Compound used as CDK7 kinase inhibitor and application thereof

Abstract

The invention relates to a compound used as a CDK7 kinase inhibitor and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula I, and the definitions of all groups and substituent groups are described in the specification. The compound provided by the invention can be used as an inhibitor of cyclin-dependent kinase 7 (CDK7), is used for treating or preventing proliferative diseases (such as cancers), and is particularly used for regulating and treating related diseases caused by abnormal activity of the cyclin-dependent kinase 7 (CDK7). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to compounds used as CDK7 kinase inhibitors, and their use in regulating CDK7 kinase activity or treating CDK7-related diseases, especially cancer. Background Art

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family. They exert physiological functions by binding to corresponding cyclins to form active dimer complexes, causing cell growth and proliferation. More than 20 CDKs have been discovered, which are divided into two categories according to their functions: CDKs that regulate the cell cycle and CDKs that regulate cell transcription. Among them, CDKs 1-6 and 14-18 are involved in the regulation of the cell cycle, and CDKs 7-13 and 19-20 are involved in the transcriptional regulation of cells.

[0003] CDK7 is an important member of the CDKs family, and its main physiological function is to regulate the cell cycle and transcription. In the cytosol, CDK7, together with cyclin H and Mat1, forms CAK (CDKs activating kinase), which participates in the regulation of the cell cycle by phosphorylating CDK1 / 2 / 4 / 6. In the cell nucleus, CDK7, as a component of the general transcription factor TFⅡH (Transcription factor Ⅱhuman), participates in the gene transcription process of the cell by phosphorylating the CTD domain (carboxy-terminal domain) of RNA polymerase Ⅱ (RNA polymerase Ⅱ) at the most important initial stage of gene transcription. Since CDK7 has the dual functions of CAK and CTD phosphorylation, it plays an important role in cell proliferation, cell cycle and gene transcription.

[0004] Due to its unique dual functions in transcription and cell cycle progression, CDK7 is widely expressed in various types of cancer, and downregulating the activity of CDK7 can lead to a reduction in cell proliferation. More importantly, it is now generally agreed that targeted transcription can selectively limit the synthesis of mRNA involved in tumor growth without interrupting the transcription of housekeeping genes. Therefore, CDK7 is considered to be a viable and very promising target for tumor therapy, which has attracted widespread attention. Many small molecules, such as THZ1, THZ2, CT7001, SY-1365, etc., have shown very good effects in inhibiting tumor growth in preclinical studies. Especially in the field of major diseases that currently lack effective treatments, such as small cell lung cancer, triple-negative breast cancer, and pancreatic cancer, there is no need to meet the needs of these diseases. Therefore, the development of specific CDK7 inhibitors is expected to be used in the above unmet clinical areas. Summary of the invention

[0005] The present invention provides a novel compound having CDK7 kinase inhibitory activity and better pharmacodynamics and pharmacokinetic properties.

[0006] In a first aspect of the present invention, a compound used as a CDK7 kinase inhibitor is provided, wherein the compound is a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof,

[0007]

[0008] in:

[0009] Ring A is selected from the following group:

[0010] Ring B is selected from the following substituted or unsubstituted groups: C3-C8 cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 4-7 membered heterocyclic group, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-9 membered hetero-bridged cycloalkyl, 5-9 membered bridged cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered spirocycloalkyl, 6-10 membered spirocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered heterocycloalkyl, 6-10 membered heterocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-6 membered heteroaryl, 5-6 membered aryl;

[0011] Ring C is selected from the following group:

[0012] L is selected from the group consisting of O, S(O), S(O) 2 NR 1 、-NR 1 -(C1-C6 alkylene)-, CR 2 R 3 , C=NH, C=NOH;

[0013] Each X 1 , X 2 , X 3 , X 4 and X 5 Independently selected from the group consisting of chemical bonds, N, O, S, NR 1 , CR 2 , CR 2 R 3 ;

[0014] X 1 , X 2 , X 3 or X 1 , X 2 , X 3 , X 4 The ring formed with the pyrimidine rings they are combined with is either aromatic or non-aromatic;

[0015] Each R 1 independently selected from the following groups substituted or unsubstituted: hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl-C1-C6 alkylene, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0016] Each R 2 and R 3independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, amino, hydroxyl, cyano, oxo (=O), carboxyl, -C(=O)-O-(C1-C6 alkyl), -NH-C(=O)-O-(C1-C6 alkyl), -OC(=O)-NH-(C1-C6 alkyl), -OC(=O)-NR5-(C1-C6 alkyl), carbamate, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkyl ... -C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 5-10 membered heteroaryl-NH- containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryloxy, C6-C10 aryl-C1-C6 alkylene, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C1-C6 alkyl-NH-, C3-C6 cycloalkyl-NH-;

[0017] R 4 Selected from the following group: H,

[0018] Each R 5 , R 6 , R 7 Independently selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0019] Each X 6 and X 7 Independently selected from the following group: O, CR 2 R 3 NR 1 ;

[0020] Ring Q is a substituted or unsubstituted 4-7 membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N, S and P;

[0021] m is selected from the following group: 0, 1, 2, 3;

[0022] Each n is independently selected from the group consisting of 0, 1, 2, 3, 4 or 5;

[0023] The substitution independently refers to substitution by a group selected from the group consisting of: -NH-C(=O)-O-(C1-C6 alkyl), amino, halogenated or unsubstituted C1-C6 alkyl, =O;

[0024] The additional condition is: when ring A is When ring B is a piperidine ring or a piperidine ring substituted with a methyl group, a carboxyl group or an amide group, ring C is not

[0025] In another preferred embodiment,

[0026] Ring A is selected from the following group:

[0027] Ring B is selected from the group consisting of:

[0028] Ring C is selected from the following group:

[0029] Each X 1 , X 2 , X 3 , X 4 and X 5 Independently selected from the group consisting of chemical bonds, N, O, S, NR 1 , CR 2 , CR 2 R 3 ;

[0030] X 1 , X 2 , X 3 or X 1 , X 2 , X 3 , X 4 The ring formed with the pyrimidine rings they are combined with is either aromatic or non-aromatic;

[0031] Each R 1 independently selected from the following groups substituted or unsubstituted: hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl-C1-C6 alkylene, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0032] Each R 2 and R 3independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, amino, hydroxyl, cyano, oxo (=O), carboxyl, -C(=O)-O-(C1-C6 alkyl), -NH-C(=O)-O-(C1-C6 alkyl), -OC(=O)-NH-(C1-C6 alkyl), -OC(=O)-NR5-(C1-C6 alkyl), carbamate, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkyl ... -C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 5-10 membered heteroaryl-NH- containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryloxy, C6-C10 aryl-C1-C6 alkylene, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C1-C6 alkyl-NH-, C3-C6 cycloalkyl-NH-;

[0033] or R 2 and R 3 Together with the carbon atoms in the ring, they form a 3-7 membered ring;

[0034] R 1 ' is selected from the following group: hydrogen, amino, -C(=O)-O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 6-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl-C1-C6 alkylene, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0035] Each n is independently selected from the group consisting of 0, 1, 2, 3, 4 or 5;

[0036] R 4 As defined above.

[0037] In another preferred embodiment,

[0038] Ring A is selected from the following group:

[0039] Ring B is selected from the group consisting of:

[0040] Each n is independently selected from the group consisting of 0, 1, 2, 3, 4 or 5.

[0041] In another preferred embodiment,

[0042] Ring A is selected from the following group:

[0043] In another preferred embodiment, ring A is Among them, R 2 Selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0044] Ring B is selected from the following substituted or unsubstituted groups: C3-C8 cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 4-7 membered heterocyclic group, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-9 membered hetero-bridged cycloalkyl, 5-9 membered bridged cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered spirocycloalkyl, 6-10 membered spirocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered heterocycloalkyl, 6-10 membered heterocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-6 membered heteroaryl, C6-C10 aryl;

[0045] L is selected from the following group: O, NR 1 、-NR 1 -(C1-C6 alkylene)-;

[0046] Ring C is selected from the following group: in,

[0047] X 1 Selected from the group consisting of: N, CH;

[0048] Each X 2 , X 3 , X 4 Independently selected from the following group: N, CR 2 ';

[0049] Each R 2 ' is independently selected from the following substituted or unsubstituted groups: hydrogen, amino, -NH-C(=O)-O-(C1-C6 alkyl), -NR 1 -C(=O)-O-(C1-C6 alkyl), -NR 1 -C(=O)-R 5 、-NR 1 -C(=O)-O-C1-C6alkylene-X 8 -C1-C6 alkyl, -OC(=O)-R 5、-OC(=O)-NH-(C1-C6 alkyl)、-OC(=O)-NR5-(C1-C6 alkyl)、 3-8 membered heterocycloalkyl (connected to C via N) containing 1, 2 or 3 heteroatoms selected from N, O, S, C1-C6 alkyl-NH-, C3-C6 cycloalkyl-NH-, hydroxyl;

[0050] R 4 is selected from the following substituted or unsubstituted groups: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, -NR 1 -C(=O)-O-(C1-C6 alkyl), -OC(=O)-R 5 、-C(=O)-R 5 , Cyano;

[0051] R 1 independently selected from the following groups substituted or unsubstituted: hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, -C(=O)-NR 8 R 9 ;

[0052] Each R 5 , R 6 , R 7 independently selected from the following groups: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl containing 1, 2 or 3 selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, NR 8 R 9 ;

[0053] Each R 8 , R9 Independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0054] Each X 6 and X 7 Independently selected from the following group: O, CR 5 R 6 NR 1 ;

[0055] Each X 8 Independently selected from the group consisting of N, O, S;

[0056] m is selected from the following group: 0, 1, 2, 3;

[0057] Each n is independently selected from the group consisting of 0, 1, 2, 3, 4 or 5;

[0058] The substitution independently refers to substitution by a group selected from the following groups: -NH-C(=O)-O-(C1-C6 alkyl), amino, halogenated or unsubstituted C1-C6 alkyl, =O, hydroxyl, -NH(C1-C6 alkyl).

[0059] In another preferred embodiment, ring A is selected from the following group:

[0060] Ring B is selected from the following substituted or unsubstituted groups: C3-C8 cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 4-7 membered heterocyclic group, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-9 membered hetero-bridged cycloalkyl, 5-9 membered bridged cycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered spirocycloalkyl, 6-10 membered spirocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 6-10 membered heterocycloalkyl, 6-10 membered heterocycloalkyl, containing 1-3 selected from N, O, S, S(O) or S(O) 2 5-6 membered heteroaryl, 5-6 membered aryl;

[0061] L is selected from the following group: O, NR 1 、-NR 1 -(C1-C6 alkylene)-;

[0062] Ring C is selected from the following group:

[0063] Among them, R 1 , R 4 , X 1 , X 2 As defined in claim 1.

[0064] In another preferred embodiment, ring B is selected from the following group:

[0065] Ring C is selected from the following group:

[0066] Among them, R 1 , R 4 , R 5 , R 6 , X 1 , X 2 , X 6 , m as defined in claim 1, Q 1 It is a 3-7 membered ring.

[0067] In another preferred embodiment, ring A is selected from the following group:

[0068] Ring C is selected from the following group:

[0069] R 4 Selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S,

[0070] Among them, R 1 , R 5 , R 6 , R 7 , X 1 , X 6 , X 7 , m, n as defined in claim 1.

[0071] In another preferred embodiment, ring A is selected from the following group:

[0072] Ring C is selected from the following group:

[0073] R 4Selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S,

[0074] L is selected from the following group: O, NR 1 ;

[0075] Among them, R 1 , R 5 , R 6 , R 7 , X 1 , X 6 , m are as defined above.

[0076] In another preferred embodiment, R 4 Selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0077] L is NH.

[0078] In another preferred embodiment, the compound is selected from the following group:

[0079]

[0080]

[0081]

[0082] In another preferred embodiment, the compound is selected from the following group:

[0083]

[0084]

[0085] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;

[0086] The inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate;

[0087] The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0088] The second aspect of the present invention provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.

[0089] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a drug used as a CDK7 kinase inhibitor.

[0090] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a drug for regulating CDK7 kinase activity or preventing and / or treating CDK7-related diseases.

[0091] In another preferred embodiment, the CDK7-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0092] In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, and uterine cancer.

[0093] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 It is the pharmacokinetic parameter of the compound of the present invention and the reference compound. DETAILED DESCRIPTION

[0095] After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with good CDK7 kinase inhibitory activity. In addition, the compounds have excellent inhibitory activity against CDK7 kinase and have better pharmacodynamics / pharmacokinetic properties. On this basis, the present invention was completed.

[0096] the term

[0097] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.

[0098] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. 2 O- is equivalent to -OCH 2 -.

[0099] "Alkyl (alone or as part of another group)" refers to a monovalent straight or branched saturated hydrocarbon group containing 1 to 12 carbon atoms consisting only of carbon and hydrogen atoms. Alkyl is preferably C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. In the present application, alkyl is also intended to include substituted alkyl, i.e., one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. "Haloalkyl" refers to an alkyl as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl include -CH 2 Cl, -CH 2 CF 3 、-CH 2 CCl 3 , perfluoroalkyl (e.g., -CF 3 )wait.

[0100] "Alkylene" refers to a divalent radical of an alkyl group, such as -CH 2 -、-CH 2 CH 2 -and-CH 2 CH 2 CH 2 -.

[0101] "Alkoxy (alone or as part of another group)" refers to an alkyl group to which an oxy group is attached, which has an alkylO-structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1 to C6 alkoxy group. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Haloalkoxy" refers to a group of the formula -OR, wherein R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0102] "Thioalkyl" refers to an alkyl group in which a carbon is replaced by S, S(O) or S(O)2.

[0103] "Alkenyl (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl" refers to an alkenyl containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

[0104] "Alkenylene" refers to an alkenyl group having two points of attachment. For example, "vinylene" refers to the group -CH=CH-. Alkenylene can also be in unsubstituted form or in substituted form with one or more substituents.

[0105] "Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by having one or more triple bonds, typically having 2 to 20 carbon atoms. In the present invention, "C2-6 alkynyl" refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment for an alkynyl substituent. In the present invention, alkynyl groups also include substituted alkynyl groups.

[0106] "Alkynylene" refers to an alkynyl group with two points of attachment. For example, "ethynylene" refers to the group: -C≡C-. Alkynylene can also be in unsubstituted form or in substituted form with one or more substituents.

[0107] "Aliphatic group" refers to a straight chain, branched chain or cyclic hydrocarbon group, including saturated and unsaturated groups such as alkyl, alkenyl and alkynyl groups.

[0108] "Aromatic ring system" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0109] "Aryl (alone or as part of another group)" refers to a monovalent group of an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl and anthracenyl; and ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, phthalimide, naphthylimide or tetrahydronaphthyl, etc. In the present invention, aryl is preferably a C6-C12 aryl group. In the present invention, aryl is also intended to include substituted aryl groups.

[0110] "Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which one or more hydrogen atoms are replaced by an aryl group, and aryl and alkyl have the definitions described above. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl, etc.

[0111] "Aryloxy" means an -O-(aryl) group wherein the aryl portion is as defined herein.

[0112] "Heteroalkyl" refers to a substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Numerical ranges may be given, for example, C1-C6 heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, -CH 2 OCH 2 CH 3 The group is referred to as a "C3" heteroalkyl. Attachment to the rest of the molecule can be through a heteroatom or a carbon in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl having one or more backbone chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.

[0113] "Carbocyclic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but in which none of the rings are aromatic.

[0114] "Carbocyclyl" refers to a monovalent group of a carbon ring system, including, for example, cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0115] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, more preferably 3-8 ring atoms. The cycloalkyl group may be optionally substituted with one or more substituents, each of which is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0116] "Cycloalkyloxy" refers to a radical of the formula -OR, where R is a cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl" refers to -(cycloalkyl)-alkyl, where the cycloalkyl and alkyl groups are as disclosed herein. "Cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl group.

[0117] "Heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered) or polycyclic ring system, wherein at least one ring is both aromatic and contains at least one heteroatom (e.g., N, O or S); and wherein none of the other rings is a heterocyclyl (as defined below). In some cases, the ring that is aromatic and contains heteroatoms contains 1, 2, 3 or 4 ring heteroatoms in the ring. At least one of the rings is heteroaromatic, and the remaining rings may be saturated, partially unsaturated or fully unsaturated rings.

[0118] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10-membered) or tricyclic group of 5 to 12 ring atoms, which contains at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, and the remaining ring atoms are C. It should be clear that the point of attachment of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo oxadiazole, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazine, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Heteroarylene refers to a heteroaryl group having two attachment sites.

[0119] "Heterocyclic ring system" refers to monocyclic, bicyclic and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but non-aromatic) and the ring contains at least one heteroatom. The heterocyclic ring system may be attached to a pendant group at any heteroatom or carbon atom that creates a stable structure and any ring atom may be optionally substituted.

[0120] "Heterocyclyl" refers to a monovalent group of a heterocyclic ring system, usually a stable monocyclic ring (such as 3-8 members, i.e. 3, 4, 5, 6, 7 or 8 members) or bicyclic ring (such as 5-12 members, i.e. 5, 6, 7, 8, 9, 10, 11 or 12 members) or polycyclic ring (such as 7-14 members, i.e. 7, 8, 9, 10, 11, 12, 13 or 14), including fused, spiro and / or bridged ring structures, which are saturated, partially unsaturated, and contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Representative heterocyclyl groups include ring systems in which (1) each ring is non-aromatic and at least one ring contains heteroatoms, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) at least one ring is (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl; and (4) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is aromatic and contains heteroatoms, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthyridine. A heterocyclyl group refers to a heterocyclyl group having two attachment sites. In the present invention, preferably, the heterocyclyl group is a bicyclic ring, one of which is a heteroaryl group, and is connected to the other parts in the general formula through the heteroaryl group. In the present invention, preferably, the heterocyclyl group is a 5-6-membered monocyclic heterocyclyl group or an 8-10-membered bicyclic heterocyclyl group.

[0121] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined above.

[0122] The "alkylamino group" refers to a group having an alkyl-NR-structure, wherein R is H, or an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like as described above.

[0123] "Cycloalkylamino" refers to a radical of the formula -NRaRb, wherein Ra is H, an alkyl radical as defined herein, or a cycloalkyl radical as defined herein, and Rb is a cycloalkyl radical as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic radical, such as tetrahydropyrrolyl. As used herein, C3-C8 cycloalkylamino refers to an amine radical containing 3-8 carbon atoms.

[0124] In the present invention, "ester group" refers to a group having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above.

[0125] In the present invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.

[0126] In the present invention, the term "sulfonamide" refers to a sulfonamide having the structure -SO 2 NRR', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.

[0127] "Ketocarbonyl" refers to RC(=O)-, where R is alkyl, cycloalkyl, etc. as described above.

[0128] When a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0129] In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclic group and the like may be substituted or unsubstituted.

[0130] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or a group containing Cl 3 alkyl), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a , SR a 、S(=O)R e 、S(=O) 2 R e 、P(=O) 2 R e 、S(=O) 2 OR e , P(=O) 2 ORe NR b R c NR b S(=O) 2 R e NR b P(=O) 2 R e 、S(=O) 2 NR b R c 、P(=O) 2 NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O) 2 NR b R c NR d P(=O) 2 NR b R c NR b C(=O)R a , or NR b P(=O) 2 R e , where R a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings, and R b , R c and R d may independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring or an aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R eIt can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring can be optionally substituted. The substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group.

[0131] "Cyano" refers to a -CN group.

[0132] "Nitro" refers to -NO 2 .

[0133] "Hydroxyl" refers to -OH.

[0134] "Amino" refers to -NH 2 or RNH-, wherein R is a ketocarbonyl group, a sulfonyl group, a sulfonamide group, R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It is an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group.

[0135] "Halogen" refers to any halogen radical, for example, -F, -Cl, -Br or -I.

[0136] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0137] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0138] The structural formula of the carbamate group is -NH-C(=O)-OR, wherein R is an aryl group or a heteroaryl group.

[0139] Active ingredients

[0140] As used herein, the term "compound of the present invention" or "active ingredient of the present invention" is used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound (such as a deuterated compound) or prodrug thereof. The term also includes racemates and optical isomers.

[0141] The compound of formula I has the following structure:

[0142]

[0143] Ring A, Ring B, Ring C and L are as defined above.

[0144] The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included in the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps in the preparation process. The compounds of the present invention may form salts, for example, Compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.

[0145] The compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide

[0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

[0146] Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.

[0147] Prodrugs and solvates (or solvates) of the compounds of the present invention are also within the scope of this invention.

[0148] The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolism or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. The compounds of the present invention include solvates, such as hydrates.

[0149] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.

[0150] All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

[0151] The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

[0152] All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0153] Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

[0154] Specific functional groups and chemical term definitions are detailed below. For purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0155] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

[0156] According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

[0157] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number than the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 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 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its good metabolic stability in certain therapies has advantages, such as increasing half-life or reducing dosage in vivo, therefore, in some cases, it can be preferred. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the schemes disclosed in the examples.

[0158] If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

[0159] As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0160] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0161] In another preferred embodiment, in the compound, any one of the groups is the corresponding group in the specific compound.

[0162] Preparation method

[0163] Methods for preparing compounds of Formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order in which the steps of the reaction schemes are carried out may be altered to facilitate the reaction or to avoid unwanted side reaction products.

[0164] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

[0165] Usually, in the preparation process, each reaction is usually carried out under the protection of inert gas in a suitable solvent at 0 to 150° C., and the reaction time is usually 2 to 24 hours.

[0166] Preferably the preparation method is as follows:

[0167] Method 1:

[0168]

[0169] Step 1: In a solvent (such as 1,2-dichloroethane, dioxane, tetrahydrofuran), under the conditions of Lewis acid (such as aluminum chloride, zinc chloride, boron trifluoride ether, etc.), SM1 and SM2 react at 70-120 degrees to generate M1;

[0170] Step 2: In an inert solvent (such as DMF, dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, etc.), under alkaline conditions (such as diisopropylethylamine, potassium acetate, DBU, etc.) or in the presence of a catalyst and a ligand (such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 In the presence of t-BuXphos, etc., M1 reacts with SM3 to generate T (i.e., compound of formula I).

[0171] Method 2:

[0172]

[0173] Step 1: In an inert solvent (such as tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dioxane, ethylene glycol dimethyl ether, etc.), SM3 and SM2 react under the catalysis of Lewis acid (zinc chloride, ferric chloride, etc.) to obtain M1;

[0174] Step 2: In an inert solvent (such as N,N-dimethylformamide, dioxane, dimethyl sulfoxide, etc.) and alkaline (such as potassium carbonate, potassium phosphate, etc.), the catalyst and ligand (such as Pd(PPh 3 ) 4 ), M1 reacts with SM1 or SM1' to generate T (ie, a compound of formula I).

[0175] In the above formulae, Ring A, Ring B, Ring C and L are as described above.

[0176] Unless otherwise specified, the above starting materials can be purchased from commercial sources or synthesized according to reported literature.

[0177] Pharmaceutical compositions and methods of administration

[0178] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0179] The compounds of general formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

[0180] The drugs or active ingredients that can be used in combination with the compounds of Formula I include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, tositumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI 188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as idelalisib, dactolisib, tasel isib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacilast, Tecodinib, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc. ), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocatinib, linsitinib, BMS-754807, GSK1838705A, etc.), ER antagonists or degraders (such as tamoxifen, fulvestrant, etc.), aromatase inhibitors (such as letrozole, etc.), BCL2 or BCL-XL inhibitors (such as ABT-199, ABT-263, etc.), Hedgehog inhibitors (such as vismodegib, cyclopamine, etc.), chemotherapy drugs (such as cisplatin, etoposide, topotecan, etc.), PARP inhibitors (such as Olaparib, Vel iparib, Rucaparib, etc.), ATR / ATM inhibitors (such as Ceralasertib, Berzosertib, etc.) or a combination thereof.

[0181] The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

[0182] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0183] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0184] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0185] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0186] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0187] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0188] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0189] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0190] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0191] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0192] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0193] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0194] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula I of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0195] The present invention also provides a treatment method, which comprises the steps of administering the compound of formula I described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition described in the present invention to a subject in need of treatment, for inhibiting CDK7.

[0196] Compared with the prior art, the present invention has the following main advantages:

[0197] (1) The compounds of the present invention have excellent inhibitory ability against CDK7 kinase;

[0198] (2) The compounds of the present invention have lower toxic side effects;

[0199] (3) The compounds of the present invention have better pharmacodynamics and pharmacokinetic properties.

[0200] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0201] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0202] Example

[0203] The technical solution of the present invention is further described below, but the protection scope of the present invention is not limited thereto.

[0204] Synthesis of intermediate 1

[0205] The structural formula of intermediate 1 is as follows:

[0206]

[0207] The experimental process is as follows:

[0208] The synthetic route is as follows:

[0209]

[0210] Synthesis steps:

[0211] (1) Synthesis of Compound 2

[0212] 175g (1.0eq) of compound 1 was dissolved in tert-butyl alcohol and stirred at room temperature. Triethylamine was added to the reaction solution, and the solution changed from clear yellow to clear reddish brown. Under nitrogen protection, DPPA (1.5eq) was slowly added dropwise, and the reaction system was slowly heated to 80°C. A large number of bubbles were generated. After the bubbles were reduced, the reaction was continued at 80°C for 3 hours, and then sodium carbonate aqueous solution was added to quench the reaction, extracted with ethyl acetate, and the organic phases were combined, dried, and spin-dried through a column to obtain 187.5g of compound 2.

[0213] (2) Synthesis of Compound 3

[0214] Under nitrogen protection, 1.0 Mol / L vinylmagnesium bromide solution (5.0 eq) was added to the reaction bottle, and then a tetrahydrofuran (THF) solution of compound 2 (1.0 eq) was slowly added dropwise under a dry ice bath under nitrogen protection. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was allowed to react overnight. An aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and spin-dried through a column to obtain 132.4 g of compound 3.

[0215] (3) Synthesis of Intermediate 1

[0216] Compound 3 (132 g) was added to a 4.0 Mol / L hydrochloric acid / 1,4-dioxane solution at room temperature and reacted for two hours. The reaction system was filtered and the filter cake was washed with methyl tert-butyl ether to obtain 53.1 g of the hydrochloride of intermediate 1.

[0217] Synthesis of intermediate 2

[0218] The structural formula of intermediate 2 is as follows:

[0219]

[0220] The experimental process is as follows:

[0221] The synthetic route is as follows:

[0222]

[0223] Synthesis steps:

[0224] (1) Synthesis of Compound 2

[0225] At room temperature, compound 1 (5.38 g, 1.0 eq) was dissolved in methanol (60 mL), and then sodium methoxide (6.4 g, 2.0 eq) was added. The temperature was then raised to reflux for 16 hours, and the reaction was complete under TLC monitoring. Then, the temperature was lowered, the methanol was evaporated, and then 100 mL of ice water was added. The pH value was adjusted to weak acidity (pH = 4-5) with 2 Mol / L hydrochloric acid, and the product was precipitated, and then filtered. The filter cake was washed with water, and the filter cake was collected and dried to obtain 6.16 g of compound 2.

[0226] (2) Synthesis of Compound 3

[0227] At room temperature, compound 2 (6.36 g, 1.0 eq) was dissolved in methanol (65 mL), then cooled to 0 °C and concentrated sulfuric acid (3.79 g, 1.2 eq) was added. Then the temperature was slowly raised to reflux and the reaction was allowed to proceed for 12 hours. TLC monitored the reaction to be complete. The mixture was cooled to room temperature, and then the methanol was evaporated off, 50 mL of ice water was added, and the pH value was adjusted to neutral with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, and the organic phase was dried and dried to obtain 5.8 g of crude compound 3. It was used directly in the next step.

[0228] (3) Synthesis of Compound 4

[0229] Compound 3 (5.8 g, 1.0 eq) was dissolved in dichloromethane (100 mL) at room temperature. The mixture was cooled to -78°C under nitrogen protection, and then boron tribromide (32.5 mL, 5.0 eq) was added dropwise. After addition, the mixture was reacted at -78°C for 1 hour. The reaction was monitored to be complete by TLC. Methanol (20 mL) was added dropwise at -78°C to quench the reaction, and then the mixture was heated to 0°C, and 200 mL of ice water was added. The mixture was extracted with dichloromethane, and the organic phases were combined, dried, concentrated, and passed through a column to obtain 2.6 g of compound 4.

[0230] (4) Synthesis of Compound 5

[0231] Compound 4 (2.6 g, 1.0 eq) was added to acetonitrile (20 mL), then cooled to -15°C, 10% potassium hydroxide aqueous solution (147.8 g, 20.0 eq) was added, and then diethyl bromodifluoromethyl phosphate (10.6 g, 3.0 eq) was slowly added dropwise. After the addition, the reaction was continued at -10°C for 2 hours, and then the temperature was slowly raised to room temperature and the reaction was continued for 3 hours. TLC monitored the reaction to be complete. Ammonium chloride aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and passed through a column to obtain 0.92 g of compound 5.

[0232] (5) Synthesis of Compound 6

[0233] Compound 5 (0.92 g, 1.0 eq) was added to tetrahydrofuran (20 mL), and then cooled to -78 °C. Vinyl magnesium bromide (11.2 mL, 1.0 mol / L, 3.0 eq) was then added dropwise at this temperature. The temperature was then slowly raised to room temperature and allowed to react overnight after the reaction was continued at -78 °C for 1 hour. The reaction was monitored by TLC until complete, and then the temperature was lowered to -10 °C, and an aqueous solution of ammonium chloride was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, and passed through a column to obtain 503 mg of compound 6.

[0234] (6) Synthesis of Compound 7

[0235] Compound 6 (500 mg, 1.0 eq) was dissolved in methanol (5 mL), and then sodium hydroxide (250 mg, 3.0 eq) was added. The temperature was raised to reflux for reaction overnight. The reaction was completed after monitoring by TLC. The methanol was then spin-dried, 20 mL of ice water was added, and the aqueous phase was extracted once with methyl tert-butyl ether. The pH value of the aqueous phase was then adjusted to 4-5 with 2 mol / L hydrochloric acid. The solid was precipitated and filtered. The filter cake was washed with water, collected, and dried to obtain 352 mg of compound 7.

[0236] (7) Synthesis of Intermediate 2

[0237] Compound 7 (350 mg, 1.0 eq) was added to dioxane (5 mL), and then triethylamine (230 mg, 1.5 eq) was added. After heating to 90 ° C, diphenylphosphoryl azide (630 mg, 1.5 eq) was slowly added dropwise. A large amount of gas was generated. The dripping rate was controlled to prevent spraying. After the addition was completed, the reaction was continued at this temperature for 1 hour, and then methanol (1 mL) was added dropwise, and then the reaction was continued for 3 hours. TLC monitored the reaction to be complete. The temperature was lowered to 0 ° C, and then 2 mol / L sodium hydroxide solution was added to quench the reaction, extracted with ethyl acetate, and the organic phases were combined and dried through a column to obtain 230 mg of intermediate 2. LC-MS [M+1]: 257.0.

[0238] Synthesis of intermediate 3

[0239] The structural formula of intermediate 3 is as follows:

[0240]

[0241] The experimental process is as follows:

[0242] The synthetic route is as follows:

[0243]

[0244] Synthesis steps:

[0245] (1) Synthesis of Compound 8

[0246] In a glove box, under nitrogen protection, silver trifluoromethanesulfonate (12.85g, 5.0eq), selective fluorine reagent (Selectfluor) (7.1g, 2.0eq), N-fluorobisbenzenesulfonamide (NFSI) (6.3g, 2.0eq), cesium fluoride (9.1g, 6.0eq) and compound 4 (2.0g, 1.0eq) were added to the reaction bottle, and then toluene (20mL) and trifluorotoluene (40mL) were added. Then, under nitrogen protection, trifluoromethyltrimethylsilane (11.36g, 8.0eq) and 2-fluoropyridine (4.85g, 5.0eq) were added. The reaction was allowed to proceed overnight at 35°C, and the reaction was complete after TLC monitoring. Then, the reaction was filtered, the filter cake was washed with ethyl acetate, the organic phase was collected, and 0.15g of compound 8 was obtained by spin drying through a column.

[0247] (2) Synthesis of Compound 9

[0248] Compound 8 (0.6 g, 1.0 eq) was added to tetrahydrofuran (20 mL), and then cooled to -78 °C. Vinyl magnesium bromide (6.7 mL, 1.0 mol / L, 3.0 eq) was then added dropwise at this temperature. The temperature was then slowly raised to room temperature and allowed to react overnight after continuing to react at -78 °C for 1 hour. The reaction was monitored by TLC until complete, and then the temperature was lowered to -10 °C, and an aqueous solution of ammonium chloride was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, and passed through a column to obtain 320 mg of compound 9.

[0249] (3) Synthesis of Compound 10

[0250] Compound 9 (300 mg, 1.0 eq) was dissolved in methanol (5 mL), and then sodium hydroxide (140 mg, 3.0 eq) was added. The temperature was raised to reflux for reaction overnight. The reaction was monitored by TLC to be complete. The methanol was then spin-dried, 20 mL of ice water was added, and the aqueous phase was extracted once with methyl tert-butyl ether. The pH value of the aqueous phase was then adjusted to 4-5 with 2 mol / L hydrochloric acid. The solid was precipitated and filtered. The filter cake was washed with water, collected, and dried to obtain 145 mg of compound 10.

[0251] (4) Synthesis of Intermediate 3

[0252] Compound 10 (100 mg, 1.0 eq) was added to dioxane (3 mL), and then triethylamine (62 mg, 1.5 eq) was added. After heating to 90°C, diphenylphosphoryl azide (168 mg, 1.5 eq) was slowly added dropwise. After the addition, the reaction was continued at this temperature for 1 hour, and then methanol (1 mL) was added dropwise, and then the reaction was continued for 3 hours. TLC monitored the reaction to be complete. The temperature was lowered to 0°C, and then an aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried by column to obtain 54 mg of intermediate 3. LC-MS [M+1]: 275.0.

[0253] Synthesis of intermediate 4

[0254] The structural formula of intermediate 4 is as follows:

[0255]

[0256] The experimental process is as follows:

[0257] The synthetic route is as follows:

[0258]

[0259] Synthesis steps:

[0260] (1) Synthesis of Compound 2

[0261] 12 g (1 eq) of compound 1 was dissolved in 200 ml of anhydrous methanol, and 7.8 g (0.8 eq) of NaHCO was added. 3 , cool to -78°C and add 12.6 g (3 eq) NaBH in batches 4 , control the temperature below -60℃, dissolve 36.4mlCbz-Cl (2.5eq) in 50ml anhydrous methanol, slowly add it dropwise to the reaction system at -78℃, and keep the temperature constant for 1.5h. After the reaction is completed, monitor the reaction by TLC. Slowly add 1mol / L NaOH (aq) to the reaction liquid for quenching, extract with EA, and get 10g.

[0262] (2) Synthesis of Compound 3

[0263] N 2 Under protection, 10 g (1 eq) of compound 2 was dissolved in 150 ml of DCE, and 1 M / L of ZnEt 2 100ml (1.5eq), add 26g (1.5eq) CH 2 I 2 , RT reaction for 6h. Add NaHCO 3 (aq) was quenched, extracted with DCM, dried, and spin-dried to give 11 g (directly used in the next step).

[0264] (3) Synthesis of Compound 4

[0265] Dissolve 11g (1eq) of compound 3 in 110ml of DCM, add 14.3g (2.5eq) of DIEA, slowly drop 6.1g (1.2eq) of MsCl, and react at rt. After the reaction is complete, add water to quench, extract with DCM, dry, spin dry, and pass through a column to get 6g.

[0266] (4) Synthesis of Compound 5

[0267] 6 g (1 eq) of compound 4 was dissolved in 30 ml of DMF, 4 g (1.2 eq) of potassium phthalimide was added, and the mixture was reacted at 100°C overnight. Water was added, the mixture was extracted with EA and dried, and 5 g of the mixture was passed through a column.

[0268] (5) Synthesis of Intermediate 4

[0269] Dissolve 5g (1eq) of compound 5 in 100ml of ethanol, add 0.3g (2eq) of 80% hydrazine hydrate, react at 80°C for 15min, spin dry, add water, extract with EA, spin dry, and obtain 1.2g. LC-MS [M+1]: 247.1.

[0270] Synthesis of intermediate 5

[0271] The structural formula of intermediate 5 is as follows:

[0272]

[0273] The experimental process is as follows:

[0274] The synthetic route is as follows:

[0275]

[0276] Synthesis steps:

[0277] (1) Synthesis of Intermediate 5

[0278] Under nitrogen, 50 g of compound 1, 11 g of sodium methyl mercaptan (1.3 eq.) and 800 mL of 1,4-dioxane solvent were added to a 1000 mL three-necked flask, the temperature was raised to reflux, and the reaction was kept warm. After TLC monitoring of complete conversion of the raw materials, heating was stopped, the mixture was cooled to room temperature, extracted with EA and water, the organic phase was dried over anhydrous sodium sulfate, the solution was concentrated by rotary evaporation, and recrystallized from EA to obtain 39 g of intermediate 5 with a yield of 71%.

[0279] Synthesis of Intermediates 6 and 7

[0280] The structural formulas of intermediate 6 and intermediate 7 are as follows:

[0281]

[0282] The experimental process is as follows:

[0283] The synthetic route is as follows:

[0284]

[0285] Synthesis steps:

[0286] (1) Synthesis of Compound 2

[0287] In a 250ml three-necked flask, add 27g (1eq) of compound 1 and dissolve it in 250ml of n-butanol, stir and dissolve, then add 27.6g (2eq) of potassium carbonate, 20g (2.0eq) of vinyl butyl ether, 2.3g (0.04eq) of Xantphos, and 0.44g (0.02eq) of palladium acetate, replace with nitrogen 3 times, and react at 95°C overnight. Monitor the reaction until it is complete by TLC. Add water, extract with ethyl acetate 2 times, transfer the ethyl acetate phase to a 250ml single-necked bottle, add 5ml (1.5eq) of concentrated hydrochloric acid and stir at room temperature for 3h. Monitor the reaction until it is complete by TLC. Purify directly by column to obtain 13.4g of compound 2.

[0288] (2) Synthesis of Intermediates 6 and 7

[0289] Add 50 mg (1 eq) of compound 1 to a 50 ml single-mouth bottle, add 1 ml of tetrahydrofuran and stir to dissolve, add 1.4 ml (3 eq) of DAST dropwise at -20 °C, warm to room temperature and react for 5 h. Monitor the reaction by TLC until it is complete. Add water under ice bath, extract with ethyl acetate twice, and purify by column to obtain 10 mg of intermediate 6 and 25 mg of intermediate 7. The NMR of intermediate 7 is as follows: 1 H NMR (400 MHz, DMSO-d 6 )δ10.68(s,1H),9.39(s,1H),7.33(d,J=8.2Hz,1H),7.25(t,J=2.8Hz,1H),6.76(d ,J=8.3Hz,1H),6.35(dd,J=3.2,2.0Hz,1H),5.72(s,1H),2.00(s,3H),1.62(s,6H).

[0290] Example T-01

[0291] The compound synthesized by the present invention:

[0292]

[0293] The experimental process is as follows:

[0294] The synthetic route is as follows:

[0295]

[0296] Synthesis steps:

[0297] (1) Synthesis of Compound 2

[0298] In a 250ml three-necked flask, add 11.5g (1.0eq) of compound 1, 18.4g (1.4eq) of DPPA, 8.7g (1.8eq) of triethylamine, and 100ml of dioxane. React at 80°C for 1h under nitrogen protection, add 3.5ml (2.0eq) of methanol, and continue to react for 3h. Monitor the reaction by TLC until it is complete. Add water, extract with EA, and purify by column to obtain 9.2g of white solid.

[0299] (2) Synthesis of Compound 3

[0300] In a 500ml three-necked flask, add 8g (1.0eq) of compound 1, 12.7g (2.0eq) of 2,4-dichloro-5-trifluoromethylpyrimidine, 6.8g (1.7eq) of aluminum chloride, and 400ml of DCE. React overnight at 80°C under nitrogen protection. Monitor the reaction until it is complete by TLC. Add water to quench the reaction, extract the aqueous phase with EA after separation, combine the organic layers, spin dry, and then add EA to slurry to obtain 5g of purple-red solid.

[0301] (3) Synthesis of Compound 4

[0302] 4.4 g (1.0 eq) of compound 3, 4.1 g (2.1 eq) of (S)-1-Boc-3-aminopiperidine, and 50 ml of DMF were added to a 100 ml round-bottom flask and reacted overnight at room temperature. TLC monitored the reaction until it was complete. Water was added, EA was extracted, and column purification was performed to obtain 4.8 g of a white solid.

[0303] (4) Synthesis of Compound T-01

[0304] 2.0 g of compound 4, 10 ml of EA, and 10 ml of 4 M / L dioxane hydrochloride were added to a 25 ml round-bottom flask and reacted at room temperature for 4 h. TLC monitored the reaction until it was complete. The filter cake was filtered and washed with tert-butyl methyl to obtain 1.1 g of the hydrochloride of compound T-01. 1 HNMR (400 MHz, DMSO-d 6 )δ12.07(s,1H),9.20(d,J=14.0Hz,1H),8.69(d,J=10.0Hz,1H),8.30(m,1H),8.08(d,J=7.6Hz,1H),7.86(s,1H),7.30(t, J=8.4Hz,1H),4.21(s,1H),3.72(s,3H),3.13(s,2H),2.89–2.69(m,2H),2.07(m,1H),1.89(t,J=10.0Hz,1H),1.62(m,2H).

[0305] The hydrochloride salt of compound T-01 (50 mg) was added with NaHCO 3The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-01. HPLC purity: 98.9%. LC-MS [M+1]: 513.0, 515.0.

[0306] Referring to the method of Example T-01, the following compounds were synthesized:

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] Example T-07

[0313] The compound synthesized by the present invention:

[0314]

[0315] The experimental process is as follows:

[0316] The synthetic route is as follows:

[0317]

[0318] Synthesis steps:

[0319] (1) Synthesis of Compound 2

[0320] 0.28g (1.1eq) thiocarbonyldiimidazole was dissolved in 5ml dry THF at -10°C, 0.3g (1eq) compound 1 (dissolved in 5ml THF) was added, and then the reaction was kept warm for 5min. Then 0.17g (1.3eq) of INT-31 (dissolved in 1.5ml THF) was added dropwise to the reaction system, and then the temperature was gradually raised to room temperature for reaction. After the reaction was completed, water was added to quench, EA was extracted and dried, and then spin-dried and passed through a column to obtain 0.36g of compound 2.

[0321] (2) Synthesis of Compound 3

[0322] 0.36g (1eq) of compound 2 was dissolved in 15ml of THF, 0.25g (6eq) of sodium hydroxide (NaOH) was added, and then 0.18g (0.9eq) of p-toluenesulfonyl chloride was added, and the mixture was reacted at room temperature for 3h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with EA, dried with EA, and then spin-dried and passed through a column to obtain 0.15g of compound 3.

[0323] (3) Synthesis of Compound 4

[0324] Dissolve 0.32 g (3 eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 10 ml of 1,2-dichloroethane (DCE) and add aluminum chloride (AlCl 3 )0.1g(1.5eq),N 2 Under protection, the reaction was carried out at 80°C for 30 minutes. Compound 3 was then added and reacted at 80°C overnight. After the reaction was completed, water was added to quench the reaction, the DCE phase was separated, the aqueous phase was extracted with EA, the DCE phase and the EA phase were combined, dried, spin-dried, and slurried with EA to obtain 0.1 g of compound 4.

[0325] (4) Synthesis of Compound 5

[0326] 0.1 g (1 eq) of compound 4 was dissolved in 1 mL of N,N-dimethylformamide (DMF), and then 0.1 g (2 eq) of (S)-1-Boc-3-aminopiperidine and N 2 Under protection, the reaction was carried out at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted with EA and dried, then spin-dried and passed through a column to obtain 0.1 g of compound 5. LC-MS [M+1]: 652.1, 654.1.

[0327] (5) Synthesis of T-07

[0328] Take 0.1g (1eq) of compound 5 and add 1ml of dioxane hydrochloride (4.0Mol / L) and react at room temperature until completion. Add NaHCO 3 The aqueous solution was made alkaline, extracted with EA, dried, and spin-dried to obtain 0.02 g of compound T-07. HPLC: 89.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.59(s,1H),8.55(s,1H),8.12(s,1H),7.65(s,1H),6.81(s,1H),4.02(m,2H),3.90(s,1H),3.06(d,J=12.0Hz ,1H),2.80(d,J=12.0Hz,1H),2.49–2.36(m,2H),2.07–1.80(m,2H),1.65(m,1H),1.57–1.34(m,4H),1.25(s,6H).

[0329] Examples T-08 and T-11

[0330] The compound synthesized by the present invention:

[0331]

[0332] The experimental process is as follows:

[0333] The synthetic route is as follows:

[0334]

[0335] Synthesis steps:

[0336] (1) Synthesis of Compound 2

[0337] Take 1.0g (1.0eq) of cyclopropanecarboxylic acid in a 50mL round-bottom flask, add 10mL of N,N-dimethylformamide (DMF), and stir at room temperature. Then add 2.7g (1.5eq) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 1.2g (2.0eq) of diisopropylethylamine (DIPEA), react at room temperature for 5min, add compound 1 (1.0eq), and continue to react at room temperature. After the reaction is completed, slowly add 100mL of water, solid precipitates, and filter to obtain 1.1g of compound 2, with a yield of 85%.

[0338] (2) Synthesis of Compound 3

[0339] In a 50 mL round-bottom flask, 1.4 g (3 eq) 2,4-dichloro-5-trifluoromethylpyrimidine, 30 mL dichloroethane (DCE) and 0.5 g (1.7 eq) AlCl 3 The temperature was raised to 80°C. N2 was used for protection. After 30 min of reaction, 0.6 g (1 eq) of compound 2 was added. 2 After the reaction was completed, water was added, EA was extracted, the organic layer was evaporated to dryness, and EA was added to slurry to obtain 200 mg of compound 3.

[0340] (3) Synthesis of Compound 4

[0341] 0.2 g (1 eq) of compound 3 was dissolved in 6 mL of DMF, and 0.18 g of (S)-1-Boc-3-aminopiperidine (2 eq) was added, and the mixture was stirred at room temperature overnight. After the reaction, water was added, and the mixture was extracted with EA and dried, and then spin-dried to obtain 0.24 g of compound 4.

[0342] (4) Synthesis of Compound 5

[0343] 110 mg (1 eq) of compound 4 was dissolved in 4 mL of methanol (MeOH), and 30 mg of Pd / C (2 eq) and 2 drops of Et 3 N, in H 2 The reaction was carried out overnight under the protection of RT and stirring. After the reaction was completed, the solution was filtered and the filtrate was dried by rotary evaporation to obtain 92 mg of compound 5.

[0344] (5) Synthesis of compound T-08:

[0345] Take 100 mg (1 eq) of compound 4 and dissolve it in 3 mL of 4M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, prepare 47 mg. HPLC: 96.4%. 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),9.85(d,J=12.0Hz,1H),8.58(d,J=20.0Hz,1H),8.23(m,1H),7.80(m,2H),7.26(t,J=7.6Hz,1H),3.90(s,1 H),3.07(d,J=11.6Hz,1H),2.87–2.72(m,1H),2.44(t,J=11.2Hz,2H),1 .97(m,3H),1.65(d,J=11.6Hz,1H),1.42(d,J=19.6Hz,3H),0.86(m,3H).

[0346] (6) Synthesis of T-11:

[0347] Take 80 mg (1 eq) of compound 5 and dissolve it in 3 mL of 2M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 The aqueous solution was adjusted to alkaline, extracted with EA, dried, and spin-dried to obtain 35 mg of compound T-11. HPLC: 96.7%. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),10.31(s,1H),8.65(d,J=5.2Hz,1H),8.31(m,2H),8.12–7.96(m,2H),7.86(s,1H),7.34( m,1H),4.30(s,1H),3.22(s,2H),2.89(t,J=10.8Hz,1H),2.00–1.84(m,2H),1.84–1.48(m,3H),1.30(s,3H),0.97–0.81(m,3H).

[0348] The following compounds were synthesized by referring to the methods of Examples T-08 and T-11:

[0349]

[0350] Example T-12

[0351] The compound synthesized by the present invention:

[0352]

[0353] The experimental process is as follows:

[0354] The synthetic route is as follows:

[0355]

[0356] Synthesis steps:

[0357] (1) Synthesis of Compound 2

[0358] 2g (1eq) of compound 1 was dissolved in 40mL THF at 0℃, 2.4g (2.5eq) of triethylamine (TEA) was added, and chloroethyl chloroformate was added dropwise into the reaction system. After the reaction of compound 1 was completed, 1.2g (5eq) of sodium hydride (NaH) was added in batches at 0℃ and reacted at room temperature. After the reaction was completed, water was added to quench, EA was extracted and dried, and then spin-dried. 1.2g of compound 2 was obtained by column. LC-MS [M+1]: 280.9, 282.9.

[0359] (2) Synthesis of Compound 3

[0360] Dissolve 2.78 g (3 eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 60 mL of 1,2-dichloroethane (DCE) and add aluminum chloride (AlCl 3 )0.85g(1.5eq), N 2 Under protection, react at 80°C for 30 min. Then add compound 2 and react at 80°C overnight. After the reaction is complete, add water, separate the DCE phase, extract the aqueous phase with EA, combine the DCE phase and the EA phase, dry, spin dry, and slurry with EA to obtain 1.3 g of compound 3. LC-MS [M+1]: 460.9, 462.9.

[0361] (3) Synthesis of Compound 4

[0362] 0.3 g (1 eq) of compound 3 was dissolved in 3 mL of N,N-dimethylformamide (DMF), and then 0.24 g (2 eq) of (S)-1-Boc-3-aminopiperidine and N 2 Under protection, the reaction was carried out at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted with EA and dried, then spin-dried and passed through a column to obtain 0.3 g of compound 4. LC-MS [M+1]: 625.1, 627.1.

[0363] (4) Synthesis of Compound T-12 Hydrochloride

[0364] 0.1 g (1 eq) of compound 4 was added with 2 mL of ethyl acetate (EA) and 1 mL of dioxane hydrochloride (4 Mol / L), and the reaction was completed at room temperature. Filtering was performed to obtain 0.06 g of hydrochloride of compound T-12. HPLC purity: 96.4%.

[0365] (5) Synthesis of Compound T-12

[0366] Take 0.1g (1eq) of compound 4 and add 2mL of dioxane hydrochloride (4Mol / L) and react at room temperature until completion. Add NaHCO 3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried. 0.03 g of compound T-12 was obtained by preparative plate separation. HPLC purity: 93.4%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.28(s,1H),8.73(s,1H),8.16(d,J=8Hz,1H),7.93(d,J=6.0Hz,1H),7.36(t,J=8.8Hz,1H),4 .60(t,J=8Hz,2H),4.34(s,1H),4.14(t,J=8Hz,2H),3.24(s,1H),2.89(s,1H),2.17-1.50(m,8H).

[0367] (6) Synthesis of Compound T-49

[0368] 0.15 g (1 eq) of compound 4 was dissolved in 10 mL of methanol (CH 3 OH), add 0.01 g of palladium carbon (Pd / C) and 3 drops of TEA, and 2 The reaction was allowed to proceed overnight at room temperature until completion, and the mixture was filtered, dried, and spin-dried to obtain 0.1 g of compound T-49.

[0369] The following compounds were synthesized by referring to the method of Example T-12:

[0370]

[0371]

[0372] Example T-14 Compound synthesized by the present invention:

[0373]

[0374] The experimental process is as follows:

[0375] The synthetic route is as follows:

[0376]

[0377] Synthesis steps:

[0378] (1) Synthesis of Compound 2

[0379] 230 mg (1 eq) of compound 1 was dissolved in 6 mL of dry DMF, and 16 mg (0.2 eq) of palladium acetate, 84 mg (0.4 eq) of Xantphos and 226 mg (8 eq) of dimethylphosphine oxide were added. 2 Under protection, the reaction was carried out at 140°C. After the reaction was completed, water was added, EA was extracted and dried, and then spin-dried to obtain 40 mg of crude compound 5.

[0380] (2) Synthesis of Compound 3

[0381] 50 mg (1 eq) of compound 4 was dissolved in 3 ml of methyl chloroformate and 100 mg of Na 2 CO 3 After the reaction, water was added, the mixture was extracted with EA and dried, and then spun dry to obtain 40 mg of crude compound 5.

[0382] (3) Synthesis of Compound T-14

[0383] Take 40 mg (1 eq) of compound 3 and dissolve it in 2 mL of 4 M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, scrape to obtain 10 mg of compound TY-2652. HPLC: 88%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.75(s,1H),8.69(s,1H),8.50–8.04(m,2H),7.95(d,J=14.7Hz,1H),7.65(s,1H),4.31(s,1H),3.71( s,3H),3.22(s,1H),3.01–2.82(m,2H),1.95(d,J=13.6Hz,6H),1.83–1.47(m,4H),1.40(d,J=4.0Hz,2H).

[0384] The following compounds were synthesized by referring to the method of Example T-14:

[0385]

[0386] Example T-15

[0387] The compound synthesized by the present invention:

[0388]

[0389] The experimental process is as follows:

[0390] The synthetic route is as follows:

[0391]

[0392] Synthesis steps:

[0393] (1) Synthesis of Compound 2

[0394] 250 mg (1 eq) of compound 1 was dissolved in 6 ml of dry DMF, and 19 mg (0.2 eq) of palladium acetate, 97 mg (0.4 eq) of Xantphos and 262 mg (8 eq) of dimethylphosphine oxide were added. 2 Under protection, the mixture was reacted at 140°C for 1.5 h. Water was added, the mixture was extracted with EA and dried, and then spin-dried to obtain 150 mg of crude compound 6.

[0395] (2) Synthesis of compound T-15:

[0396] Take 150 mg (1 eq) of compound 2 and add it to 4 mL of 4M / L dioxane hydrochloride for reaction at rt. After the reaction is completed, add NaHCO 3 The aqueous solution was adjusted to alkaline, extracted with EA, dried, and spin-dried to obtain 10 mg of compound T-15. HPLC: 96.7%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.73(s,1H),10.36(d,J=30.0Hz,1H),8.57(d,J=14.8Hz,1H),8.16(d,J=193.2Hz,2H),7.80(s,1H),7.39(s,1H),7. 27–7.03(m,1H),3.94(s,1H),3.11(s,2H),2.87(d,J=16.9Hz,2H),2.07(s,3H),1.90(m,6H),1.68(s,2H),1.47(s,2H).

[0397] Example T-16

[0398] The compound synthesized by the present invention:

[0399]

[0400] The experimental process is as follows:

[0401] The synthetic route is as follows:

[0402]

[0403] Synthesis steps:

[0404] (1) Synthesis of Compound 2

[0405] 220 mg (1 eq) of compound 1 was dissolved in 6 mL of MeOH, and 50 mg of Pd / C and 3 drops of Et3 N, in H 2 The reaction was carried out overnight under the protection of , stirring at room temperature. After the reaction was completed, the solution was filtered and the filtrate was dried by rotary evaporation to obtain 200 mg of compound 5.

[0406] (2) Synthesis of Compound T-16

[0407] Take 200 mg (1 eq) of compound 2 and dissolve it in 3 mL of 4 M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, prepare 10 mg of compound T-16. HPLC: 92.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.78(s,1H),9.63(s,1H),8.51(d,J=18.4Hz,1H),8.26(m,1H),7.77(d,J=12.4Hz,2H),7.68(d,J=8.0Hz,1H),7.16(m,1H),3.9 0(d,J=31.2Hz,1H),3.68(s,3H),3.16–2.97(m,1H),2.88–2.70(m,1H),2.43(m,2H),2.12–1.86(m,1H),1.65(s,1H),1.45(m,2H).

[0408] Example T-17

[0409] The compound synthesized by the present invention:

[0410]

[0411] The experimental process is as follows:

[0412] The synthetic route is as follows:

[0413]

[0414] Synthesis steps:

[0415] (1) Synthesis of Compound 2

[0416] 0.5 g (1.0 eq) of compound 1 was dissolved in 10 mL of dioxane and 1 mL of water, and 0.34 g (3 eq) of K2CO3, 0.35 g (5 eq) of cyclopropaneboronic acid and 0.12 g (0.2 eq) of Pd(dppf)Cl2 were added, and the mixture was protected by N2 and reacted at 100°C. After the reaction, water was added, and the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain 0.40 g of compound 3.

[0417] (2) Synthesis of Compound T-17

[0418] Take 200 mg (1 eq) of compound 3, add it to 4 mL of 4M / L hydrochloric acid dioxane solution and 3 mL of EA at room temperature, and react at room temperature. After the reaction is completed, filter and wash the filter cake with methyl tert-butyl ether to obtain 175 mg of the hydrochloride of compound T-17. HPLC: 93.9%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.47(d,J=13.6Hz,1H),8.82(d,J=13.6Hz,1H),8.53(d,J=18.4Hz,1H),8 .16(m,1H),7.82–7.58(m,2H),7.11(s,1H),3.90(s,1H),3.66(s,3H),3.05( m,1H),2.80(d,J=12.0Hz,2H),2.05–1.82(m,2H),1.64(d,J=10.4Hz,1H),1. 42(d,J=18.8Hz,2H),1.23(s,1H),1.08–0.92(m,2H),0.53(d,J=5.6Hz,2H).

[0419] The following compounds were synthesized by referring to the method of Example T-17:

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] Example T-20 Compound synthesized by the present invention:

[0426]

[0427] The experimental process is as follows:

[0428] The synthetic route is as follows:

[0429]

[0430] Synthesis steps:

[0431] (1) Synthesis of Compound 2

[0432] 0.25 g (1 eq) of compound 1 was dissolved in 3 mL (N,N-dimethylformamide) DMF, 0.14 g (1.1 eq) of (1S,3S)-3-aminocyclohexylcarbamic acid tert-butyl ester (CAS: 1788036-28-1) was added, and the mixture was reacted overnight at room temperature. Water was added, the mixture was extracted with EA, dried, and then filtered to obtain 0.2 g of compound 2. LC-MS [M+1]: 627.1, 629.1.

[0433] (2) Synthesis of T-20 hydrochloride and T-20

[0434] 0.2 g (1 eq) of compound 2 was dissolved in 5 mL of ethyl acetate (EA), and 2 mL of dioxane hydrochloride (4.0 Mol / L) was added, and the reaction was completed at room temperature. Filtering was performed to obtain 0.13 g of compound T-20 hydrochloride. HPLC: 98.7%. 1 H NMR (400 MHz, Methanol-d 4 )δ8.63(s,1H),8.37(s,1H),8.16(s,1H),7.61(s,1H),4.69(s,1H),3.78(s,3H),3.61-3.44(m,1H),2.52-1.39(m,9H).

[0435] Compound T-20 hydrochloride (50 mg) was added with NaHCO 3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-20. HPLC purity: 98.4%. LC-MS [M+1]: 527.1, 529.1.

[0436] The following compounds were synthesized by referring to the method of Example T-20:

[0437]

[0438]

[0439]

[0440] Example T-27 Compound synthesized by the present invention:

[0441]

[0442] The experimental process is as follows:

[0443] The synthetic route is as follows:

[0444]

[0445] Synthesis steps:

[0446] (1) Synthesis of Compound 2

[0447] 0.5 g (1.0 eq) of compound 1 was dissolved in 6 mL of DMF, and 0.22 g (3 eq) of CuCN was added, and the mixture was reacted overnight at 100°C. After the reaction, ammonia and water were added, and the mixture was extracted with EA and dried, and then spin-dried to obtain 0.13 g of crude compound 2. LC-MS [M+1]: 560.2.

[0448] (2) Synthesis of Compound T-27

[0449] Take 130 mg (1 eq) of compound 2 and dissolve it in 4 mL of 4M / L dioxane hydrochloride and 4 mL of EA and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, separate on a preparative plate to obtain 40 mg of compound T-27. HPLC: 95.1%. LC-MS [M+1]: 460.1. 1 H NMR (400 MHz, DMSO-d 6 )δ9.81(s,1H),8.67–8.52(m,1H),8.16(m,2H),7.81(s,1H),7.25(m,1H),3.90(d,J=10.1Hz,1H),3.71(s,3H), 3.07(d,J=12.0Hz,1H),2.81(s,1H),2.44(s,2H),1.97(d,J=13.4Hz,1H),1.66(s,1H),1.46(d,J=10.1Hz,2H).

[0450] Example T-28

[0451] The compound synthesized by the present invention:

[0452]

[0453] The experimental process is as follows:

[0454] The synthetic route is as follows:

[0455]

[0456] Synthesis steps:

[0457] (1) Synthesis of Compound 2

[0458] To a 100-mL three-necked flask, 200 mg of compound 1, INT-1 (2.0 eq) and 15 mL of DMF as solvent were added, and the reaction was carried out at room temperature under nitrogen. After the reaction, the DMF solvent was removed by rotary evaporation, and the mixture was separated and purified by silica gel column chromatography to obtain 220 mg of compound 2 with a yield of 77.5%. LC-MS [M+1]: 639.1, 641.1.

[0459] (2) Synthesis of T-28 hydrochloride and T-28

[0460] 220 mg of compound 2 was added to a 50 mL three-necked flask, dissolved with 10 mL of ethyl acetate, and then 3 mL of 1 M hydrochloric acid dioxane solution was added. The reaction was stirred at room temperature under nitrogen for 1 hour. After the reaction was completed, the solid was filtered and washed with appropriate amounts of ethyl acetate and ether to obtain 100 mg of yellow solid T-28 hydrochloride. The yield was 50.5%, LC-MS [M+1]: 539.1, 541.1, and HPLC purity was 99.0%

[0461] Compound T-28 hydrochloride (50 mg) was added with NaHCO 3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-28. HPLC purity: 98.8%. LC-MS [M+1]: 539.1, 541.1.

[0462] The following compounds were synthesized by referring to the method of Example T-28:

[0463]

[0464]

[0465] Examples T-32 and T-33

[0466] The compound synthesized by the present invention:

[0467]

[0468] The experimental process is as follows:

[0469] The synthetic route is as follows:

[0470]

[0471] Synthesis steps:

[0472] (1) Synthesis of Compound 2

[0473] 0.2g (300mg, 1eq) of compound 1 was dissolved in 5ml of DMF, and then INT-4 (146mg, 1.1eq) and DIPEA (118.3mg, 1.5eq) were added, and the reaction was carried out overnight at rt under N2 protection. After the reaction was completed, water was added to the system, and the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain compound 2 (470mg).

[0474] (2) Synthesis of Compound 3

[0475] Compound 2 (200 mg, 1.0 eq) was dissolved in DCM (5 ml), and the temperature was lowered to -45°C under nitrogen protection. Then, a DCM (1.0 ml) solution of boron tribromide (151.4 mg, 1.5 eq) was added dropwise. After the addition was completed, the temperature was raised to -30°C and the mixture was reacted for 10 min. The mixture was then naturally raised to room temperature and reacted for 2 h. After the reaction was completed, sodium bicarbonate aqueous solution was added to quench the mixture, and the mixture was extracted with DCM. The mixture was separated and dried to obtain compound 3 (130 mg).

[0476] (3) Synthesis of Compound 4

[0477] Compound 3 (130 mg, 1.0 eq) was added to DCM (5 ml), which was insoluble, and then phenyl chloroformate (42 mg, 1.0 eq) was added to dissolve, and then TEA (27 mg, 1.0 eq) was added to react at room temperature for 2 h. After the reaction was completed, water was added to the system, and then DCM was added for extraction, and the liquid was separated, dried, and filtered to obtain compound 4 (112 mg).

[0478] (4) Synthesis of Compound 5 and Compound 6:

[0479] Compound 4 (112 mg, 1.0 eq) was dissolved in THF (5 ml), and then a dimethylamine aqueous solution (6 ml) was added and allowed to react overnight. After the reaction was completed, water was added to the system, and then EA was added for extraction. The liquids were separated and dried on a scraper to obtain compound 5 (23 mg) and compound 6 (31 mg).

[0480] (5) Synthesis of compounds T-32 and T-33

[0481] Compound 5 (23 mg) and compound 6 (31 mg) were dissolved in methanol, and then Pd / C was added and H 2 After overnight reaction, the mixture was filtered and dried to obtain the final product, compound T-32 (12 mg), HPLC purity 95.6%, LC-MS [M+1]: 477.2. Compound T-33 (8 mg), HPLC purity 94.2%, LC-MS [M+1]: 477.2.

[0482] Example T-34

[0483] The compound synthesized by the present invention:

[0484]

[0485] The experimental process is as follows:

[0486] The synthetic route is as follows:

[0487]

[0488] Synthesis steps:

[0489] (1) Synthesis of Compound 2

[0490] Under anhydrous and anaerobic conditions, 300 mg of compound 1, methyl fluorosulfonyl difluoroacetate (5.0 eq), and CuI (5.0 eq) were added to a 10 mL reaction branch tube, and the temperature was raised to 100°C for reaction. After the reaction was completed, the mixture was cooled to room temperature, several milliliters of 1 M dilute hydrochloric acid were added, and the mixture was extracted with water and EA. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 110 mg of compound 2 with a yield of 37.3%. LC-MS [M+1]: 603.2.

[0491] (2) Synthesis of compound T-34

[0492] 110 mg of compound 2 was added to a 50 mL three-necked flask, and 6 mL of dichloromethane was added. After dissolving, 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for half an hour. After the reaction was completed, the excess solvent was removed by concentration, and then the pH value was adjusted to alkaline, EA was extracted, and the mixture was spin-dried. After separation and purification by medium-pressure preparative reverse column, 60 mg of compound T-34 was obtained, with a yield of 65.2%, HPLC purity of 95.0%, and LC-MS [M+1]: 503.1.

[0493] The following compounds were synthesized by referring to the method of Example T-34:

[0494]

[0495]

[0496]

[0497] Example T-37 Compound synthesized by the present invention:

[0498]

[0499] The experimental process is as follows:

[0500] The synthetic route is as follows:

[0501]

[0502] Synthesis steps:

[0503] (1) Synthesis of Compound 2

[0504] At 0°C, compound 1 (10.0 g, 1.0 eq) was dissolved in methanol (100 ml), and then sodium methoxide (6.9 g, 2.0 eq) was added. After the addition was completed, the temperature was raised to 65°C for reaction for 3 h. The reaction was monitored by TLC. After cooling, the solvent was dried and a small amount of methanol was added for pulping, and the filter cake was collected to obtain compound 2 (10.06 g).

[0505] (2) Synthesis of Compound 3

[0506] Compound 2 (3.0 g, 1.0 eq) was dissolved in tert-butanol (15 ml), and then diphenylphosphoryl azide (DPPA) (5.86 g, 1.4 eq) and triethylamine (2.77 g, 1.8 eq) were added. The temperature was raised to 80°C under nitrogen protection for 2 h. The reaction was completed after TLC monitoring. After cooling, water was added to the system, and then EA was added for extraction. The EA phase was collected, dried over anhydrous sodium sulfate, filtered and dried through a column to obtain compound 3 (2.2 g).

[0507] (3) Synthesis of Compound 4

[0508] HCl / dioxane (10 ml) was added to compound 3 (2.2 g), and the mixture was stirred at room temperature for 1.5 h. The reaction of the raw material was monitored by a plate. After the solvent was dried, petroleum ether was added to slurry, and the mixture was filtered to obtain compound 4 (1.2 g).

[0509] (4) Synthesis of Compound 5

[0510] Methyl chloroformate (10 ml) was added to compound 4 (1.2 g, 1.0 eq), the temperature was lowered to 0°C, sodium carbonate (3.0 g, 4.0 eq) was added in batches, and the temperature was naturally raised to room temperature to react overnight. TLC monitored the reaction to be complete, water was added to the system, and then EA was added for extraction, the EA phase was collected, dried over anhydrous sodium sulfate, filtered, and dried by column to obtain compound 5 (1.3 g).

[0511] (5) Synthesis of Compound 6

[0512] Compound 5 (1.0 g, 1.0 eq) was dissolved in dry THF (10 ml), evacuated to replace nitrogen, then cooled to -78 ° C, 1 Mol / L vinyl magnesium bromide (26.5 ml, 6.0 eq) was added dropwise, and the mixture was naturally warmed to room temperature and stirred overnight. TLC monitoring showed that the raw materials reacted completely, the temperature was lowered, and an aqueous ammonium chloride solution (20 ml) was added to the system, stirred for 0.5 h, and then EA was added for extraction, separated, the EA phase was collected, anhydrous sodium sulfate was added for drying, filtered, and dried by column to obtain compound 6 (0.3 g).

[0513] (6) Synthesis of Compound 7

[0514] 0.58 g (3.0 eq) of 2,4-dichloro-5-trifluoromethylpyrimidine was dissolved in 6 mL of dichloroethane (DCE), and aluminum chloride (AlCl 3 )0.18g(1.5eq),N 2 Under protection, react at 80°C for 30 min. Then add compound 6 (0.2 g, 1.0 eq) and react at 80°C overnight. After the reaction is completed, add water, separate the DCE phase, extract the aqueous phase with EA, combine the DCE phase and the EA phase, dry, spin dry, slurry with EA, and filter to obtain compound 7 (60 mg).

[0515] (7) Synthesis of Compound 8

[0516] 60 mg (1.0 eq) of compound 7 was dissolved in 1 mL of DMF, and then (S)-1-Boc-3-aminopiperidine (60 mg, 2 eq) was added, and the mixture was reacted at room temperature overnight under N2 protection. After the reaction was completed, water was added to the system, and the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain compound 8 (70 mg).

[0517] (8) Synthesis of Compound T-37 Hydrochloride:

[0518] HCl / dioxane (5 ml) was added to compound 8 (70 mg), and the mixture was stirred at room temperature for 1.5 h. The reaction of the raw material was monitored by plate counting. After the solvent was dried, petroleum ether was added for slurrying, and the mixture was filtered to obtain T-37 (43 mg, purity 97.2%). 1 H NMR (400 MHz, DMSO-d 6 )δ12.12-11.93(m,1H),9.17-8.78(m,3H),8.03(d,J=10.1Hz,1H),7.74(s,1H),7.33(d,J=12.8Hz,1H),4.27(s,1H),3.8 7(s,3H),3.65(s,3H),3.19(s,1H),2.95-2.77(m,2H),1.95(d,J=32.2Hz,2H),1.72(d,J=12.5Hz,2H),1.31-1.13(m,2H).

[0519] The following compounds were synthesized by referring to the method of Example T-37:

[0520]

[0521]

[0522]

[0523]

[0524] Example T-40 Compound synthesized by the present invention:

[0525]

[0526] The experimental process is as follows:

[0527] The synthetic route is as follows:

[0528]

[0529] Synthesis steps:

[0530] (1) Synthesis of Compound 2

[0531] 350 mg (1 eq) of compound 1 was dissolved in 4 mL of DMF, and 200 mg (2.5 eq) of K 2 CO 3 , 410 mg (5 eq) iodomethane (CH 3 I), react at room temperature. After the reaction, add 40 mL of water, extract with EA, dry, and spin dry to obtain 250 mg of crude compound 2.

[0532] (2) Synthesis of Compound T-40

[0533] Take 250 mg (1 eq) of compound 5 (crude product) from the previous step and add it to 4 mL of 4M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, separate by preparative chromatography to obtain 40 mg of compound T-40. HPLC: 96.2%. LC-MS [M+1]: 527.0, 529.0. 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(d,J=12.8Hz,1H),8.59(d,J=19.2Hz,1H),8.18(m,1H),7.89–7.72(m,2H),7.18(d,J=8.4Hz,1H),4.22(d,J=1.6Hz,3H ),3.86(m,1H),3.65(s,3H),3.03(m,1H),2.88–2.68(m,1H),2.45–2.33(m,2H),1.93(s,1H),1.70–1.57(m,1H),1.44(m,2H).

[0534] Example T-41

[0535] The compound synthesized by the present invention:

[0536]

[0537] The experimental process is as follows:

[0538] The synthetic route is as follows:

[0539]

[0540] Synthesis steps:

[0541] (1) Synthesis of Compound 2

[0542] 500 mg (1 eq) of compound 1 was dissolved in 6 mL of THF, and 267 mg (6 eq) of NaH was added under a salt ice bath and stirred for 5 min, followed by the addition of 1.39 g (5 eq) of CH 3 I, and react at room temperature. After the reaction, 40 mL of water was added, extracted with EA and dried, and then spin-dried to obtain 500 mg of crude compound 2. LC-MS [M+1]: 477.0, 479.0.

[0543] (2) Synthesis of Compound 3

[0544] 0.5 g (1.0 eq) of compound 2 was dissolved in 6 mL of DMF, and 0.46 g (2.2 eq) of (S)-1-Boc-3-aminopiperidine was added, and the mixture was stirred at room temperature and reacted overnight. After the reaction, water was added, and the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain 0.21 g of compound 3. LC-MS [M+1]: 641.1, 643.1.

[0545] (3) Synthesis of Compound T-41

[0546] Take 150 mg (1 eq) of compound 5 and dissolve it in 3 mL of 4 M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 The aqueous solution was adjusted to alkaline, extracted with EA, dried, and spin-dried to obtain 25 mg of compound T-41. HPLC: 94.1%. LC-MS [M+1]: 541.1, 543.1. 1 H NMR (400 MHz, DMSO-d 6)δ8.65–8.52(m,1H),8.19(m,1H),7.85(t,J=4.8Hz,2H),7.18(q,J=8.0Hz,1H),4.23(s,3H),3.89(s,1H),3.70(s,1H),3.52(d,J=4.2Hz ,3H),3.16(d,J=11.5Hz,3H),3.04(d,J=11.6Hz,1H),2.97–2.72(m,2H),2.44(s,1H),1.95(m,1H),1.84–1.61(m,1H),1.61–1.42(m,2H).

[0547] Example T-42

[0548] The compound synthesized by the present invention:

[0549]

[0550] The experimental process is as follows:

[0551] The synthetic route is as follows:

[0552]

[0553] Synthesis steps:

[0554] (1) Synthesis of Compound 2

[0555] Under nitrogen, 250 mg of compound 1 and 5 mL of anhydrous ethanol were added to a 10 mL reaction tube. After dissolution, DPPA (10.0 eq) and Et 3 N (5.0eq), heated to reflux for two hours, cooled to room temperature after the reaction, quenched with water, extracted with EA and water, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 116 mg of compound 2 with a yield of 43.2% and an HPLC purity of 95.1%.

[0556] (2) Synthesis of Compound T-42 Hydrochloride and T-42

[0557] 156 mg of compound 2 was added to a 50 mL three-necked flask, dissolved with 5 mL of ethyl acetate, and then 2 mL of 1 M hydrochloric acid dioxane solution was added. The reaction was stirred under nitrogen at room temperature for 1 hour. After the reaction was completed, it was filtered and the solid was washed with appropriate amounts of ethyl acetate and ether in turn to obtain 116 mg of yellow solid T-42 hydrochloride with a yield of 82.8%, LC-MS [M+1]: 527.1, 529.1, and HPLC purity of 95.3%.

[0558] Compound T-42 hydrochloride (40 mg) was added with NaHCO3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-42. HPLC purity: 95.3%. LC-MS [M+1]: 527.1, 529.1.

[0559] The following compound was synthesized by referring to the method of Example T-42:

[0560]

[0561]

[0562] Example T-52

[0563] The compound synthesized by the present invention:

[0564]

[0565] The experimental process is as follows:

[0566] The synthetic route is as follows:

[0567]

[0568] Synthesis steps:

[0569] (1) Synthesis of Compound 2

[0570] 274 mg (1.0 eq) of compound 1 was added to a mixed solvent of dioxane (4 ml) and water (0.4 ml), and then 150 mg (5.0 eq) of methylboronic acid and 207 mg of Pd(dppf)Cl were added. 2 (0.2eq) and potassium carbonate 207mg (3.0eq), N 2 The mixture was reacted at 100°C under protection until the reaction was completed. Water was added, the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain compound 2 (121 mg).

[0571] (2) Synthesis of compound T-52:

[0572] 100 mg of compound 3, 1 ml of TFA, and 4 ml of DCM were added to the reaction system at room temperature. After 5 hours, the reaction was detected by TLC. The T-52 was purified by preparative liquid phase to obtain 58 mg of T-52 with a purity of 98.7%. LC-MS [M+1]: 449.1, 1 H NMR (400 MHz, DMSO-d 6)δ11.76(d,J=16.4Hz,1H),8.95(s,1H),8.54(d,J=19.8Hz,1H),8.10(dd,J=51.7,8.6Hz,1H), 7.81-7.60(m,2H),7.06(d,J=8.6Hz,1H),4.03(q,J=7.1Hz,1H),3.90(d,J=21.7Hz,1H),3.64( s,3H),3.06(dd,J=12.0,4.0Hz,1H),2.81(d,J=12.2Hz,1H),2.48-2.38(m,2H),2.35(d,J=2.2 Hz, 3H), 1.99 (s, 2H), 1.69-1.56 (m, 1H), 1.52-1.39 (m, 2H), 1.23 (s, 1H), 1.17 (t, J = 7.1Hz, 1H).

[0573] Example T-57

[0574] The compound synthesized by the present invention:

[0575]

[0576] The experimental process is as follows:

[0577] The synthetic route is as follows:

[0578]

[0579] Synthesis steps:

[0580] (1) Synthesis of Compound 2

[0581] To a 100-mL three-necked flask, 379 mg of compound 1, INT-2 (2.0 eq.) and 15 mL of DMF as solvent were added, and the reaction was carried out at room temperature under nitrogen. After the reaction, the DMF solvent was removed by rotary evaporation and the mixture was purified by silica gel column chromatography to obtain 386 mg of compound 2 with a yield of 74.7%. LC-MS [M+1]: 613.1, 615.1.

[0582] (2) Synthesis of T-57 hydrochloride and T-57

[0583] 253 mg of compound 2 was added to a 50 mL three-necked flask, dissolved with 10 mL of ethyl acetate, and then 3 mL of 4 M hydrochloric acid dioxane solution was added. The reaction was stirred under nitrogen at room temperature for 1 hour. After the reaction was completed, it was filtered and the solid was washed with appropriate amounts of ethyl acetate and ether to obtain 190 mg of yellow solid T-57 hydrochloride with a yield of 83.7%. LC-MS [M+1]: 513.1, 515.1, and HPLC purity was 95.7%.

[0584] Compound T-57 hydrochloride (60 mg) was added with NaHCO 3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-57. HPLC purity: 95.7%. LC-MS [M+1]: 513.1, 515.1.

[0585] The following compounds were synthesized by referring to the method of Example T-57:

[0586]

[0587]

[0588] Example T-60 Compound synthesized by the present invention:

[0589]

[0590] The experimental process is as follows:

[0591] The synthetic route is as follows:

[0592]

[0593] Synthesis steps:

[0594] (1) Synthesis of Compound 2

[0595] 0.2 g (1 eq) of compound 1 was added to a mixed solvent of 4 ml of dioxane and 0.4 ml of water, followed by 0.2 g (5 eq) of phenylboronic acid, Pd(dppf)Cl 2 0.05g (0.2eq) and potassium carbonate 0.14g (3eq), N 2 The mixture was reacted at 100°C under protection until the reaction was completed. Water was added to quench the mixture, and the mixture was extracted with EA and dried, then spin-dried and passed through a column to obtain 0.2 g of compound 2.

[0596] (2) Synthesis of T-60

[0597] 0.2 g (1 eq) of compound 2 was dissolved in 5 mL of EA, and 2 ml of dioxane hydrochloride was added, and the reaction was completed at room temperature. Filtering gave 0.17 g of compound T-60 hydrochloride. HPLC: 95.4%. 1 H NMR (400 MHz, Methanol-d 4 )δ8.60(s,1H),8.35(s,1H),8.14(s,1H),7.57m,6H),3.62(s,3H),3.37(m,2H),3.06(m,2H),2.41-1.74(m,5H).

[0598] Example T-62

[0599] The compound synthesized by the present invention:

[0600]

[0601] The experimental process is as follows:

[0602] The synthetic route is as follows:

[0603]

[0604] Synthesis steps:

[0605] (1) Synthesis of Compound 2

[0606] Under anhydrous and oxygen-free ice-water bath conditions, 5 mL of 2-methoxyethyl chloroformate and sodium carbonate (2.0 eq) were added to a 25 mL three-necked flask in sequence. After stirring and reacting for half an hour, 500 mg of compound 1 was added, and the temperature was gradually raised to room temperature to continue the reaction. After the reaction was completed, water was added to quench the reaction, and the liquid was separated by extraction with water and EA. The organic layer was dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain 597 mg of compound 2 with a yield of 80.5%.

[0607] (2) Synthesis of Compound 3

[0608] Under nitrogen, 2,4-dichloro-5-trifluoromethylpyrimidine (1.5 eq) and aluminum chloride (2.0 eq) were added to a three-necked flask containing 150 mL of dichloroethane. The temperature was raised to reflux. After reacting for half an hour, 2.34 g of compound 2 was added. The reaction was kept warm overnight. After the reaction was completed, ice water was added to quench the reaction. The liquid was extracted with DCM and water, and most of the DCM was removed by concentration. The product was recrystallized with EA and filtered to obtain 1.5 g of solid compound 3 with a yield of 40.8%.

[0609] (3) Synthesis of Compound 4

[0610] 500 mg of compound 3, (S)-1-Boc-3-aminopiperidine (2.0 eq) and 15 mL of DMF as solvent were added to a 100 mL three-necked flask and reacted under nitrogen at room temperature. After the reaction, the DMF solvent was removed by rotary evaporation and purified by silica gel column chromatography to obtain 430 mg of compound 4 with a yield of 64.6%. LC-MS [M+1]: 657.1, 659.1.

[0611] (4) Synthesis of Compound T-62 Hydrochloride and T-62

[0612] 420 mg of compound 4 was added to a 50 mL three-necked flask, dissolved with 10 mL of ethyl acetate, and then 3 mL of 1 M hydrochloric acid dioxane solution was added. The reaction was stirred under nitrogen at room temperature for 1 hour. After the reaction was completed, it was filtered and the solid was washed with appropriate amounts of ethyl acetate and ether in turn to obtain 320 mg of yellow solid compound T-62 hydrochloride with a yield of 84.4%. LC-MS [M+1]: 557.1, 559.1, and HPLC purity was 97.9%.

[0613] Compound T-62 hydrochloride (100 mg) was added with NaHCO 3 The aqueous solution was made alkaline (pH=8.0), extracted with EA, dried, and spin-dried to obtain compound T-62. HPLC purity: 97.7%. LC-MS [M+1]: 557.1, 559.1.

[0614] Examples T-63, T-65 and T-66

[0615] The compound synthesized by the present invention:

[0616]

[0617] The experimental process is as follows:

[0618] The synthetic route is as follows:

[0619]

[0620] Synthesis steps:

[0621] (1) Synthesis of Compound 2

[0622] Compound 1 (7.4 g, 1.0 eq) was dissolved in N,N-dimethylformamide (80 mL), and then sodium isopropylthiolate (8.0 g, 2.5 eq) was added, and then the temperature was raised to 50°C for 2 hours. The reaction was complete after TLC monitoring, and then cooled to room temperature, and then 80 mL of ice water was added, and the pH was adjusted to 5 with 2 mol / L hydrochloric acid, and then extracted with ethyl acetate, and the organic phases were combined, dried, and spin-dried to obtain 11.5 g of crude compound 2.

[0623] (2) Synthesis of Compound 3

[0624] Under nitrogen, compound 2 (9.64 g, 1.0 eq) was dissolved in tert-butyl alcohol (100 mL), and then triethylamine (10 mL, 1.8 eq) and diphenylphosphoryl azide (13.2 g, 1.2 eq) were added. Then the mixture was slowly heated to 80 °C (the heating rate was controlled to prevent spraying due to the release of a large amount of gas) and the reaction was allowed to proceed for 12 hours. TLC monitored the reaction to be complete. The reaction solution was cooled to room temperature, and then 100 mL of water was added, extracted with ethyl acetate, the organic phase was dried, and the column was dried to obtain 8.5 g of compound 3 with a yield of 68%.

[0625] (3) Synthesis of Compound 4

[0626] Compound 3 (8.5 g, 1.0 eq) was added to 120 mL of 4 mol / L dioxane hydrochloride solution and reacted at room temperature overnight. The reaction was complete as monitored by TLC, and the filter cake was collected by filtration and dried to obtain 6.7 g of compound 4 with a yield of 100%.

[0627] (4) Synthesis of Compound 5

[0628] Compound 4 (6.7 g, 1.0 eq) was added to methyl chloroformate (90 mL), and then sodium carbonate (17.4 g, 4.0 eq) was added in batches at 0°C. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was monitored by TLC, and the mixture was filtered. The filter cake was washed with 120 mL of ethyl acetate, and the organic phase was collected and directly dried to obtain 8 g of crude compound 5. The yield was 94%.

[0629] (5) Synthesis of Compound 6

[0630] Under nitrogen, compound 5 (4.0 g, 1.0 eq) was added to 80 mL of tetrahydrofuran, then cooled to -78 °C, and vinylmagnesium bromide (113 mL, 6.0 eq) was slowly added dropwise. After addition, the mixture was reacted at this temperature for 1 hour, and then slowly heated to room temperature for 1 hour. The reaction was monitored by TLC to be complete. The system was cooled to -10 °C, and then an aqueous solution of ammonium chloride was added to quench the reaction, extracted with ethyl acetate, and the organic phases were combined and dried by column to obtain 1.2 g of compound 6 with a yield of 30%.

[0631] (6) Synthesis of Compound 7

[0632] Under nitrogen conditions, 2,4-dichloro-5-trifluoromethylpyrimidine (1.72 g, 3.0 eq) and aluminum chloride (0.706 g, 2.0 eq) were added to a three-necked flask containing 50 mL of dichloroethane. The temperature was raised to reflux. After reacting for half an hour, 0.7 g of compound 6 was added and the mixture was kept warm overnight. After the reaction was completed, ice water was added to quench the mixture. The mixture was extracted with DCM and water, concentrated, and passed through a column to obtain 0.4 g of the compound 7 with a yield of 34%.

[0633] (7) Synthesis of Compound 8

[0634] In a 50 mL three-necked flask, 175 mg of compound 7, (S)-1-Boc-3-aminopiperidine (158 mg, 2.0 eq), 2 mL of DMF and 2 mL of acetonitrile as solvent were added. The mixture was reacted for 14 hours at room temperature under nitrogen. After the reaction, the acetonitrile solvent was removed by rotary evaporation. The remaining reaction solution was poured into 10 mL of water, the filter cake was collected, and then the filter cake was filtered through a column to obtain 72 mg of compound 8 with a yield of 30%.

[0635] (8) Synthesis of Compound 9

[0636] Compound 8 (100 mg, 1.0 eq) was added to dichloromethane (2 mL), and then m-chloroperbenzoic acid (45.2 mg, 0.99 eq) was added at -10°C. The mixture was reacted for 2 hours at this temperature, and then the temperature was raised to room temperature and reacted overnight. TLC monitored the reaction to be complete. The mixture was filtered, and the filtrate was washed with 10% sodium hydroxide solution. The organic phase was then dried and passed through a column to obtain 80 mg of compound 9, with a yield of 77%.

[0637] (9) Synthesis of Compound 10

[0638] Compound 8 (100 mg, 1.0 eq) was added to 2 mL of dichloromethane, and then m-chloroperbenzoic acid (114 mg, 2.5 eq) was added at room temperature and reacted overnight. TLC monitored the reaction to be complete. Filtered, the filtrate was washed with 10% sodium hydroxide aqueous solution, and the organic phase was dried and passed through a column to obtain 90 mg of compound 10, with a yield of 86%.

[0639] (10) Synthesis of Compounds T-63, 65 and 66 Hydrochlorides

[0640] To three 25 mL three-necked flasks, 100 mg of compound 8, compound 9 and compound 10 were added respectively, and then 3 mL of dioxane hydrochloride solution was added respectively. The mixture was stirred under nitrogen at room temperature for 1 hour. After the reaction was completed, the mixture was filtered and the solid was washed with appropriate amounts of ether to obtain 50 mg of compound T-63 hydrochloride, 69 mg of compound T-65 hydrochloride and 48 mg of compound T-66 hydrochloride.

[0641] The following compounds were synthesized by referring to the method of Example T-63:

[0642]

[0643] Examples T-69 and T-70

[0644] The compound synthesized by the present invention:

[0645]

[0646] The experimental process is as follows:

[0647] The synthetic route is as follows:

[0648]

[0649] Synthesis steps:

[0650] (1) Synthesis of Compound 2

[0651] The raw material compound 1 1.0 g (1.0 eq), isopropylene borate 1.37 g (5.0 eq), Pd (dppf) Cl 2 0.24g (0.2eq), 0.67g (3.0eq) of potassium carbonate, 20ml of dioxane solvent, 2ml of water were mixed evenly, replaced with nitrogen three times, protected by nitrogen, heated to 100°C in an oil bath, and reacted for 18h. TLC showed that no raw material remained, water and EA were added to extract and dry, and the sample was mixed and passed through a column to obtain 0.7g. The yield was 75%.

[0652] (2) Synthesis of Compound 3

[0653] 200 mg (1 eq) of compound 2, 3 ml of methanol and 10 mg of Pd / C were added to the reaction system in sequence. 2 After replacing the air, the mixture was reacted overnight under a closed pressure of a hydrogen balloon. After 36 hours of reaction, the excess palladium carbon was removed by filtration on diatomaceous earth, and the mother liquor was dried by spin drying to obtain 150 mg of crude product 3.

[0654] (3) Synthesis of Compound T-69

[0655] 150mg of compound 3, 2ml of 4M HCl / dioxane solution and 4mL of EA were added to the reaction system. After 5h at room temperature, the reaction was detected by TLC and the crude target product was obtained by suction filtration. The HPLC purity was 84%. It was freed with saturated sodium bicarbonate solution, extracted with EA and purified by climbing a large plate to obtain 38mg of T-69 with a purity of 93.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.50(s,1H),8.60(d,J=8.9Hz,1H),8.21(d,J=8.6Hz,1H),8.06-7.86(m,1H),7.80-7.63(m,1H),6.95(t,J=10.9Hz,1H),4. 20(s,1H),3.62(s,2H),3.08(d,J=13.0Hz,1H),2.80(dd,J=20.8,11.1Hz,2H),1.99(s,1H),1.38(d,J=7.1Hz,4H),1.23(s,2H).

[0656] (4) Synthesis of Compound T-70

[0657] 400 mg (1 eq) of compound 2, 3 mL of 4M hydrochloric acid / dioxane solution and 5 mL of EA were added to the reaction system in sequence and reacted at room temperature overnight. After the reaction was completed, the mixture was freed with saturated sodium bicarbonate solution, extracted and dried by spin drying. 53 mg of T-70 was obtained by preparative liquid phase separation. 1 H NMR (400 MHz, DMSO-d 6 )δ11.51(s,1H),8.65-8.48(m,1H),7.72(s,1H),7.13(d,J=8.9Hz,1H),5.51-5.38(m,1H),5.03(s,1H),3.60(s,2H),3.35(s,8H ),3.06(d,J=11.8Hz,1H),2.80(d,J=12.5Hz,1H),2.07(s,2H),1.99(s,1H),1.72-1.53(m,1H),1.52-1.36(m,1H),1.23(s,1H).

[0658] Example T-71

[0659] The compound synthesized by the present invention:

[0660]

[0661] The experimental process is as follows:

[0662] The synthetic route is as follows:

[0663]

[0664] Synthesis steps:

[0665] (1) Synthesis of Compound 2

[0666] Under nitrogen, 2,4,5-trichloropyrimidine (1.5 eq) and aluminum chloride (2.0 eq) were added to a three-necked flask containing 100 mL of dichloroethane, and the temperature was raised to reflux. After reacting for half an hour, 2.78 g of compound 1 was added and the reaction was kept overnight. After the reaction was completed, ice water was added to quench, and the liquid was extracted with DCM and water. Most of the DCM was removed by concentration, and the mixture was recrystallized with EA. After filtration, 1.16 g of solid compound 2 was obtained with a yield of 27.2%.

[0667] (2) Synthesis of Compound 3

[0668] In a 100 mL three-necked flask, 400 mg of compound 2, (S)-1-Boc-3-aminopiperidine (2.0 eq), DIPEA (5.0 eq) and 15 mL of NMP as solvent were added and reacted at room temperature under nitrogen. After the reaction was completed, the mixture was extracted with EA and water, and the organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 230 mg of compound 3 with a yield of 41.3%.

[0669] (3) Synthesis of Compound T-71

[0670] 100 mg of compound 3 was added to a 50 mL three-necked flask, and 5 mL of dichloromethane was added. After dissolving, 2 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for half an hour. After the reaction was completed, the excess solvent was removed by concentration, the pH value was adjusted to alkaline, the extraction was spin-dried, and 40 mg of compound 4 was obtained by separation and purification by medium-pressure preparative reverse column. The yield was 48.4%, the HPLC purity was 96.6%, and LC-MS [M+1]: 479.0, 481.0.

[0671] The following compounds were synthesized by referring to the methods of Examples T-01 and T-71:

[0672]

[0673] Example T-79

[0674] The compound synthesized by the present invention:

[0675]

[0676] The experimental process is as follows:

[0677] The synthetic route is as follows:

[0678]

[0679] Synthesis steps:

[0680] (1) Synthesis of Compound 2

[0681] Under nitrogen conditions, 20 g of compound 1 and 200 mL of anhydrous tetrahydrofuran were added to a 500 mL three-necked flask, the temperature was lowered to -78 ° C, and a THF solution of vinyl magnesium bromide (10 e.q.) was added dropwise to react under temperature control. After the reaction was completed, water was added to quench, and EA and water were used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain 3.56 g of compound 2.

[0682] (2) Synthesis of Compound 3

[0683] Into a 150 mL three-necked flask, 3.56 g of compound 2 and 35 mL of anhydrous ethanol were added respectively, and concentrated sulfuric acid (1.0 eq) was used as a catalyst. The mixture was refluxed overnight under nitrogen. After the reaction was completed, it was cooled to room temperature, concentrated to remove excess solvent, and separated and purified by silica gel column chromatography to obtain 1.6 g of compound 3.

[0684] (3) Synthesis of Compound 4

[0685] Under nitrogen, 2,4-dichloro-5-trifluoromethylpyrimidine (2.0 eq) and aluminum chloride (3.0 eq) were added to a three-necked flask containing 50 mL of dichloroethane. The temperature was raised to reflux. After reacting for half an hour, 1.7 g of compound 3 was added. The reaction was kept warm overnight. After the reaction was completed, ice water was added to quench the reaction. The liquid was extracted with DCM and water, and most of the DCM was removed by concentration. The product was recrystallized with EA and filtered to obtain 500 mg of solid compound 4 with a yield of 16.3%. LC-MS [M+1]: 404.0, 406.0.

[0686] (4) Synthesis of Compound 5

[0687] In a 100 mL three-necked flask, 500 mg of compound 4, (S)-1-Boc-3-aminopiperidine (2.0 eq) and 10 mL of DMF as solvent were added and reacted at room temperature under nitrogen. After the reaction, the DMF solvent was removed by rotary evaporation and the mixture was separated and purified by silica gel column chromatography to obtain 384 mg of compound 5 with a yield of 54.6%. LC-MS [M+1]: 568.1, 570.1.

[0688] (5) Synthesis of Compound 6

[0689] 384 mg of compound 5 was added to a 50 mL three-necked flask, dissolved with 10 mL of ethanol, and then 5 M aqueous sodium hydroxide solution (5.0 eq) was added dropwise. The mixture was kept warm at 50°C overnight to obtain 353.1 mg of hydrolysis product 6 with a yield of 97.0%.

[0690] (6) Synthesis of Compound 7

[0691] Under nitrogen, 150 mg of compound 6 and 5 mL of anhydrous methanol were added to a 10 mL reaction tube. After dissolution, DPPA (10.0 eq) and Et 3 N (5.0eq), heated to reflux for two hours, cooled to room temperature after the reaction, quenched with water, extracted with EA and water, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 100 mg of compound 7 with a yield of 63.3%, LC-MS [M+1]: 569.2, 571.2.

[0692] (7) Synthesis of Compound T-79

[0693] Under nitrogen conditions, 100 mg of compound 7, 6 mL of dichloromethane and 2 mL of trifluoroacetic acid were added to a 50 mL three-necked flask, and the reaction was stirred at room temperature. After the reaction was completed, the mixture was concentrated, the pH value was adjusted to 8, and then extracted, dried, and passed through a column to obtain 40 mg of compound T-79 with a yield of 48.8%, HPLC purity of 93%, and LC-MS [M+1]: 469.1, 471.1.

[0694] Example T-80

[0695] The compound synthesized by the present invention:

[0696]

[0697] The experimental process is as follows:

[0698] The synthetic route is as follows:

[0699]

[0700] Synthesis steps:

[0701] (1) Synthesis of Compound 2

[0702] Dissolve 20g of compound 1 in tert-butyl alcohol (300mL), stir at room temperature, add triethylamine (20.2g, 0.2mol) to the reaction solution, the solution changes from clear yellow to clear reddish brown, nitrogen protection, slowly add DPPA (41.3g, 0.15mol), control the reaction temperature well to prevent spraying. The thermometer monitors the temperature to stabilize at 80℃, and react for 3-5 hours. Add ammonium chloride aqueous solution to quench the reaction, then extract with EA. After extraction, combine the organic phases, wash once with saturated sodium chloride, dry with anhydrous sodium sulfate, spin dry through a column, and pure EA / PE = 10:1 to obtain 26g of compound 2.

[0703] (2) Synthesis of Compound 3

[0704] Under nitrogen protection, vinyl magnesium bromide (670mL, 1mol / L, 0.67moL) was added to the reaction bottle, and stirred in a liquid nitrogen bath until the temperature dropped to -70℃ to -80℃. Then compound 2 (26g) was dissolved in THF (100mL), and slowly added dropwise to the reaction solution under nitrogen protection. After the addition was completed, the temperature was naturally raised to room temperature and reacted overnight. It was quenched with saturated ammonium chloride under an ice bath. A large number of bubbles were generated at the beginning, and the temperature rose quickly. Pay attention to the dropwise addition speed to prevent spraying. After quenching with saturated ammonium chloride, a large amount of solid precipitated, and then EA was added for extraction. The insoluble solid can be dissolved with water. After extraction, the organic phases were combined and washed once with saturated sodium chloride, dried with anhydrous sodium sulfate, and spin-dried through a column PE:EA=5:1 to obtain 13g of compound 3.

[0705] (3) Synthesis of Compound 4

[0706] Compound 3 (13 g) was added to a reaction bottle under an ice bath, and then 50 mL of 1,4-dioxane was added, and then 4 mol / L hydrochloric acid / 1,4-dioxane solution (80 mL) was added dropwise under stirring, and then reacted for 5 hours. After the reaction was completed, a large amount of solid was produced, which was filtered to obtain 12 g of compound 4.

[0707] (4) Synthesis of Compound 5

[0708] Under nitrogen protection, compound 4 (12 g) was added to the reaction bottle in an ice bath, followed by 100 mL of dichloromethane, followed by sodium carbonate (40.7 g, 0.3 mol), and finally, methyl chloroformate (11.3 g, 0.12 mol) was slowly added dropwise. After the addition, the ice bath was maintained for 3 h. Ice water was then added to quench the reaction, followed by extraction with EA. After the extraction, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then passed through a column with PE:EA = 2:1 to obtain 4 g of compound 5.

[0709] (5) Synthesis of Compound 6

[0710] Under nitrogen, aluminum chloride (0.03 mol) was added to a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (0.034 mol) in DCE (150 mL), and then the temperature was raised to 80°C for 30 min, and then 4 g of compound 5 was slowly added, and the reaction was continued at 80°C overnight. The reaction was quenched with water, and then extracted with dichloromethane. After extraction, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and after rotary evaporation, the solid was slurried with EA (50 mL) to obtain 3 g of compound 6.

[0711] (6) Synthesis of Compound T-80

[0712] In a 100 mL three-necked flask, 400 mg of compound 2, (S)-6,6-dimethyl-3-aminopiperidine hydrochloride (2.0 eq), DIPEA (5.0 eq) and 15 mL of NMP as solvent were added and reacted at room temperature under nitrogen. After the reaction, the mixture was extracted with EA and water, and the organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 130 mg of compound T-80 with a yield of 26.1%.

[0713] The following compounds were synthesized by referring to the methods of Examples T-79 and T-80:

[0714]

[0715]

[0716]

[0717] Example T-98

[0718] The compound synthesized by the present invention:

[0719]

[0720] The experimental process is as follows:

[0721] The synthetic route is as follows:

[0722]

[0723] Synthesis steps:

[0724] (1) Synthesis of Compound 2

[0725] In a 250ml three-necked flask, add 17g (1eq) of intermediate 5 and dissolve it in 170ml of n-butanol, stir and dissolve, then add 10.1g (2eq) of potassium carbonate, 7.4g (2.0eq) of vinyl butyl ether, 3.3g (0.4eq) of Xantphos, 1.6g (0.2eq) of palladium acetate, replace with nitrogen 3 times, and react at 95°C overnight. Monitor the reaction until it is complete by TLC. Add water, extract with ethyl acetate 2 times, transfer the ethyl acetate phase to a 250ml single-necked bottle, add 5ml (1.5eq) of concentrated hydrochloric acid and stir at room temperature for 3h. Monitor the reaction until it is complete by TLC. Purify directly by column to obtain 13.4g of compound 2.

[0726] (2) Synthesis of Compound 3

[0727] Dissolve 8g of compound 2 in 160mL of DCM in a 250ml single-necked bottle, cool to 0°C in an ice bath, add 9.7g (3eq) of m-CPBA under stirring, react at room temperature for 3h, a large amount of solid precipitates, and the reaction is monitored by TLC until it is complete. Filter directly, rinse with DCM, and dry to obtain 5.4g of compound 3.

[0728] (3) Synthesis of Compound 4

[0729] In a 50 ml single-mouth bottle, 500 mg of compound 3 was dissolved in 5 ml of DMF, 440 mg (2 eq) (S)-1-Boc-3-aminopiperidine and 0.28 g (2 eq) of diisopropylethylamine were added, and the mixture was reacted at room temperature for 5 h. The reaction was monitored by TLC until it was complete. Water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 300 mg of compound 4.

[0730] (4) Synthesis of T-98

[0731] Add 300 mg of compound 4 and 10 ml of 4M / L dioxane hydrochloride to a 50 ml round-bottom flask, react at room temperature for 3 h, and monitor the reaction by TLC until it is complete. Add saturated sodium bicarbonate solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and spin dry. Purify on a plate to obtain 100 mg of compound T-98. 1 H NMR (400 MHz, DMSO-d 6 )δ11.59(s,1H),9.80(s,1H),8.60(d,J=8.4Hz,1H),8.55–8.37(m,1H),7.80(m,2H),7.22(d,J=8.6Hz,1H),3.96–3.81(m,1H),3.69(s,3H) ,3.15–3.00(m,1H),2.84–2.77(m,1H),2.53(d,J=1.5Hz,3H),1.99(s ,1H),1.70–1.60(m,1H),1.47(m,2H),1.24(m,1H),0.89–0.79(m,2H).

[0732] Example T-99

[0733] The compound synthesized by the present invention:

[0734]

[0735] The experimental process is as follows:

[0736] The synthetic route is as follows:

[0737]

[0738] Synthesis steps:

[0739] (1) Synthesis of Compound 2

[0740] Add 1g (1eq) of compound 1 to a 50ml single-mouth bottle, add 20ml of tetrahydrofuran and stir to dissolve, add 3ml (3eq) of DAST dropwise under ice bath, and react at room temperature overnight. Monitor the reaction until complete by TLC. Add water under ice bath, extract with ethyl acetate twice, and purify by column to obtain 150mg of compound 2.

[0741] (2) Synthesis of compound 3:

[0742] In a 25 ml single-mouth bottle, 150 mg of compound 2 was dissolved in 2 ml of tetrahydrofuran, and 125 mg (2 eq) (S)-1-Boc-3-aminopiperidine and 81 mg (2 eq) of diisopropylethylamine were added. The mixture was reacted at room temperature for 3 h and monitored by TLC until the reaction was complete. Water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 100 mg of compound 3.

[0743] (3) Synthesis of T-99:

[0744] In a 25 ml round-bottom flask, add 100 mg of compound 3 and 3 ml of 4 M / L dioxane hydrochloride, react at room temperature for 3 h, and monitor the reaction until it is complete by TLC. Add saturated sodium bicarbonate solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and spin dry. Purify on a plate to obtain 40 mg of compound T-99. 1 H NMR (400 MHz, DMSO-d 6 )δ11.54(s,1H),8.89(d,J=18.0Hz,1H),8.64(d,J=5.6Hz,1H),8.46(d,J =8.4Hz,1H),8.07(s,1H),7.79(d,J=8.4Hz,1H),7.10(t,J=10.0Hz,1H), 4.22(s,1H),3.63(s,3H),3.15(s,1H),2.82(s,2H),2.08(t,J=19.2Hz,3 H),1.89(d,J=12.0Hz,1H),1.64(s,2H),1.24(s,1H),0.99–0.74(m,2H).

[0745] Referring to the method of Example T-98 and Example T-99, the following compounds were synthesized:

[0746]

[0747]

[0748] Example T-102 Compound synthesized by the present invention:

[0749]

[0750] The experimental process is as follows:

[0751] The synthetic route is as follows:

[0752]

[0753] Synthesis steps:

[0754] (1) Synthesis of Compound 2

[0755] 4.7 g (1 eq) of compound 1 was dissolved in 10 mL of THF, 1.8 g (6 eq) of NaH was added in a salt ice bath, and stirred for 5 min, followed by 1.6 g (5 eq) of CH 3 After the reaction was completed, 50 mL of water was added, and the mixture was extracted with EA and dried, and then spin-dried to obtain 4.9 g of crude compound 2.

[0756] (2) Synthesis of Compound 3

[0757] 4.9 g (1 eq) of compound 1 was dissolved in 40 mL of THF and heated at -78 °C under N 2 Under protective conditions, slowly add vinylmagnesium bromide (6 eq) dropwise, and warm to room temperature for reaction after the addition is completed. After the reaction is completed, add 50 mL of water, extract with EA, dry, spin dry, and pass through a column to obtain 1.5 g of compound 3.

[0758] (3) Synthesis of Compound 4

[0759] Take 1.5g (1eq) of compound 5 and dissolve it in 10mL of 4M / L dioxane hydrochloride and react at room temperature. After the reaction is completed, add NaHCO 3 Aqueous solution, adjust the solution to alkalinity, extract with EA, dry, spin dry, and prepare and separate to obtain 1.0 g of compound 4. LC-MS [M+1]: 224.9, 226.9.

[0760] (4) Synthesis of Compound 5

[0761] 1.0 g (1 eq) of compound 4 was dissolved in 6 ml of methyl chloroformate and 300 mg of Na 2 CO 3 After the reaction, water was added, and the mixture was extracted with EA and dried, and then spin-dried to obtain 0.86 g of crude compound 5.

[0762] (5) Synthesis of Compound 6

[0763] In a 50 mL round-bottom flask, 1.5 g (3 eq) 2,4-dichloro-5-trifluoromethylpyrimidine, 25 mL DCE and 0.5 g (1.7 eq) AlCl 3 Heat to 80°C. 2 After 30 min of reaction, 0.5 g (1 eq) of compound 2 was added and the reaction was continued under N 2 Under protection, the reaction was carried out at 80°C. After the reaction was completed, water was added, EA was extracted, the organic layer was evaporated to dryness, and EA was added to slurry to obtain 0.3 g of compound 6. LC-MS [M+1]: 462.9, 464.9.

[0764] (6) Synthesis of Compound 7

[0765] 0.3 g (1.0 eq) of compound 3 was dissolved in 6 mL of DMF, and 0.3 g (2.2 eq) of (S)-1-Boc-3-aminopiperidine was added, and the mixture was stirred at room temperature overnight. After the reaction, water was added, and the mixture was extracted with EA and dried, and then spin-dried and passed through a column to obtain 0.3 g of compound 7.

[0766] (7) Synthesis of Compound T-102

[0767] 250 mg (1 eq) of compound 7 was added to 6 mL of 4M / L dioxane hydrochloride and 4 mL of EA and reacted at room temperature. After the reaction was completed, the mixture was filtered and the filter cake was washed with methyl tert-butyl ether to obtain 200 mg of compound T-102. HPLC: 97.4%. LC-MS [M+1]: 527.0, 529.0. 1 H NMR (400 MHz, DMSO-d 6 )δ12.40–12.06(m,1H),8.66(d,J=7.2Hz,1H),8.27(m,2H),7.84(s,1H),7.34–6.92(m,1H),4.31(s,1H),4.03(q,J=7.2Hz ,1H),3.71(s,1H),3.55(d,J=18.3Hz,3H),3.21(s,3H),3.00–2.72(m,2H),1.95(d,J=36.9Hz,2H),1.67(d,J=61.6Hz,2H).

[0768] The following compounds were synthesized by referring to the method of Example T-102:

[0769]

[0770]

[0771] Referring to patent WO2020093006A1, compound 101 in the patent was synthesized as a comparative example of the present invention, and the structural formula is as follows:

[0772]

[0773] Test Example 1 Enzyme Activity Test

[0774] The following biological activity tests were conducted on some of the compounds in the above examples and comparative examples.

[0775] The biological activity test experimental process is as follows:

[0776] Test compound CDK7 kinase IC 50 Value testing (tested at Wuxi Baiaode Company).

[0777] 1. Compound preparation:

[0778] The compound powder was dissolved in 100% DMSO to prepare a 10mM stock solution, which was further diluted to 0.5mM as the starting concentration and diluted three times continuously to obtain 10 compound solutions of different concentrations. The compound and enzyme pre-incubation time was 0 minutes and 60 minutes, respectively, using a multiple well assay. Staurosporine compound (structural formula: ) was used as a positive control, and the activity of the compound on CDK kinases such as CDK7, CDK9, CDK12 and CDK2 was detected using the mobile shift assay method.

[0779] 2. Kinase reaction process:

[0780] 1) Compound solution and positive control were diluted 8.3 times with double distilled water and added to 384-well plates, with 2uL / well for each concentration;

[0781] (2) Add 6 nM CDK7 / Cyclin H / MAT1 kinase solution to the compound wells and positive control wells respectively;

[0782] (3) incubation at room temperature for 0 and 60 min;

[0783] (4) Add 2 mM ATP and 2 pM 5-FAM-CDK7 peptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) solution (the CDK9 inhibition reaction uses 8 nM CDK9 / Cycl in T1 polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate; the CDK12 inhibition reaction uses 50 nM CDK12 (aa686-1082) / Cycl in K polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate; the CDK2 inhibition reaction uses 0.5 nM CDK2 / Cyclin El polymer and 2 pM 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK peptide substrate);

[0784] (5) Incubate the 384-well plate at 25°C for 30 minutes;

[0785] (6) Add 4uL 120mM EDTA to stop the kinase reaction;

[0786] (7) Read the conversion rate using Caliper / LabChip EZ Reader (Perkin Elmer);

[0787] (8) IC was obtained by curve fitting using GraphPad Prism 8 software. 50 Numeric value.

[0788] Through the above detection, the inhibitory activity IC of the test sample on CDK7 kinase was obtained. 50 (nM) values ​​are shown in Table 1, where A≤50nM; 50nM <B<500nM;C≥500nM。

[0789] Table 1

[0790]

[0791]

[0792]

[0793]

[0794]

[0795] Note: NT stands for Not Tested

[0796] As can be seen from the above table, through in vitro biological activity screening, using staurosporine as a reference substance, the compounds synthesized in the present application have a good inhibitory ability against CDK7 kinase and have good selectivity, and are expected to be further developed into drugs for regulating CDK7 kinase activity or treating CDK7-related diseases.

[0797] Experimental Example 2 Cell Antiproliferation Experiment

[0798] 1. Experimental materials and equipment:

[0799] Human breast cancer cells MDA-MB 231, MDA-MB453, ovarian cancer cells OVCAR3 and A2780, colorectal cancer cells HCT-116 and WiDr, and lung cancer cells Calu-6 were purchased from Beijing Beina Chuanglian Biotechnology Co., Ltd. DMEM medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazolyl blue), 0.25% EDTA-Tripsin (trypsin digestion solution), 1xPBS (phosphate buffer, pH 7.2), 96-well plates (Corning), fetal bovine serum (FBS), 10,000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), and enzyme-linked immunosorbent assay (Tecan Spark).

[0800] 2. Experimental preparation:

[0801] 1. Cell plating

[0802] A) Tumor cells were cultured in DMEM (high glucose, containing 10% FBS and 100 U / mL penicillin-G / streptomycin) at 37°C, 5% CO2 and saturated humidity to 80-90% confluence.

[0803] B) Remove the culture medium from the 10 cm culture dish;

[0804] C) Rinse the cells once with 10 ml 1xPBS;

[0805] D) Add 4 ml of 0.25% EDTA-Tripsin and place in a 37°C, 5% CO2 incubator for trypsin digestion for 5 minutes, transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, and discard the supernatant to obtain a cell pellet;

[0806] E) Resuspend in 4 ml DMEM medium, count and adjust to 50,000 cells / ml.

[0807] F) The cell suspension was added to a 96-well plate at a volume of 100 μL per well and cultured overnight in a 37° C., 5% CO 2 incubator.

[0808] 2. Compound treatment

[0809] Compound dilution

[0810] A) Preparation of gradient dilution solutions of the test compound: Prepare the test compound into 10mM and 1mM stock solutions. First, dissolve 1μl and 0.5μl of the 10mM stock solution in 1ml of DMSO-free culture medium to obtain 10 and 5μM concentrations of diluted compounds. Then dissolve 1.5μl of the 1mM stock solution in 1.5ml of DMSO-free culture medium to obtain a 1μM concentration of diluted compound, and then perform 3-fold continuous gradient dilution with 0.025% DMSO culture medium, for a total of 7 concentrations. The concentrations of the 10 compounds after all the above dilutions are as follows:

[0811] 10μM, 5μM, 1μM, 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM

[0812] B) After thorough mixing, 100 μL of the culture compound solution was taken to replace the culture medium in the cell culture plate, with 4 replicate wells for each concentration;

[0813] C) Transfer the cells to an incubator and incubate for 3 days.

[0814] 3. MTT assay

[0815] A) Take out the cell culture plate and add 10 μL of 5 mg / ml MTT in a biosafety cabinet;

[0816] B) Place the cell culture plate back into the incubator and continue incubating for 3 hours;

[0817] C) Take out the cell culture plate, remove the culture medium, add 100 μL of isopropanol (containing 0.4 mM HCl, 0.1% NP-40), and shake at room temperature for 30 minutes;

[0818] D) Select 570 nm wavelength to measure the absorbance value on TECAN enzyme-linked immunosorbent assay instrument.

[0819] 4. Data Analysis

[0820] The following formula was used to calculate the cell viability (% Cell Viability):

[0821] %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC)

[0822] Lum_HC: 0.1% DMSO control group cell reading

[0823] Lum_Sample: Cell readout with added compound

[0824] Lum_LC: Blank medium reading

[0825] The IC50 value was obtained by curve fitting using GraphPad Prism 8 software.

[0826] As shown in Table 2.

[0827] Table 2

[0828]

[0829]

[0830] Note: NT stands for Not Tested

[0831] As can be seen from Table 2, the compounds of the present invention have very good inhibitory effects on human breast cancer cells MDA-MB 231, MDA-MB453, ovarian cancer OVCAR3 and A2780, colorectal cancer cells HCT-116 and WiDr, and lung cancer cells Calu-6, and are more active than the best compound compound 101 in patent WO2020093006A1.

[0832] Test Example 3 Pharmacokinetics of Compounds

[0833] A head-to-head pharmacokinetic comparison of the compound T-01 of the present invention and the control compound (compound 101 in patent WO2020093006A1) after oral administration.

[0834] Rat Pharmacokinetics Protocol

[0835] (1) Required animals: 3 healthy adult SD rats, male, 6-8 weeks old, weighing 200-300 g.

[0836] (2) Required equipment: analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0837] (3) Required reagents: EDTA-Na2 anticoagulant, etc. Weigh 11.2 g of EDTA-Na2, place in a reagent bottle, add 100 mL of normal saline, and shake to completely dissolve. After preparation, divide into 1.5 mL centrifuge tubes, 20 uL each, for whole blood sample collection.

[0838] (3) Accurately weigh about 10 mg of the sample to be tested, add 5% DMSO to dissolve, then add 30% PEG400 and 65% (10% Hp-β-CD in PBS), sonicate, and vortex to mix to obtain a solution with a concentration of 1 mg / mL; prepare freshly before use.

[0839] (4) Pipette 0.1 mL of sample into a 1.5 mL centrifuge tube and store at -80°C for analysis of dosing solution concentration.

[0840] (5) The animals were kept in rat cages and fasted for no less than 10 hours but not water from the day before the experiment. They were weighed and marked on the tail on the day of the experiment. Blank blood was collected before administration. Blood was collected from the tail vein.

[0841] (6) Administration route: oral administration (po); dosage: 10 mg / kg; administration volume: 10 mL / kg.

[0842] (7) Operation procedure: Hold the rat with your left hand wearing a bite-proof glove and make it stand upright. Insert a No. 16 gavage needle into the rat's mouth and throat. Test to see if there is any obvious resistance. Then inject the drug into the stomach.

[0843] (8) Before administration and 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, 0.2ml of whole blood was collected from the test animals in EDTA-Na2 anticoagulant tubes, inverted 3-4 times to mix, centrifuged at 10000g for 5min at 4℃ to separate plasma, and stored at -80℃ for testing. Blood was collected from the tail vein.

[0844] (9) An LC-MS / MS method was established to determine the unchanged drug concentration in plasma, the plasma drug concentration-time curve was plotted, and the main pharmacokinetic parameters were calculated using a non-compartmental model.

[0845] (10) The pharmacokinetic parameters of T-01 and the reference compound are as follows: Figure 1 As shown (wherein the ordinate is the concentration of the drug in plasma).

[0846] from Figure 1 It can be seen that the compound of the present invention has better pharmacokinetic parameters than the reference compound (compound 101), and is about 5 times better than the reference compound in terms of both blood drug concentration Cmax and AUC.

[0847] Preparation Example 1

[0848] The compound synthesized by the present invention:

[0849]

[0850] The experimental process is as follows:

[0851] 1. Synthesis of intermediate SM1

[0852] The synthetic route is as follows:

[0853]

[0854] 1. Synthesis of Compound 2

[0855] In a 2L three-necked flask, add 730mL (6eq) of vinyl magnesium bromide under nitrogen protection, cool the liquid nitrogen-ethanol to -78°C, dissolve 30g of compound 1 in 700mL of anhydrous tetrahydrofuran, and slowly drop it into the reaction bottle under stirring, keeping the temperature no higher than -70°C. After the addition is complete, slowly warm it to room temperature and stir overnight. TLC shows that there is no raw material, and the target product point is the main point. Add ammonium chloride aqueous solution to quench, adjust the pH to 2 with dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and reduce the pressure until a large amount of solid precipitates, and filter under reduced pressure to obtain 16g of compound 2 as a filter cake. LC-MS [M+1]: 240, 242.

[0856] 2. Synthesis of Compound 3

[0857] In a 100mL three-necked flask, 8g of compound 2 was dissolved in 15mL of DMF, cooled to 0°C in an ice bath, and 11g (2eq) of CDI was slowly added under stirring. After stirring for 1h, 50mL of ammonia water (10eq) was slowly added under an ice bath, and the reaction was monitored by TLC until it was complete. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 6g of compound 3. LC-MS [M+1]: 239, 241.

[0858] 3. Synthesis of intermediate SM1

[0859] In a 100 mL three-necked flask, 6 g of compound 3 and 25.5 g (10 eq) of triethylamine were dissolved in DCM, cooled to 0°C in an ice bath, and 23 g (8 eq) of methanesulfonyl chloride was added under stirring. The mixture was allowed to stand overnight at room temperature and monitored by TLC until the reaction was complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 3.3 g of compound 4. LC-MS [M+1]: 221, 223.

[0860] 2. Synthesis of Compound 01

[0861] The synthetic route is as follows:

[0862]

[0863] 1. Synthesis of Compound 5

[0864] In a 100mL round-bottom flask, 9g (3eq) 2,4-dichloro-5-trifluoromethylpyrimidine was dissolved in 150mL DCE, and 3g (1.5eq) anhydrous aluminum chloride was added under stirring. The temperature was raised to 80°C under nitrogen protection and stirred for half an hour. The temperature was lowered to room temperature, 3g compound SM1 was added, the temperature was raised to 80°C, and the reaction was monitored by TLC until it was complete. The reaction product had two positional isomers, and the content ratio was close to 3:1. Water was added, and ethyl acetate was extracted. The mixture was decompressed and vortexed until a large amount of solid precipitated. The filter cake of single-configuration compound 5 was obtained by vacuum filtration, and 1.2g of the filtrate was separated by column chromatography to obtain 1.6g of compound 5 mixed with two configurations. LC-MS [M+1]: 401, 403.

[0865] 2. Synthesis of Compound 6

[0866] In a 100 mL round-bottom flask, 1.2 g of compound 5, 1 g (1.2 eq) (S)-6,6-dimethylpiperidin-3-amine, 1.5 g (4 eq) DIPEA, and 6 mL N-methylpyrrolidone were added. Under nitrogen protection, the mixture was stirred and heated to 130°C for 3 h. The reaction was monitored by TLC until it was complete. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography to obtain 1.2 g of compound 6. LC-MS [M+1]: 493, 495.

[0867] 3. Synthesis of Compound 01

[0868] In a 100mL three-necked flask, add 0.1g of compound 6, 0.02g (1.2eq) of dimethylphosphine oxide, 0.03g (0.2eq) of Xantphos, 0.09g (2eq) of tripotassium phosphate, 0.005g (0.1eq) of palladium acetate, and 1mL of DMF. Protect with nitrogen, heat to 140°C, and monitor the reaction by TLC until it is complete. Add water and ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 5mg of compound 01. LC-MS [M+1]: 517.

[0869] Referring to the method of method 1 or method 2 of preparation example 1, the following compounds were synthesized:

[0870]

[0871]

[0872]

[0873]

[0874] Test Example 1 Enzyme Activity Test

[0875] The following biological activity tests were conducted on some of the compounds in the above examples and comparative examples.

[0876] The biological activity test experimental process is as follows:

[0877] Test compound CDK7 kinase IC 50 Value testing (tested at Wuxi Baiaode Company).

[0878] 1. Compound preparation:

[0879] The compound powder was dissolved in 100% DMSO to prepare a 10mM stock solution, which was further diluted to 0.5mM as the starting concentration and diluted three times continuously to obtain 10 compound solutions of different concentrations. The compound and enzyme pre-incubation time was 0 minutes and 60 minutes, respectively, using a multiple well assay. Staurosporine compound (structural formula: ) was used as a positive control, and the activity of the compound on CDK kinases such as CDK7, CDK9, CDK12 and CDK2 was detected using the mobile shift assay method.

[0880] 2. Kinase reaction process:

[0881] 1) Compound solution and positive control were diluted 8.3 times with double distilled water and added to 384-well plates, with 2uL / well for each concentration;

[0882] (2) Add 6 nM CDK7 / Cyclin H / MAT1 kinase solution to the compound wells and positive control wells respectively;

[0883] (3) incubation at room temperature for 0 and 60 min;

[0884] (4) Add 2 mM ATP and 2 pM 5-FAM-CDK7 peptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) solution (the CDK9 inhibition reaction uses 8 nM CDK9 / Cycl in T1 polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate; the CDK12 inhibition reaction uses 50 nM CDK12 (aa686-1082) / Cycl in K polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate; the CDK2 inhibition reaction uses 0.5 nM CDK2 / Cyclin El polymer and 2 pM 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK peptide substrate);

[0885] (5) Incubate the 384-well plate at 25°C for 30 minutes;

[0886] (6) Add 4uL 120mM EDTA to stop the kinase reaction;

[0887] (7) Read the conversion rate using Caliper / LabChip EZ Reader (Perkin Elmer);

[0888] (8) IC was obtained by curve fitting using GraphPad Prism 8 software. 50 Numeric value.

[0889] Through the above detection, the inhibitory activity IC of the test sample on CDK7 kinase was obtained. 50 (nM) values ​​are shown in Table 3, where A≤10nM; 10nM <B<500nM;C≥500nM。

[0890] Table 3

[0891]

[0892] As can be seen from the above table, through in vitro biological activity screening, using staurosporine as a reference substance, the compounds synthesized in the present application have a good inhibitory ability against CDK7 kinase, and are expected to be further developed into drugs for regulating CDK7 kinase activity or treating CDK7-related diseases.

[0893] Experimental Example 2 Cell Antiproliferation Experiment

[0894] 1. Experimental materials and equipment:

[0895] Human breast cancer cells MDA-MB 231, MDA-MB453, ovarian cancer cells OVCAR3, colorectal cancer cells HCT-116 and lung cancer cells NCI-H209 were purchased from Beijing Beina Chuanglian Biotechnology Co., Ltd. DMEM medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazolyl blue), 0.25% EDTA-Tripsin (trypsin digestion solution), 1xPBS (phosphate buffer, pH 7.2), 96-well plates (Corning), fetal bovine serum (FBS), 10,000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent assay (Tecan Spark).

[0896] 2. Experimental preparation:

[0897] 1. Cell plating

[0898] A) Tumor cells were cultured in DMEM (high glucose, containing 10% FBS and 100 U / mL penicillin-G / streptomycin) at 37°C, 5% CO2 and saturated humidity to 80-90% confluence.

[0899] B) Remove the culture medium from the 10 cm culture dish;

[0900] C) Rinse the cells once with 10 ml 1xPBS;

[0901] D) Add 4 ml of 0.25% EDTA-Tripsin and place in a 37°C, 5% CO2 incubator for trypsin digestion for 5 minutes, transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, and discard the supernatant to obtain a cell pellet;

[0902] E) Resuspend in 4 ml DMEM medium, count and adjust to 50,000 cells / ml.

[0903] F) The cell suspension was added to a 96-well plate at a volume of 100 μL per well and cultured overnight in a 37° C., 5% CO 2 incubator.

[0904] 2. Compound treatment

[0905] Compound dilution

[0906] A) Prepare the test compound gradient dilution solutions: TY 2600 1mM, TY 2601 1mM, TY-2648a 1mM, TY-2648b 1mM and TY-2650 1mM stock solutions. Then dissolve 1.5μl of the stock solution in 1.5ml of DMSO-free culture medium, and then perform 3-fold serial gradient dilutions in 0.1% DMSO culture medium, for a total of 9 concentrations. The compound concentrations after dilution are as follows:

[0907] 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM

[0908] B) After thorough mixing, 100 μL of the culture compound solution was taken to replace the culture medium in the cell culture plate, with 4 replicate wells for each concentration;

[0909] C) Transfer the cells to an incubator and incubate for 3 days.

[0910] 3. MTT assay

[0911] A) Take out the cell culture plate and add 10 μL of 5 mg / ml MTT in a biosafety cabinet;

[0912] B) Place the cell culture plate back into the incubator and continue incubating for 3 hours;

[0913] C) Take out the cell culture plate, remove the culture medium, add 100 μL of isopropanol (containing 0.4 mM HCl, 0.1% NP-40), and shake at room temperature for 30 minutes;

[0914] D) Select 570 nm wavelength to measure the absorbance value on TECAN enzyme-linked immunosorbent assay instrument.

[0915] 4. Data Analysis

[0916] The following formula was used to calculate the cell viability (% Cell Viability):

[0917] %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC)

[0918] Lum_HC: 0.1% DMSO control group cell reading

[0919] Lum_Sample: Cell readout with added compound

[0920] Lum_LC: Blank medium reading

[0921] The IC50 value was obtained by curve fitting using GraphPad Prism 8 software.

[0922] As shown in Table 4, where A≤10nM; 10nM <B<500nM;C≥500nM。

[0923] Table 4

[0924] Compound MDA-MB 231(nM) MDA-MB453(nM) OVCAR3(nM) HCT-116(nM) 01 B B B B 14 B B B B 20 B B B B 31 B B B B 48 B B B B

[0925] As can be seen from Table 4, the compounds of the present invention have very good inhibitory effects on human breast cancer cells MDA-MB 231, MDA-MB453, ovarian cancer OVCAR3, and colorectal cancer cells HCT-116.

[0926] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound used as a CDK7 kinase inhibitor, characterized in that The compound is a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, in: Ring A is Wherein, R2 is selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; Ring B is selected from the following groups which are substituted or unsubstituted: 4-7 membered heterocyclyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 5-9 membered heterobridged cycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 5-9 membered bridged cycloalkyl, 6-10 membered heterospirocycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 6-10 membered spirocycloalkyl, 6-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 6-10 membered cycloalkyl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S, S(O) or S(O)2, C6-C10 aryl; L is selected from the following group: O, NR1, -NR1-(C1-C6 alkylene)-; Ring C is in, X1 is selected from the group consisting of N, CH; X2 is selected from the group consisting of N, CR2'; R2' is independently selected from the following substituted or unsubstituted groups: hydrogen, amino, -NR1-C(=O)-O-(C1-C6 alkyl), -NR1-C(=O)-R5, -NR1-C(=O)-O-C1-C6 alkylene-X8-C1-C6 alkyl, -OC(=O)-NR1R5, Hydroxyl; R4 is selected from the following groups substituted or unsubstituted: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, -NR1-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R5, -C(=O)-R5, Cyano; R1 is independently selected from the following groups, substituted or unsubstituted: hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, -C(=O)-NR8R9; Each R5, R6, R7 is independently selected from the following group: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl containing 1, 2 or 3 selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, NR8R9; Each R8, R9 is independently selected from the group consisting of hydrogen, C1-C6 alkyl; Each X6 and X7 is independently selected from the group consisting of O, CR5R6, NR1; Each X8 is independently selected from the group consisting of N, O, S; m is selected from the following group: 0, 1, 2, 3; Each n is independently selected from the group consisting of 0, 1, 2, 3, 4 or 5; The substitution independently refers to substitution by a group selected from the following groups: -NH-C(=O)-O-(C1-C6 alkyl), amino, halogenated or unsubstituted C1-C6 alkyl, =O, hydroxyl, -NH(C1-C6 alkyl).

2. The compound according to claim 1, characterized in that The compound is a compound of formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, R2 is selected from trifluoromethyl, chloro, bromo, methyl, ethyl or isopropyl; Ring B is selected from the following substituted or unsubstituted groups: 4-7 membered heterocyclyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 5-9 membered heterobridged cycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 5-9 membered bridged cycloalkyl, 6-10 membered heterospirocycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 6-10 membered spirocycloalkyl, 6-10 membered heterocycloalkyl containing 1-3 selected from N, O, S, S(O) or S(O)2, 6-10 membered cycloalkyl, 6-10 membered cycloalkyl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S, S(O) or S(O)2, 5-6 membered aryl; L is selected from the following group: O, NR1, -NR1-(C1-C6 alkylene)-; Ring C is Wherein, R1, R4, X1, and X2 are as defined in claim 1.

3. The compound according to claim 1, characterized in that Ring B is selected from the group consisting of: Ring C is selected from the following group: wherein R1, R4, R5, R6, X1, X2, X6, and m are as defined in claim 1, and Q1 is a 3-7 membered ring.

4. The compound according to claim 1, characterized in that Ring A is selected from the following group: Ring C is selected from the following group: R4 is selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein R1, R5, R6, R7, X1, X6, X7, m, and n are as defined in claim 1.

5. The compound according to claim 1, characterized in that The compound is selected from the group consisting of: Ring A is selected from the following group: Ring C is selected from the following group: R4 is selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, L is selected from the group consisting of O, NR1; wherein R1, R5, R6, R7, X1, X6, and m are as defined in claim 1.

6. The compound according to claim 5, characterized in that R4 is selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S; L is NH.

7. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

8. The compound according to claim 1, characterized in that The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt; The inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

9. A pharmaceutical composition, characterized in that Contains a preventive and / or therapeutically effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

10. A use of the compound according to claim 1, characterized in that: Used for preparing drugs for regulating CDK7 kinase activity or preventing and / or treating CDK7 related diseases.

11. The use according to claim 10, characterized in that The CDK7-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

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