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.53 (s, 1H), 5.07 (dd, J = 9.2, 8.2 Hz, 1H), 3.82 (s, 1H), 3.55-3.48 (m, 2H), 3.40 (t, J = 6.9 Hz, 2H), 2.88 (dtd, J = 13.5, 9.2, 8.8, 7.0 Hz, 1H), 2.68 - 2.57 (m, 1H), 2.06 (qd, J = 7.6, 7.0, 4.4 Hz, 6H), 1.85 - 1.79 (m, 2H), 1.07 (s, 3H).

[0578] Procedure for the preparation of Example I-17:

[0579] Compound I-17 (100 mg, 0.214 mmol, 66%) was prepared from 10a (100 mg, 0.33 mmol) and tert-butyl 5-bromobenzo[d]isothiazole-2(3H)-carboxylate, 1,1-dioxide 11k (100 mg, 0.4 mmol) following the synthetic procedure of Reference Example 11 for I-1a. 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.53 (s, 1H), 5.07 (dd, J = 9.2, 8.2 Hz, 1H), 3.82 (s, 1H), 3.55-3.48 (m, 2H), 3.40 (t, J = 6.9 Hz, 2H), 2.88 (dtd, J = 13.5, 9.2, 8.8, 7.0 Hz, 1H), 2.68 - 2.57 (m, 1H), 2.06 (qd, J = 7.6, 7.0, 4.4 Hz, 6H), 1.85 - 1.79 (m, 2H), 1.07 (s, 3H).

[0580] Procedure for the preparation of Example I-17:

[0581] To a solution of 6-bromoisoindolin-1-one (100 mg, 0.47 mmol) in THF (5 mL) was added 4-dimethylaminopyridine (5.8 mg, 0.047 mmol) and di-tert-butyl dicarbonate (154 mg, 0.707 mmol) at room temperature. The reaction was stirred for 12 h. The reaction was quenched by the addition of saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (50 mL) for three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography to give the title compound 11l (100 mg, 0.32 mmol, 68%) as a white solid. LC-MS (ESI), C 12 H 15 NO4SBr[M+H]+: m / z = 313.5.

[0582] Reference to the procedure for the synthesis of I-1 in Reference Example 1, compound I-18 (20 mg, 0.0466 mmol, 62%) was prepared from 10a (40 mg, 0.134 mmol) and tert-butyl 6-bromo-1-oxoisoindoline-2-carboxylate 11l (50 mg, 0.16 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.2, 2.1 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 5.14 (s, 1H), 5.07 (t, J = 8.1 Hz, 1H), 4.32 (s, 2H), 2.69 (tdd, J = 10.5, 8.6, 7.5, 4.3 Hz, 1H), 2.45 - 2.35 (m, 1H), 1.94 - 1.89 (m, 3H), 1.87 (t, J = 2.9 Hz, 2H), 1.82 (t, J = 3.5 Hz, 2H), 0.93 (s, 3H).

[0583] Preparation of Example I-19:

[0584] To a solution of 5-bromo-2,3-dihydroisoindolin-1-one (100 mg, 0.47 mmol) in THF (5 mL) was added 4-dimethylaminopyridine (5.8 mg, 0.047 mmol) and di-tert-butyl dicarbonate (154 mg, 0.707 mmol) at room temperature. The reaction was stirred for 12 h. The reaction was quenched by the addition of saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (50 mL) for three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography to give the title compound 11m (110 mg, 0.35 mmol, 75%) as a white solid. LC-MS (ESI), C 12 H15 NO4SBr [M+H] + = 313.5.

[0585] Compound I-19 (20 mg, 0.0466 mmol, 62%) was prepared from 10a (40 mg, 0.134 mmol) and 5-bromo-l-oxoisoindoline-2-carboxylic acid tert-butyl ester 11m (50 mg, 0.16 mmol) following the synthetic procedure of Reference Example 1 for I-1. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.3, 1.9 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 5.14 - 5.05 (m, 2H), 4.34 (s, 2H), 2.71 (dd, J = 13.7, 7.9 Hz, 1H), 2.47 - 2.35 (m, 1H), 1.99 - 1.91 (m, 4H), 1.90 - 1.86 (m, 2H), 1.83 (q, J = 4.7, 4.2 Hz, 2H), 0.93 (s, 3H).

[0586] Preparation of Example I-20:

[0587] Compound I-20 (15 mg, 0.031 mmol, 42%) was prepared from 10a (30 mg, 0.1 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 11n (29 mg, 0.11 mmol) following the synthetic procedure of Reference Example 1 for I-1a. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.3, 1.9 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 5.14 - 5.05 (m, 2H), 4.34 (s, 2H), 2.71 (dd, J = 13.7, 7.9 Hz, 1H), 2.47 - 2.35 (m, 1H), 1.99 - 1.91 (m, 4H), 1.90 - 1.86 (m, 2H), 1.83 (q, J = 4.7, 4.2 Hz, 2H), 0.93 (s, 3H).

[0588] Preparation of Example I-21:

[0589] Reference to the synthesis method of I-la in Example 1, compound I-21 (15 mg, 0.031 mmol, 42%) was prepared from 10a (30 mg, 0.1 mmol) and 5-bromo-6-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 11o (29 mg, 0.11 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.91 - 7.82 (m, 2H), 5.06 - 4.99 (m, 2H), 4.44 - 4.31 (m, 2H), 2.58 (dd, J = 13.5, 7.6 Hz, 1H), 2.42 - 2.31 (m, 1H), 1.95 (q, J = 4.2, 3.5 Hz, 2H), 1.84 (q, J = 4.9, 4.2 Hz, 2H), 1.81 - 1.69 (m, 4H), 0.86 (s, 3H).

[0590] Example I-10

[0591] (1R,2R)-1-methyl-2-(5'-((1-(methylsulfonyl)piperidin-4-yl)amino)-3'H-spiro[cyclopropane-1,8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-3'-yl)cyclopentan-1-ol (I-10)

[0592] 1): (1R,2R)-2-(5'-bromo-3'-spiro[cyclopropane-8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-3'-yl)-1-methylcyclopentan-1-ol (14a)

[0593] To a solution of 10a (1.05 g, 3.54 mmol) in dibromomethane (35 mL) was added antimony tribromide (1.92 g, 5.31 mmol) at -10 °C, then tert-butyl nitrite (1.7 mL, 14.2 mmol) was added dropwise. After the addition, the reaction was stirred at room temperature for 6 h, quenched with aqueous Na2CO3 solution, the aqueous phase was extracted with dichloromethane (100 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound 14a (0.92 g, 2.55 mmol, 72%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 1.3 Hz, 1H), 5.08 (t, J = 8.5 Hz, 1H), 3.44 (s, 1H), 2.86 - 2.74 (m, 1H), 2.64 - 2.56 (m, 1H), 2.18 (q, J = 4.7 Hz, 2H), 2.10 - 1.98 (m, 5H), 1.93 (q, J = 4.6 Hz, 2H), 1.04 (d, J = 1.4 Hz, 3H).

[0594] 2) : (1R, 2R)-1 -methyl-2-(5'-((1 -(methylsulfonyl)piperidin-4-yl)amino)-3'- spiro[cyclopropane-8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-3'-yl)cyclopentan-1 -ol (I-10)

[0595] To a solution of 1 -(methylsulfonyl)piperidin-4-amine 11p (191 mg, 0.50 mmol) and 14a (119 mg, 0.33 mmol) in dimethyl sulfoxide (0.6 mL) was added diisopropylethylamine (0.57 ml, 3.3 mmol) at room temperature, and the reaction mixture was warmed to 100 °C for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (20 mL) and half-saturated aqueous sodium bicarbonate solution (20 mL), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 mL) three times, and the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol = 98:2) to give the title compound 1-10 (98 mg, 0.21 mmol, 65%) as a white solid. LC-MS (ESI) C 21 H 30 N7O3S [M+H] + : m / z = 460.2. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 5.22 (s, 1H), 4.89 (dd, J = 10.3, 7.9 Hz, 1H), 3.98 - 3.85 (m, 1H), 3.78 (dt, J = 12.5, 4.1 Hz, 2H), 2.95 (t, J = 11.7 Hz, 2H), 2.82 (s, 4H), 2.65 (ddd, J = 11.5, 9.4, 6.4 Hz, 1H), 2.20 (d, J = 12.9 Hz, 2H), 2.11 - 2.06 (m, 1H), 1.99 (t, J = 3.3 Hz, 2H), 1.96 - 1.92 (m, 1H), 1.72 (q, J = 4.3 Hz, 2H), 1.64 (t, J = 10.2 Hz, 4H), 1.06 (s, 3H).

[0596] Table 2 Example I-11

[0597] Reference Example I-10 was prepared from 14a (119 mg, 0.33 mmol) and (3R,4S)-4- aminotetrahydro-2H-pyran-3-ol 11q (59 mg, 0.50 mmol) according to the synthetic procedure described in Example I-1 to give compound I-11 (99 mg, 248 μmol, 75%). 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 5.27 (d, J = 5.4 Hz, 1H), 4.90 (dd, J = 9.6, 8.0 Hz, 1H), 4.07 (dd, J = 11.5, 4.8 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.79 (d, J = 11.2 Hz, 1H), 3.65 (dt, J = 8.8, 4.4 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.23 (t, J = 10.4 Hz, 1H), 2.87 - 2.76 (m, 1H), 2.61 (dq, J = 13.2, 7.7, 7.3 Hz, 1H), 2.11 - 2.03 (m, 2H), 2.04 - 1.99 (m, 4H), 1.99 - 1.92 (m, 2H), 1.78 - 1.65 (m, 4H), 1.07 (s, 3H).

[0598] Example I-12

[0599] 3'-isopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)-3'H-spiro[cyclopropane-1,8'- [1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-amine (I-12)

[0600] 1): Refer to the synthesis of 8a, reaction of compound 6 (1.52 g, 10.0 mmol) gave 8b (1.31 g, 6.0 mmol, 60%). LC-MS (ESI) C 12 H 18 N3O [M+H] + : m / z = 220.1.

[0601] 2): Refer to the synthesis of 9a, reaction of compound 8b (1.31 g, 6.0 mmol) gave 9b (0.94 g, 4.92 mmol, 82%). LC-MS (ESI) C 10 H 14 N3O [M+H] + : m / z = 192.2. 1 H NMR (400 MHz, Chloroform-d) δ 4.98 (s, 1H), 4.00 (q, J = 7.0 Hz, 2H), 1.75 (q, J = 4.3 Hz, 2H), 1.61 (d, J = 6.8 Hz, 8H), 1.43 (d, J = 7.3 Hz, 3H).

[0602] 3): Refer to the synthesis of 10a, reaction of compound 9b (0.94 g, 4.92 mmol) gave 10b (0.86 g, 3.54 mmol, 72%). LC-MS (ESI) C 12 H 15 N6 [M+H] + : m / z = 243.1. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 5.18 - 5.12 (m, 1H), 5.10 (d, J = 5.1 Hz, 2H), 1.95 (q, J = 4.6 Hz, 2H), 1.75 (d, J = 6.8 Hz, 6H), 1.70 - 1.67 (m, 2H).

[0603] 4): Refer to the synthesis of 14a, reaction of compound 10b (0.86 g, 3.54 mmol) gave 14b (0.81 g, 2.66 mmol, 75%). LC-MS (ESI) C 12 H 13 N5Br [M+H] + : m / z = 306.0. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 5.20 (pd, J = 6.8, 1.7 Hz, 1H), 2.15 (q, J = 4.7 Hz, 2H), 1.90 (qd, J = 4.8, 1.5 Hz, 2H), 1.78 (dd, J = 6.8, 1.6 Hz, 6H).

[0604] 5): Referring to the procedure for the synthesis of 1-10, reaction of side chain 11p (191 mg, 0.50 mmol) and 14b (100 mg, 0.33 mmol) gave 1-12 (89 mg, 0.22 mmol, 68%). LC-MS (ESI) C 18 H 26 N7O2S [M+H] + : m / z = 404.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 5.14 (dt, J = 13.6, 6.6 Hz, 2H), 4.06 - 3.94 (m, 1H), 3.80 - 3.71 (m, 2H), 3.01 - 2.91 (m, 2H), 2.83 (s, 3H), 2.23 (dt, J = 13.0, 3.8 Hz, 2H), 1.94 (q, J = 4.6 Hz, 2H), 1.76 (d, J = 6.8 Hz, 6H), 1.71 (d, J = 3.5 Hz, 4H).

[0605] Table 3 Example 1-13

[0606] Referring to the procedure for the synthesis of Reference Example 1-10, compound 1-13 (88 mg, 257 μmol, 78%) was prepared from 14b (100 mg, 0.33 mmol) and 11q (59 mg, 0.50 mmol). 1 H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 5.25 (s, 1H), 5.13 (h, J = 6.8 Hz, 1H), 4.09 (dd, J = 11.4, 4.9 Hz, 1H), 4.01 (dd, J = 11.9, 4.7 Hz, 1H), 3.91 - 3.78 (m, 1H), 3.65 (td, J = 9.5, 4.9 Hz, 1H), 3.48 (td, J = 11.9, 2.3 Hz, 1H), 3.23 - 3.14 (m, 1H), 2.10 - 2.02 (m, 1H), 1.97 (q, J = 4.6 Hz, 2H), 1.76 (t, J = 6.4 Hz, 8H), 1.69 (q, J = 4.6 Hz, 2H).

[0607] Example I-14

[0608] 3'-Cyclopentyl-N-(1-(methylsulfonyl)piperidin-4-yl)-3'H-spiro[cyclopropane-1,8'- [1,2,3]triazolo[4',5':4,5]cyclopentano[1,2-d]pyrimidin]-5'-amine (I-14)

[0609] 1): Refer to the synthesis method of 8a, react compound 6 (1.52 g, 10.0 mmol) to obtain 8c (1.52 g, 6.2 mmol, 62%). LC-MS (ESI) C 14 H 20 N3O [M+H] + : m / z = 246.2. 1 H NMR (400 MHz, Chloroform-d, ppm) δ 5.05 (p, J = 7.9 Hz, 1H), 4.97 (s, 1H), 3.98 (q, J = 7.0 Hz, 2H), 2.27 - 2.13 (m, 4H), 1.95 (ddt, J = 7.3, 5.5, 2.4 Hz, 2H), 1.74 (q, J = 4.3 Hz, 4H), 1.41 (dd, J = 7.4, 4.5 Hz, 5H).

[0610] 2): Refer to the synthesis method of 9a, react compound 8c (1.52 g, 6.2 mmol) to obtain 9c (1.09 g, 5.02 mmol, 81%). LC-MS (ESI) C 12 H 16 N3O [M+H] + : m / z = 218.2.

[0611] 3): Refer to the synthesis method of 10a, react compound 9c (1.09 g, 5.02 mmol) to obtain 10c (0.91 g,.3.41 mmol, 68%). LC-MS (ESI) C 14 H 17 N6 [M+H] + : m / z = 269.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 5.28 - 5.17 (m, 1H), 5.08 (s, 2H), 2.43 - 2.25 (m, 4H), 2.05 (ddt, J = 10.4, 5.2, 2.7 Hz, 2H), 1.95 (d, J = 3.2 Hz, 2H), 1.78 (dd, J = 7.2, 4.9 Hz, 2H), 1.70 - 1.65 (m, 2H).

[0612] 4): Refer to the synthesis method of 14a, react compound 10c (0.91 g, 3.41 mmol) to get 14c (0.82 g, 2.46 mmol, 72%). LC-MS (ESI) C 14 H 15 N5Br[M+H] + :m / z = 333.1. 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 5.30 (p, J = 7.5 Hz, 1H), 2.36 (ddt, J = 10.2, 7.6, 3.8 Hz, 4H), 2.17 - 2.12 (m, 2H), 2.12 - 2.05 (m, 2H), 1.92 - 1.86 (m, 2H), 1.85 - 1.76 (m, 2H).

[0613] 5): Refer to the synthesis method of I-10, react side chain 11p (191 mg, 0.50 mmol) and 14c (110 mg, 0.33 mmol) to get compound I-14 (103 mg, 0.24 mmol, 72%). LC-MS (ESI) C 20 H 28 N7O2S[M+H] + :m / z = 430.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 5.25 (td, J = 16.3, 15.8, 8.4 Hz, 1H), 5.09 (d, J = 7.4 Hz, 1H), 4.00 (dtt, J = 10.7, 7.8, 3.9 Hz, 1H), 3.78 (dt, J = 12.7, 4.1 Hz, 2H), 3.01 - 2.90 (m, 2H), 2.83 (s, 3H), 2.47 - 2.28 (m, 4H), 2.22 (dt, J = 13.0, 4.0 Hz, 2H), 2.09 - 1.98 (m, 2H), 1.95 (q, J = 4.6 Hz, 2H), 1.82 (tt, J = 11.0, 8.4, 3.6 Hz, 2H), 1.75 - 1.65 (m, 4H).

[0614] Table 4 Example I-15

[0615] Refer to the synthesis method of Example I-10, react 14c (110 mg, 0.33 mmol) and 11q (59 mg, 0.50 mmol) to get compound I-15 (88 mg, 237 μmol, 72%). 1H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 5.26 - 5.16 (m, 2H), 4.09 (dd, J = 11.3, 5.0 Hz, 1H), 4.01 (dd, J = 11.9, 4.7 Hz, 1H), 3.84 (d, J = 10.5 Hz, 1H), 3.64 (td, J = 9.5, 4.9 Hz, 1H), 3.47 (td, J = 11.9, 2.2 Hz, 1H), 3.20 (dd, J = 11.4, 9.9 Hz, 1H), 2.44 - 2.27 (m, 4H), 2.11 - 2.01 (m, 3H), 1.96 (q, J = 4.6 Hz, 2H), 1.86 - 1.72 (m, 4H), 1.70 - 1.67 (m, 2H).

[0616] Example I-22

[0617] (S)-N-ethyl-3-((3'-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-3'H-spiro[cyclopropane-1,8'- [1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)amino)pyrrolidine-1 -sulfonamide (I-22)

[0618] 1): (3S)-3-((3'-(1R,2R)-2-hydroxy-2-methylcyclopentyl)-3a',8a'-dihydro-3'H-spiro[cyclopropane- 1,8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)aminopyrrolidine-1-carboxylic acid tert-butyl ester (I-22a)

[0619] To the reaction tube was added compound 14a (70.0 mg, 0.19 mmol) and (S)-3- aminopyrrolidine-1-carboxylic acid tert-butyl ester 11r (39 mg, 0.21 mmol), N,N- diisopropylethylamine (73.0 mg, 0.57 mmol), tetrahydrofuran (1.0 mL) sequentially at room temperature. The reaction was allowed to proceed for 12 h, diluted with ethyl acetate (20 mL) and half-saturated aqueous sodium bicarbonate solution (20 mL), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (30 mL) three times, the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound I-22a (80.0 mg, 0.17 mmol, 90%). LC-MS (ESI), C 24 H 34 N7O3 [M+H] + = 470.6.

[0620] 2): (1R, 2R)-1 -methyl-2-(5'-(((S)-pyrrolidin-3-yl)amino)-3a',8a'-dihydro-3'H- spiro[cyclopropane-1,8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-3'- yl)cyclopentan-1 -ol (I-22b)

[0621] To a solution of compound I-22a (95.0 mg, 0.134 mmol) in dichloromethane (1.0 mL) was added 4 M HC1 in dioxane (1.0 mL) at room temperature. The reaction was stirred at room temperature for 12 h. Most of the solvent was removed under reduced pressure. The reaction system was adjusted to be basic by adding appropriate amount of NaHC03. The resulting residue was purified by flash column chromatography on silica gel to give brownish solid which was compound I-22b (39.0 mg, 0.11 mmol, 62%). LC-MS (ESI), C 19 H 25 N7O [M+H] + = 370.5.

[0622] 3): (S)-N-ethyl-3-((3'-((1R, 2R)-2-hydroxy-2-methylcyclopentyl)-3'H-spiro[cyclopropane- 1,8'-[1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)amino)pyrrolidine-1 - sulfonamide (I-22)

[0623] Compound I-22b (39.0 mg, 0.11 mmol) was dissolved in dichloromethane at 0 °C. TEA (33.4 mg, 0.33 mmol) was added. The reaction was allowed to proceed for half an hour. N-ethyl chlorosulfonamide (23.7 mg, 0.165 mmol) was added. The reaction was allowed to proceed for 2 h. The resulting residue was purified by flash column chromatography on silica gel to give white solid which was compound I-22 (21 mg, 0.0497 mmol, 62%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.59 (s, 1H), 7.10 (t, J = 5.7 Hz, 1H), 5.09 - 4.98 (m, 2H), 4.40 (q, J = 6.2 Hz, 1H), 3.51 (dd, J = 9.8, 6.4 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.24 (ddd, J = 9.5, 7.7, 6.3 Hz, 1H), 3.10 (dd, J = 9.9, 5.3 Hz, 1H), 2.94 (qd, J = 7.2, 5.7 Hz, 2H), 2.76 (s, 1H), 2.42 (dd, J = 8.7, 4.6 Hz, 1H), 2.22 (dd, J = 13.0, 6.5 Hz, 1H), 2.04 - 1.69 (m, 9H), 1.05 (t, J = 7.2 Hz, 3H), 0.90 (s, 3H).

[0624] Table 3 Examples I-23 to I-24

[0625] Process for the preparation of example I-23:

[0626] Compound I-23 (15 mg, 0.039 mmol, 48%) was prepared from 14a (40 mg, 0.11 mmol) and (S)-1-tert-butoxycarbonyl-3-aminopiperidine 11s (44 mg, 0.22 mmol) following the synthetic procedure of Reference Example I-22, I-22b. 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 5.62 (s, 1H), 5.11 (s, 1H), 4.32 (s, 1H), 3.25 (s, 1H), 2.96 - 2.85 (m, 1H), 2.82 - 2.58 (m, 3H), 2.05 - 1.91 (m, 9H), 1.72 - 1.67 (m, 2H), 1.29 - 1.21 (m, 4H), 1.01 (s, 3H).

[0627] Process for the preparation of example I-24:

[0628] Compound I-24 (22 mg, 0.059 mmol, 42%) was prepared from 14a (60 mg, 0.14 mmol) and (1S,3S)-tert-butyl 3-aminocyclopentylcarbamate 11t (34 mg, 0.16 mmol) following the synthetic procedure of Reference Example I-22, I-22b. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.39 (s, 1H), 5.01 (s, 1H), 4.36 (s, 1H), 3.68-3.64 (m, 11H), 1.78-1.74 (m, 10H), 0.89 (s, 2H).

[0629] Example I-25

[0630] 4-((3'-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-3'H-spiro[cyclopropane-1,8'- [1,2,3]triazolo[4',5':4,5]cyclopenta[1,2-d]pyrimidin]-5'-yl)amino)-N-(methyl-d3) benzenesulfonamide (I-25)

[0631] To a solution of 4-amino-N-(methyl-d3)benzenesulfonamide 11u (11.3 mg, 0.06 mmol) and 14a (20 mg, 0.055 mmol) in 1,4-dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium 2.87 mg, 0.00277 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.2 mg, 0.0055 mmol) and potassium carbonate (12 mg, 0.083 mmol) at room temperature. After addition, the reaction vessel was purged with argon twice and then heated to 110 °C for 4 h. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (20 mL) and half-saturated aqueous sodium bicarbonate solution (20 mL), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 mL) three times, and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound I-25 (10 mg, 0.021 mmol, 38%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.84 (d, J = 1.4 Hz, 4H), 7.66 (s, 1H), 5.07 (dd, J = 9.5, 8.2 Hz, 1H), 4.49 (s, 1H), 4.06 (s, 1H), 2.97 - 2.83 (m, 1H), 2.62 (td, J = 9.8, 9.0, 5.4 Hz, 1H), 2.05 (ddd, J = 11.9, 7.8, 3.9 Hz, 6H), 1.82 (t, J = 3.8 Hz, 2H), 1.07 (s, 3H).

[0632] Table 4 Examples I-26 to I-29

[0633] Procedure for the preparation of Example I-26:

[0634] Compound I-26 (150 mg, 0.32 mmol, 57%) was prepared according to the synthetic procedure of Reference Example I-25 from 14a (202 mg, 0.55 mmol) and 4-(vinylsulfonyl)-aniline 11v (113 mg, 0.6 mmol). 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (s, 1H), 7.90 - 7.83 (m, 4H), 7.61 (s, 1H), 6.67 (dd, J = 16.5, 9.8 Hz, 1H), 6.42 (d, J = 16.5 Hz, 1H), 5.99 (d, J = 9.9 Hz, 1H), 5.08 (dd, J = 9.4, 8.3 Hz, 1H), 3.82 (s, 1H), 2.98 - 2.83 (m, 1H), 2.62 (dt, J = 17.8, 7.1 Hz, 1H), 2.06 (ddd, J = 9.2, 6.7, 2.9 Hz, 6H), 1.83 (t, J = 3.7 Hz, 2H), 1.07 (s, 3H).

[0635] Procedure for the preparation of Example I-27:

[0636] Compound I-27 (120 mg, 0.247 mmol, 48%) was prepared according to the synthetic procedure of Reference Example I-25 from 14a (200 mg, 0.55 mmol) and 4-amino-3-fluoro-N-methylbenzenesulfonamide 11w (122.5 mg, 0.6 mmol). 1 H NMR (400 MHz, Chloroform-d) δ 8.80 (t, J = 8.3 Hz, 1H), 8.23 (s, 1H), 7.71 - 7.58 (m, 3H), 5.12 (t, J = 8.7 Hz, 1H), 4.41 (q, J = 5.4 Hz, 1H), 2.91 (td, J = 9.2, 3.7 Hz, 1H), 2.70 (d, J = 5.3 Hz, 3H), 2.61 (dd, J = 14.0, 8.4 Hz, 1H), 2.10 - 2.04 (m, 6H), 1.86 - 1.81 (m, 2H), 1.06 (s, 3H).

[0637] Procedure for the preparation of Example I-28:

[0638] Compound I-28 (200 mg, 0.42 mmol, 80%) was prepared according to the synthetic procedure of Reference Example I-25 from 14a (200 mg, 0.55 mmol) and 6-amino-N-methylpyridine-3-sulfonamide 11x (114 mg, 0.6 mmol).1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.12 (dd, J = 9.0, 2.5 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 5.19 - 5.11 (m, 2H), 2.92 - 2.81 (m, 1H), 2.52 (d, J = 5.0 Hz, 4H), 2.06 (d, J = 3.4 Hz, 3H), 1.95 (t, J = 3.4 Hz, 5H), 0.99 (s, 3H).

[0639] Preparation of Example I-29:

[0640] Reference to the synthesis method of Example I-25, compound I-29 (100 mg, 0.21 mmol, 37%) was prepared from 14a (200 mg, 0.55 mmol) and 4-amino-3-fluoro-N-(methyl-d3)benzenesulfonamide 11y (124 mg, 0.6 mmol). 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (t, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.65 - 7.53 (m, 3H), 5.05 (t, J = 8.7 Hz, 1H), 4.46 (s, 1H), 3.37 (d, J = 43.5 Hz, 1H), 2.84 (td, J = 9.2, 4.3 Hz, 1H), 2.53 (dd, J = 13.9, 8.1 Hz, 1H), 2.01 (dd, J = 7.7, 3.5 Hz, 6H), 1.77 (d, J = 3.2 Hz, 2H), 0.99 (s, 3H).

[0641] Biological Example 1

[0642] Kinase activity test

[0643] CDK / cyclin catalyzed substrate phosphorylation, with the concomitant consumption of ATP to produce ADP, was assessed by measuring the amount of ADP produced in the presence of small molecule inhibitors (% inhibition). Test compounds were vortexed to mix well and diluted with DMSO to 100x the concentration to be tested. A nanoliter scale liquid handling system (Caliper LabChips®) was used to dispense 10 nl of each compound at the 100x concentration into the reaction mixture. 655SYSTEM) to the 384 assay plate. 2x kinase solution was prepared with lx kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT), 2 μΐ^of kinase solution was transferred to the 384 assay plate, centrifuged at 1000 rpm for 60 seconds using a microplate centrifuge, and incubated at 25 °C in a biochemical incubator for 10 minutes. After preparing 2x substrate and ATP mix with kinase reaction buffer, 2 μΐ^of substrate and ATP mix was added to the 384 assay plate, centrifuged at 1000 rpm for 60 seconds using a microplate centrifuge, and incubated at 25 °C in a biochemical incubator for 60 minutes. 4 μΐ^of ADP-Glo Reagent (Cat# V9103, Promega) incubated at 25 °C in a biochemical incubator was added to each well of the 384 assay plate, centrifuged at 1000 rpm for 60 seconds using a microplate centrifuge, and incubated at 25 °C in a biochemical incubator for 40 minutes. 8 μΐ^of Detection Reagent incubated at 25 °C in a biochemical incubator was added to each well of the 384 assay plate, centrifuged at 1000 rpm for 60 seconds using a microplate centrifuge, and incubated at 25 °C in a biochemical incubator for 40 minutes. Finally, luminescence signal was read using a multi-function microplate reader (Model: PHERAstar FSX, BMG). IC50values were calculated using GraphPad Prism software with non-linear fit concentration-response curve. 50

[0644] The compounds of the present application were tested in a kinase activity assay and found to have good inhibitory activity against CDK2 / cyclin E, CDK4 / cyclin D1, CDK6 / cyclin D3 and CDK9 / cyclin T1. The results of the enzyme inhibitory activity of the most representative compounds of the present application are shown in Table 5.

[0645] Table 5. Cyclin enzyme inhibitory activity of representative compounds of the present application

[0646] While the preferred embodiments of the application have been shown and described herein, it will be apparent to those skilled in the art that many changes, modifications, and substitutions can be made thereto without departing from the application. It is to be understood that various alternatives to the embodiments described herein are possible. The following claims are intended to define the scope of the application and encompass methods and structures equivalent to those claimed and their elocutions.​

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof: wherein L1is selected from -O-C 0-6 alkyl- or -NH-C 0-6 alkyl-; L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl-, -S(O) m -C 0-6 alkyl-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 2-6 alkynylene-; Ring A is selected from C 3-10 cycloalkylene, 3-10 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; said ring A is optionally substituted with 1, 2, 3, 4 or 5 R#; R1 and R2 are independently selected from H, D, halogen, -CN, and -OR. a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; or R1and R2are joined together with the carbon atom to which they are attached to form a C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein the C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene and 5-10 membered heteroarylene are optionally substituted with oxo or thioxo; R3is selected from -OR, -SR, -NR'R", -C 1-6 alkylene-R5, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 R5groups; or R3and ring A form a fused ring, for example selected from C 5-12 cycloalkyl, 5-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said fused ring optionally substituted with 1, 2, 3, 4, or 5 R5groups; R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, 3, 4 or 5 R6groups; each R5is independently selected from H, D, halogen, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo; each R6is independently selected from H, D, halogen, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; m is selected from 0, 1 or 2; R, R' and R" are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, -C 0-6 alkylene-OR a or -C 0-6 alkylene-NR a R b ; each R#is independently selected from H, D, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl; R a , R b and R c are independently selected from H, halogen, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH2, -C 0-6 alkylene-CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C 0-6 alkylene-C 3-7 cycloalkyl, -C 0-6 alkylene-3-7 membered heterocyclyl, -C 0-6 alkylene-C 6-10 aryl, or -C 0-6 alkylene-5-10 membered heteroaryl; or, R b , R c form together with the N atom a 3-7 membered heterocyclyl; each of the above groups can optionally be substituted with 1 or more deuterium atoms, up to full deuteration.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, L1is -NH-C 0-6 alkyl-, for example -NH- or -NHCH2-, preferably -NH-.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-, preferably a chemical bond, -C(O)- or -S(O) m -, m is selected from 0, 1 or 2.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, R1and R2are independently selected from H, halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; Preferably, R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are linked together with the carbon atom to which they are attached to form C 3-7 cycloalkylene or 3-7 membered heterocyclyl, preferably C 3-5 cycloalkylene or 3-5 membered heterocyclyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, R4is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, or 3 R6groups; R4is selected from C 1-6 alkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, preferably C 5-6 cycloalkyl or 5-6 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups; More preferably, R4is selected from Preferably 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein, L1is selected from -O-C 0-6 alkyl- or -NH-C 0-6 alkyl-; L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-; Ring A is selected from C 3-10 cycloalkylene, 3-10 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; said ring A is optionally substituted with 1, 2, 3, 4 or 5 R#; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form a C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein the C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene and 5-10 membered heteroarylene are optionally substituted with oxo or thioxo; R3is selected from -OR, -NR'R", -C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 R5groups; or R3and ring A form a fused ring, for example selected from C 5-12 cycloalkyl, 5-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said fused ring optionally substituted with 1, 2, or 3 R5groups; R4is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, 3, 4 or 5 R6groups; each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo; each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; m is selected from 0, 1 or 2; R, R' and R" are independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, -C 0-6 alkylene-OR a or -C 0-6 alkylene-NR a R b ; each R#is independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl; R a , R b , and R c are independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein, L1is selected from -NH- or -NH-C 1-6 alkyl-; L2is selected from a chemical bond, -O-, -NH-, -C(O)- or -S(O)2-; ring A is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-7 membered heteroarylene, preferably C 5-6 cycloalkylene, 5-6 membered heterocyclylene, phenylene or 5-6 membered heteroarylene; said ring A is optionally substituted with 1, 2 or 3 R#; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are linked, together with the carbon atom to which they are attached, to form C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; R3is selected from -NR'R", -C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, 3-7 membered heterocyclyl, or 5-10 membered heteroaryl, said R3is optionally substituted with 1, 2, 3, or 4 R5groups; or R3is connected to ring A to form a fused ring, for example selected from C 6-12 aryl or 5-12 membered heteroaryl, which fused ring is optionally substituted with 1, 2, or 3 R5groups; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups; each R5is independently selected from H, halo, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo; each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl, for example OH or CH3; each R#is independently selected from H, halogen, OH, or C 1-6 alkyl, for example F, OH, or CH3; R, R' and R" are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl, e.g. H, CH3, CF3, CD3 or -CH2CH3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein, L1is selected from -NH- or -NH-CH2-; L2is selected from a chemical bond, -C(O)- or -S(O)2-; Ring A is selected from are preferably selected from the group consisting of R1and R2are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3is selected from CH3, -CH=CH2, -NH2, -NHCH3, -NHCD3, -NHCH2CH3, -NHCF3, -NH-(CH2)2-OH, -(CH2)2-OH, or R3and ring A are joined to form a fused ring, for example R4is selected from Preferably 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compounds have the structure of Formula (I-1), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), Formula (VI), Formula (VI-1), Formula (VI-2), Formula (VI-3), Formula (VII), Formula (VII-1), Formula (VII-2), or Formula (VII-3): wherein X1is selected from CR X1 or N, preferably N, CH or CF; X2is selected from CR X2 or N, preferably CR X2 , for example CH; X3is selected from CR X3 or N, preferably CR X3 , for example CH; X4is selected from CR X1 or N, preferably N, CH or CF; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; Ring C is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said ring C is optionally substituted with 1, 2, 3, 4 or 5 R5groups; L2, R1, R2, R3, R4, R5are as defined in claim 1; Preferably, Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; Ring C is selected from C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3, or 4 R5groups; More preferably, Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; Ring C together with the ring on which X1, X4 are located forms the following structure:

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (II): wherein X1is selected from CR X1 or N; R X1 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are linked, together with the carbon atom to which they are attached, to form C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; R3is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3is optionally substituted with 1, 2, 3, 4, or 5 R5groups; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally substituted with 1, 2, 3, 4, or 5 R6groups; each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo; each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; Preferably, X1is selected from CR X1 or N; R X1 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R3is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3being optionally substituted by 1, 2 or 3 R5groups; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2 or 3 R6groups; each R5is independently selected from H, halogen, OH, CN, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo; each R6is independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl; More preferably; X1is selected from CR X1 or N, preferably CH or N; R X1 selected from H, halogen or C 1-4 alkyl, preferably H; R1and R2are independently selected from H or C 1-4 alkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3is selected from C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R3optionally being substituted with 1, 2, or 3 R5groups; For example, R3is selected from R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups; For example, R4is selected from Preferably each R5is independently selected from H, -NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2or C 1-4 alkyl; or two R5on the same carbon atom together form oxo or thioxo; each R6is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3.

11. The compound of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (II-1) or (II-2): wherein R1, R2, R3, R4and X1are as defined in claim 10; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; Preferably, Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; More preferably, Ring B is selected from C 3-5 Cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (III), (III-1) or (III-2): wherein X1is selected from CR X1 or N; X2is selected from CR X2 or N; X3is selected from CR X3 or N; R X1 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; R X2 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; R X3 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; L2is selected from a chemical bond, -O-C 0-6 alkyl-, -NH-C 0-6 alkyl-, -C(O)-C 0-6 alkyl- or -S(O) m -C 0-6 alkyl-, m is selected from 0, 1 or 2, and L2is preferably not a chemical bond; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; R3 is selected from -OH, -NH2, and -NHC. 1-6 Alkyl, -NHC 1-6 Haloalkyl, -N(C) 1-6 Alkyl)2, -N(C 1-6 (halogenated alkyl)2, -NHC 1- 6-Deuterated alkyl, -N(C) 1-6 (deuterated alkyl)2, -OC 1-6 Alkylene-R5, -NH-C 1-6 Alkylene-R5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, preferably selected from -OH, -NH2, and -NHC 1-6 Alkyl, -NHC 1-6 Haloalkyl, -N(C) 1-6 Alkyl)2, -N(C 1-6 (halogenated alkyl)2, -OC 1-6 Alkylene-R5, -NH-C 1-6 Alkylene-R5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the R3 is optionally substituted with 1, 2 or 3 R5 groups; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, or 3 R6groups; each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo; each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; Preferably, X1is selected from CR X1 or N, preferably N, CF or CH; X2is selected from CR X2 or N, preferably CR X2 ; X3is selected from CR X3 or N, preferably CR X3 ; R X1 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R X2 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R X3 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; L2is selected from a chemical bond, -O-, -NH-, -C(O)- or -S(O)2-, preferably L2is other than a chemical bond; R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R3is selected from -NH2, -NH(C 1-6 alkyl), -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; preferably R3is selected from -NH2, -NH(C 1-6 alkyl), -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1- 6haloalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted by 1, 2 or 3 R6groups; each R5is independently selected from H, halo, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo; each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl; More preferably, X1is selected from CR X1 or N, preferably N, CH or CF, more preferably CH or CF; X2is selected from CR X2 or N, preferably CR X2 , for example CH; X3is selected from CR X3 or N, preferably CR X3 , for example CH; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; R X2 selected from H, halogen or C 1-4 alkyl, preferably H; R X3 selected from H, halogen or C 1-4 alkyl, preferably H; L2is selected from a chemical bond, -C(O)- or -S(O)2-, preferably -C(O)- or -S(O)2-; R1and R2are independently selected from H or C 1-4 alkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3 is selected from -NH2, -NH(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl), N(C) 1-4 Alkyl)2、-NHC 1-4 Deuterated alkyl, -N(C) 1-4 (deuterated alkyl)2, -NH-C 1-4 Alkylene-R5, C 1-4 Alkyl, C 2-4 alkenyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups, preferably selected from -NH2, -NH(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl), N(C) 1-4 Alkyl)2、-NH-C 1-4 Alkylene-R5, C 1-4 Alkyl, C 2-4 alkenyl, C 3-7 Cycloalkyl or 4-7 membered heterocyclic group; wherein R3 is optionally substituted by 1, 2 or 3 R5 groups; R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably C 3-7 cycloalkyl, said R4being optionally substituted with 1, 2 or 3 R6groups; each R5is independently selected from H, halo, OH, -NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2or C 1-4 alkyl; or two R5on the same atom together form an oxo or thioxo; each R6is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3; More preferably, R3is selected from -NH2, -NHCH3, -NH-CF3, -NHCD3, -CH=CH2, -NH-CH2CH2OH, R4is selected from Preferably 13. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (IV), (IV-1) or (IV-2): wherein X1is selected from CR X1 or N, preferably N, CH or CF; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; R3is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups; each R5is independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo; R1, R2, R4, R a , R b and R c are as defined in claim 12; Preferably, X1is selected from CR X1 or N, preferably N or CH, more preferably CH; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R3is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5groups; each R5is independently selected from H, halo, OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl; R1, R2and R4are as defined in claim 12; More preferably, X1is N or CH, more preferably CH; Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3is selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl (preferably 5-7 membered heterocyclyl, more preferably 5 membered heterocyclyl or 7 membered heterocyclyl); said R3is optionally substituted with 1, 2, or 3 R5groups; each R5is independently selected from H, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl or C 1-6 haloalkyl, for example H, NH2, NHCH3, N(CH3)2or CH3; For example, R3is selected from R1, R2and R4are as defined in claim 12.

14. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (V), (V-1) or (V-2): wherein X1is selected from CR X1 or N, preferably N or CH, more preferably CH; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; R3is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -NHC 1- 6deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; said R3is optionally substituted with 1, 2, or 3 R5groups; R4is selected from -OH, -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 deuteroalkyl)2, -O-C 1-6 alkylene-R5, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; said R4is optionally substituted with 1, 2, or 3 R5groups; each R5is independently selected from H, halo, OH, C 1-6 alkyl or C 1-6 haloalkyl; R1, R2and R4are as defined in claim 12; Preferably, X1is selected from CR X1 or N, preferably N, CH or CF; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl; preferably -NH2, -NHC 1-6 alkyl, -NHC 1- 6 haloalkyl, -N(C 1-6 alkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl; said R3is optionally substituted with 1, 2 or 3 R5groups; each R5is independently selected from H, halo, OH, C 1-6 alkyl or C 1-6 haloalkyl; R1, R2and R4are as defined in claim 12; More preferably, X1is N, CH or CF, more preferably CH or CF; Ring B is selected from C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -NHC 1-6 deuteroalkyl, -N(C 1-6 deuteroalkyl)2, -NH-C 1-6 alkylene-R5, C 1-6 alkyl, C 2-6 alkenyl or 5-7 membered heterocyclyl, more preferably -NH2, -NHC 1-6 alkyl, -NH-C 1-6 alkylene-OH or 5-7 membered heterocyclyl; said R3is optionally substituted with 1, 2 or 3 R5groups; For example, R3is selected from -CH=CH2, -NH2, -NHCH3, -NH-CF3, -NHCD3, -NH-CH2CH2OH, or More preferred are -CH=CH2, -NH2, -NHCH3, -NH-CH2CH2OH or each R5is independently selected from H, halo, OH, C 1-6 alkyl or C 1-6 haloalkyl; R1, R2and R4are as defined in claim 12.

15. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (VI): wherein X1is selected from CR X1 or N; X4is selected from CR X4 or N; R X1 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; R X4 selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; Ring C is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said Ring C is optionally substituted with 1, 2, 3, 4 or 5 R5groups; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-10 cycloalkylene, 3-10 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, or 3 R6groups; each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form oxo or thioxo; each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; Preferably, X1is selected from CR X1 or N; X4is selected from CR X4 or N; R X1 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R X4 selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; Ring C is selected from C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3, or 4 R5groups; R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4being optionally substituted by 1, 2 or 3 R6groups; each R5is independently selected from H, halogen, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl; or two R5on the same atom together form an oxo or thioxo (e.g., form a -C(O)- structure on the same carbon atom or a -S(O)2- structure on the same sulfur atom); each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl; More preferably, X1is selected from CR X1 or N, preferably N, CH or CF; X4is selected from CR X4 or N, preferably N, CH or CF; R X1 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F; R X4 selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or F, more preferably H; Ring C is selected from C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said ring C being optionally substituted with 1, 2, 3 or 4 R5groups; R1and R2are independently selected from H or C 1-4 alkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R4is selected from C 1-4 alkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, preferably C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups; For example, R4is selected from Preferably each R5is independently selected from H, halogen, OH, or C 1-4 alkyl; or two R5on the same atom together form an oxo or thio (e.g., -S(O)2- structure on the same sulfur atom); each R6is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3; More preferably, Ring C together with the ring on which X1, X4 are located forms the following structure: Preferably the structure is formed as follows: More preferably the structure is formed as follows:

16. The compound of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (VI-1), (VI-2) or (VI-3): wherein X1, X4, ring C, R1, R2and R4are as defined in claim 15; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; Preferably, Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; More preferably, Ring B is selected from C 3-5 Cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

17. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (VII): wherein Ring A is selected from C 3-7 Cycloalkylene, 4-7 membered heterocyclic alkylene, C 6-10 The ring A is optionally replaced by one, two or three R# radicals, and is a 5-10 aryl or 5-10 heteroaryl compound. each R#is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl; L2is selected from a chemical bond, -0-, -C(O)-, or -S(O) m - and m is selected from 0, 1 or 2; R1and R2are independently selected from H, halogen, -CN, -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene; R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R3optionally substituted with 1, 2, 3, 4, or 5 R5; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said R4optionally being substituted with 1, 2, 3, 4 or 5 R6groups; each R5is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; each R6is independently selected from H, halogen, -OR a , -NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl; R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; m is selected from 0, 1 or 2; Preferably, Ring A is selected from C 3-7 cycloalkylene or 4-7 membered heterocyclylene, said ring A being optionally substituted with 1, 2, or 3 R#; each R#is independently selected from H, halogen, OH, C 1-6 alkyl or C 1-6 haloalkyl; L2is selected from a chemical bond, -C(O)- or -S(O)2-; R1and R2are independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-7 cycloalkylene or 3-7 membered heterocyclylene; R3is selected from -NH2, -NHC 1-6 alkyl, -NHC 1-6 haloalkyl, -N(C 1-6 alkyl)2, -N(C 1-6 haloalkyl)2, -C 1-6 alkylene-R5, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from -C 1-6 alkylene-R5, C 6-10 aryl or 5-10 membered heteroaryl; said R3is optionally substituted with 1, 2, or 3 R5; R4is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 4-7 membered heterocyclyl, said R4optionally being substituted with 1, 2 or 3 R6groups; each R5is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl; each R6is independently selected from H, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, OH or C 1-6 alkyl; More preferably, Ring A is selected from C 5-6 cycloalkylene or 5-6 membered heterocyclylene, said ring A being optionally substituted with 1, 2, or 3 R#; each R#is independently selected from H, OH, or C 1-4 alkyl, such as H, OH, or CH3, preferably H; L2is selected from a chemical bond or -S(O)2-; R1and R2are independently selected from H or C 1-4 alkyl; or R1and R2are joined together with the carbon atom to which they are attached to form C 3-5 cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene; R3is selected from -NH2, -NHC 1-4 alkyl, -C 1-4 alkylene-R5, C 1-4 alkyl or 5-6 membered heteroaryl, preferably selected from -C 1-4 alkylene-R5or 5-6 membered heteroaryl, said R3being optionally substituted with 1 or 2 R5; R4is selected from C 1-4 alkyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl, preferably C 5-6 cycloalkyl or 5-6 membered heterocyclyl, said R4being optionally substituted by 1, 2 or 3 R6groups; each R5is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3; each R6is independently selected from H, OH, or C 1-4 alkyl, preferably H, OH, or CH3; More preferably, selected from the group consisting of Preferably More preferred are R4is selected from Preferably 18. The compound of claim 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is of the structure of formula (VII-1), (VII-2), or (VII-3): wherein ring A, L2, R3and R4are as defined in claim 17; Ring B is selected from C 3-7 cycloalkylene, 3-7 membered heterocyclyl, C 6-10 arylene or 5-10 membered heteroarylene; Preferably, Ring B is selected from C 3-7 cycloalkylene or 3-7 membered heterocyclylene; More preferably, wherein Ring B is selected from C 3-5 Cycloalkylene or 3-5 membered heterocyclylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, wherein, The compound is selected from:

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and a pharmaceutically acceptable excipient.

21. The pharmaceutical composition according to claim 20, further comprising an additional therapeutic agent.

22. A kit comprising a first container comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof; and optionally, a second container comprising an additional therapeutic agent; and optionally, a third container comprising a pharmaceutically acceptable excipient for diluting or suspending the compound and / or additional therapeutic agent.

23. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, for the manufacture of a medicament for the treatment and / or prevention of a disease; preferably, the disease is a CDK2-mediated disease, e.g., cancer; preferably, the CDK2-mediated disease is selected from a cancer associated with myc amplification and / or overexpression; preferably, the CDK2-mediated disease is selected from a cancer associated with amplification and / or overexpression of cyclin El (CCNE1) gene; preferably, the disease is cancer; More preferably, the cancer is selected from uterine cancer (including uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including invasive breast carcinoma (BRCA), TNBC (triple negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), ER+ HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2 low breast cancer (human epidermal growth factor 2 low breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV)), gastric cancer (including stomach adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), biliary tract cancer, adrenocortical carcinoma (ACC), or mesothelioma; More preferably, the cancer is breast cancer, e.g., HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor 2 negative) breast cancer, or ER+ HER2- breast cancer; More preferably, the cancer is HR+ HER2- (human epidermal growth factor 2 negative) breast cancer; More preferably, the cancer is responsive to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) is resistant to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) progresses despite treatment with a CDK4 / 6 inhibitor, or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) progresses despite treatment with platinum; More preferably, the cancer (e.g., breast cancer) has CCNE1 amplification and / or overexpression; More preferably, the cancer (e.g., breast cancer) does not have CCNE1 amplification and / or overexpression; More preferably, the cancer (e.g., breast cancer) has myc amplification and / or overexpression; More preferably, the cancer (e.g. breast cancer) does not have myc amplification and / or overexpression. More preferably, the cancer is a cancer characterized by CCNE1 or myc amplification and / or overexpression, e.g. a refractory or relapsed solid tumor, such as, e.g., hormone refractory prostate cancer, relapsed or refractory non-Hodgkin lymphoma, relapsed follicular lymphoma, etc.

24. A method of treating and / or preventing a disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of claim 20 or 21; Preferably, the disease is a CDK2-mediated disease, e.g. a cancer; Preferably, the CDK2-mediated disease is selected from a cancer associated with myc amplification and / or overexpression; Preferably, the CDK2-mediated disease is selected from a cancer associated with amplification and / or overexpression of the Cyclin El (CCNE1) gene; Preferably, the disease is a cancer; More preferably, the cancer is selected from uterine cancer (including uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including invasive breast carcinoma (BRCA), TNBC (triple negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), ER+ HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2 low breast cancer (human epidermal growth factor 2 low breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g. ovarian serous cystadenocarcinoma (OV)), gastric cancer (including stomach adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g. EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), biliary tract cancer, adrenocortical carcinoma (ACC), or mesothelioma; More preferably, the cancer is breast cancer, e.g. HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor 2 negative) breast cancer, or ER+ HER2- (human epidermal growth factor 2 negative) breast cancer; More preferably, the cancer is HR+ HER2- (human epidermal growth factor 2 negative) breast cancer; More preferably, the subject has a cancer that is responsive to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the subject has a cancer (e.g., breast cancer) that is resistant to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the subject has a cancer (e.g., breast cancer) that progresses despite treatment with a CDK4 / 6 inhibitor, or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the subject has a cancer (e.g., breast cancer) that progresses despite treatment with a platinum; More preferably, the subject has a cancer (e.g., breast cancer) that has a CCNE1 amplification and / or overexpression signature; More preferably, the subject has a cancer (e.g., breast cancer) that does not have a CCNE1 amplification and / or overexpression signature; More preferably, the subject has a cancer (e.g., breast cancer) that has a myc amplification and / or overexpression signature; More preferably, the subject has a cancer (e.g., breast cancer) that does not have a myc amplification and / or overexpression signature. More preferably, the cancer is a cancer that has a CCNE1 or myc amplification and / or overexpression signature, e.g., a refractory or recurrent solid tumor, such as, e.g., hormone-refractory prostate cancer, relapsed or refractory non-Hodgkin's lymphoma, relapsed follicular lymphoma, etc.

25. A compound of any one of claims 1-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of claim 20 or 21, for use in the treatment and / or prevention of a CDK-mediated disease; Preferably, the disease is a CDK2-mediated disease, e.g., a cancer; Preferably, the CDK2-mediated disease is selected from a cancer associated with myc amplification and / or overexpression; Preferably, the CDK2-mediated disease is selected from a cancer associated with amplification and / or overexpression of the cyclin E1 (CCNE1) gene; Preferably, the disease is a cancer; Preferably, the disease is a cancer; More preferably, the cancer is selected from uterine cancer (including uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including invasive breast carcinoma (BRCA), TNBC (triple negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+ HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), ER+ HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2 low breast cancer (human epidermal growth factor 2 low breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV)), gastric cancer (including stomach adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), biliary tract cancer, adrenocortical carcinoma (ACC), or mesothelioma; More preferably, the cancer is breast cancer, e.g., HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor 2 negative) breast cancer, or ER+ HER2- breast cancer; More preferably, the cancer is HR+ HER2- (human epidermal growth factor 2 negative) breast cancer; More preferably, the cancer is responsive to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) is resistant to treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib, etc.), or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) progresses despite treatment with a CDK4 / 6 inhibitor, or a CDK4 / 6 inhibitor in combination with an endocrine (e.g., fulvestrant, etc.); More preferably, the cancer (e.g., breast cancer) progresses despite treatment with platinum; More preferably, the cancer (e.g., breast cancer) has CCNE1 amplification and / or overexpression; More preferably, the cancer (e.g., breast cancer) does not have CCNE1 amplification and / or overexpression; More preferably, the cancer (e.g., breast cancer) has myc amplification and / or overexpression; More preferably, the cancer (e.g., breast cancer) does not have myc amplification and / or overexpression. More preferably, the cancer is a cancer characterized by CCNE1 or myc amplification and / or overexpression, e.g., a refractory or relapsed solid tumor, such as, e.g., hormone-refractory prostate cancer, relapsed or refractory non-Hodgkin's lymphoma, relapsed follicular lymphoma, etc.

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