1H-[1, 2, 3] triazolo [4, 5-H] quinazoline compound as protein kinase inhibitor

Abstract

Provided are 1H-[1, 2, 3] triazolo [4, 5-h] quinazolines of general formula (I) which are useful in the treatment of cell proliferation disorders. The compounds are effective inhibitors of cyclin dependent kinase (CDK).

Description

1H-[1,2,3]triazolo[4,5-H]quinazolines as protein kinase inhibitors

[0001] The present invention claims priority to Chinese patent application No. 202310664526.9 filed on June 1, 2023, which is incorporated herein by reference in its entirety. Field of the Invention

[0002] The present invention provides a 1H-[1,2,3]triazolo[4,5-h]quinazoline compound as a cyclin-dependent kinase (CDK) inhibitor with broad-spectrum, strong inhibitory activity against CDKs. The compound of the present invention is effective for treating diseases such as cancer and inflammation. Background Art

[0003] Cyclin-dependent kinases (CDKs) and cyclins are important factors in cell cycle regulation. CDKs can bind to cyclins to form heterodimers, with CDKs acting as catalytic subunits and cyclins as regulatory subunits. These complexes form various cyclin-CDK complexes, phosphorylating different substrates and promoting and transforming different phases of the cell cycle.

[0004] Over the past decade, CDK inhibitors have become a hot topic in the development of new anti-cancer drugs, with over 20 CDK inhibitors entering clinical trials. Despite impressive preclinical pharmacodynamics, most clinical trials have yielded disappointing results. Key challenges include a lack of efficacy in solid tumors and significant toxicity. Some CDK inhibitors lack selectivity for specific CDK isoforms, resulting in significant side effects.

[0005] CDK4 and CDK6 are two closely related kinases that bind to Cyclin D during the tumor cell cycle, promoting progression from the G1 phase to the S phase and are essential for cell cycle progression. Activation of CDK4 and CDK6 has been shown to lead to cell cycle alterations in human tumors, such as breast cancer and myeloma. Inhibition of CDK4 and CDK6 can prevent the inactivation of the tumor suppressor protein Rb and interfere with tumor cell cycle progression.

[0006] Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. The cyclin E / CDK2 complex plays an important role in regulating G1 / S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin D / CDK4 / 6 and cyclin E / CDK2 releases the G1 transcription factor E2F and promotes S phase entry. Activation of cyclin A / CDK2 during the early S phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete the S phase. (Asghar et al., The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug. Discov. 2015; 14(2): 130-146).

[0007] Cyclin-dependent kinase 9 (CDK9) participates in the formation of positive transcription elongation factor (P-TEFb) and plays a key role in transcriptional regulation, particularly in the regulation of the transcription of short-lived anti-apoptotic proteins, which are crucial for the survival of various tumor cells. Therefore, CDK9 has become an important target for cancer treatment. Small molecule inhibitors with CDK9 inhibitory activity, dinaciclib (MK-7965) and seliciclib (CYC202), have been approved for use in clinical trials for breast cancer and hematological malignancies, as well as in combination with chemotherapy for advanced solid tumors.

[0008] Although many CDK inhibitor compounds have been disclosed, more CDK inhibitors are still needed to treat CDK-related diseases.

[0009] Summary of the Invention

[0010] The present invention provides 1H-[1,2,3]triazolo[4,5-h]quinazoline compounds as cyclin-dependent kinase inhibitors with potent inhibitory activity. Furthermore, compared with existing drugs, the compounds of the present invention further enhance pharmacokinetic properties, including significant improvements in metabolic stability and clearance.

[0011] In one aspect, the present invention 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:

[0012] in,

[0013] L is selected from -C(O)- or -S(O)2-, preferably -C(O)-;

[0014] Ring A is a 5-10 membered heterocyclic group;

[0015] Ring B is C 6-10 aryl;

[0016] R1 is selected from H, D, halogen, -C 0-6 Alkylene -CN, -C 0-6 Alkylene-NR 1a R 1b 、-C 0-6 Alkylene-OR 1a 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0017] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0018] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0019] m is selected from 0, 1, 2, 3, 4 or 5;

[0020] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, -C 0-6 Alkylene -CN, -C 0-6 Alkylene -NH2 or -C 1-6 Alkylene-OH, wherein R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace;

[0021] R 2a Selected from H, D, halogen, OR a 、CN、NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0022] R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0023] R a 、R b and R c Selected from H, C 1-6 Alkyl or C1-6 alkyl halide;

[0024] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated;

[0025] Provided that, when R2 is isopropyl and R3 is H, Ring A is not a 6-membered heterocyclyl.

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

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, which may also contain another therapeutic agent.

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

[0029] In another aspect, the present invention provides use of a compound of the present invention in the preparation of a medicament for treating and / or preventing a CDK-mediated disease.

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

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

[0032] In certain embodiments, the disease comprises a cell proliferative disorder, for example, a solid tumor such as a sarcoma and a carcinoma (e.g., a fibrosarcoma, a myxosarcoma, a liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon cancer, a pancreatic cancer, a breast cancer, an ovarian cancer, a prostate cancer, a squamous cell carcinoma, a basal cell carcinoma, adenocarcinoma, a sweat adenoma, a sebaceous gland carcinoma, a papillary carcinoma, Papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, embryonal carcinoma sarcoma, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0033] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0034] definition

[0035] Chemical definition

[0036] Definitions of specific functional groups and chemical terms are described in more detail below.

[0037] When a numerical range is listed, it is intended to include every value and sub-range within the stated 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.

[0038] It should be understood that when described herein, any of the moieties defined below may be substituted with a number of substituents, and that the corresponding definitions are within their scope listed below, including such substituted moieties. Unless otherwise stated, the term "substituted" is as defined below.

[0039] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6"Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 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).

[0040] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 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 in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0041] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 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. 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 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] "-C 1-6 Alkylene-, -C 2-6 Alkenylene- or -C 2-6 Alkyne-" refers to the above-defined "C 1-6 Alkyl, C 2-6 Alkenyl or C2-6 "alkynyl" divalent group.

[0043] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene is particularly preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes 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- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0044] “C 0-6 "Alkylene" means a chemical bond and "C 1-6 "Alkylene".

[0045] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-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.

[0046] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0047] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0048] “C 1-6 "Haloalkyl" means the above-mentioned "C 1-6 "alkyl", which is substituted by one or more halogen groups. Examples include monohalogen, dihalogen and polyhalogenated alkyl groups including perhalogenation. A monohalogen substituent may have one iodine, bromine, chlorine or fluorine atom in the group; dihalogen substituents and multiple halogen substituents may have two or more of the same halogen atoms or a combination of different halogens. Preferred examples of haloalkyl include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0049] “C 5-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 5 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 5-6 Cycloalkyl is particularly preferred, more preferably C 5-6Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like.

[0050] "5-10 membered heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 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 may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 5- to 8-membered heterocyclyl is preferred, which is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5- to 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-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0051] 5-10 membered heterocyclic groups also include spiro heterocyclic groups, i.e., groups in which two rings (e.g., a heterocycle and a carboalkane) share a carbon atom, wherein at least one ring is a heterocyclic group as defined above. More specifically, the spiro heterocyclic group is a spiro ring formed by two 4-membered rings, two 5-membered rings, a 4-membered ring and a 5-membered ring, or a 4-membered ring and a 6-membered ring. Specific spiro heterocyclic groups include, but are not limited to:

[0052] The 5-10 membered heterocyclic group also includes the case where the carbon atoms or heteroatoms on the heterocyclic ring are oxidized or sulfurized, and also includes the case where the carbon atoms or heteroatoms on the heterocyclic ring are oxidized by one or more oxygen atoms, for example wait.

[0053] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system.

[0054] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 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 may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. 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 thienyl. 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, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0055] "Carbonyl," whether used alone or in combination with other terms (eg, aminocarbonyl), is represented by -C(O)-.

[0056] "Oxo" means =0.

[0057] "Thio" means =S.

[0058] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl etc. defined herein are optionally substituted groups. Generally, the term "substituted", whether or not there is the term "optional" in front, refers to at least one hydrogen present on a group (e.g., carbon or nitrogen atom) being replaced by a permissible substituent, e.g., a substituent that produces a stable compound when substituted, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise stated, 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 at each position is the same or different. The term "substituted" includes substitutions with all permissible substituents of an organic compound (resulting in any substituent described herein that forms a stable compound). For the present invention, heteroatoms such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatoms and results in the formation of a stable moiety.

[0059] 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(=NR bb)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(OR cc)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 replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0060] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =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 replace;

[0061] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0062] R bb Each of the following 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(R cc)2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0063] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0064] R dd Each of the 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(=NRff )N(R ff )2、-NR ff C(=NR ff )N(R 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 by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0065] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0066] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0067] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C1-6 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 1-6 alkyl), -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(C 1-6alkyl), -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 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic group, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0068] Exemplary substituents on nitrogen atoms 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)2Raa 、-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 attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0069] Other definitions

[0070] As used herein, "cancer" refers to any disease caused or resulting from inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Examples of cancer include, but are not limited to, leukemias (e.g., acute leukemias, acute lymphocytic leukemias, acute myeloid leukemias, acute granulocytic leukemias, acute promyelocytic leukemias, acute myelomonocytic leukemias, acute monocytic leukemias, acute erythroleukemias, chronic leukemias, chronic myelocytic leukemias, chronic lymphocytic leukemias), polycythemia vera, lymphomas (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain diseases, and solid tumors.

[0071] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0072] As used herein, the term "pharmaceutically acceptable" means that the substances are suitable for use in contact with the tissues of patients within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and are effective for their intended application, including (where possible) zwitterionic forms of the compounds of the present invention.

[0073] The term "salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound free base form with a suitable organic or inorganic acid and isolating the resulting salt.

[0074] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0075] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0076] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. 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.

[0077] "Disease," "disorder," and "condition" are used interchangeably herein.

[0078] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0079] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, 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.

[0080] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0081] As used herein, unless otherwise specified, 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 a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0082] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG1 shows the results of immunoblotting to detect phosphorylated Ser780 and Ser807 / 811 Rb in Example I-10.

[0084] FIG2 is the result of immunoblotting detection of CDK9 downstream molecular pathways and apoptosis molecular pathways in Example I-10.

[0085] FIG3 shows the results of the growth inhibition effects of Example I-10 and the control on the OVCAR-3 tumor model.

[0086] FIG4 shows the results of the growth inhibition effects of Example I-10 and the control on the MKN1 tumor model. Specific implementation plan

[0087] Herein, "compounds of the present invention" refers to the following compounds of formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof.

[0088] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise indicated) all optical isomers and mixtures thereof are encompassed. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may exist in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but rather are intended to encompass all tautomeric forms.

[0089] In one embodiment, the present invention 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:

[0090] in,

[0091] L is selected from -C(O)- or -S(O)2-, preferably -C(O)-;

[0092] Ring A is a 5-10 membered heterocyclic group;

[0093] Ring B is C 6-10 aryl;

[0094] R1 is selected from H, D, halogen, -C 0-6 Alkylene -CN, -C 0-6 Alkylene-NR 1a R 1b 、-C 0-6 Alkylene-OR 1a 、C 1-6 Alkyl, C 1- 6 haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0095] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0096] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0097] m is selected from 0, 1, 2, 3, 4 or 5;

[0098] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, -C 0-6 Alkylene -CN, -C 0-6 Alkylene -NH2 or -C 1-6 Alkylene-OH, wherein R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace;

[0099] R 2a Selected from H, D, halogen, OR a 、CN、NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0100] R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0101] R a 、R b and R c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0102] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated;

[0103] Provided that, when R2 is isopropyl and R3 is H, Ring A is not a 6-membered heterocyclyl.

[0104] L

[0105] In one specific embodiment, L is -C(O)-; in another specific embodiment, L is -S(O)2-.

[0106] Ring A

[0107] In one embodiment, Ring A is a 5-10 membered heterocyclyl; in another embodiment, Ring A is a 5-8 membered heterocyclyl; in another embodiment, Ring A is a 5 membered heterocyclyl; in another embodiment, Ring A is a 7-10 membered heterocyclyl; in another embodiment, Ring A is a 7 membered heterocyclyl.

[0108] m

[0109] In a specific embodiment, m is selected from 0, 1, 2, 3, 4 or 5.

[0110] In one embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for

[0111] Ring B

[0112] In one embodiment, Ring B is C 6-10 Aryl.

[0113] R1

[0114] In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen; in another embodiment, R1 is F; in another embodiment, R1 is -C 0-6 Alkylene-CN, such as CN; in another embodiment, R1 is -C 0-6 Alkylene-NR 1a R 1b In another embodiment, R1 is NR 1a R 1b In another embodiment, R1 is NH2; In another embodiment, R1 is In another embodiment, R1 is -C 0-6 Alkylene-OR 1a In another embodiment, R1 is -C 1-6 Alkylene-OH; In another embodiment, R1 is -C 1-4 Alkylene-OH; in another embodiment, R1 is OH; in another embodiment, R1 is C 1-6 Alkyl; In another embodiment, R1 is C 1-4 Alkyl; In another embodiment, R1 is C 1-6 In another embodiment, R1 is C 2-6 In another embodiment, R1 is C 2-6 Alkynyl.

[0115] R2

[0116] In one embodiment, R2 is C 1-6 Alkyl; In another embodiment, R2 is C 1-4 Alkyl; In another embodiment, R2 is C 1-6 In another embodiment, R2 is C 5-10 In another embodiment, R2 is C 5-8 In another embodiment, R2 is a 5-10 membered heterocyclyl; In another embodiment, R2 is -C 0-6Alkylene-CN; In another embodiment, R2 is -C 0-6 Alkylene-NH2; In another embodiment, R2 is -C 1-6 Alkylene-OH; In another embodiment, R2 is -C 1-4 Alkylene-OH; In another embodiment, R2 is -C 1-2 Alkylene-OH.

[0117] In a more specific embodiment, R2 is selected from In another more specific embodiment, R2 is In another more specific embodiment, R2 is In another more specific embodiment, R2 is In another more specific embodiment, R2 is In another more specific embodiment, R2 is In another more specific embodiment, R2 is

[0118] In one embodiment, said R2 is not substituted; in another embodiment, said R2 is optionally substituted with n R 2a In another embodiment, said R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace.

[0119] R3

[0120] In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is halogen; in another embodiment, R3 is C 1-6 Alkyl; In another embodiment, R3 is C 1-6 In another embodiment, R3 is C 1-4 Haloalkyl, such as CHF2.

[0121] R 1a

[0122] In a specific embodiment, R 1a is H; in another embodiment, R 1a is D; in another embodiment, R 1a C 1-6 Alkyl; in another embodiment, R 1a C 1-4 Alkyl, such as CH3 or isopropyl; in another embodiment, R 1a C1-6 Halogenated alkyl.

[0123] R 1b

[0124] In a specific embodiment, R 1b is H; in another embodiment, R 1b is D; in another embodiment, R 1b C 1-6 Alkyl; in another embodiment, R 1b C 1-4 Alkyl, such as CH3; in another embodiment, R 1b C 1-6 Halogenated alkyl.

[0125] R 2a

[0126] In a specific embodiment, R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is halogen; in another embodiment, R 2a OR a , such as OH; in another embodiment, R 2a is CN; in another embodiment, R 2a NR b R c , such as NH2; in another embodiment, R 2a C 1-6 Alkyl; in another embodiment, R 2a C 1-4 Alkyl, such as CH3; in another embodiment, R 2a C 1-6 alkyl halide;

[0127] R 2b

[0128] In a specific embodiment, R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is OH; in another embodiment, R 2b is CN; in another embodiment, R 2b is NH2; in another embodiment, R 2b C 1-6 Alkyl; in another embodiment, R 2b C1-4 Alkyl, such as CH3; in another embodiment, R 2b C 1-6 Halogenated alkyl.

[0129] R 2c

[0130] In a specific embodiment, R 2c is H; in another embodiment, R 2c is D; in another embodiment, R 2c C 1-6 Alkyl; in another embodiment, R 2c C 1-4 Alkyl, such as CH3; in another embodiment, R 2c C 1-6 Halogenated alkyl.

[0131] n

[0132] In a specific embodiment, n is selected from 0, 1, 2, 3, 4 or 5.

[0133] R a 、R b and R c

[0134] In a specific embodiment, R a is H; in another embodiment, R a C 1-6 Alkyl groups, such as C 1-4 Alkyl; in another embodiment, R a C 1-6 Halogenated alkyl.

[0135] In a specific embodiment, R b is H; in another embodiment, R b C 1-6 Alkyl groups, such as C 1-4 Alkyl; in another embodiment, R b C 1-6 Halogenated alkyl.

[0136] In a specific embodiment, R c is H; in another embodiment, R c C 1-6 Alkyl groups, such as C 1-4 Alkyl; in another embodiment, R c C 1-6 Halogenated alkyl.

[0137] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0138] Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in any other specific embodiment. For example, any technical solution or any combination thereof for L may be combined with any technical solution or any combination thereof for Ring A, Ring B, R1-R3, m, and n, etc. The present invention is intended to include all combinations of these technical solutions, but due to space limitations, they are not listed one by one.

[0139] In a specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein,

[0140] in,

[0141] L is selected from -C(O)- or -S(O)2-, preferably -C(O)-;

[0142] Ring A is a 5-10 membered heterocyclic group;

[0143] R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b 、-C 1-6 Alkylene-OH, C 1-6 Alkyl or C 1-6 alkyl halide;

[0144] R 1a Selected from H, D or C 1-6 alkyl;

[0145] R 1b Selected from H, D or C 1-6 alkyl;

[0146] m is selected from 0, 1, 2, 3, 4 or 5;

[0147] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 5-10 Cycloalkyl or -C 1-6 Alkylene-OH, wherein R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace;

[0148] R 2a Selected from H, D, OH or C 1-6 alkyl;

[0149] R3 is selected from H, D, halogen or C1-6 Haloalkyl, preferably H or CHF2, more preferably H;

[0150] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0151] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0152] R2 is selected from C 1-4 Alkyl, C 5-8 Cycloalkyl or -C 1-4 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace;

[0153] R 2a Selected from H, D, OH or C 1-6 Alkyl, preferably H, D, OH or CH3;

[0154] Preferably,

[0155] R2 is selected from

[0156] More preferably, R2 is

[0157] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0158] Ring A is a 5-8 membered heterocyclic group;

[0159] R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b 、-C 1-4 Alkylene -OH or C 1-4 alkyl;

[0160] R 1a Selected from H, D or C 1-4 Alkyl, preferably, R 1a is selected from H, CH3 or isopropyl;

[0161] R 1b Selected from H, D or C 1-4 Alkyl, preferably, R 1b Selected from H or CH3;

[0162] m is selected from 0, 1, 2 or 3;

[0163] Preferably,

[0164] Selected from

[0165] More preferably,

[0166] Selected from

[0167] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of the general formula (III):

[0168] in,

[0169] Ring A is a 5-8 membered heterocyclic group;

[0170] R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b 、-C 1-4 Alkylene -OH or C 1-4 alkyl;

[0171] R 1a Selected from H, D or C 1-4 Alkyl, preferably, R 1a is selected from H, CH3 or isopropyl;

[0172] R 1b Selected from H, D or C 1-4 Alkyl, preferably, R 1b Selected from H or CH3;

[0173] m is selected from 0, 1, 2 or 3;

[0174] R2 is selected from C 1-4 Alkyl, C 5-8 Cycloalkyl or -C 1-4 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace;

[0175] R 2a Selected from H, D, OH or C 1-6 Alkyl, preferably H, OH or CH3;

[0176] R3 is selected from H, D or C1-6 Haloalkyl, preferably H or CHF2, more preferably H;

[0177] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0178] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0179] Selected from Preferably, Selected from

[0180] R2 is selected from isopropyl, cyclopentyl or -C 1-2 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace;

[0181] R 2a Selected from H, D, OH or C 1-4 Alkyl, preferably selected from H, OH or CH3;

[0182] Preferably, R2 is selected from Preferably

[0183] R3 is selected from H, D or C 1-4 Haloalkyl, preferably H or CHF2, more preferably H;

[0184] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0185] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein the compound has the following structure:

[0186] in,

[0187] R 2b Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0188] R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0189] The remaining variables are as defined above.

[0190] In a specific embodiment, the present invention provides a compound of formula (IV), (IV-1) or (IV-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which is:

[0191] in,

[0192] R1 is selected from halogen, OH, CN or NR 1a R 1b ;

[0193] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0194] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0195] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H;

[0196] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0197] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (IV), (IV-1) or (IV-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0198] R1 is selected from halogen, OH, CN or NR 1a R 1b ;

[0199] R 1a Selected from H, D or C 1-4 alkyl;

[0200] R 1b Selected from H, D or C 1-4 alkyl;

[0201] R3 is selected from H, D or C1-4 Haloalkyl, preferably H;

[0202] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0203] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (IV), (IV-1) or (IV-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0204] R1 is selected from F, OH or NR 1a R 1b ;

[0205] R 1a is selected from H, CH3 or isopropyl;

[0206] R 1b Selected from H or CH3;

[0207] R3 is selected from H or CHF2, preferably H.

[0208] In a specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:

[0209] in,

[0210] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0211] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0212] Preferably,

[0213] R 1a Selected from H, D or C 1-4 alkyl;

[0214] R 1b Selected from H, D or C 1-4 alkyl;

[0215] More preferably,

[0216] R 1a is selected from H, CH3 or isopropyl;

[0217] R 1b Selected from H or CH3;

[0218] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0219] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of the general formula (VI), (VI-1) or (VI-2):

[0220] in,

[0221] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0222] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H;

[0223] Preferably,

[0224] R 1a Selected from H, D or C 1-4 Alkyl, preferably H or methyl;

[0225] R3 is selected from H, D or C 1-4 Haloalkyl, preferably H or CHF2, more preferably H;

[0226] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0227] In a specific embodiment, the present invention provides a compound of formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof:

[0228] in,

[0229] Ring A is a 5-10 membered heterocyclic group;

[0230] R1 is selected from H, D, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl or NR 1a R 1b ;

[0231] R1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0232] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0233] m is selected from 0, 1, 2, 3, 4 or 5;

[0234] R2 is C 5-10 Cycloalkyl, preferably cyclopentyl, wherein R2 is optionally replaced by n R 2a replace;

[0235] R 2a Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0236] n is selected from 0, 1, 2, 3, 4 or 5;

[0237] Preferably,

[0238] Ring A is selected from a 5-membered heterocyclic group or a 7-10-membered heterocyclic group;

[0239] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0240] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein,

[0241] Ring A is a 5-8 membered heterocyclic group;

[0242] R1 is selected from H, D, C 1-4 Alkyl or NR 1a R 1b ;

[0243] R 1a Selected from H, D or C 1-4 Alkyl, preferably H, CH3 or isopropyl;

[0244] R 1b Selected from H, D or C 1-4 Alkyl, preferably H or CH3;

[0245] m is selected from 0, 1, 2 or 3;

[0246] R2 is C 5-8Cycloalkyl, preferably cyclopentyl, wherein R2 is optionally replaced by n R 2a replace;

[0247] R 2a Selected from H, OH or C 1-4 alkyl;

[0248] n is selected from 0, 1, 2 or 3;

[0249] Preferably,

[0250] Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group;

[0251] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0252] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (VII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein,

[0253] Selected from Preferably

[0254] R2 is a cyclopentyl group, said R2 is optionally replaced by n R 2a replace;

[0255] R 2a Selected from H, OH or CH3;

[0256] n is selected from 0, 1 or 2;

[0257] Preferably, R2 is

[0258] In a specific embodiment, the present invention provides a compound of formula (VIII), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which is a compound of formula (VIII):

[0259] in,

[0260] R 2b Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0261] Preferably,

[0262] R2b Selected from H, D, OH or C 1-4 alkyl;

[0263] More preferably,

[0264] R 2b selected from H, D or CH3;

[0265] The other variables are as defined above.

[0266] In a specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof:

[0267] in,

[0268] Ring A is a 5-10 membered heterocyclic group;

[0269] R1 is selected from H, D, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or NR 1a R 1b ;

[0270] R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0271] R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0272] m is selected from 0, 1, 2, 3, 4 or 5;

[0273] R 2a Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0274] R 2b Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0275] R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0276] Preferably,

[0277] Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group;

[0278] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0279] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0280] Ring A is a 5-8 membered heterocyclic group;

[0281] R1 is selected from H, D, C 1-4 Alkyl or NR 1a R 1b ;

[0282] R 1a Selected from H, D or C 1-4 Alkyl, preferably selected from H, CH3 or isopropyl;

[0283] R 1b Selected from H, D or C 1-4 Alkyl, preferably H or CH3;

[0284] m is selected from 0, 1, 2 or 3;

[0285] R 2a Selected from H, D or C 1-4 Alkyl, preferably H or CH3;

[0286] R 2b Selected from H, D or C 1-4 Alkyl, preferably H or CH3;

[0287] R 2c Selected from H, D or C 1-4 Alkyl, preferably H or CH3;

[0288] Preferably,

[0289] Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group;

[0290] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0291] In a specific embodiment, the present invention provides a compound of the above-mentioned general formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein:

[0292] Selected from

[0293] R 2a Selected from H or CH3;

[0294] R 2b Selected from H or CH3;

[0295] R 2c Selected from H or CH3;

[0296] Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

[0297] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0298] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0299] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0300] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0301] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0302] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which 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 introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, 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. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0303] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and 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 of which is incorporated herein by reference.

[0304] The present invention also provides a pharmaceutical preparation 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 thereof. All of these forms belong to the present invention.

[0305] Preferred compounds of the present invention include, but are not limited to, the compounds listed below, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof:

[0306] Pharmaceutical compositions, kits, and administration

[0307] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0308] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0309] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the 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 compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0310] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0311] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0312] Example

[0313] The following examples are provided so as to provide those skilled in the art with a complete disclosure and description of how to perform, prepare and evaluate the methods and compounds claimed herein and are intended to be merely illustrative of the invention and not to limit the scope of the invention.

[0314] The preparation scheme of the compound of the present invention is shown in Reaction Scheme 1.

[0315] Reaction 1

[0316] The compound of formula I can be prepared according to the above general reaction formula. First, 1,2-cyclohexanedione (1) is refluxed in toluene / ethanol under the catalysis of p-toluenesulfonic acid to obtain an enone intermediate (2). Then, (2) is reacted with N,N-dimethylformamide dimethyl acetal, and the resulting enamine intermediate is further reacted with O-methylisourea to obtain 8-ethoxy-2-methoxy-5,6-dihydroquinazoline (3). (3) is hydrolyzed under acidic conditions to obtain 2-methoxy-6,7-dihydroquinazoline-8(5H)-one (4). (4) reacts with 1-azido-4-nitrobenzene and amine (5) to obtain 1-substituted 8-methoxy-4,5-dihydro-1H-[1,2,3]triazolo[4,5-H]quinazoline (6). Next, (6) is subjected to an oxidation-aromatization reaction under the action of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to obtain 1-substituted 8-methoxy-1H-[1,2,3]triazolo[4,5-H]quinazoline (7). (7) is subjected to a halogenation reaction to obtain a halide (8), which is then converted into the corresponding deuterated or alkyl or haloalkyl intermediate (9). Subsequently, (9) is trifluoromethanesulfonylated to obtain a trifluoromethanesulfonyl ester (10). Compound (10) is coupled with an amine (11), or the protecting agent is further removed (when a Boc protecting group is present in the molecule) to obtain a compound of formula (I).

[0317] Amine (11) can be prepared according to the above general reaction formula. First, acid (12) and amine (13) are condensed under the action of EDCI to obtain nitro compound (14), which is then subjected to palladium / carbon catalyzed hydrogenation reduction reaction to obtain aromatic amine (11).

[0318] Example I-1

[0319] (S)-(3-Fluoropyrrolidin-1-yl)(4-((1-isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl)amino)phenyl)methanone (I-1)

[0320] 1): 2-Ethoxy-cyclohex-2-en-1-one (2a)

[0321] 1,2-Cyclohexanedione 1a (90 g, 803.2 mmol) and p-toluenesulfonic acid (13.8 g, 80.3 mmol) were suspended in toluene / ethanol (2:1, 1000 mL), heated to reflux, and the reaction continued for 36 hours. After the reaction mixture cooled to room temperature, the majority of the solvent was removed by distillation under reduced pressure. The reaction mixture was then neutralized with saturated aqueous sodium bicarbonate (500 mL) and extracted three times with dichloromethane (200 mL). The combined organic layers were dried (over anhydrous sodium sulfate), filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 20:1) to afford the title compound 2a (91.1 g, 650.6 mmol, 81%) as a pale yellow oil. 1 H NMR(400MHz,Chloroform-d,ppm)δ5.84(t,J=4.6Hz,1H),3.74(q,J=7.0Hz,2H),2.5 6–2.45(m,2H),2.41(q,J=5.5Hz,3H),1.95(p,J=6.2Hz,2H),1.36(t,J=7.0Hz,3H).

[0322] 2): 8-Ethoxy-2-methoxy-5,6-dihydroquinazoline (3a)

[0323] A solution of 2a (91.1 g, 650.6 mmol) and N,N-dimethylformamide dimethyl acetal (431 mL, 3253 mol, 5 equiv.) in N,N-dimethylformamide (600 mL) was stirred at 120°C for 13 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain a brown oil, which was the enamine intermediate. This crude product was used directly in the next reaction without further purification. LC-MS (ESI), C 13 H 20 N3O[M+H] + :m / z=234.2.

[0324] The crude product from the previous step, O-methylisourea sulfate (320.5 g, 608.9 mmol), and anhydrous sodium acetate (213.5 g, 2602.1 mmol) were suspended in N,N-dimethylformamide (800 mL). The temperature was raised to 80°C and the reaction was allowed to proceed for 24 hours. After the reaction mixture cooled to room temperature, it was diluted with dichloromethane (500 mL), filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to afford the title compound 3a (65.1 g, 315.8 mmol, 53%) as a pale yellow solid. 1H NMR (400MHz, Chloroform-d, ppm) δ8.20 (s, 1H), 5.46 (t, J = 4.7Hz, 1H), 3.99 (s, 3H), 3.92 ( q, J=7.0Hz, 2H), 2.70 (t, J=7.9Hz, 2H), 2.40 (td, J=7.9, 4.8Hz, 2H), 1.44 (t, J=7.0Hz, 3H).

[0325] 3): 2-methoxy-6,7-dihydroquinazolin-8(5H)-one (4a)

[0326] In an ice-water bath, slowly add hydrogen chloride (162.6 mL, 4 M in dioxane, 650.5 mmol) to a solution of 3a (65.1 g, 315.8 mmol) in methanol (400 mL). Warm to room temperature and allow to react overnight. Add saturated aqueous sodium bicarbonate dropwise to the reaction mixture in an ice-water bath until the pH reaches ≈ 8. Extract the reaction mixture three times with dichloromethane (200 mL). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate. The resulting pale yellow solid is the title compound 4a (49.8 g, 280.2 mmol, 93%). 1 H NMR (400MHz, Chloroform-d, ppm) δ8.66 (s, 1H), 4.05 (s, 3H), 2.92 (t, J = 6.1Hz, 2H), 2.84–2.72 (m, 2H), 2.18 (ddd, J = 12.7, 7.2, 5.7Hz, 2H).

[0327] 4): 1-Isopropyl-8-methoxy-4,5-dihydro-1H-[1,2,3]triazolo[4,5-H]quinazoline (6a)

[0328] Dissolve 4a (17.9 g, 100.8 mmol) in toluene (300 mL). Add isopropylamine 5a (103.0 mL, 302.3 mmol), 1-azido-4-nitrobenzene (33.1 g, 201.6 mmol), and glacial acetic acid (1.72 mL, 30.3 mmol) sequentially at room temperature. Heat the reaction mixture to 100°C and stir overnight. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Purify the resulting residue by flash chromatography on silica gel (petroleum ether / ethyl acetate = 3:1) to afford the title compound 6a (13.3 g, 54.1 mmol, 58%) as a pale yellow solid. 1H NMR (400MHz, Chloroform-d, ppm) δ8.38 (s, 1H), 5.73 (p, J = 6.7Hz, 1H), 4.03 (s, 3 H), 3.08 (ddd, J=7.9, 6.6, 1.8Hz, 2H), 3.05–2.92 (m, 2H), 1.70 (d, J=6.7Hz, 6H).

[0329] 5): 1-Isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-H]quinazoline (7a)

[0330] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (36.8 g, 162.4 mmol) was added to a toluene (300 mL) solution of 6a (13.3 g, 54.1 mmol). The temperature was raised to 50°C and the reaction was continued for 24 hours. The resulting residue was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 6:1) to obtain the title compound 7a (10 g, 41.3 mmol, 76%) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ9.32 (s, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.68 (d, J = 8.9Hz, 1H), 6.15 (p, J = 6.7Hz, 1H), 4.21 (s, 3H), 1.87 (d, J = 6.8Hz, 6H).

[0331] 6): 1-Isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl trifluoromethanesulfonate (10a)

[0332] 1-Isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-H]quinazoline 7a (10 g, 41 mmol) was dissolved in HBr / AcOH (1:2, 82 mL). The reaction mixture was heated to 65°C and stirred for 12 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain a white solid. LC-MS (ESI), C 11 H 12 N5O[M+H]+: m / z=230.2.

[0333] The white solid from the previous step was suspended in dichloromethane (205 ml), and diisopropylethylamine (28.5 ml, 164 mmol) was added dropwise. After stirring until the solution was clear, trifluoromethanesulfonic anhydride (13.8 ml, 82 mmol) was added dropwise. The reaction was stirred for 1 hour. 200 ml of water was added, and the mixture was extracted three times with dichloromethane (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to obtain the title compound 10a (11.84 g, 32.8 mmol, 80%) as a white solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ9.53 (s, 1H), 8.29 (d, J = 8.9Hz, 1H), 7.86 (d, J = 8.9Hz, 1H), 6.05 (p, J = 6.7Hz, 1H), 1.86 (d, J = 6.6Hz, 6H).

[0334] 7): (S)-(3-Fluoropyrrolidin-1-yl)(4-nitrophenyl)methanone (14a)

[0335] To a suspension of (S)-3-fluoropyrrolidine 13a (0.22 g, 2.42 mmol, 1.0 eq) in MeCN (2.5 ml) were added p-nitrobenzoic acid 12a (0.44 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. DIPEA (0.79 ml, 4.84 mmol, 2.0 eq) was then added dropwise. The mixture was heated to 50°C and allowed to react 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 rinsed with water (2 ml). The resulting wet product was dried under reduced pressure in vacuo for 2 h to give the title compound 14a (0.49 g, 2.35 mmol, 95%) as a yellow solid. LC-MS (ESI), C 11 H 11 FN2O3[M+H] + :m / z=239.2.

[0336] 8): (S)-(4-Aminophenyl)(3-fluoropyrrolidin-1-yl)methanone (11a)

[0337] At room temperature, 14a (0.49 g, 2.35 mmol, 1.0 eq) was dissolved in MeOH (5 ml), and Pd / C (49 mg) was added to displace H2. The reaction was stirred for 12 h. The filtration funnel was padded with silica gel (0.1 cm) and diatomaceous earth (0.1 cm) from bottom to top. The filtrate was filtered with suction, and the filtrate was concentrated by rotary evaporation under reduced pressure and dried under reduced pressure for 1 h to obtain a yellow solid, the title compound 11a (0.48 g, 2.29 mmol, 97%). LC-MS (ESI), C 11 H 13 FN2O[M+H] + :m / z=209.2.

[0338] 9): (S)-(3-Fluoropyrrolidin-1-yl)(4-((1-isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl)amino)phenyl)methanone (I-1)

[0339] (S)-(4-Aminophenyl)(3-fluoropyrrolidin-1-yl)methanone 11a (104 mg, 0.5 mmol, 1.2 eq) and 10a (150 mg, 0.41 mmol, 1.0 eq) were suspended in DMSO (1 ml) at room temperature. The reaction temperature was raised to 80°C, and DIPEA (82 μl, 50.0 mmol, 1.2 eq) was added dropwise to the reaction system. The reaction was allowed to react for 3 h, followed by the addition of water (3 ml) and stirring for 20 min. The reaction system was cooled to room temperature and stirred for another 2 h. Filtration afforded the title compound (I-1) (141 mg, 0.35 mmol, 86%) as a yellow solid. 1 H NMR(400MHz,Chloroform-d,ppm)δ9.20(s,1H),7.91(d,J=8.8Hz,1H),7.81(d,J=8.4Hz,2H),7.69–7.54(m,4H ), 6.22 (p, J = 6.7Hz, 1H), 5.31 (t, J = 48.3Hz, 1H), 4.04–3.64 (m, 4H), 2.17 (m, 2H), 1.86 (dd, J = 6.8, 3.0Hz, 6H).

[0340] Table 1 Examples I-2 to I-3

[0341] Preparation process of Example 1-2:

[0342] Referring to the synthesis method of 11a, compound (R)-(4-aminophenyl)(3-fluoropyrrolidin-1-yl)methanone 11b (1.3 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and (R)-3-fluoropyrrolidine 13b (0.59 g, 6.6 mmol). LC-MS (ESI), C 11 H 14 N2OF[M+H] + :m / z=209.2.

[0343] Referring to the synthesis method of I-1 in Example 1, compound I-2 (167 mg, 279 μmol, 68%) was prepared from 10a (150 mg, 416 μmol) and 11b (104 mg, 499 μmol). 1 H NMR (400MHz, Chloroform-d, ppm) δ9.20 (s, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.60 (h, J = 12.0, 10.8 Hz, 4H), 6.22 (p, J=6.8Hz, 1H), 5.37 (d, J=51.2Hz, 1H), 4.04–3.57 (m, 4H), 2.17 (m, 2H), 1.86 (dd, J=6.8, 3.0Hz, 6H).

[0344] Preparation process of Example 1-3:

[0345] Referring to the synthesis method of 11a, compound 11c (1.3 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and pyrrolidin-3-ol 13c (0.57 g, 6.6 mmol). 11 H 15 N2O2[M+H]+:m / z=207.1.

[0346] Referring to the synthesis method of I-1 in Example 1, compound I-3 (123 mg, 295 μmol, 72%) was prepared from 10a (150 mg, 416 μmol) and (4-aminophenyl)(3-hydroxypyrrolidin-1-yl)methanone 11c (102 mg, 499 μmol). 1H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.46(s,1H),7.90(dd,J=12.0,8.6Hz,3H),7.80(d,J=8.9Hz,1H),7.60(dd,J=8.5,4.2Hz,2H),6.18(p ,J=6.8Hz,1H),4.98(dd,J=30.5,3.3Hz,1H),4.37–4.20(m,1H),3.73–3 .55(m,2H),3.55–3.36(m,2H),2.03–1.82(m,2H),1.78(d,J=6.7Hz,6H).

[0347] Example I-4

[0348] (S)-(3-Aminopyrrolidin-1-yl)(4-((1-isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl)amino)phenyl)methanone (I-4)

[0349] 1): tert-Butyl (S)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamate (11d)

[0350] Referring to the synthesis method of 11a, compound (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamate 11d (1.9 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate 13d (1.3 g, 6.6 mmol). 16 H 24 N3O[M+H]+: m / z=306.2.

[0351] 2): (S)-tert-Butyl (1-(4-((1-isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl)amino)benzoyl)pyrrolidin-3-yl)carbamate (I-4a)

[0352] At room temperature, 11d (152 mg, 0.5 mmol, 1.2 eq) and 10a (150 mg, 0.41 mmol, 1.0 eq) were suspended in DMSO (1 ml). The reaction temperature was raised to 80°C, and DIPEA (82 μl, 50.0 mmol, 1.2 eq) was added dropwise to the reaction system. The reaction was allowed to react for 3 h, and then water (3 ml) was added to the reaction system and stirred for 20 min. The reaction system was cooled to room temperature and stirred for another 2 h. The mixture was filtered to obtain a yellow solid, the title compound I-4a (180 mg, 0.35 mmol, 86%). LC-MS (ESI), C27 H 33 N8O3[M+H] + :m / z=517.3.

[0353] 3): (S)-(3-aminopyrrolidin-1-yl)(4-((1-isopropyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl)amino)phenyl)methanone (I-4)

[0354] To a solution of I-4a (180 mg, 0.35 mmol, 1.0 eq) in dichloromethane / methanol (9:1, 3.5 ml) was added dropwise HCl (4 M in EA, 0.88 ml, 3.5 mmol, 10 eq) at room temperature. The reaction was stirred for 2 h and concentrated under reduced pressure. The pH of the aqueous phase was adjusted to >10 with aqueous NaOH (4 N). The aqueous phase was extracted with DCM (20 ml). The combined organic phases were washed sequentially with saturated brine (20 ml) and then with H2O (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound I-4 (140 mg, 0.34 mmol, 96%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6,ppm)δ10.38(s,1H),9.46(s,1H),8.02–7.74(m,4H),7.59(d,J=8.4Hz,2H),6 .18(q,J=7.2Hz,1H),3.54(d,J=59.1Hz,4H),3.25–3.11(m,1H),2.00(s,3H),1.78(d,J=6.7Hz,6H), 1.64(s,1H).

[0355] Table 2 Examples I-5 to I-37

[0356] Preparation process of Example 1-5:

[0357] Referring to the synthesis method of 11a, compound (R)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester 11e (1.8 g, 6.1 mmol, 92%) was prepared from 12a (1 g, 7.3 mmol) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester 13e (1.3 g, 6.6 mmol). 16 H 24 N3O[M+H]+: m / z=306.2.

[0358] Referring to the synthesis method of I-4 in Example 1, compound I-5 (106 mg, 254 μmol, two steps 42%) was prepared from 10a (150 mg, 416 μmol) and 11e (152 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.84–7.76(m,2H),7.69–7.55(m,4H),6.21(p,J=6 .7Hz,1H),3.88–3.68(m,3H),3.60(s,1H),3.44–3.24(m,1H),2.20(d,J=11.5Hz,1H),1.85(d,J=6.7Hz,6H),1.76(s,1H).

[0359] Preparation process of Example 1-6:

[0360] Referring to the synthesis method of 11a, compound (S)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)(methyl)carbamic acid tert-butyl ester 11f (1.9 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and (S)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester 13f (1.3 g, 6.6 mmol). 17 H 26 N3O2[M+H]+:m / z=320.2.

[0361] Referring to the synthesis method of I-4 in Example 1, compound I-6 (116 mg, 270 μmol, two steps 66%) was prepared from 10a (150 mg, 416 μmol) and 11f (159 mg, 499 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.45(s,1H),7.90(dd,J=11.8,8.7Hz,3H),7.80(d,J=8.8Hz,1H),7.60(d,J=8.3Hz,2H),6.18(p,J=6.8Hz, 1H),3.69–3.54(m,2H),3.50(d,J=9.8Hz,1H),3.37–3.23(m,2H),3.23–3.0 9(m,1H),2.26(d,J=42.6Hz,3H),2.03–1.93(m,1H),1.78(d,J=6.7Hz,7H).

[0362] Preparation process of Example I-7:

[0363] Referring to the synthesis method of 11a, 11 g (2.0 g, 6.2 mmol, 94%) of (R)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)(methyl)carbamic acid tert-butyl ester was prepared from 12a (1 g, 7.3 mmol) and 13 g (1.3 g, 6.6 mmol). 17 H 26 N3O2[M+H]+:m / z=320.2.

[0364] Referring to the synthesis method of I-4 in Example 1, compound I-7 (111 mg, 258 μmol, two steps 63%) was prepared from 10a (150 mg, 416 μmol) and 11g (159 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.79(d,J=8.3Hz,2H),7.68–7.56(m,4H),6.35–6.07(m,1H),3.93–3 .65(m,3H),3.61–3.48(m,1H),3.41–3.25(m,1H),2.45(d,J=39.9Hz,3H),2.25–2.13(m,1H),2.07(d,J=17.0Hz,1H),1.85(d,J=6.7Hz,6H).

[0365] Preparation process of Example 1-8:

[0366] Referring to the synthesis method of 11a, compound (S)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)(isopropyl)carbamic acid tert-butyl ester 11h (2.2 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and (S)-isopropyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester 13h (1.5 g, 6.6 mmol). 19 H 30 N3O3[M+H]+:m / z=348.2.

[0367] Referring to the synthesis method of I-4 in Example 1, compound I-8 (79 mg, 172 μmol, two steps 42%) was prepared from 10a (150 mg, 416 μmol) and 11h (152 mg, 499 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.79(d,J=8.3Hz,2H),7.67–7.53(m,4H),6.22(p,J=6.6Hz,1H),3.95(m,1H),3. 85–3.64(m,2H),3.58–3.23(m,2H),2.89(d,J=56.1Hz,1H),2.23(s,1H),2. 07(d,J=25.6Hz,1H),1.86(d,J=6.7Hz,6H),1.79(s,1H),1.17–0.98(m,6H).

[0368] Preparation process of Example I-9:

[0369] Referring to the synthesis method of 11a, compound 11i (2.1 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and (R)-isopropyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester 13i (1.5 g, 6.6 mmol). 19 H 30 N3O3[M+H]+:m / z=348.2.

[0370] Referring to the synthesis method of I-4 in Example 1, compound I-9 (77 mg, 168 μmol, two steps, 41%) was prepared from 10a (150 mg, 416 μmol) and ester 11i (152 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.79(d,J=8.4Hz,2H),7.67–7.54(m,4H),6.21(p,J=6.8Hz,1H),3.96(m,1H),3.85 (m,J=88.8Hz,2H),3.58(m,2H),2.89(d,J=57.8Hz,1H),2.23(s,1H),2.17–1 .87(m,1H),1.85(d,J=6.7Hz,6H),1.80(d,J=10.6Hz,1H),1.20–0.90(m,6H).

[0371] Preparation process of Example I-10:

[0372] Referring to the synthesis method of 11a, compound (S)-(4-aminophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone 11j (1.4 g, 6 mmol, 91%) was prepared from 12a (1 g, 7.3 mmol) and (S)-N,N-dimethylpyrrolidin-3-amine 13j (0.75 g, 6.6 mmol).

[0373] C 13 H 20 N3O[M+H]+: m / z=234.2.

[0374] Referring to the synthesis method of I-1 in Example 1, compound I-10 (60 mg, 140 μmol, 40%) was prepared from 10a (150 mg, 416 μmol) and 11j (116 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.80(t,J=6.0Hz,2H),7.61(dt,J=12.5,6.4Hz,4H),6.22(p,J=6.8Hz,1H),3 .91(dt,J=44.8,10.5Hz,1H),3.80–3.54(m,2H),3.45(dt,J=20.0,9.9Hz ,1H),2.87–2.64(m,1H),2.33(s,3H),2.24(s,4H),1.86(d,J=6.8Hz,7H).

[0375] Preparation process of Example I-11:

[0376] Referring to the synthetic method of 11a, compound (R)-(4-aminophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone 11k (1.4 g, 6 mmol, 91%) was prepared from 12a (1 g, 7.3 mmol) and (S)-N,N-dimethylpyrrolidin-3-amine 13k (0.75 g, 6.6 mmol). 13 H 20 N3O[M+H]+: m / z=234.2.

[0377] Referring to the synthesis method of I-1 in Example 1, compound I-11 (59 mg, 133 μmol, 32%) was prepared from 10a (150 mg, 416 μmol) and 11k (116 mg, 499 μmol). 1H NMR (400MHz, Chloroform-d, ppm) δ9.19 (s, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.80 (d, J = 8.2Hz, 2H), 7.59 (q, J = 9.0Hz ,4H),6.27–6.16(m,1H),4.04–3.34(m,4H),2.75(d,J=40.7Hz,1H),2.29(d,J=35.3Hz,6H),2.18–1.88(m,2H).

[0378] Preparation process of Example I-12:

[0379] Referring to the synthesis method of 11a, tert-butyl (3R,4R)-1-(4-aminobenzoyl)-4-methylpiperidin-3-yl)carbamate 111 (2.1 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl (3R,4R)-4-methylpiperidin-3-yl)carbamate 131 (1.4 g, 6.6 mmol). 18 H 28 N3O3[M+H]+:m / z=334.2.

[0380] Referring to the synthesis method of I-4 in Example 1, compound I-12 (136 mg, 308 μmol, two steps 75%) was prepared from 10a (150 mg, 416 μmol) and 111 (166 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.18(s,1H),7.89(d,J=8.8Hz,1H),7.78(d,J=8.5Hz,2H),7.68–7.44(m,4H), 6.21(p,J=6.7Hz,1H),3.31–3.18(m,1H),3.06(s,2H),1.85(d,J=6.7Hz,8H),1.01(m,3H),1.01(d,J=6.8Hz,3H).

[0381] Preparation process of Example I-13:

[0382] Referring to the synthesis method of 11a, tert-butyl (3R,4R)-1-(4-aminobenzoyl)-4-hydroxypiperidin-3-yl)carbamate 11m (2.1 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl (3R,4R)-4-hydroxypiperidin-3-yl)carbamate 13m (1.4 g, 6.6 mmol). 17 H 26N3O4[M+H]+:m / z=336.2.

[0383] Referring to the synthesis method of I-4 in Example 1, compound I-13 (102 mg, 300 μmol, two steps 56%) was prepared from 10a (150 mg, 416 μmol) and 11m (167 mg, 499 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.37(s,1H),9.46(s,1H),7.90(dd,J=10.7,8.6Hz,3H),7.80(d,J=8.8Hz,1H),7.46(d,J=8.3 Hz, 2H), 6.18 (p, J = 6.7Hz, 1H), 4.89 (d, J = 4.5Hz, 1H), 3.25 (s, 3H), 1.77 (dd, J = 6.8, 2.8Hz, 9H), 1.35 (q, J = 10.5, 9.8Hz, 1H).

[0384] Preparation process of Example I-14:

[0385] Referring to the synthesis method of 11a, compound 11n (2.1 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl (3R, 4S)-4-hydroxypiperidin-3-yl)carbamate 13n (1.4 g, 6.6 mmol). 17 H 26 N3O4[M+H]+:m / z=336.2.

[0386] Referring to the synthesis method of I-4 in Example 1, compound I-14 (95 mg, 213 μmol, two steps 52%) was prepared from 10a (150 mg, 416 μmol) and tert-butyl (3R, 4S)-1-(4-aminobenzoyl)-4-hydroxypiperidin-3-yl)carbamate 11n (167 mg, 499 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.35(s,1H),9.45(s,1H),7.89(dd,J=8.6,5.0Hz,3H),7.80(d,J=8.8Hz,1H),7.48(s,2H),6.28–6.08 (m,1H),4.76(s,1H),3.59(d,J=57.6Hz,1H),3.25(m,2H),3.12(s,1H),2.88(s,1H),1.77(d,J=6.6Hz,6H),1.64(d,J=24.7Hz,2H).

[0387] Preparation process of Example I-15:

[0388] Referring to the synthesis method of 11a, compound (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone 11o (1.5 g, 5.9 mmol, 89%) was prepared from 12a (1 g, 7.3 mmol) and N,N-dimethylpiperidin-4-amine 13o (0.85 g, 6.6 mmol). 14 H 22 N3O[M+H]+: m / z=248.2.

[0389] Referring to the synthesis method of I-4a in Example 1, compound I-15 (113 mg, 246 μmol, 60%) was prepared from 10a (150 mg, 416 μmol) and 11o (159 mg, 499 μmol). 1 H NMR (600MHz, DMSO-d6, ppm) δ10.39(d,J=3.4Hz,1H),9.46(d,J=3.9Hz,1H),7.93(dd,J=8.6,3.6Hz,2H),7.89(dd,J=8.8,4.1Hz,1H),7.81(dd,J =9.0,3.7Hz,1H),7.48(dd,J=8.6,3.5Hz,2H),6.18(dq,J=12.7,6.7Hz,1H),2.62(s,5H),1.99(s,2H),1.77(dd,J=7.2,3.8Hz,6H),1.57(s,2H).

[0390] Preparation process of Example I-16:

[0391] Referring to the synthesis method of 11a, tert-butyl (1-(4-amino-2-fluorobenzoyl)piperidin-4-yl)carbamate 11p (2.1 g, 6.1 mmol, 93%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl piperidin-4-ylcarbamate 13p (1.3 g, 6.6 mmol). 17 H 25 FN3O3[M+H]+:m / z=338.2.

[0392] Referring to the synthesis method of I-4 in Example 1, compound I-16 (132 mg, 295 μmol, two steps 72%) was prepared from 10a (150 mg, 416 μmol) and 11p (167 mg, 499 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.21(d,J=1.2Hz,1H),8.05(dd,J=12.3,2.0Hz,1H),7.94(d d,J=8.9,1.2Hz,1H),7.68(s,1H),7.61(dd,J=8.8,1.2Hz,1H),7.41(t,J=7.9Hz,1H),7.22(dd ,J=8.3,2.0Hz,1H),6.22(p,J=6.7Hz,1H),4.66(d,J=13.5Hz,1H),3.69(d,J=13.7Hz,1H),3.1 4(s,1H),3.06–2.91(m,2H),1.97(d,J=13.2Hz,1H),1.88(d,J=6.8Hz,7H),1.47–1.28(m,2H).

[0393] Preparation process of Example I-17:

[0394] Referring to the synthesis method of 11a, compound 11q (1.5 g, 5.8 mmol, 88%) was prepared from 12a (1 g, 7.3 mmol) and N,N-dimethylpiperidin-4-amine 13q (0.84 g, 6.6 mmol). 14 H 21 N3OF[M+H]+: m / z=266.2.

[0395] Referring to the synthesis method of I-4a in Example 1, compound I-17 (93 mg, 209 μmol, 51%) was prepared from 10a (150 mg, 416 μmol) and (4-amino-2-fluorophenyl)(4-(dimethylamino)piperidin-1-yl)methanone 11q (132 mg, 499 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.58 (s, 1H), 9.50 (s, 1H), 8.03 (dd, J = 12.8, 2.0Hz, 1H), 7.9 4(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),7.61(dd,J=8.4,2.0Hz,1H),7.44(t,J=8.2Hz,1 H),6.19(p,J=6.7Hz,1H),4.57(d,J=13.1Hz,1H),3.59(d,J=13.6Hz,1H),3.17–3.07(m,1 H), 2.82 (t, J = 12.5Hz, 2H), 2.49 (s, 6H), 1.99 (s, 2H), 1.78 (d, J = 6.7Hz, 6H), 1.45 (s, 2H).

[0396] Preparation process of Example I-18:

[0397] Referring to the synthesis method of 11a, compound (4-aminophenyl)(4-fluoropiperidin-1-yl)methanone 11r (1.4 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and 4-fluoropiperidine 13r (0.68 g, 6.6 mmol). 12 H 16 N2OF[M+H]+: m / z=223.1.

[0398] Referring to the synthesis method of I-4a in Example 1, compound I-18 (114 mg, 258 μmol, 63%) was prepared from 10a (150 mg, 416 μmol) and 11r (110 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.85–7.76(m,2H),7.59(d,J=8.8Hz,1H),7.55 (s,1H),7.52–7.46(m,2H),6.21(p,J=6.7Hz,1H),5.03–4.82(m,1H),3.68(s,4H),1.93(s,4H),1.85(d,J=6.7Hz,6H).

[0399] Preparation process of Example I-19:

[0400] Referring to the synthesis method of 11a, tert-butyl 4-(4-amino-2-fluorobenzoyl)piperazine-1-carboxylate 11s (2 g, 6.1 mmol, 92%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl piperazine-1-carboxylate 13s (1.2 g, 6.6 mmol). 16 H 23 N3O3[M+H]+:m / z=324.2.

[0401] Referring to the synthesis method of I-4 in Example 1, compound I-19 (112 mg, 258 μmol, two steps 63%) was prepared from 10a (150 mg, 416 μmol) and 11s (161 mg, 499 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),8.05(dd,J=12.3,2.1Hz,1H),7.94(d,J=8.8Hz,1H),7.77(s,1H),7.61(d,J=8.9Hz,1H),7. 43(t,J=7.9Hz,1H),7.26–7.22(m,1H),6.21(p,J=6.7Hz,1H),3.83(t,J=5.1Hz,2H),3.43(s,2H),3.06–2.85(m,4H),1.88(d,J=6.7Hz,6H).

[0402] Preparation process of Example 1-20:

[0403] Referring to the synthesis method of 11a, compound (S)-4-(4-aminobenzoyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 11t (1.9 g, 6 mmol, 91%) was prepared from 12a (1 g, 7.3 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 13t (1.3 g, 6.6 mmol). 17 H 26 N3O3[M+H]+:m / z=320.2.

[0404] Referring to the synthesis method of I-4 in Example 1, compound I-20 (114 mg, 267 μmol, two steps 65%) was prepared from 10a (150 mg, 416 μmol) and 11t (159 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.9Hz,1H),7.80(d,J=8.3Hz,2H),7.63–7.54(m,2H),7.49(d,J=8.5Hz, 2H), 6.31–6.07 (m, 1H), 4.50 (d, J = 75.7Hz, 1H), 3.79 (s, 1H), 2.95 (d, J = 75.3Hz, 4H), 1.85 (d, J = 6.7Hz, 7H), 1.14 (d, J = 38.2Hz, 3H).

[0405] Preparation process of Example I-21:

[0406] Referring to the synthesis method of 11a, compound (R)-4-(4-aminobenzoyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 11u (1.9 g, 6 mmol, 91%) was prepared from 12a (1 g, 7.3 mmol) and (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 13u (1.3 g, 6.6 mmol). 17 H 26 N3O3[M+H]+:m / z=320.2.

[0407] Referring to the synthesis method of I-4 in Example 1, compound I-21 (107 mg, 250 μmol, two steps 61%) was prepared from 10a (150 mg, 416 μmol) and 11u (159 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.80(d,J=8.3Hz,2H),7.68–7.56(m,2H),7.49(d,J=8.3 Hz, 2H), 6.21 (p, J = 6.7Hz, 1H), 4.59 (s, 1H), 3.87 (d, J = 63.1Hz, 1H), 2.95 (d, J = 76.0Hz, 5H), 1.85 (d, J = 6.7Hz, 6H), 1.09 (s, 3H).

[0408] Preparation process of Example 1-22:

[0409] Referring to the synthesis method of 11a, compound 4-(4-aminobenzoyl)-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester 11v (2.1 g, 6.2 mmol, 94%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate 13v (1.4 g, 6.6 mmol). 18 H 28 N3O3[M+H]+:m / z=334.2.

[0410] Referring to the synthesis method of I-4 in Example 1, compound I-22 (136 mg, 371 μmol, two steps 75%) was prepared from 10a (150 mg, 416 μmol) and 11v (166 mg, 499 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.86–7.73(m,2H),7.67–7.53(m,2H),7.48 (d,J=8.2Hz,2H),6.21(p,J=6.7Hz,1H),3.49(s,4H),2.99(s,2H),1.85(d,J=6.7Hz,6H),1.17(d,J=13.5Hz,6H).

[0411] Preparation process of Example 1-23:

[0412] Referring to the synthesis method of 11a, compound (2R,6S)-4-(4-aminobenzoyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester 11w (2.1 g, 6.2 mmol, 94%) was prepared from 12a (1 g, 7.3 mmol) and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester 13w (1.4 g, 6.6 mmol). 18 H 28 N3O3[M+H]+:m / z=334.2.

[0413] Referring to the synthesis method of I-4 in Example 1, compound I-23 (96 mg, 217 μmol, two steps 53%) was prepared from 10a (150 mg, 416 μmol) and 11w (166 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.85–7.74(m,2H),7.59(d,J=8.6Hz,2H),7.53–7.46 (m,2H),6.22(p,J=6.7Hz,1H),4.63(s,1H),3.74(s,1H),2.67(d,J=180.8Hz,4H),1.85(d,J=6.7Hz,6H),1.22–0.89(m,6H).

[0414] Preparation process of Example 1-24:

[0415] Referring to the synthetic method of 11a, 12a (1 g, 7.3 mmol) and 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 13x (1.3 g, 6.6 mmol) were used to prepare compound 3-(4-aminobenzoyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 11x (1.58 g, 5.8 mmol, 88%), C17 H 24 N3O3[M+H]+:m / z=318.2.

[0416] Referring to the synthesis method of I-4 in Example 1, compound I-24 (79 mg, 185 μmol, two steps 45%) was prepared from 10a (150 mg, 416 μmol) and 11x (158 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.87–7.76(m,2H),7.64–7.49(m,4H),6.22(p,J= 6.7Hz, 1H), 4.14 (d, J = 13.6Hz, 1H), 3.95–3.65 (m, 5H), 2.81–2.70 (m, 1H), 1.86 (d, J = 6.7Hz, 6H), 1.60 (d, J = 9.1Hz, 2H).

[0417] Preparation process of Example 1-25:

[0418] Referring to the synthesis method of 11a, compound 11y (1.9 g, 5.9 mmol, 89%) was prepared from 12a (1 g, 7.3 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate 13y (1.4 g, 6.6 mmol). 18 H 26 N3O3[M+H]+:m / z=332.2.

[0419] Referring to the synthesis method of I-4 in Example 1, compound I-25 (79 mg, 176 μmol, two steps 43%) was prepared from 10a (150 mg, 416 μmol) and 3-(4-aminobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 11y (165 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.84–7.75(m,2H),7.59(d,J=8.9Hz,2H),7 .49–7.40(m,2H),6.21(p,J=6.7Hz,1H),4.52(s,1H),3.52(d,J=64.1Hz,4H),3.06(s,1H),1.85(d,J=6.7Hz,10H).

[0420] Preparation process of Example 1-26:

[0421] Referring to the synthesis method of 11a, compound 11z (1.4 g, 6 mmol, 91%) was prepared from 12a (1 g, 7.3 mmol) and 1-methylpiperazine 13z (0.66 g, 6.6 mmol). 12 H 17 N3OF[M+H]+: m / z=238.1.

[0422] Referring to the synthesis method of I-1 in Example 1, compound I-26 (66 mg, 148 μmol, 36%) was prepared from 10a (150 mg, 416 μmol) and (4-amino-2-fluorophenyl)(4-methylpiperazin-1-yl)methanone 11z (118 mg, 499 μmol). 1 H NMR(600MHz,Chloroform-d,ppm)δ9.22(s,1H),8.06(dd,J=12.2,2.1Hz,1H),7.95(d,J=8.8Hz,1H),7.69(s,1H),7.62(d,J=8.8Hz,1H),7.44(t, J=8.0Hz,1H),7.25–7.23(m,1H),6.26–6.16(m,1H),3.95(s,2H),3.57(s ,2H),2.63(d,J=61.0Hz,4H),2.46(s,3H),1.87(dd,J=14.3,6.7Hz,6H).

[0423] Preparation process of Example 1-27:

[0424] Referring to the synthetic method of 11a, compound (R)-(4-aminophenyl)(3,4-dimethylpiperazin-1-yl)methanone 11z1 (1.3 g, 5.7 mmol, 87%) was prepared from 12a (1 g, 7.3 mmol) and (R)-1,2-dimethylpiperazine 13z1 (0.75 g, 6.6 mmol). 13 H 20 N3O[M+H]+: m / z=234.2.

[0425] Referring to the synthesis method of I-1 in Example 1, compound I-27 (62 mg, 139 μmol, 34%) was prepared from 10a (150 mg, 416 μmol) and 11z1 (116 mg, 499 μmol). 1H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.46(s,1H),7.97–7.72(m,4H),7.46(d,J=8.3Hz,2H),6.18(p,J=6.7Hz,1H ), 4.44–4.00(m,1H),2.96–2.51(m,4H),2.20(s,3H),2.14–1.97(m,2H),1.77(d,J=6.7Hz,6H),0.92(d,J=51.9Hz,3H).

[0426] Preparation process of Example 1-28:

[0427] Referring to the synthesis method of 11a, compound (S)-(4-aminophenyl)(3,4-dimethylpiperazin-1-yl)methanone 11z2 (1.4 g, 5.9 mmol, 90%) was prepared from 12a (1 g, 7.3 mmol) and (S)-1,2-dimethylpiperazine 13z2 (0.75 g, 6.6 mmol). 13 H 20 N3O[M+H]+: m / z=234.2.

[0428] Referring to the synthesis method of I-1 in Example 1, compound I-28 (76 mg, 172 μmol 42%) was prepared from 10a (150 mg, 416 μmol) and 11z2 (116 mg, 499 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.46(s,1H),7.91(dd,J=13.0,8.6Hz,3H),7.80(d,J=8.8Hz,1H),7.46(d,J=8.5Hz,2H),6.18(p,J=6. 7Hz,1H),3.91(d,J=246.5Hz,1H),3.31(s,2H),2.71(d,J=28.9Hz,2H), 2.21 (s, 3H), 2.07 (d, J = 24.6Hz, 2H), 1.77 (d, J = 6.6Hz, 6H), 0.98 (s, 3H).

[0429] Preparation process of Example 1-29:

[0430] Referring to the synthetic method of 11a, compound (4-aminophenyl)(4-ethylpiperazin-1-yl)methanone 11z3 (1.4 g, 5.9 mmol, 90%) was prepared from 12a (1 g, 7.3 mmol) and 1-ethylpiperazine 13z3 (0.75 g, 6.6 mmol). 13 H 20N3O[M+H]+: m / z=234.2.

[0431] Referring to the synthesis method of I-1 in Example 1, compound I-29 (98 mg, 221 μmol, 54%) was prepared from 10a (150 mg, 416 μmol) and 11z3 (116 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.84–7.77(m,2H),7.62–7.53(m,2H),7.53–7.46( m, 2H), 6.21 (p, J = 6.7Hz, 1H), 3.70 (d, J = 64.2Hz, 4H), 2.48 (q, J = 7.2Hz, 6H), 1.85 (d, J = 6.7Hz, 6H), 1.12 (t, J = 7.2Hz, 3H).

[0432] Preparation process of Example 1-30:

[0433] Referring to the synthesis method of 11a, the compound (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone 11z4 (1.5 g, 6.1 mmol, 92%) was prepared from 12a (1 g, 7.3 mmol) and 1-isopropylpiperazine 13z4 (0.85 g, 6.6 mmol). 14 H 22 N3O[M+H]+: m / z=248.2.

[0434] Referring to the synthesis method of I-1 in Example 1, compound I-30 (118 mg, 258 μmol, 63%) was prepared from 10a (150 mg, 416 μmol) and 11z4 (123 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.82–7.75(m,2H),7.63–7.55(m,2H),7.53–7.46(m, 2H), 6.21 (p, J = 6.7Hz, 1H), 3.71 (d, J = 67.2Hz, 4H), 2.78 (s, 1H), 2.58 (s, 4H), 1.85 (d, J = 6.7Hz, 6H), 1.09 (d, J = 6.5Hz, 6H).

[0435] Preparation process of Example I-31:

[0436] Referring to the synthesis method of 11a, compound (4-aminophenyl)(4-(3-hydroxypropyl)piperazin-1-yl)methanone 11z5 (1.5 g, 6.1 mmol, 92%) was prepared from 12a (1 g, 7.3 mmol) and 3-(piperazin-1-yl)propan-1-ol 13z5 (0.85 g, 6.6 mmol). 14 H 22 N3O[M+H]+: m / z=264.2.

[0437] Referring to the synthesis method of I-1 in Example 1, compound I-31 (114 mg, 241 μmol, 58%) was prepared from 10a (150 mg, 416 μmol) and 11z5 (131 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.12(s,1H),7.83(d,J=8.8Hz,1H),7.64–7.57(m,2H),7.54-7.48(m,2H),7.45-7.38(m,2H),6. 14(p,J=6.7Hz,1H),4.43(s,1H),4.26(s,2H),3.85(d,J=5.3Hz,4H),3.00(s,2H),2.79(s,4H),1.80(d,J=6.7Hz,6H),1.65(m,2H).

[0438] Preparation process of Example 1-32:

[0439] Referring to the synthesis method of 11a, compound (4-aminophenyl)(1,1-dioxythiomorpholinyl)methanone 11z6 (1.6 g, 6.3 mmol, 96%) was prepared from 12a (1 g, 7.3 mmol) and thiomorpholine 1,1-dioxide 13z6 (0.89 g, 6.6 mmol). 11 H 15 N2O3S[M+H]+:m / z=255.1.

[0440] Referring to the synthesis method of I-1 in Example 1, compound I-32 (139 mg, 300 μmol, 72%) was prepared from 10a (150 mg, 416 μmol) and 11z6 (127 mg, 499 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.22(s,1H),7.94(d,J=8.9Hz,1H),7.87(d,J=8.6Hz,2H),7.63–7. 57(m,2H),7.52(d,J=8.5Hz,2H),6.23–6.17(m,1H),4.17(s,4H),3.10(s,4H),1.87(d,J=6.7Hz,6H).

[0441] Preparation process of Example 1-33:

[0442] Referring to the synthesis method of 11a, compound 11z7 (1.9 g, 6.1 mmol, 92%) was prepared from 12a (1 g, 7.3 mmol) and 1,4-diazepane-1-carboxylic acid tert-butyl ester 13z7 (1.3 g, 6.6 mmol). 17 H 26 N3O3[M+H]+:m / z=320.2.

[0443] Referring to the synthesis method of I-4 in Example 1, compound I-33 (134 mg, 312 μmol, two steps 76%) was prepared from 10a (150 mg, 416 μmol) and tert-butyl 4-(4-aminobenzoyl)-1,4-diazepane-1-carboxylate 11z7 (159 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.79(d,J=8.2Hz,2H),7.59(d,J=8.3Hz,2H),7. 49(d,J=8.2Hz,2H),6.21(p,J=6.7Hz,1H),3.81(s,2H),3.57(s,2H),3.11(s,1H),2.97(s,3H),1.85(d,J=6.7Hz,8H).

[0444] Preparation process of Example 1-34:

[0445] Referring to the synthesis method of 11a, compound (4-aminophenyl)(4-methyl-1,4-diazepan-1-yl)methanone 11z8 (1.5 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and 1-methyl-1,4-diazepane 13z8 0.75 g, 6.6 mmol).

[0446] C 13 H 20N3O[M+H]+: m / z=234.2.

[0447] Referring to the synthesis method of I-1 in Example 1, compound I-34 (102 mg, 229.6 μmol, 56%) was prepared from 10a (150 mg, 416 μmol) and 11z8 (159 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.79(d,J=8.3Hz,2H),7.59(d,J=8.8Hz,1H),7.52(d,J=20.5Hz,3H),6.21(p,J= 6.7Hz,1H),3.73(dd,J=83.7,18.7Hz,4H),2.84(s,1H),2.65(d,J=23.8Hz, 3H), 2.43 (d, J = 28.9Hz, 3H), 2.00 (d, J = 33.6Hz, 2H), 1.85 (d, J = 6.7Hz, 6H).

[0448] Preparation process of Example 1-35:

[0449] Referring to the synthesis method of 11a, compound (4-aminophenyl)(morpholinyl)methanone 11z9 (1.5 g, 6.3 mmol, 95%) was prepared from 12a (1 g, 7.3 mmol) and morpholine 13z9 (0.57 g, 6.6 mmol). 12 H 17 N2O2[M+H]+:m / z=221.1.

[0450] Referring to the synthesis method of I-1 in Example 1, compound I-35 (109 mg, 262 μmol, 63%) was prepared from 10a (150 mg, 416 μmol) and 11z9 (110 mg, 499 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.20(s,1H),7.91(d,J=8.8Hz,1H),7.81(d,J=8.2Hz,2H),7.6 2–7.54(m,2H),7.50(d,J=8.2Hz,2H),6.21(p,J=6.7Hz,1H),3.74(s,8H),1.86(d,J=6.7Hz,6H).

[0451] Preparation process of Example 1-36:

[0452] Referring to the synthetic method of 11a, 12a (1 g, 7.3 mmol) and piperidine-4-ol 13z were synthesized.10 (0.67 g, 6.6 mmol) to prepare compound (4-aminophenyl)(4-hydroxypiperidin-1-yl)methanone 11z 10 (1.4 g, 6.1 mmol, 93%), C 13 H 20 N3O[M+H]+: m / z=221.1.

[0453] Referring to the synthesis method of I-1 in Example 1, 10a (150 mg, 416 μmol) and 11z 10 (110 mg, 499 μmol) was used to prepare compound I-36 (146 mg, 339 μmol, 68%). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.82–7.77(m,2H),7.59(d,J=8.8Hz,2H),7. 50–7.46(m,2H),6.21(p,J=6.8Hz,1H),4.02(s,1H),3.36(s,2H),1.95(s,2H),1.85(d,J=6.7Hz,6H).1.63(m,4H).

[0454] Preparation process of Example 1-37:

[0455] Referring to the synthesis method of 11a, 12a (1 g, 7.3 mmol) and 4,4-difluoropyridine 13z were synthesized. 11 (0.8 g, 6.6 mmol) to prepare compound (4-aminophenyl)(4,4-difluoropiperidin-1-yl)methanone 11z 11 (1.4 g, 6.1 mmol, 93%), C 12 H 15 FN2O[M+H]+: m / z=241.1.

[0456] Referring to the synthesis method of I-1 in Example 1, 10a (150 mg, 416 μmol) and 11z 11 (120 mg, 499 μmol) was used to prepare compound I-37 (122 mg, 270 μmol, 65%). 1H NMR (400MHz, Chloroform-d, ppm) δ9.20 (s, 1H), 7.92 (d, J = 8.8Hz, 1H), 7.82 (d, J = 8.2Hz, 2H), 7.63–7. 54(m,2H),7.54–7.47(m,2H),6.21(p,J=6.7Hz,1H),3.78(s,4H),2.04(s,4H),1.86(d,J=6.7Hz,6H).

[0457] Preparation of intermediate 1-cyclopentyl-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl trifluoromethanesulfonate (10b)

[0458] 1) Referring to the synthesis method of 6a in Example 1, compound 4a (1.2 g, 6.74 mmol) was reacted to obtain 1-cyclopentyl-8-methoxy-4,5-dihydro-1H-[1,2,3]triazolo[4,5-H]quinazoline 6b (1.06 g, 3.91 mmol, 58%). 1 H NMR(400MHz,Chloroform-d,ppm)δ8.46(s,1H),4.68(d,J=7.4Hz,2H),3.92(s,3H),3.15–2.88(m,4 H), 2.42 (dq, J=13.2, 6.4Hz, 2H), 2.32 (m, 1H),, 2.10 (td, J=13.2, 6.4Hz, 2H), 1.88 (d, J=8.0Hz, 4H).

[0459] 2): Referring to the synthesis steps of 7a in Example 1, 7b (705 mg, 2.62 mmol, 71%) was prepared from 6b (1.0 g, 3.69 mmol). LC-MS (ESI), C 14 H 16 N5O[M+H] + :m / z=270.1.

[0460] 3) Referring to the synthesis steps of 10a in Example 1, 10b (862 mg, 2.23 mmol, 85%) was prepared from 7b (705 mg, 2.62 mmol). 1H NMR (400MHz, Chloroform-d, ppm) δ9.39 (s, 1H), 8.21 (dd, J=8.9, 0.8Hz, 1H), 7.76 (dd, J=8.9, 0.9Hz, 1H), 6.14 (p, J=6.7Hz, 1H), 2.26 (tdd, J=14.4, 7.5, 4.3Hz, 4H), 2.05–1.92 (m, 2H), 1.85–1.71 (m, 2H).

[0461] Table 3 Examples I-38 to I-42

[0462] Preparation of Example 1-38:

[0463] Referring to the synthesis method of I-4 in Example 1, compound I-38 (108 mg, 244 μmol, two steps 63%) was prepared from 10b (150 mg, 387 μmol) and (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamate 11d (142 mg, 465 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.40(s,1H),9.46(s,1H),7.91(dd,J=13.7,8.6Hz,3H),7.80(d,J=8.8Hz,1H),7.57(t,J=7.3Hz,2H),6.33 (t,J=6.8Hz,1H),4.47(s,2H)3.66(s,3H),3.52(s,2H),2.36(q,J=7.2Hz,2H),2.33–2.23(m,2H),2.11–1.93(m,3H),1.87–1.68(m,3H).

[0464] Preparation of Example 1-39:

[0465] Referring to the synthesis method of I-4 in Example 1, compound I-39 (102 mg, 224.6 μmol, two steps 58%) was prepared from 10b (150 mg, 387 μmol) and (S)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)(methyl)carbamic acid tert-butyl ester 11f (148 mg, 465 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.20(s,1H),7.92(d,J=8.8Hz,1H),7.82(d,J=8.2Hz,2H),7.63(dt,J=19.7,5.8Hz,4H),6.39(p,J=6 .8Hz,1H),3.96–3.70(m,3H),3.63–3.51(m,1H),3.35(d,J=44.0Hz,1H),2.58–2.36(m,7H),2.27–2.05(m,3H),1.90(d,J=13.6Hz,3H).

[0466] Preparation of Example I-40:

[0467] Referring to the synthesis method of I-1 in Example 1, compound I-40 (75 mg, 159 μmol, 41%) was prepared from 10b (150 mg, 387 μmol) and (S)-(4-aminophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone 11j (108 mg, 465 μmol). 1 H NMR(400MHz,Chloroform-,ppm d)δ9.19(s,1H),7.90(d,J=8.8Hz,1H),7.81(d,J=8.1Hz,2H),7.60(t,J=9.0Hz,4H),6.37(t,J=6.9Hz,1H),3.69(t,J= 67.8Hz, 4H), 2.81 (d, J = 47.2Hz, 1H), 2.46–2.36 (m, 6H), 2.28 (s, 2H), 2.11 (s, 2H), 1.91 (d, J = 18.9Hz, 4H), 1.66 (s, 2H).

[0468] Preparation of Example I-41:

[0469] Referring to the synthesis method of I-4 in Example 1, compound I-41 (104 mg, 252 μmmol, two steps 65%) was prepared from 10b (150 mg, 387 μmol) and tert-butyl 4-(4-aminobenzoyl)-1,4-diazepane-1-carboxylate 11z7 (148 mg, 465 μmol). 1H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.46(s,1H),7.95–7.87(m,3H),7.80(d,J=8.8Hz,1H),7.47(d,J=8.1Hz,2H),6.33(p,J= 6.8Hz,1H),3.65(d,J=102.0Hz,4H),3.23–3.06(m,4H),2.41–2.32(m,2H),2.32–2.22(m,2H),2.03–1.87(m,4H),1.87–1.74(m,2H).

[0470] Preparation of Example I-42:

[0471] Referring to the synthesis method of I-1 in Example 1, compound I-42 (69 mg, 147 μmol, 38%) was prepared from 10b (150 mg, 387 μmol) and (4-aminophenyl)(4-methyl-1,4-diazepan-1-yl)methanone 11z8 (108 mg, 465 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.19(s,1H),7.91(d,J=8.8Hz,1H),7.83(d,J= 8.2Hz,2H),7.65(s,1H),7.59(d,J=8.8Hz,1H),7.51(d,J=7.7Hz,2H),6.35(p,J= 6.9Hz,1H),4.20–3.53(m,4H),3.25(s,1H),3.02(s,1H),2.73(s,2H),2.40(dq,J =15.2, 7.9Hz, 5H), 2.11 (d, J = 8.4Hz, 3H), 1.86 (q, J = 6.5, 6.0Hz, 3H), 1.25 (s, 2H).

[0472] Preparation of intermediate 4-(difluoromethyl)-1-isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-H]quinazoline (10c)

[0473] 1): 4-Bromo-1-isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-h]quinazoline (8a)

[0474] To a solution of 7a (3.9 g, 16.0 mmol) in AcOH / MeOH (1:1, 120 mL) was added Br2 (12.5 g, 80.0 mmol) at 0°C and allowed to react for 2 hours. The reaction was quenched by the addition of saturated aqueous Na2S2O3 (60 mL). The aqueous phase was extracted with CH2Cl2 (150 mL x 3). The combined organic phases were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to afford the title compound 8a (4.89 g, 15.2 mmol, 95%) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ9.25 (s, 1H), 7.89 (s, 1H), 6.13 (h, J = 6.7Hz, 1H), 4.20 (s, 3H), 1.86 (d, J = 6.7Hz, 6H).

[0475] 2): 1-Isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-h]quinazoline-4-carboxylic acid methyl ester (9a)

[0476] To a solution of 8a (4.9 g, 15.2 mmol) in N,N-dimethylformamide (38 mL) and methanol (38 mL) was added 1,3-bis(diphenylphosphino)propane (1.3 g, 2.28 mmol), palladium acetate (340 mg, 1.5 mmol), and N,N-diisopropylethylamine (10.5 mL, 76 mmol) at room temperature. The reaction mixture was then air-purified twice with carbon monoxide gas and heated to 80°C under a carbon monoxide balloon for 12 h. The reaction mixture was diluted with ethyl acetate (60 mL) and saturated aqueous sodium bicarbonate solution (50 mL), the organic phase was separated, washed with water (50 mL × 2) and saturated brine (60 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give the title compound 9a (4.1 g, 13.3 mmol, 88%) as a white solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ9.41 (s, 1H), 8.50 (s, 1H), 6.19 (h, J = 6.8Hz, 1H), 4.24 (s, 3H), 4.14 (s, 3H), 1.86 (d, J = 6.8Hz, 6H).

[0477] 3): 1-Isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-h]quinazoline-4-carbaldehyde (9b)

[0478] Under ice, lithium aluminum tetrahydride (2.0 g, 53.5 mmol) was added portionwise to a solution of 9a (4.1 g, 13.4 mmol) in tetrahydrofuran (133 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction flask was then transferred to an ice-water bath, diluted with ethyl acetate (40 mL), and quenched by the careful dropwise addition of saturated sodium potassium tartrate (30 mL). The reaction mixture was again warmed to room temperature and stirred for 1 hour. The aqueous layer was separated and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 1), dried (over anhydrous sodium sulfate), filtered, and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (100 mL), manganese dioxide (3 g) was added, and the mixture was stirred at reflux overnight. The residue was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 12:1) to give the title compound 9b (2.7 g, 9.8 mmol, 73%) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ 10.92 (s, 1H), 9.47 (s, 1H), 8.34 (s, 1H), 6.16 (h, J = 6.8Hz, 1H), 4.26 (s, 3H), 1.89 (d, J = 6.7Hz, 6H).

[0479] 4): 4-(Difluoromethyl)-1-isopropyl-8-methoxy-1H-[1,2,3]triazolo[4,5-h]quinazoline (9c)

[0480] To a solution of 9b (2.7 g, 9.8 mmol) in dichloromethane (100 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (4.3 g, 19.5 mmol) at room temperature and allowed to react overnight with stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 6:1) to afford the title compound 9c (2.4 g, 8.2 mmol, 84%) as a pale yellow solid. 1 H NMR (400MHz, Chloroform-d, ppm) δ9.36 (s, 1H), 7.94 (t, J = 1.8Hz, 1H), 7.52 (d, J = 55.0Hz, 1H), 6.14 (p, J = 6.7Hz, 1H), 4.22 (s, 3H) 1.86 (d, J = 6.7Hz, 6H).

[0481] 5): Referring to the synthesis steps of 10a in Example 1, 10c (2.6 g, 6.2 mmol, 76%) was prepared from 9c (2.4 g, 8.2 mmol). 1H NMR (400MHz, Chloroform-d, ppm) δ9.61 (s, 1H), 8.14 (t, J = 1.8Hz, 1H), 7.52 (t, J = 54.6Hz, 1H), 6.06 (hept, J = 6.7Hz, 1H), 1.87 (d, J = 6.7Hz, 6H).

[0482] Table 4 Examples I-43 to I-47

[0483] Preparation of Example I-43:

[0484] Referring to the synthesis method of I-4 in Example 1, compound I-43 (67 mg, 151 μmol, two steps 62%) was prepared from 10c (100 mg, 243 μmol) and (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamate 11d (89 mg, 292 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.54(s,1H),9.54(s,1H),8.09(t,J=1.9Hz,1H),7.96–7.86(m,2H),7.72–7.49(m,3H),6.20(p,J=6.5Hz,1H),3 .69–3.55(m,2H),3.46(dq,J=13.5,6.4,5.6Hz,3H),3.16(d,J=10.7Hz,1H),2.04–1.86(m,2H),1.78(d,J=6.7Hz,6H),1.65(d,J=6.7Hz,1H).

[0485] Preparation of Example I-44:

[0486] Referring to the synthesis method of I-4 in Example 1, compound I-44 (65 mg, 136 μmol, two steps 56%) was prepared from 10c (100 mg, 243 μmol) and (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)(methyl)carbamate 11f (93 mg, 292 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.26(s,1H),7.88(s,1H),7.80(d,J=8.3Hz,2H),7.75(s,1H),7.67(d,J=7.8Hz,2H),7.53(d,J=55.2Hz,1H),6 .22(p,J=6.7Hz,1H),3.95–3.70(m,3H),3.63–3.48(m,1H),3.41–3.28( m,1H),2.48(d,J=39.6Hz,3H),2.26–2.02(m,1H),1.87(d,J=6.7Hz,7H).

[0487] Preparation of Example I-45:

[0488] Referring to the synthesis method of I-1 in Example 1, compound I-45 (50 mg, 105 μmol, 43%) was prepared from 10c (100 mg, 243 μmol) and (S)-(4-aminophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone 11j (68 mg, 292 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.25(s,1H),7.87(t,J=1.8Hz,1H),7.79(d,J=8.2Hz,2H),7.69–7.61(m,3H),7.51(d,J=55.1Hz,1H),6.20 (q,J=6.7Hz,1H),4.04–3.81(m,1H),3.77–3.41(m,3H),2.78(d,J=41.8Hz,1H),2.31(d,J=35.8Hz,6H),2.16–1.89(m,2H),1.87–1.79(m,6H).

[0489] Preparation of Example I-46:

[0490] Referring to the synthesis method of I-4 in Example 1, compound I-46 (77 mg, 156 μmmol, two steps 64%) was prepared from 10c (100 mg, 243 μmol) and tert-butyl 4-(4-aminobenzoyl)-1,4-diazepane-1-carboxylate 11z7 (93 mg, 292 μmol). 1H NMR (400MHz, DMSO-d6, ppm) δ10.50(s,1H),9.52(s,1H),8.08(d,J=2.4Hz,1H),7.89(d,J=8.2Hz,2H),7.71–7.43(m,3H ), 6.19 (p, J = 6.7Hz, 1H), 3.61 (d, J = 17.1Hz, 2H), 3.41 (d, J = 19.2Hz, 3H), 2.83 (d, J = 44.4Hz, 6H), 1.77 (d, J = 6.7Hz, 6H).

[0491] Preparation of Example I-47:

[0492] Referring to the synthesis method of I-1 in Example 1, compound I-47 (51 mg, 102 μmol, 42%) was prepared from 10c (100 mg, 243 μmol) and (4-aminophenyl)(4-methyl-1,4-diazepan-1-yl)methanone 11z8 (68 mg, 292 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.25(s,1H),7.87(d,J=2.3Hz,1H),7.80(d,J=8.2Hz,2H),7.65(s,1H),7.60–7.30(m,3H),6.20(p,J=6.7 Hz,1H),4.03–3.59(m,4H),3.08(s,1H),2.82(d,J=30.4Hz,2H),2.62(s,3H),2.45(s,1H),2.13(s,1H),1.85(d,J=6.7Hz,6H),1.68(s,1H).

[0493] Preparation of intermediate (S)-1-(1-((triisopropylsilyl)oxy)propan-2-yl)-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl trifluoromethanesulfonate (10d)

[0494] 1): (S)-8-Methoxy-1-(1-((triisopropylsilyl)oxy)prop-2-yl)-4,5-dihydro-1H-[1,2,3]triazolo[4,5-H]quinazoline (6d)

[0495] Dissolve 4a (1.8 g, 10.0 mmol) in toluene (50 mL) and add (S)-1-((triisopropylsilyl)oxy)propan-2-amine 5d (6.5 g, 28.0 mmol), 1-azido-4-nitrobenzene (2.1 g, 13.0 mmol), and glacial acetic acid (171 μL, 3 mmol) in sequence at room temperature. The reaction mixture was heated to 100°C and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound 6d (2.8 g, 6.8 mmol, 68%) as a pale yellow solid. LC-MS (ESI): C 21 H 34 N5O2Si[M+H]+: m / z=416.2.

[0496] 2): (S)-8-Methoxy-1-(1-((triisopropylsilyl)oxy)prop-2-yl)-1H-[1,2,3]triazolo[4,5-h]quinazoline (7d)

[0497] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (3.1 g, 13.6 mmol) was added to a toluene (68 mL) solution of 6d (2.8 g, 6.8 mmol), the temperature was raised to 50°C, and the reaction was continued for 24 hours. The resulting residue was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 6:1) to obtain a light yellow solid, the title compound 7d (2.4 g, 5.8 mmol, 85%). LC-MS (ESI), C 21 H 34 N5O2Si[M+H]+: m / z=416.2.

[0498] 3: Referring to the synthesis steps of 10a in Example 1, 10d (2.3 g, 4.3 mmol, 74%) was prepared from 7d (2.4 g, 5.8 mmol, 85%). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.51(d,J=0.9Hz,1H),8.28(dd,J=8.9,1.2Hz,1H),7.84(dd,J=9.0,1.3Hz,1H),6.27–6.10(m, 1H), 4.33 (dd, J=10.0, 7.9Hz, 1H), 4.30–4.20 (m, 1H), 1.87 (dd, J=6.9, 3.8Hz, 3H), 0.92–0.81 (m, 3H), 0.79 (dd, J=6.9, 2.1Hz, 9H).

[0499] Table 5 Examples I-48 to I-49

[0500] Preparation of Example 1-48:

[0501] Referring to the synthetic method of 11a, 12a (1 g, 7.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester 13z were prepared. 12 (1.2 g, 6.6 mmol) to prepare compound 4-(4-aminobenzoyl)piperazine-1-carboxylic acid tert-butyl ester 11z 12 (1.4 g, 6.1 mmol, 93%), C 16 H 24 N2O3[M+H]+:m / z=306.2.

[0502] Referring to the synthesis method of I-4 in Example 1, 10d (150 mg, 188 μmol) and 11z 12 (69 mg, 225 μmol) was used to prepare compound I-48 (43 mg, 99 μmol, two steps 53%). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.41(s,1H),9.46(s,1H),7.95(d,J=8.4Hz,2H),7.90(d,J=8.8Hz,1H),7.80(d ,J=8.8Hz,1H),7.50(d,J=8.4Hz,2H),6.21–6.14(m,1H),5.15(t,J=5.5Hz,1H),4.11(dt,J=12.3,5.8Hz,1H).

[0503] Preparation of Example I-49:

[0504] Referring to the synthesis method of I-4a in Example 1, compound I-49 (54 mg, 124 μmol, 66%) was prepared from 10d (150 mg, 188 μmol) and (4-aminophenyl)(morpholinyl)methanone 11z9 (46 mg, 225 μmol). 1 H NMR (600MHz, DMSO-d6, ppm) δ10.37(s,1H),9.45(s,1H),7.99–7.76(m,4H),7.47(d,J=8.2Hz,2H),6.18(q,J=6.7Hz,1H),5.1 1(t,J=5.5Hz,1H), 4.10(dq,J=13.0,6.4Hz,1H), 3.99(dt,J=11.1,4.9Hz,1H), 3.58(d,J=52.5Hz,9H), 1.71(d,J=6.9Hz,3H).

[0505] Preparation of intermediate (R)-1-(1-((triisopropylsilyl)oxy)propan-2-yl)-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl trifluoromethanesulfonate (10e)

[0506] 1) Referring to the synthesis method of 6a in Example 1, compound 4a (1.8 g, 10.0 mmol) was reacted to obtain 6e (2.5 g, 6.2 mmol, 62%). LC-MS (ESI), C 21 H 36 N5O2Si[M+H] + :m / z=418.3.

[0507] 2) Referring to the synthesis method of 7a in Example 1, 6e (2.5 g, 6.2 mmol) was reacted to obtain 7e (2.3 g, 5.5 mmol, 88%). LC-MS (ESI), C 21 H 34 N5O2Si[M+H] + :m / z=416.2.

[0508] 3): Referring to the synthesis steps of 10a in Example 1, 10e (2.2 g, 4.1 mmol, 75%) was prepared from 7e (2.3 g, 5.5 mmol). LC-MS (ESI), C 21 H 31 F3N5O4Si[M+H] + :m / z=534.2.

[0509] Table 6 Examples I-50 to I-51

[0510] Preparation of Example I-50:

[0511] Referring to the synthesis method of I-4 in Example 1, 10e (150 mg, 188 μmol) and 4-(4-aminobenzoyl)piperazine-1-carboxylic acid tert-butyl ester 11z were prepared. 12 (69 mg, 225 μmol) was used to prepare compound I-50 (40 mg, 92 μmol, two steps 49%). 1H NMR (400MHz, DMSO-d6, ppm) δ10.42(s,1H),9.46(s,1H),7.96(d,J=8.6Hz,2H),7.90(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,1H),7.52(d,J=8.4Hz,2H),6 .20(p,J=6.6Hz,1H),5.20–5.14(m,1H),4.16–4.07(m,1H),3.98(dt,J=11 .0,5.4Hz,1H),3.76(s,4H),3.16(t,J=5.2Hz,4H),1.72(d,J=6.8Hz,3H).

[0512] Preparation of Example I-51:

[0513] Referring to the synthesis method of I-4a in Example 1, compound I-51 (47 mg, 109 μmol, 58%) was prepared from 10e (150 mg, 188 μmol) and (4-aminophenyl)(morpholinyl)methanone 11z9 (46 mg, 225 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.38(s,1H),9.45(s,1H),7.98–7.91(m,2H),7.89(d,J=8.8Hz,1H),7.79(d,J=8.9Hz,1H),7.50–7.44(m,2 H),6.21–6.14(m,1H),5.13(s,1H),4.11(dd,J=10.9,7.5Hz,1H),3.99(dt,J=10.9,6.2Hz,1H),3.71–3.44(m,8H),1.71(d,J=6.8Hz,3H).

[0514] Preparation of Intermediate 1-(2-hydroxy-2-methylpropyl)-1H-[1,2,3]triazolo[4,5-H]quinazolin-8-yl trifluoromethanesulfonate (10f)

[0515] 1) Referring to the synthesis method of 6a in Example 1, compound 4a (1.8 g, 10.0 mmol) was reacted to obtain 6f (1.8 g, 6.5 mmol, 65%). LC-MS (ESI), C 13 H 18 N5O2[M+H] + :m / z=276.1.

[0516] 2) Referring to the synthesis method of 7a in Example 1, 6f (1.8 g, 6.5 mmol) was reacted to obtain 7f (1.5 g, 5.5 mmol, 85%). LC-MS (ESI), C 13 H 16 N5O2[M+H] + :m / z=274.1.

[0517] 3): Referring to the synthesis steps of 10a in Example 1, 10f (1.5 g, 3.9 mmol, 70%) was prepared from 7f (1.5 g, 5.5 mmol). 1 H NMR (400MHz, Chloroform-d, ppm) δ9.53 (s, 1H), 8.30 (d, J = 8.9Hz, 1H), 7.87 (d, J = 8.9Hz, 1H), 5.28 (s, 2H), 2.77 (s, 1H), 1.38 (s, 6H).

[0518] Table 7 Examples I-52 to I-53

[0519] Preparation of Example I-52:

[0520] Referring to the synthesis method of I-4 in Example 1, 10f (150 mg, 384 μmol) and 4-(4-aminobenzoyl)piperazine-1-carboxylic acid tert-butyl ester 11z were prepared. 12 (140 mg, 460 μmol) was used to prepare compound I-52 (91 mg, 203 μmol, two steps 53%). 1 H NMR (400 MHz, DMSO-d 60 ,ppm)δ10.35(d,J=6.1Hz,1H),9.45(d,J=1.8Hz,1H),7.96(dd,J=8.3,5.1Hz,2H),7.90(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,1H) ,7.44(t,J=8.3Hz,2H),5.27(s,2H),4.79(d,J=4.0Hz,1H),3.65–3.38(m,4H),3.17(d,J=4.5Hz,2H),2.70(s,3H),1.15(s,6H).

[0521] Preparation of Example I-53:

[0522] Referring to the synthesis method of I-1 in Example 1, compound I-53 (111 mg, 249 μmol, 65%) was prepared from 10f (150 mg, 384 μmol) and (4-aminophenyl)(morpholinyl)methanone 11z9 (95 mg, 460 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.22(d,J=0.9Hz,1H),7.94(dd,J=8.8,0.9Hz,1H),7.77–7.68(m ,2H),7.63(dd,J=8.9,0.9Hz,1H),7.58–7.49(m,3H),5.31–5.26(m,3H),3.72(s,8H),1.23(s,6H).

[0523] Example I-54

[0524] ((S)-3-Aminopyrrolidin-1-yl)(4-((1-((R)-3-hydroxy-3-methylbutan-2-yl)-1H-[1,2,3]triazolo[4,5-h]quinazolin-8-yl)amino)phenyl)methanone (I-54)

[0525] 1): Referring to the synthesis method of 6a, compound 4a (3.6 g, 20.0 mmol) was reacted to obtain 6g (3.6 g, 12.4 mmol, 62%). 1 H NMR (400MHz, Chloroform-d, ppm) δ8.59 (s, 1H), 5.59 (q, J = 7.0Hz, 1H), 3.89 (s, 3H), 3. 19(q,J=2.8,1.7Hz,4H),2.96(s,1H),1.73(d,J=7.0Hz,3H),1.32(s,3H),1.17(s,3H).

[0526] 2): Referring to the synthesis method of 7a, 6g (3.6g, 12.4mmol) was reacted to obtain 7g (3.0g, 10.3mmol, 83%). LC-MS (ESI), C 14 H 18 N5O2[M+H]+:m / z=288.1.

[0527] 3): Referring to the synthesis steps of 10a in Example 1, 10g (3.2g, 7.8mmol, 76%) was prepared from 7g (3.0g, 10.3mmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.54(s,1H),8.30(d,J=8.9Hz,1H),7.87(d,J=9.0Hz, 1H), 6.09 (q, J = 7.0Hz, 1H), 2.85 (s, 1H), 1.90 (d, J = 7.1Hz, 3H), 1.35 (s, 3H), 1.27 (s, 3H).

[0528] 4): tert-Butyl ((S)-1-(4-((1-((R)-3-hydroxy-3-methylbutan-2-yl)-1H-[1,2,3]triazolo[4,5-h]quinazolin-8-yl)amino)benzoyl)pyrrolidin-3-yl)carbamate (I-54a)

[0529] To a solution of 10 g (150 mg, 0.35 mmol) and 11d (158 mg, 0.52 mmol) in 1,4-dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 10 mol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol), and potassium carbonate (57 mg, 0.42 mmol) at room temperature. After the addition, the atmosphere was replaced with argon twice, and the temperature was raised to 100°C with a sealed tube for 4 hours. After the reaction mixture cooled to room temperature, it was diluted with ethyl acetate (20 mL) and a semi-saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica gel column chromatography (dichloromethane / methanol = 98:2) to give a light yellow solid as the title compound I-54a (150 mg, 0.27 mmol, 78%). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.93(d,J=8.9Hz,1H),7.74(d,J =8.2Hz,2H),7.62(d,J=9.0Hz,4H),6.23(q,J=7.0Hz,1H),4.65(s,1H),4.26(d,J =52.7Hz,1H),3.96–3.72(m,2H),3.70–3.35(m,3H),2.23(d,J=30.7Hz,1H),1.9 2(d,J=8.8Hz,1H),1.87(d,J=7.0Hz,3H),1.61(s,9H),1.36(s,3H),1.19(s,3H).

[0530] 5): Referring to the synthesis method of I-4 in Example 1, compound I-54 (134 mg, 290.9 μmmol, 95%) was prepared from I-54a (150 mg, 0.35 mmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.37 (s, 1H), 9.45 (s, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.90 (d ,J=8.8Hz,1H),7.80(d,J=8.9Hz,1H),7.58(t,J=6.4Hz,2H),6.35(q,J=7.0Hz,1H),4. 80(s,1H),3.73–3.55(m,3H),3.49(d,J=7.3Hz,2H),3.29–3.17(m,2H),2.00(d,J=6.8 Hz,1H),1.77(d,J=7.0Hz,3H),1.73–1.65(m,1H),1.26(s,3H),1.10(d,J=2.5Hz,3H).

[0531] Table 8 Examples I-55 to I-61

[0532] Preparation of Example I-55:

[0533] The synthesis method of I-54 in Example 1 was used to prepare compound I-55 (150 mg, 270 μmol, 73%) from 10 g (100 mg, 370 μmol) and 11 h (154 mg, 445 μmol) of tert-butyl (S)-(1-(4-aminobenzoyl)pyrrolidin-3-yl)(isopropyl)carbamate. 1 H NMR (400MHz, DMSO-d6, ppm) δ10.39 (s, 1H), 9.46 (s, 1H), 7.96 (d, J = 8.3Hz, 2H), 7. 90(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,1H),7.58(d,J=8.2Hz,2H),6.35(q,J=7.0Hz ,1H),4.80(s,1H),3.71(s,1H),3.57(d,J=43.6Hz,4H),3.17(d,J=3.7Hz,1H),2. 10(s,1H),1.77(d,J=7.1Hz,3H),1.24(d,J=8.4Hz,6H),1.11(s,6H),1.01(s,2H).

[0534] Preparation of Example I-56:

[0535] Referring to the synthesis method of I-54 in Example 1, 10 g (100 mg, 370 μmol) and tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate 11z 12 (136 mg, 445 μmol) was used to prepare compound I-56 (105 mg, 230 μmol, two steps, 62%). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.37(s,1H),9.45(s,1H),7.95(d,J=8.5Hz,2H),7.90(d,J=8.7Hz,1H),7.79(d,J=8.8Hz,1H),7.44(d,J=8 .5Hz,2H),6.32(t,J=7.1Hz,1H),4.78(s,1H),3.62–3.41(m,4H),2.81(s,4H),1.76(d,J=7.0Hz,3H),1.23(s,3H),1.10(d,J=6.6Hz,3H).

[0536] Preparation of Example I-57:

[0537] Referring to the synthesis method of 11a, compound (4-aminophenyl)(4-methylpiperazin-1-yl)methanone 11z was prepared from 12a (1 g, 7.3 mmol) and 13z (0.66 g, 6.6 mmol). 14 (1.34 g, 6.1 mmol, 93%), C 12 H 18 N3O[M+H]+: m / z=220.1.

[0538] Referring to the synthesis method of I-54a in Example 1, 10 g (155 mg, 384 μmol) and 11 z 14 (1 mg, 445 μmol) was used to prepare compound I-57 (97 mg, 167 μmol, 45%). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.93(d,J=8.9Hz,1H),7.73(d,J=8.2Hz,2H),7.62(d,J=8.8Hz,1H),7.58(s,1H),7.50(d ,J=8.2Hz,2H),6.21(q,J=7.0Hz,1H),3.58(d,J=51.9Hz,5H),2.46(s,4H),2.35(s,3H),1.86(d,J=7.0Hz,3H),1.37(s,3H),1.07(s,3H).

[0539] Preparation of Example I-58:

[0540] Referring to the synthesis method of I-54a in Example 1, compound I-58 (123 mg, 267 μmol, 72%) was prepared from 10 g (155 mg, 384 μmol) and (4-aminophenyl)(morpholinyl)methanone 11z9 (92 mg, 445 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.93(d,J=8.8Hz,1H),7.78–7.72(m,2H),7.62(d,J=8.9Hz,1H),7.58(s, 1H),7.53–7.48(m,2H),6.21(q,J=7.0Hz,1H),3.73(s,8H),3.50(s,1H),1.86(d,J=7.0Hz,3H),1.37(s,3H),1.09(s,3H).

[0541] Preparation of Example I-59:

[0542] Referring to the synthesis method of I-54a in Example 1, compound I-59 (130 mg, 256 μmol, 69%) was prepared from 10 g (155 mg, 384 μmol) and (4-aminophenyl)(1,1-dioxothiodimorpholinyl)methanone 11z6 (113 mg, 445 μmol). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.39(s,1H),9.46(s,1H),7.96(d,J=8.2Hz,2H),7.90(d,J=8.7Hz,1H),7.79(d,J=8.8Hz,1H),7.54(d,J =8.2Hz, 2H), 6.33 (q, J = 7.0Hz, 1H), 4.77 (s, 1H), 3.91 (s, 4H), 3.27 (t, J = 5.3Hz, 4H), 1.78 (d, J = 7.0Hz, 3H), 1.24 (s, 3H), 1.08 (s, 3H).

[0543] Preparation of Example I-60:

[0544] Referring to the synthesis method of I-54 in Example 1, compound I-60 (107 mg, 226 μmol, two steps 61%) was prepared from 10 g (100 mg, 370 μmol) and tert-butyl 4-(4-aminobenzoyl)-1,4-diazepane-1-carboxylate 11z7 (255 mg, 445 μmol). 1H NMR(400MHz,DMSO-d6,ppm)δ10.37(s,1H),9.46(s,1H),7.99–7.93(m,2H), 7.90(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,1H),7.47(d,J=8.2Hz,2H),6.35(q ,J=7.1Hz,1H),4.78(s,1H),3.64(d,J=93.8Hz,4H),3.18(s,1H),3.08(s,4 H), 1.90 (s, 2H), 1.77 (d, J = 7.1Hz, 3H), 1.24 (s, 3H), 1.10 (d, J = 3.8Hz, 3H).

[0545] Preparation of Example I-61:

[0546] Referring to the synthesis method of I-54a in Example 1, compound I-61 (96 mg, 196.3 μmol, 53%) was prepared from 10 g (155 mg, 384 μmol) and (4-aminophenyl)(4-methyl-1,4-diazepan-1-yl)methanone 11z8 (104 mg, 446 μmol). 1 H NMR (400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.93(d,J=8.8Hz,1H),7.73(d,J=8.3Hz,2H),7.62(d,J=8.8Hz,1H),7.58(s,1H),7.51(d,J=7.7Hz,2H),6. 23–6.18(m,1H),3.83(d,J=22.9Hz,2H),3.58(t,J=26.0Hz,3H),2.78(d,J= 75.9Hz, 4H), 2.03 (s, 2H), 1.86 (d, J = 7.0Hz, 3H), 1.37 (s, 3H), 1.08 (s, 3H).

[0547] Preparation of the intermediate 1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1H-[1,2,3]triazolo[4,5-h]quinazolin-8-yl trifluoromethanesulfonate (10h)

[0548] 1) Referring to the synthesis method of 6a in Example 1, compound 4a (1.78 g, 10.0 mmol) was reacted to obtain 6h (2.26 g, 7.5 mmol, 75%). 1H NMR(400MHz,Chloroform-d,ppm)δ8.58(s,1H),5.67(dd,J=8.4,6.9Hz,1H),3.92(s,3H),3.18(d,J =3.3Hz,4H),2.70(ddd,J=13.9,9.5,7.0Hz,1H),2.57–2.43(m,2H),2.08–1.91(m,4H),0.95(s,3H).

[0549] 2) Referring to the synthesis method of 7a in Example 1, 6h (2.26 g, 7.5 mmol) was reacted to obtain 7h (1.9 g, 6.5 mmol, 87%). LC-MS, (ESI) C 15 H 18 N5O2[M+H]+:m / z=300.1.

[0550] 3) Referring to the synthesis steps of 10a in Example 1, 10h (2.1 g, 5.1 mmol, 78%) was prepared from 7h (1.9 g, 6.5 mmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.55(s,1H),8.30(d,J=8.9Hz,1H),7.88(d,J=8.9Hz,1H),6.19(dd,J=8.4,6.6Hz,1H), 2.89(dtd,J=15.8,9.0,8.3,4.2Hz,1H),2.68(dtd,J=13.7,8.5,4.6Hz,1H),2.57(s,1H),2.24–1.94(m,4H),0.90(s,3H).

[0551] Table 9 Examples I-62 to I-71

[0552] Preparation of Example I-62:

[0553] Referring to the synthesis method of I-54 in Example 1, compound I-62 (110 mg, 234 μmol, two steps 65%) was prepared from 10h (150 mg, 360 μmol) and (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)carbamate 11d (132 mg, 432 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.91(d,J=8.8Hz,1H),7.82–7.71(m,2H),7.64(q,J=8.9Hz,4H),6.25(s ,1H),3.94–3.26(m,6H),2.85(s,1H),2.63(s,1H),2.26–2.01(m,4H),1.91(d,J=4.6Hz,1H),1.76(s,2H),0.87(s,3H).

[0554] Preparation of Example I-63:

[0555] Referring to the synthesis method of I-54 in Example 1, compound I-63 (104 mg, 201 μmol, 56%) was prepared from 10h (150 mg, 360 μmol) and (S)-tert-butyl (1-(4-aminobenzoyl)pyrrolidin-3-yl)(isopropyl)carbamate 11h (150 mg, 432 μmol). 1 HNMR(400MHz,Chloroform-d,ppm)δ9.20(s,1H),7.90(d,J=8.8Hz,1H),7.82(s,1H),7.74(s,2H),7.61(dd,J=12.1,8.5Hz,3H),6.27(d,J=7.7Hz,1H), 3.98–3.30(m,5H),2.90(d,J=50.0Hz,2H),2.64(s,1H),2.28–2.05(m,5H), 1.91(d,J=9.6Hz,3H),1.79(s,2H),1.13(s,2H),1.06(s,2H),0.89(s,3H).

[0556] Preparation of Example I-64:

[0557] Referring to the synthesis method of I-54a in Example 1, compound I-64 (95 mg, 191 μmol, 53%) was prepared from 10h (150 mg, 360 μmol) and (S)-(4-aminophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone 11j (101 mg, 432 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.91(d,J=8.8Hz,1H),7.77(dd,J=16.5,8.4Hz,3H),7.67–7.52(m,3H),6.26(dd,J=19.2,7.8Hz,1H),3 .88(dd,J=47.4,9.6Hz,1H),3.75–3.41(m,3H),3.00–2.48(m,4H),2.32(s, 3H),2.26(s,3H),2.23–2.05(m,4H),1.96–1.82(m,2H),0.89–0.87(m,3H).

[0558] Preparation of Example 1-65:

[0559] Referring to the synthesis method of I-54 in Example 1, 10h (150 mg, 360 μmol) and 4-(4-aminobenzoyl)piperazine-1-carboxylic acid tert-butyl ester 11z were prepared. 12 (132 mg, 432 μmol) was used to prepare compound I-65 (112 mg, 237 μmol, two steps 66%). 1 HNMR(400MHz,Chloroform-d,ppm)δ9.22(s,1H),7.91(d,J=8.8Hz,1H),7.75(d ,J=8.3Hz,2H),7.61(d,J=8.4Hz,2H),7.51(d,J=8.2Hz,2H),6.22(t,J=7.6Hz, 1H),3.56(d,J=57.7Hz,4H),3.27–2.72(m,5H),2.61(dt,J=9.0,4.1Hz,1H),2. 10(ddd,J=18.2,9.9,5.8Hz,3H),1.97–1.82(m,1H),1.49(s,1H),0.86(s,3H).

[0560] Preparation of Example I-66:

[0561] Referring to the synthesis method of I-54a in Example 1, 10h (150 mg, 360 μmol) and (4-aminophenyl)(4-methylpiperazin-1-yl)methanone 11z were prepared. 14 (95 mg, 432 μmol) was used to prepare compound I-66 (84 mg, 173 μmol, 48%). 1H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.91(d,J=8.8Hz,1H),7.80–7.69(m,3H),7.61(d,J=8.8Hz,1H),7.51(d,J=8.2Hz,2H),6. 22(t,J=7.6Hz,1H),3.70(d,J=44.9Hz,4H),2.89(dq,J=15.3,7.8Hz,1H),2.65–2.42(m,4H),2.35(s,3H),2.23–1.88(m,6H),0.86(s,3H).

[0562] Preparation of Example I-67:

[0563] Referring to the synthesis method of I-54a in Example 1, compound I-67 (141 mg, 299 μmol, 83%) was prepared from 10h (150 mg, 360 μmol) and (4-aminophenyl)(morpholinyl)methanone 11z9 (89 mg, 432 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.22(s,1H),7.92(d,J=8.8Hz,1H),7.77(d,J=8.1Hz,2H),7.62(d,J=9.7Hz,2H ),7.52(d,J=8.1Hz,2H),6.22(t,J=7.6Hz,1H),3.73(s,8H),3.07(s,1H),2.89(dd,J=14.0,7.4Hz,1H),2.61(d,J= 6.7Hz, 1H), 2.10 (dq, J=19.9, 13.6, 9.3Hz, 3H), 1.88 (d, J=10.6Hz, 1H), 0.86 (s, 3H).

[0564] Preparation of Example 1-68:

[0565] Referring to the synthesis method of I-54a in Example 1, compound I-68 (110 mg, 212 μmol, 59%) was prepared from 10h (150 mg, 360 μmol) and (4-aminophenyl)(1,1-dioxidothiomorpholinyl)methanone 11z6 (110 mg, 432 μmol). 1H NMR(400MHz,Chloroform-d,ppm)δ9.24(s,1H),7.94(d,J=8.8Hz,1H),7.84(d,J=8.3Hz,2H),7.69(s,1H),7.63(d,J=8.9Hz,1H),7.55(d,J=8.4H z,2H),6.25(t,J=7.3Hz,1H),4.16(s,4H),3.10(s,4H),2.98–2.74(m,2H ),2.74–2.53(m,1H),2.30–1.97(m,3H),1.97–1.82(m,1H).0.88(s,3H).

[0566] Preparation of Example 1-69:

[0567] Referring to the synthesis method of I-54 in Example 1, compound I-69 (126 mg, 259 μmol, two steps, 72%) was prepared from 10h (150 mg, 360 μmol) and tert-butyl 4-(4-aminobenzoyl)-1,4-diazepane-1-carboxylate 11z7 (138 mg, 432 μmol). 1 H NMR(400MHz,Chloroform-d,ppm)δ9.21(s,1H),7.91(d,J=8.8Hz,1H),7.75(d,J=8.1Hz,2H),7.61(d,J=8.4Hz,2H),7.51(d,J=8.2Hz,2H),6.24(t,J =7.5Hz,1H),3.69(d,J=89.5Hz,4H),2.98(t,J=51.0Hz,6H),2.62(d,J=11 .9Hz,1H),2.17–1.98(m,3H),1.98–1.84(m,2H),1.79(s,1H),0.87(s,3H).

[0568] Preparation of Example I-70:

[0569] Referring to the synthesis method of I-54a in Example 1, compound I-70 (104 mg, 209 μmol, 58%) was prepared from 10h (150 mg, 360 μmol) and (4-aminophenyl)(4-methyl-1,4-diazepan-1-yl)methanone 11z8 (101 mg, 432 μmol). 1H NMR (400MHz, Chloroform-d, ppm) δ9.21 (s, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.75 (d, J=7.8Hz,3H),7.70–7.45(m,3H),6.24(t,J=7.5Hz,1H),3.81(d,J=13.8Hz,2H) ,3.62(d,J=26.5Hz,2H),2.84(t,J=8.0Hz,2H),2.68(s,1H),2.65–2.56(m,2H) ,2.41(d,J=23.7Hz,3H),2.17–2.01(m,4H),1.91(d,J=7.2Hz,4H),0.87(s,3H).

[0570] Preparation of Example I-71:

[0571] Referring to the synthetic method of 11a, 12b (1 g, 0.58 mmol) of p-aminobenzenesulfonic acid and 13z (1 g, 0.58 mmol) of morpholino 2-aminoethane-1-ol were synthesized. 13 (0.32 g, 0.53 mmol) to prepare compound 4-amino-N-(2-hydroxyethyl)benzenesulfonamide 11z 13 (0.91 g, 0.42 mmol, 80%), C8H 13 N2O3S[M+H]+: m / z=217.1.

[0572] Referring to the synthesis method of I-54a in Example 1, 10h (150 mg, 360 μmol) and 4-amino-N-(2-hydroxyethyl)benzenesulfonamide 11z were prepared. 13 (93 mg, 432 μmol) was used to prepare compound I-71 (135 mg, 281 μmol, 78%). 1 H NMR (400MHz, DMSO-d6, ppm) δ10.58 (s, 1H), 9.50 (s, 1H), 8.19 (d, J = 8.6Hz, 2H) ,7.94(d,J=8.8Hz,1H),7.86–7.78(m,3H),7.44(t,J=6.0Hz,1H),6.41(dd,J=8 .2,3.8Hz,1H),5.16(s,1H),4.67(s,1H),3.39(t,J=6.5Hz,2H),2.81(q,J=6.3 Hz,2H),2.67–2.61(m,1H),2.41–2.31(m,1H),2.15–1.85(m,5H),0.85(s,3H).

[0573] Biological Example 1

[0574] Kinase activity assay

[0575] CDK / cyclin catalyzes substrate phosphorylation, which consumes ATP and produces ADP. The inhibition rate (%) in the presence of small molecule inhibitors is assessed by measuring the amount of ADP generated in the reaction. The test compound is thoroughly mixed by vortexing and diluted with DMSO to 100× the test concentration. A nanoliter pipetting system ( 655 SYSTEM) transfer 40 nL of compound to a 384 assay plate. Prepare a 2x kinase solution with 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). Transfer 2 μL of the kinase solution to the 384 assay plate and centrifuge at 1000 rpm for 60 seconds in a microplate centrifuge. Incubate in a biochemical incubator at 25°C for 10 minutes. Prepare a 2x substrate and ATP mixture in kinase reaction buffer and add 2 μL of the substrate and ATP mixture to the 384 assay plate. Centrifuge at 1000 rpm for 60 seconds in a microplate centrifuge. Incubate in a biochemical incubator at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​Reagent (Cat. No. V9103, Promega) incubated in a biochemical incubator at 25°C to each well of the 384 assay plate. Centrifuge at 1000 rpm for 60 seconds in a microplate centrifuge and incubate in a biochemical incubator at 25°C for 40 minutes. Add 8 μL of Detection Reagent incubated in a biochemical incubator at 25°C to each well of the 384 assay plate. Centrifuge at 1000 rpm for 60 seconds in a microplate centrifuge and incubate in a biochemical incubator at 25°C for 40 minutes. Finally, read the chemiluminescence signal using a multifunctional microplate reader (Model: PHERAstar FSX, Manufacturer: BMG). Calculate the IC50 value using GraphPad Prism software using a nonlinear fit of the concentration-response curve.

[0576] The compounds of the present invention were tested in kinase activity assays 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 invention are shown in the table below.

[0577] Biological Example 2

[0578] Cell proliferation assay

[0579] Human ovarian cancer OVCAR3 cells were seeded at 2000 cells / well in a 96-well plate and cultured overnight in RPMI 1640 medium supplemented with 20% FBS at 37°C in a 5% CO2 incubator. The next day, the compound was serially diluted three-fold in DMSO, starting at a peak concentration of 2 mM, to a total of nine concentrations. The compound was then diluted 3:200 in growth medium and finally diluted 1:3 in cell culture supernatant, resulting in a 0.5% DMSO supernatant with compound treatment concentrations ranging from 10 μM to 0.1 nM. Cells and compounds were incubated at 37°C in 5% CO2 for 6 days. Cell proliferation assays were then performed using the CellTiter-Glo (Promega, Cat. No. G9242) and chemiluminescence signals were read using a multi-function microplate reader (Synergy H1, BiotTek). IC50 values ​​were calculated by concentration-response curve fitting using GraphPad Prism software using a four-parameter analysis method.

[0580] The proliferation assays of human colon cancer HCT-116 cells, human breast cancer MCF-7 cells, human breast cancer HCC1806 cells, human acute myeloid leukemia MV-4-11 cells, and human gastric cancer MKN1 cells were performed according to the same method, with different seeding densities set according to different cell growth characteristics.

[0581] The IC50 (nM) of the cell proliferation inhibitory activity of the most representative compounds of the present invention are shown in the following table.

[0582] Biological Example 3

[0583] Immunoblotting to detect phosphorylated Ser780, Ser807 / 811 Rb

[0584] OVCAR3 cells were seeded at 500,000 cells / well in a 6-well plate and cultured overnight in RPMI 1640 medium containing 20% ​​FBS at 37°C in a 5% CO2 incubator. The next day, the compound of Example 1-10 was diluted 200-fold in DMSO to the respective treatment concentration, then diluted to 5-fold in growth medium, and finally diluted 1:5 in the cell culture supernatant for 24 hours. The cells were lysed on ice using RIPA lysis buffer containing protease and phosphatase inhibitors, and the supernatant was obtained by centrifugation. The protein concentration in the supernatant was determined using the BCA protein quantification method, and the protein bands were separated by SDS-PAGE gel electrophoresis and electrotransferred to a PVDF membrane. PVDF membranes were blocked with 5% nonfat dry milk and then incubated overnight at 4°C with antibodies against phospho-Ser780-Rb (manufacturer: CST, Catalog No. 8180S), phospho-Ser807 / 811-Rb (manufacturer: CST, Catalog No. 8516S), and GADPH (manufacturer: Abclonal, Catalog No. AC002). The membranes were washed to remove unbound antibodies and then incubated with a species-appropriate horseradish peroxide-conjugated secondary antibody at room temperature for 1 hour. After washing, the membranes were incubated with a chemiluminescent substrate and developed. The results are shown in Figure 1.

[0585] Immunoblotting technology detects CDK9 downstream molecular pathways and apoptosis molecular pathways

[0586] MV-4-11 cells were seeded at 2×10⁶ cells / well in a 6-well plate and cultured overnight in RPMI 1640 medium containing 10% FBS at 37°C in a 5% CO₂ incubator. The next day, the compound of Example 1-10 was diluted 200-fold in DMSO to the respective treatment concentration, then diluted to 5-fold in growth medium, and finally diluted 1:5 in the cell culture supernatant for 8 hours (CYC065 was used as a control compound). The cells were lysed on ice using RIPA lysis buffer containing protease and phosphatase inhibitors, and the supernatant was obtained by centrifugation. The protein concentration in the supernatant was determined using the BCA protein quantification method, and the protein bands were separated by SDS-PAGE gel electrophoresis and electrotransferred to a PVDF membrane. PVDF membranes were blocked with 5% skim milk powder and incubated overnight at 4°C with antibodies against RNAP II (Merck, Catalog No. 05-623), phosphorylated Ser2 RNAP II (Merck, Catalog No. 3864963), c-Myc (CST, Catalog No. 18583S), Mcl-1 (CST, Catalog No. 39224S), Caspase 3 (CST, Catalog No. 9662), Cleaved Caspase 3 (CST, Catalog No. 9664), and GADPH (Abclonal, Catalog No. AC002). The membranes were washed to remove unbound antibodies and then incubated with a species-appropriate horseradish peroxidase-conjugated secondary antibody at room temperature for 1 hour. After washing, the membranes were incubated with a chemiluminescent substrate and developed. The results are shown in Figure 2.

[0587] Biological Example 4

[0588] Tumor models

[0589] OVCAR-3 tumor model

[0590] Human ovarian cancer OVCAR-3 tumor cells were cultured in RPMI 1640 medium containing 20% ​​FBS at 37°C in a 5% CO2 incubator. Matrigel was mixed with serum-free RPMI 1640 medium at a ratio of 1:1 and used to resuspend the OVCAR-3 tumor cells at a concentration of 2×107 / 0.2ml. The cells were then inoculated subcutaneously in the right flank of NOD-SCID female mice. When tumors reached approximately 100-150 mm3, the mice were randomly divided into treatment groups, with six animals per group. The compound of Example 1-10 was formulated in a 20% aqueous solution of hydroxypropyl gamma-cyclodextrin containing an equivalent amount of hydrochloric acid and administered orally (po) at doses of 5, 10, and 15 mg / kg twice daily, 8 hours apart, for a total of 22 days. The PF06873600-treated group served as a positive control, while the untreated group received solvent by gavage. The tumor volume was measured twice a week using a vernier caliper to measure the long and short diameters of the tumor. The tumor volume was calculated using the following formula: volume (mm 3 ) = (long diameter (mm) × short diameter (mm) × short diameter (mm) / 2. The mice were weighed every day.

[0591] The therapeutic effect of drugs was evaluated by tumor growth inhibition (TGI%), and the calculation formula was: TGI = (1-(TV treated / last -TV treated / day0 ) / (TV vehicle / last -TV vehicle / day0 ))×100%, TV represents tumor volume, and the subscripts represent group and time, respectively. Figure 3 shows the growth inhibitory effect of Example I-10 on the OVCAR-3 tumor model, showing a dose-dependent relationship.

[0592] MKN1 tumor model

[0593] Human gastric cancer MKN1 tumor cells were cultured in RPMI 1640 medium containing 10% FBS at 37°C in a 5% CO2 incubator. Matrigel was mixed with serum-free RPMI 1640 medium at a ratio of 1:1 and then used to resuspend MKN1 tumor cells into 1×10 7 / 0.1ml, and then inoculated subcutaneously on the right flank of BALB / c nude female mice. 3 Around 24 hours after treatment, mice were randomly divided into treatment groups, with 6 animals in each group. The compound was prepared with a 20% hydroxypropyl gamma-cyclodextrin aqueous solution containing an equivalent amount of hydrochloric acid and administered orally (po) at doses of 10, 20, and 30 mg / kg once a day for a total of 22 days. The untreated group was treated with solvent gavage. Tumor volume was measured twice a week with a vernier caliper to measure the long and short diameters of the tumor. The tumor volume was calculated as follows: volume (mm3 ) = (long diameter (mm) × short diameter (mm) × short diameter (mm) / 2. The mice were weighed every day.

[0594] The therapeutic effect of drugs was evaluated by tumor growth inhibition (TGI%), and the calculation formula was: TGI = (1-(TV treated / last -TV treated / day0 ) / (TV vehicle / last -TV vehicle / day0 ))×100%, TV represents tumor volume, and the subscripts represent group and time, respectively. Figure 4 shows the growth inhibitory effect of Example I-10 on the MKN1 tumor model, showing a dose-dependent relationship.

Claims

1. A compound of the general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof: in, L is selected from -C(O)- or -S(O)2-, preferably -C(O)-; Ring A is a 5-10 membered heterocyclic group; Ring B is C 6-10 Aryl; R1 is selected from H, D, halogen, -C 0-6 Alkylene -CN, -C 0-6 Alkylene-NR 1a R 1b , -C 0-6 Alkylene-OR 1a , C 1-6 Alkyl, C 1- 6 haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, -C 0-6 Alkylene -CN, -C 0-6 Alkylene -NH2 or -C 1-6 Alkylene-OH, wherein R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace; R 2a Selected from H, D, halogen, OR a 、CN、NR b R c or C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R a , R b and R c Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated; Provided that, when R2 is isopropyl and R3 is H, Ring A is not a 6-membered heterocyclic group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein: in, L is selected from -C(O)- or -S(O)2-, preferably -C(O)-; Ring A is a 5-10 membered heterocyclic group; R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b , -C 1-6 Alkylene-OH, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1a Select from H, D or C 1-6 alkyl; R 1b Select from H, D or C 1-6 alkyl; m is selected from 0, 1, 2, 3, 4 or 5; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 5-10 Cycloalkyl or -C 1-6 Alkylene-OH, wherein R2 is optionally replaced by 1, 2, 3, 4 or 5 R 2a replace; R 2a Selected from H, D, OH or C 1-6 alkyl; R3 is selected from H, D, halogen or C 1-6 Haloalkyl, preferably H or CHF2, more preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

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 a mixture thereof, wherein: R2 is selected from C 1-4 Alkyl, C 5-8 Cycloalkyl or -C 1-4 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace; R 2a Selected from H, D, OH or C 1-6 Alkyl, preferably H, D, OH or CH3; Preferably, R2 is selected from More preferably, R2 is 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein: Ring A is a 5-8 membered heterocyclic group; R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b , -C 1-4 Alkylene -OH or C 1-4 alkyl; R 1a Select from H, D or C 1-4 Alkyl, preferably, R 1a is selected from H, CH3 or isopropyl; R 1b Select from H, D or C 1-4 Alkyl, preferably, R 1b Selected from H or CH3; m is selected from 0, 1, 2 or 3; Preferably, Selected from More preferably, Selected from 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of general formula (III): in, Ring A is a 5-8 membered heterocyclic group; R1 is selected from H, D, halogen, OH, CN, NR 1a R 1b , -C 1-4 Alkylene -OH or C 1-4 alkyl; R 1a Select from H, D or C 1-4 Alkyl, preferably, R 1a is selected from H, CH3 or isopropyl; R 1b Select from H, D or C 1-4 Alkyl, preferably, R 1b Selected from H or CH3; m is selected from 0, 1, 2 or 3; R2 is selected from C 1-4 Alkyl, C 5-8 Cycloalkyl or -C 1-4 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace; R 2a Selected from H, D, OH or C 1-6 Alkyl, preferably H, OH or CH3; R3 is selected from H, D or C 1-6 Haloalkyl, preferably H or CHF2, more preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

6. The compound of claim 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein: Selected from Preferably, Selected from R2 is selected from isopropyl, cyclopentyl or -C 1-2 Alkylene-OH, wherein R2 is optionally replaced by 1, 2 or 3 R 2a replace; R 2a Selected from H, D, OH or C 1-4 Alkyl, preferably selected from H, OH or CH3; Preferably, R2 is selected from Best for R3 is selected from H, D or C 1-4 Haloalkyl, preferably H or CHF2, more preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein: The compound has the following structure: in, R 2b Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 Haloalkyl; R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; The remaining variables are as defined in claims 1-6.

8. The compound of claim 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of formula (IV), (IV-1) or (IV-2): in, R1 is selected from halogen, OH, CN or NR 1a R 1b ; R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

9. The compound of claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein: R1 is selected from halogen, OH, CN or NR 1a R 1b ; R 1a Select from H, D or C 1-4 alkyl; R 1b Select from H, D or C 1-4 alkyl; R3 is selected from H, D or C 1-4 Haloalkyl, preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein: R1 is selected from F, OH or NR 1a R 1b ; R 1a is selected from H, CH3 or isopropyl; R 1b Selected from H or CH3; R3 is selected from H or CHF2, preferably H.

11. The compound of claim 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of general formula (V), (V-1) or (V-2): in, R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; Preferably, R 1a Select from H, D or C 1-4 alkyl; R 1b Select from H, D or C 1-4 alkyl; More preferably, R 1a is selected from H, CH3 or isopropyl; R 1b Selected from H or CH3; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

12. The compound of claim 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of formula (VI), (VI-1) or (VI-2): in, R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably H; Preferably, R 1a Select from H, D or C 1-4 Alkyl, preferably H or methyl; R3 is selected from H, D or C 1-4 Haloalkyl, preferably H or CHF2, more preferably H; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

13. The compound of claim 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of formula (VII): in, Ring A is a 5-10 membered heterocyclic group; R1 is selected from H, D, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl or NR 1a R 1b ; R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; R2 is C 5-10 Cycloalkyl, preferably cyclopentyl, wherein R2 is optionally replaced by n R 2a replace; R 2a Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 Haloalkyl; n is selected from 0, 1, 2, 3, 4 or 5; Preferably, Ring A is selected from a 5-membered heterocyclic group or a 7-10-membered heterocyclic group; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

14. The compound of claim 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein: Ring A is a 5-8 membered heterocyclic group; R1 is selected from H, D, C 1-4 Alkyl or NR 1a R 1b ; R 1a Select from H, D or C 1-4 Alkyl, preferably H, CH3 or isopropyl; R 1b Select from H, D or C 1-4 Alkyl, preferably H or CH3; m is selected from 0, 1, 2 or 3; R2 is C 5-8 Cycloalkyl, preferably cyclopentyl, wherein R2 is optionally replaced by n R 2a replace; R 2a Selected from H, OH or C 1-4 alkyl; n is selected from 0, 1, 2 or 3; Preferably, Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, wherein: Selected from Preferably R2 is a cyclopentyl group, said R2 is optionally replaced by n R 2a replace; R 2a Selected from H, OH or CH3; n is selected from 0, 1 or 2; Preferably, R2 is 16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, which is a compound of formula (VIII): in, R 2b Selected from H, D, OH, CN, NH2, C 1-6 Alkyl or C 1-6 Haloalkyl; Preferably, R 2b Selected from H, D, OH or C 1-4 alkyl; More preferably, R 2b is selected from H, D or CH3; The other variables are as defined in claims 13-15.

17. The compound of claim 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, which is a compound of formula (IX), (IX-1) or (IX-2): in, Ring A is a 5-10 membered heterocyclic group; R1 is selected from H, D, OH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or NR 1a R 1b ; R 1a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; R 2a Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 2b Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R 2c Selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; Preferably, Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

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: Ring A is a 5-8 membered heterocyclic group; R1 is selected from H, D, C 1-4 Alkyl or NR 1a R 1b ; R 1a Select from H, D or C 1-4 Alkyl, preferably selected from H, CH3 or isopropyl; R 1b Select from H, D or C 1-4 Alkyl, preferably H or CH3; m is selected from 0, 1, 2 or 3; R 2a Select from H, D or C 1-4 Alkyl, preferably H or CH3; R 2b Select from H, D or C 1-4 Alkyl, preferably H or CH3; R 2c Select from H, D or C 1-4 Alkyl, preferably H or CH3; Preferably, Ring A is selected from a 5-membered heterocyclic group or a 7-membered heterocyclic group; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, wherein: Selected from R 2a Selected from H or CH3; R 2b Selected from H or CH3; R 2c Selected from H or CH3; Each of the above groups may be optionally substituted by one or more deuterium atoms until fully deuterated.

20. A compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein the compound is selected from:

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

22. The pharmaceutical composition according to claim 21, further comprising another therapeutic agent.

23. A kit comprising A first container containing a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof; and optionally, a second container containing other therapeutic agents; and optionally, a third container containing a pharmaceutical excipient for diluting or suspending the compound and / or other therapeutic agents.

24. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof in the preparation of a medicament for treating and / or preventing a CDK-mediated disease.

25. A method for treating and / or preventing a CDK-mediated disease in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of claim 21 or 22.

26. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition according to claim 21 or 22 for use in the treatment and / or prevention of a CDK-mediated disease.

27. The use of claim 24 or the method of claim 25 or the use of the compound or composition of claim 26, wherein the CDK-mediated disease comprises a cell proliferative disease, including but not limited to a cell proliferative disease, for example, solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, embryonal carcinoma sarcoma, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

Images