Compounds used as CDK7 kinase inhibitors and their applications

Abstract

The present invention relates to compounds used as CDK7 kinase inhibitors and their applications. Specifically, the compounds of the present invention have the structure shown in Formula I, where the definitions of each group and substituent are as described in the specification. The compounds of the present invention can be used as inhibitors of cyclin-dependent kinase 7 (CDK7), which are used in the treatment or prevention of proliferative diseases (e.g., cancer), particularly in the regulation and treatment of related diseases caused by the abnormal activity of cyclin-dependent kinase 7 (CDK7). [Formula 1] JPEG2023535746000182.jpg2754

Description

[Technical field]

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

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family, which bind to corresponding cyclins to form active dimeric complexes and exert physiological functions, thereby causing cell growth and proliferation. Currently, more than 20 types of CDKs have been discovered, and according to their functions, they are classified into two types: CDKs that regulate the cell cycle and CDKs that regulate cell transcription, where CDKs1-6 and 14-18 are involved in the regulation of the cell cycle, and CDKs7-13 and 19-20 are involved in the regulation of cell transcription.

[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 cellular solution, CDK7 forms CAK (CDKs activating kinase) together with cyclin H and Mat1, and 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 cellular gene transcription process by phosphorylating the CTD domain (carboxy-terminal domain) of RNA polymerase II at the most important initiation step of gene transcription. CDK7 has the dual functions of CAK and CTD phosphorylation, and therefore plays an important role in all cell proliferation, cell cycle and gene transcription processes.

[0004] Due to the dual unique functions of CDK7 in transcription and cell cycle progression, CDK7 is widely expressed in various types of cancers, and downregulation of CDK7 activity can lead to reduced cell proliferation. More importantly, it is now agreed that targeting transcription selectively limits the synthesis of mRNAs involved in tumor growth without disrupting the transcription of housekeeping genes. Therefore, CDK7 is considered to be a feasible and highly promising target for tumor therapy and has attracted wide attention, where many small molecules such as THZ1, THZ2, CT7001, and SY-1365 have shown very good effects in inhibiting tumor growth in preclinical studies. In particular, there are significant unsatisfied disease areas such as small cell lung cancer, triple negative breast cancer, and pancreatic cancer, which currently lack effective treatments. Therefore, the development of specific CDK7 inhibitors is expected to be used in the above unsatisfied areas. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides novel compounds that have CDK7 kinase inhibitory activity and have superior pharmacodynamic and pharmacokinetic properties. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound for use as a CDK7 kinase inhibitor, said compound being of formula I, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof: [ka] Where: Ring A is [ka] is selected from the group consisting of Ring B is selected from a substituted or unsubstituted C3-C8 cycloalkyl group, a 4-7 membered heterocyclic group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged cycloalkyl group, a 6-10 membered heterospirocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered spirocycloalkyl group, a 6-10 membered fused heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered fused cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-6 membered aryl group; Ring C is [ka] is selected from the group consisting of L is selected from the group consisting of O, S(O), S(O)2, NR1, -NR1-(C1-C6 alkylene)-, CR2R3, C=NH, C=NOH; Each X1, X2, X3, X4 and X5 is independently selected from the group consisting of a chemical bond, N, O, S, NR1, CR2, CR2R3; The ring formed by X1, X2, X3 or X1, X2, X3, X4 and the pyrimidine ring to which they are bonded is an aromatic ring or a non-aromatic ring; Each R1 is independently selected from a substituted or unsubstituted hydrogen, an amino group, -C(=O)-O-(C1-C6 alkyl), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a halogenated C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, a C6-C10 aryl-C1-C6 alkylene group, and a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S; Each R2 and R3 is independently a substituted or unsubstituted hydrogen, halogen, amino group, hydroxyl group, cyano group, oxo (=O), carboxyl group, -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 group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, group), C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C6-C10 aryl group, 5-10 membered heteroaryl group 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 group, C6-C10 aryl-C1-C6 alkylene group, 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, C1-C6 alkyl-NH-, C3-C6 cycloalkyl-NH-; R4 is H, [ka] is selected from the group consisting of Each R5, R6, and R7 is independently selected from the group consisting of a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a C6-C10 aryl group, and a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S; each X6 and X7 is independently selected from the group consisting of O, CR2R3, and NR1; Ring Q is a substituted or unsubstituted 4- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N, S and P; m is selected from the group consisting of 0, 1, 2, and 3; each n is independently selected from the group consisting of 0, 1, 2, 3, 4, or 5; The substitution is independently selected from the group consisting of -NH-C(=O)-O-(C1-C6 alkyl), an amino group, a halogenated or unsubstituted C1-C6 alkyl group, and =O; The additional condition is that ring A is [ka] and 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 [ka] This is not the case.

[0007] In another preferred embodiment, Ring A is [ka] is selected from the group consisting of Ring B is [ka] is selected from the group consisting of Ring C is [ka] is selected from the group consisting of Each X1, X2, X3, X4 and X5 is independently selected from the group consisting of a chemical bond, N, O, S, NR1, CR2, CR2R3; a ring formed by X1, X2, X3 or X1, X2, X3, X4 and the pyrimidine ring to which they are bonded is an aromatic ring or a non-aromatic ring; Each R1 is independently selected from substituted or unsubstituted hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, halogenated C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C6-C10 aryl group, 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl-C1-C6 alkylene group, 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S; Each R2 and R3 is independently a substituted or unsubstituted hydrogen, halogen, amino group, hydroxyl group, cyano group, oxo (=O), carboxyl group, -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 group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 heteroalkyl group, C3-C 6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C6-C10 aryl group, 5-10 membered heteroaryl group 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 group, C6-C10 aryl-C1-C6 alkylene group, 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, C1-C6 alkyl-NH-, C3-C6 cycloalkyl-NH-; or R2 and R3 together with the carbon atoms on the ring form a 3- to 7-membered ring; R1' is selected from the group consisting of hydrogen, amino group, -C(=O)-O-C1-C6 alkyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, halogenated C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C6-C10 aryl group, 6-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, C6-C10 aryl-C1-C6 alkylene group, 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S; each n is independently selected from the group consisting of 0, 1, 2, 3, 4, or 5; R4 is as defined above.

[0008] In another preferred embodiment, Ring A is [ka] is selected from the group consisting of Ring B is [ka] is selected from the group consisting of Each n is independently selected from the group consisting of 0, 1, 2, 3, 4, or 5.

[0009] In another preferred embodiment, Ring A is [ka] is selected from the group consisting of:

[0010] In another preferred embodiment, ring A is [ka] where R2 is selected from the group consisting of halogen, C1-C6 alkyl groups, and halogenated C1-C6 alkyl groups; Ring B is selected from a substituted or unsubstituted C3-C8 cycloalkyl group, a 4-7 membered heterocyclic group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged cycloalkyl group, a 6-10 membered heterospirocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered spirocycloalkyl group, a 6-10 membered fused heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered fused cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a C6-C10 aryl group; L is selected from the group consisting of O, NR1, -NR1-(C1-C6 alkylene)-; Ring C is [ka] wherein: X1 is selected from the group consisting of N and CH; Each X2, X3, and X4 is independently selected from the group consisting of N and CR2′; Each R2' is independently a substituted or unsubstituted hydrogen, an amino group, -NH-C(=O)-O-(C1-C6 alkyl), -NR1-C(=O)-O-(C1-C6 alkyl), -NR1-C(=O)-R5, -NR1-C(=O)-O-C1-C6 alkylene-X8-C1-C6 alkyl group, -OC(=O)-R5, -OC(=O)-NH-(C1-C6 alkyl), -OC(=O)-NR5-(C1-C6 alkyl); [ka] selected from a 3-8 membered heterocycloalkyl group (bonded to C via N) containing 1, 2 or 3 heteroatoms selected from N, O, S; C1-C6 alkyl-NH-; C3-C6 cycloalkyl-NH-; and a hydroxyl group; R4 is a substituted or unsubstituted H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S; [ka] -NR1-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R5, -C(=O)-R5, [ka] cyano group, R1 is independently selected from substituted or unsubstituted hydrogen, amino, -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C6-C10 aryl group, 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, S, 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, -C(=O)-NR8R9; Each R5, R6, and R7 is independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkylamino group, a 3-8 membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, and NR8R9; Each R8, R9 is independently selected from the group consisting of hydrogen, C1-C6 alkyl groups; each X6 and X7 is independently selected from the group consisting of O, CR5R6, and NR1; Each X8 is independently selected from the group consisting of N, O, and S; m is selected from the group consisting of 0, 1, 2, and 3; each n is independently selected from the group consisting of 0, 1, 2, 3, 4, or 5; The substitution refers to being substituted independently with a group selected from the group consisting of -NH-C(=O)-O-(C1-C6 alkyl), an amino group, a halogenated or unsubstituted C1-C6 alkyl group, =O, a hydroxyl group, and -NH(C1-C6 alkyl).

[0011] In another preferred embodiment, ring A is [ka] is selected from the group consisting of Ring B is selected from a substituted or unsubstituted C3-C8 cycloalkyl group, a 4-7 membered heterocyclic group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-9 membered bridged cycloalkyl group, a 6-10 membered heterospirocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered spirocycloalkyl group, a 6-10 membered fused heterocycloalkyl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 6-10 membered fused cycloalkyl group, a 5-6 membered heteroaryl group containing 1-3 selected from N, O, S, S(O) or S(O)2, a 5-6 membered aryl group; L is selected from the group consisting of O, NR1, -NR1-(C1-C6 alkylene)-; Ring C is [ka] is selected from the group consisting of Here, R1, R4, X1, and X2 are as defined above.

[0012] In another preferred embodiment, ring B is [ka] is selected from the group consisting of Ring C is [ka] is selected from the group consisting of Here, R1, R4, R5, R 6、 X1, X2, X6 and m are as defined above, and Q1 is a 3- to 7-membered ring.

[0013] In another preferred embodiment, ring A is [ka] is selected from the group consisting of Ring C is [ka] is selected from the group consisting of R4 is H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, [ka] is selected from the group consisting of Here, R1, R5, R6, R7, X1, X6, X7, m, and n are as defined above.

[0014] In another preferred embodiment, ring A is [ka] is selected from the group consisting of Ring C is [ka] is selected from the group consisting of R4 is H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, [ka] is selected from the group consisting of L is selected from the group consisting of O, NR1; Here, R1, R5, R6, R7, X1, X6, and m are as defined above.

[0015] In another preferred example, R4 is selected from the group consisting of H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, and a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, and S; L is NH.

[0016] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka]

[0017] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka]

[0018] In another preferred embodiment, the pharma- ceutically acceptable salt is an inorganic or 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 salts include formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, and the like. The salt is selected from the group consisting of methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0019] A second aspect of the invention provides a pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound according to the first aspect of the invention, and a pharma- ceutically acceptable carrier.

[0020] A third aspect of the invention provides the use of a compound according to the first aspect of the invention for use in the preparation of a medicament for use as a CDK7 kinase inhibitor.

[0021] A fourth aspect of the invention provides the use of a compound according to the first aspect of the invention for use in the preparation of a medicament for modulating CDK7 kinase activity or for preventing and / or treating a CDK7-related disease.

[0022] In another preferred embodiment, the CDK7-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immune disease, and metabolic disease.

[0023] 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, renal cancer, esophageal cancer, and uterine cancer. Effect of the Invention

[0024] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief description of the drawings]

[0025] [Figure 1] Pharmacokinetic parameters of the compounds of the present invention and reference compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] As a result of extensive and thorough research, the present inventors have unexpectedly discovered a compound with better CDK7 kinase inhibitory activity. Moreover, the compound has better inhibitory activity against CDK7 kinase and better pharmacodynamics / pharmacokinetic performance. Based on this, the inventors have completed a counter-invention.

[0027] term Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions set forth below. Where a substituent is depicted by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0028] "Alkyl group (alone or as part of another group)" refers to a monovalent straight or branched chain saturated hydrocarbon group consisting solely of carbon and hydrogen atoms and containing 1 to 12 carbon atoms. The alkyl group is preferably a C1-C6 alkyl group (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, s-butyl, t-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl groups are intended to include substituted alkyl groups, i.e., one or more positions of the alkyl group are substituted, and in particular, one to four substituents may be substituted at any position. "Halogenated alkyl group" refers to an alkyl group, as defined herein, in which one or more hydrogens are replaced by the same or different halogens. Examples of halogenated alkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

[0029] An "alkylene group" refers to a divalent radical of an alkyl group, such as -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0030] "Alkoxy group (alone or as part of another group)" refers to an alkyl group having an alkylO- structure with an oxy group attached thereto, where the alkyl group has the definition set forth above, and preferably the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy groups, and the like. "Halogenated alkoxy group" refers to a group of the formula -OR, where R is a halogenated alkyl group as defined herein. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0031] A "thioalkyl group" refers to a carbon in an alkyl group being replaced by S, S(O), or S(O)2.

[0032] The term "alkenyl group (alone or as part of another group)" refers to an aliphatic group that generally has 2 to 20 carbon atoms and contains at least one double bond. In the present invention, the term "C2-C6 alkenyl group" refers to an alkenyl group that contains 2, 3, 4, 5 or 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl groups, propenyl groups, butenyl groups, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl groups include substituted alkenyl groups.

[0033] An "alkenylene group" refers to an alkenyl group that has two points of attachment. For example, a "vinylene group" refers to the group -CH=CH-. Alkenylene groups can be unsubstituted or substituted with one or more substituents.

[0034] "Alkynyl group (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, generally having from 2 to 20 carbon atoms. In the present invention, "C2-6 alkynyl group" refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl group, propargyl group, and 3-hexynyl group. One of the triple bond carbons may optionally be the point of attachment of an alkynyl group substituent. In the present invention, alkynyl groups further include substituted alkynyl groups.

[0035] An "alkynylene group" refers to an alkynyl group that has two points of attachment. For example, an "ethynylene group" refers to the group: -C≡C-. Alkynylene groups can be unsubstituted or substituted with one or more substituents.

[0036] "Aliphatic group" refers to straight-chain, branched-chain, or cyclic hydrocarbon groups, including saturated and unsaturated groups, such as alkyl, alkenyl, and alkynyl groups. "Aromatic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0037] "Aryl group (alone or as part of another group)" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems such as phenyl, naphthyl and anthryl groups, as well as ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, phthalimide, naphthylimino or tetralyl groups. In the present invention, the aryl group is preferably a C6-C12 aryl group. In the present invention, the aryl group is further intended to include substituted aryl groups.

[0038] An "arylalkyl group" or "aralkyl group" refers to an alkyl group in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl groups include groups in which one or more hydrogen atoms are replaced by an aryl group, where the aryl and alkyl groups are as defined above. Examples of "arylalkyl groups" or "aralkyl groups" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

[0039] An "aryloxy group" refers to an --O-(aryl) group, where the aryl portion is as defined herein.

[0040] "Heteroalkyl group" refers to a substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given, e.g., a C1-C6 heteroalkyl group refers to the number of carbons in the chain that contain from 1 to 6 carbon atoms. For example, a -CH2OCH2CH3 group would be referred to as a "C3" heteroalkyl group. Attachment to the remainder of the molecule can be through a heteroatom or a carbon in the heteroalkyl group chain. "Heteroalkylene group" refers to an optionally substituted divalent alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.

[0041] "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 none of the rings is aromatic.

[0042] A "carbocyclyl group" refers to a monovalent group of a carbon ring system, such as a cycloalkyl group (such as a cyclopentyl group, a cyclobutyl group, a cyclopropyl group, a cyclohexyl group, etc.) and a cycloalkenyl group (such as a cyclopentenyl group, a cyclohexenyl group, a cyclopentadienyl group, etc.).

[0043] "Cycloalkyl group" refers to a monovalent saturated carbocyclyl group consisting of a monocyclic or bicyclic ring having 3 to 12, preferably 3 to 10, more preferably 3 to 8 ring atoms. The cycloalkyl group can be optionally substituted with one or more substituents, where each substituent is independently a hydroxyl group, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, an amino group, a monoalkylamino group, or a dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

[0044] "Cycloalkoxy group" refers to a group of the formula -OR, where R is a cycloalkyl group, as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl group" refers to a -(cycloalkyl)-alkyl group, wherein the cycloalkyl and alkyl groups are as disclosed herein. A "cycloalkylalkyl group" is attached to the parent molecular structure via a cycloalkyl group.

[0045] "Heteroaromatic ring system" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (6-12 membered) or polycyclic system in which at least one ring is not only aromatic but also contains at least one heteroatom (e.g., N, O or S) and in which none of the other rings are heterocyclic groups (e.g., as defined below). In certain cases, aromatic heteroatom-containing rings contain 1, 2, 3 or 4 ring heteroatoms in the ring. At least one ring is heteroaromatic and the remaining rings can be saturated, partially unsaturated or fully unsaturated rings.

[0046] A "heteroaryl group" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10 membered), or tricyclic group of 5-12 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O, or S, and at least one aromatic ring in which the remaining ring atoms are C, it being understood that the point of attachment of the heteroaryl group must be located on the aromatic ring. Examples of heteroaryl groups include an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyrazinyl group, a thienyl group, a furyl group, a pyranyl group, a pyridyl group, a pyrrolyl group, a pyrazolyl group, a pyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzofuranyl group, a benzofuranyl group, a benzothienyl group, a pyrazinyl group, a pyrazinyl group, a pyridyl group, a pyrrolyl group, a pyrazolyl group, a pyrimidinyl group, a quinolinyl group, a isoquinolinyl group, a benzofuranyl group, a benzothienyl group, a pyrazin ... group, benzothiopyranyl group, benzimidazolyl group, benzoxazolyl group, benzoxadiazolyl group, benzothiazolyl, benzothiadiazolyl group, benzopyranyl group, indolyl group, isoindolyl group, triazolyl group, triazinyl group, quinoxalinyl groupExamples of heteroaryl groups include, but are not limited to, a heteroaryl group, a purinyl group, a quinazolinyl group, a quinazinyl group, a naphthyridinyl group, a pterridinyl group, a carbazolyl group, an azepine group, a diazepine group, an acridinyl group, and the like. A heteroarylene group refers to a heteroaryl group having two binding sites.

[0047] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom. The heterocyclic ring system can be attached to a pendant group at any heteroatom or carbon atom that results in the creation of a stable structure, and any of the ring atoms can be optionally substituted.

[0048] "Heterocyclic group" refers to a monovalent radical of a heterocyclic ring system, typically a stable monocyclic (e.g., 3-8 membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered) or bicyclic (e.g., 5-12 membered, i.e., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) or polycyclic (e.g., 7-14 membered, i.e., 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) ring system, including fused, spiro, and / or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.Representative heterocyclic groups include ring systems in which (1) each ring is non-aromatic and at least one ring contains a heteroatom, such as, for example, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a pyrrolidinyl group, a pyrrolidonyl group, a piperidinyl group, a pyrrolinyl group, a decahydroquinolinyl group, an oxazolidinyl group, a piperazinyl group, a dioxanyl group, a dioxolanyl group, a diazepinyl group, an oxazepinyl group, a thiazepinyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a pyrrolidinyl group, a pyrrolidinyl group, a piperidinyl group, a pyrrolinyl group, a decahydroquinolinyl group, an oxazolidinyl group, a piperazinyl group, a dioxanyl group, a dioxolanyl group, a diazepinyl group, a thiazepinyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a pyrrolidinyl group, a pyrrolidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a decahydroquinolinyl group, a ... group), morpholinyl group and quinuclidinyl group, (2) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is aromatic carbocyclic, such as 1,2,3,4-tetrahydroquinolinyl group and 1,2,3,4-tetrahydroisoquinolinyl group, and (3) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is aromatic and contains a heteroatom, such as 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthyridine. Heterocyclylene group refers to a heterocyclic group having two binding sites. In the present invention, the heterocyclylene group is preferably bicyclic, one of which is a heteroaryl group and is bonded to the other part of the general formula via the heteroaryl group. In the present invention, the heterocyclylene group is preferably a 5- to 6-membered monocyclic heterocyclylene group or an 8- to 10-membered bicyclic heterocyclylene group.

[0049] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocycle group, where the heterocycle and alkyl groups are as defined above.

[0050] An "alkylamino group" refers to a group having the structure alkyl-NR-, where R is H or an alkyl, cycloalkyl, aryl, heteroaryl, etc., group, as defined above.

[0051] "Cycloalkylamino group" refers to a group of formula -NRaRb, where Ra is H, an alkyl group as defined herein or a cycloalkyl group as defined herein, Rb is a cycloalkyl group 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 group, such as a tetrahydropyrrolyl group. As used herein, a C3-C8 cycloalkylamino group refers to an amine group containing 3 to 8 carbon atoms.

[0052] In the present invention, an "ester group" refers to having the structure -C(O)-OR or -RC(O)-O-, where R independently represents a hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group, as defined above.

[0053] In the present invention, the term "amide group" refers to a group having the structure -CONRR', where R and R' can independently represent hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, an aryl group or a substituted aryl group, a heterocycle or a substituted heterocycle, as defined above. R and R' can be the same or different in a dialkylamine fragment.

[0054] In the present invention, the term "sulfonamide group" refers to a group having the structure -SONRR', where R and R' can independently represent hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, an aryl group or a substituted aryl group, a heterocycle or a substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.

[0055] A "ketocarbonyl group" refers to RC(=O)--, where R is an alkyl group, cycloalkyl group, etc., as defined above. When a substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to an alkyleneoxy group.

[0056] In the present invention, each of the above alkyl groups, alkoxy groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, ring heteroalkyl groups, alkenyl groups, alkynes, heterocycles, heterocyclic groups, and the like may be substituted or unsubstituted.

[0057] In the present invention, the term "substituted" refers to one or more hydrogen atoms of a specific group being replaced by a specific substituent. The specific substituents are the corresponding substituents described above or the substituents appearing in each example. Unless otherwise specified, a specific substituted group can have one substituent selected from a specific group at any substitutable position of the group, and the substituents can be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are stable or chemically feasible combinations. Typical substitutions include, for example, hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents such as alkyl groups containing, for example, trifluoromethyl or Cl), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic ring, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(

[0046] In one embodiment, R is an alkyl group, and R is an aryl group. In another embodiment, R is an alkyl group, and R is an aryl group. In another embodiment, R is an aryl group. In another embodiment, R is an aryl group. In another embodiment, R is an aryl group. In another embodiment, R is an aryl group. In another embodiment, R is an aryl group. 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 can form a heterocycle together with the N atom, R ecan independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring. The above-mentioned typical substituents such as an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring can be optionally substituted. Examples of the substituents include, but are not limited to, halogen, a hydroxyl group, a cyano group, a carboxyl group (-COOH), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-12 membered heterocyclic group, an aryl group, a heteroaryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, an amine group, a C1-C6 alkoxy group, a C1-C10 sulfonyl group, and a C1-C6 ureido group.

[0058] "Cyano" refers to the radical -CN. A "nitro group" refers to --NO.sub.2. "Hydroxyl group" refers to -OH.

[0059] An "amino group" refers to -NH2 or RNH-, where 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 is an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like.

[0060] "Halogen (halogenated)" refers to any halogen radical such as -F, -Cl, -Br or -I. The term "deuteride" refers to a compound obtained by replacing a hydrogen atom (H) or multiple hydrogen atoms (H) in a compound with a deuterium atom (D).

[0061] In the present invention, "plurality" refers independently to 2, 3, 4, or 5. The structural formula of the carbamate group is -NH-C(=O)-OR, where R is an aryl or heteroaryl group.

[0062] Active ingredients As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably to refer to a compound of Formula I, or a pharma- ceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound) or prodrug thereof. The terms further include racemates, optical isomers.

[0063] The compound of formula I has the structure: [ka] Ring A, ring B, ring C and L are as defined above.

[0064] Salts that can be formed by the compounds of the present invention are also within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acid or base salts formed with inorganic or organic acids and bases. In addition, when the compounds of the present invention contain one basic fragment, which includes but is not limited to pyridine or imidazole, and when the compounds of the present invention contain one acid fragment, which includes but is not limited to carboxylic acid, zwitterions ("inner salts") that can be formed are included within the scope of the term "salt". Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful in the separation or purification step during the preparation process. The compounds of the present invention can form salts, for example, compound I is reacted with a certain amount of acid or base, such as an equivalent amount, and salted out by mediation or lyophilized in an aqueous solution.

[0065] Basic fragments contained in the compounds of the present invention include, but are not limited to, amines or pyridine or imidazole rings that can form salts with organic or inorganic acids.Typical acids from which salts can be formed include acetates (e.g., using acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorsulfonic acid, cyclopentane propionates, diglycolate, lauryl sulfate, and the like. sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (e.g., 2-isethionate), lactate, maleate, methanesulfonate, naphthalenesulfonate, sulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, peroxysulphate, phenpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulphonate, tartrate, sulfocyanate, toluenesulfonate, such as p-toluenesulfonate, dodecanoate, and the like.

[0066] Acidic fragments that may be included in certain compounds of the present invention include, but are not limited to, carboxylic acids, which may form salts with various organic or inorganic bases. Exemplary salts formed with bases include alkali metal salts such as ammonium salts, sodium salts, lithium salts, and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts formed with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hibramin (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, and tert-butylamine, as well as salts formed with amino acids such as arginine and lysine. Basic nitrogen-containing groups can form quaternary ammonium salts with halides such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., decyl, dodecyl, and tetradecyl chlorides, bromides, iodides), and aralkyl halides (e.g., benzyl and phenyl bromides).

[0067] Prodrugs and solvates (or solvates) of the compounds of the invention are also included within their scope. Herein, the term "prodrug" refers to a compound that undergoes a chemical conversion during metabolic or chemical processes to produce a compound, salt, or solvate of the present invention during the treatment of a related disease. The compounds of the present invention include solvates such as hydrates.

[0068] The compounds, salts or solvates of the present invention may exist in their tautomeric form (for example as amides and imino ethers). All such tautomers are part of the present invention.

[0069] All stereoisomers of the compounds (e.g., asymmetric carbon atoms that may be present due to various substitutions), including their enantiomeric and diastereomeric forms, are all within the contemplation of the present invention. Individual stereoisomers of the compounds of the present invention may be present either simultaneously with other isomers (e.g., with specific activity as pure or substantially pure optical isomers) or in mixtures, such as racemates, or in mixtures formed with all other stereoisomers or some of them. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 proposal of the International Union of Theoretical and Applied Sciences (IUPAC). Racemic forms can be resolved via physical methods, such as fractional crystallization, or separated by derivatization into diastereoisomers, or by chiral column chromatography. Single optical isomers can be obtained from the racemates by suitable methods, including, but not limited to, conventional methods, such as salt formation with optically active acids followed by recrystallization.

[0070] In the compound of the present invention, the weight content of the compound obtained by sequentially preparing, separating and purifying is 90% or more, for example, 95% or more, 99% or more ("highly pure" compound), as described herein. Such "highly pure" compound of the present invention as described herein is also used as part of the present invention.

[0071] All configurational isomers of the compounds of the present invention are included within their scope, whether in admixture, pure or highly pure form. The definition of the compounds of the present invention includes the two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings. Throughout the specification, groups and substituents can be chosen to provide stable fragments and compounds.

[0072] Definitions of specific functional groups and chemical terms are explained in detail below. In the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of certain functional groups are also set forth therein. Additionally, basic principles of organic chemistry and certain functional groups and reactivities are also set forth in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, the entire contents of which are incorporated by reference herein.

[0073] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention includes 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 groups. All isomers and mixtures thereof are included in the present invention.

[0074] According to the present invention, the ratio of isomers contained in the isomer mixture can vary. For example, a mixture having only two isomers can have combinations such as 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 and ratios of more complex isomer mixtures that are readily understood by those skilled in the art are also within the scope of the present invention.

[0075] The present invention further includes isotopically labeled compounds equivalent to the original compounds disclosed herein.However, in practice, it is common that one or more atoms are replaced by atoms with different atomic weights or masses.Examples of isotopes that can be included in the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, each of which can be, for example, 2 H,3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharma- ceutically acceptable salts or solvates that contain isotopes of the above compounds or other isotopic atoms are within the scope of the present invention. 3 H and 14 Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of C, are useful in drug and substrate tissue distribution studies. Tritium, i.e. 3 H and carbon-14, i.e. 14 C is the preferred choice of isotope because its preparation and detection are relatively simple. Furthermore, deuterium, i.e. 2 Substitution of heavier isotopes such as H may be considered a priority in some cases due to better metabolic stability that may provide advantages to certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically labeled compounds can be prepared using common methods and schemes disclosed in the examples by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0076] When designing the synthesis of a particular enantiomer of a compound of the invention, it can be prepared by asymmetric synthesis or derivatized with a chiral auxiliary, the resulting diastereomeric mixture separated, and the chiral auxiliary removed to yield the pure enantiomers. Additionally, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, which can then be separated by conventional means, such as preparative crystallization or chromatography, to yield the pure enantiomers.

[0077] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand the scope of inclusion. In general, whether the term "substituted" appears before or after the term "optionally", the general formula in which the composition of the present invention includes a substituent refers to replacing a hydrogen radical with the specified structural substituent. When multiple positions in a particular structure are substituted with multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the heteroatom nitrogen can have a hydrogen substituent or any of the above permissible organic compounds to supplement the valence state. Furthermore, the present invention does not intend to limit the organic compounds in which substitution is permitted in any way. The present invention considers that the combination of substituents and variable groups is very good for treating diseases in the form of a stable compound. The term "stable" as used herein refers to having a compound that is stable enough to maintain the structural integrity of the compound for a sufficient period of time, and preferably is detectable as being effective for a sufficient period of time, as used herein for the above purposes.

[0078] The claims of this application also include metabolic products of the compounds of this application and their pharma- ceutically acceptable salts, as well as prodrugs that can be converted in vivo to the structures of the compounds of this application and their pharma- ceutically acceptable salts. In another preferred embodiment, in the compound, any one of the groups is the corresponding group in each of the specific compounds.

[0079] Preparation method The following schemes and examples describe the method of preparing compounds of formula I. Raw materials and intermediates are purchased from commercial sources, prepared by known steps, or otherwise described. In certain cases, the order of carrying out steps of the reaction schemes can be changed to facilitate the reaction or avoid undesired side reaction products.

[0080] The preparation method of the compound of the structure of formula I of the present invention will be described in more detail below, but these specific methods do not limit the configuration of the present invention. The compound of the present invention can be easily prepared by selectively combining various synthetic methods described herein or known in the art, and such combination can be easily carried out by those skilled in the art.

[0081] In general, in the preparation process, each reaction is usually carried out under inert gas protection in a suitable solvent at 0 to 150° C., and the reaction time is usually 2 to 24 hours.

[0082] The preferred preparation method is as follows. Method one: [ka] First step: SM1 and SM2 are reacted at 70 to 120° C. under Lewis acid conditions (e.g., aluminum trichloride, zinc chloride, boron trifluoride etherate, etc.) in a solvent (e.g., 1,2-dichloroethane, dioxane, tetrahydrofuran) to produce M1; Second step: M1 is reacted with SM3 in an inert solvent (e.g., DMF, dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, etc.) under basic (e.g., diisopropylethylamine, potassium acetate, DBU, etc.) conditions or in the presence of a catalyst and a ligand (e.g., Pd(PPh3)4, Pd2(dba)3\t-BuXphos, etc.) to produce T (i.e., the compound of formula I).

[0083] Method two: [ka] First step: reacting SM3 with SM2 in an inert solvent (e.g., tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dioxane, ethylene glycol dimethyl ether, etc.) under the catalysis of a Lewis acid (e.g., zinc chloride, ferric chloride, etc.) to give M1; Second step: M1 is reacted with SM1 or SM1' in the presence of a catalyst and a ligand (e.g., Pd(PPh3)4) under basic conditions (e.g., potassium carbonate, potassium phosphate, etc.) in an inert solvent (e.g., N,N-dimethylformamide, dioxane, dimethylsulfoxide, etc.) to produce T (i.e., a compound of formula I).

[0084] In each of the above formulas, ring A, ring B, ring C and L are as described above. Unless otherwise stated, the above starting materials can be purchased from commercial sources or synthesized according to reported literature.

[0085] Pharmaceutical Compositions and Methods of Administration The pharmaceutical compositions according to the present invention are used for preventing and / or treating diseases such as inflammation, cancer, cardiovascular diseases, infectious diseases, immune diseases, metabolic diseases, and the like.

[0086] The compound described in general formula I can be used in combination with other drugs known to treat or improve similar pathologies. In the case of combined administration, the administration method and dosage of the original drug can be maintained unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, preferably, a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time can be used. The combination of drugs also includes administering the compound of formula I and one or more other known drugs during an overlapping period. When the compound of formula I is combined with one or several other drugs, the dose of the compound of formula I or the known drug can be lower than the dose of their step-by-step administration.

[0087] Drugs or active ingredients that can be used in combination with the compounds according to general formula I include PD-1 inhibitors (e.g., Nivolumab, Pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (e.g., Durvalumab, Atezolizumab, ), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (e.g., Rituximab, Obinutuzumab, Ofatumumab, Tositumomab, Ibritumomab, etc.), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, T TI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., Ceritinib, Alectinib, Brigatinib, Lorlatinib, Alkotinib), PI3K inhibitors (e.g., Idelalisib, Dactolisib, Taselisib, Buparlisib) etc.), BTK inhibitors (e.g., Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, etc.), VEGFR inhibitors (e.g., Sorafenib,Pazopanib, Lenvatinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (e.g., Givinostat, Droxinostat, Entinostat, Dacinostat, Tacedinaline, etc.), CDK inhibitors (e.g., Palbociclib, Ribo Ribociclib, Abemaciclib, Lerocilib, etc.), MEK inhibitors (e.g., Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (e.g., MK-2206, Ipatasertib, Capivasertib, Afuresertib ( Afuresertib, Uprosertib, etc.), mTOR inhibitors (e.g., Vistasertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (e.g., Ceritinib, Alkotinib, Linsitinib, BMS-754807, GSK1838705A, etc.), ER antagonists or degraders (e.g., Tamoxifen, Fulvestran, Fulvestrant, etc.), aromatase inhibitors (e.g., Letrozole, etc.), BCL2 or BCL-XL inhibitors (e.g., ABT-199, ABT-263, etc.), Hedgehog inhibitors (e.g., vismodegib, cyclopamine, etc.), chemotherapy drugs (e.g., cisplatin, etoposide, topotecan, etc.), PARP inhibitors (e.g., Olaparib,These include, but are not limited to, veliparib, rucaparib, etc.), ATR / ATM inhibitors (e.g., ceralasertib, berzosertib, etc.), or combinations thereof.

[0088] The dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, films, drop pills, external liniments, controlled or sustained release or nano formulations.

[0089] The pharmaceutical composition of the present invention contains 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. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0090] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly decreasing the efficacy of the compounds of the present invention and among themselves. Some examples of pharma- ceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0091] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0092] 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, for example, sodium citrate or dicalcium phosphate, or with other suitable carriers, such as: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption enhancers, such as quaternary amine compounds; (g) glyceryl monostearate, cetyl alcohol, and glyceryl monostearate; (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include buffering agents.

[0093] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of 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 be formed into microcapsules with one or more of the above-mentioned excipients.

[0094] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0095] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0096] Compositions for parenteral injection can 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.

[0097] Dosage forms of the compounds of the present invention used for topical administration 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 which may be required. The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0098] When the pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0099] The present invention further provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharma- ceutically acceptable carrier with a compound of general formula I according to the present invention or a crystalline form, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof, to form a pharmaceutical composition.

[0100] The present invention further provides a method of treatment comprising administering to a subject in need of treatment a compound of formula I as described herein, or a crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, to inhibit CDK7.

[0101] Compared with the prior art, the present invention has the following main advantages: (1) The compounds of the present invention have excellent inhibitory activity against CDK7 kinase. (2) The compounds of the present invention have less toxicity and side effects. (3) The compounds of the present invention have superior pharmacodynamic and pharmacokinetic properties.

[0102] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0104] Working Example The technical solutions of the present invention are further explained below, but the protection scope of the present invention is not limited thereto.

[0105] Synthesis of intermediate 1 The structural formula of intermediate 1 is as follows: [ka]

[0106] The experimental process is as follows. The synthetic route is as follows: [ka]

[0107] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 175g (1.0eq) of compound 1 in t-butanol and stir at room temperature. Add triethylamine to the reaction solution until the solution changes from transparent yellow to transparent reddish brown. Under nitrogen gas protection, slowly add DPPA (1.5eq) dropwise and slowly heat the reaction system to 80°C, while a large amount of bubbles are generated. After the bubbles decrease, continue to react at 80°C for 3 hours, then add aqueous sodium carbonate solution to quench the reaction, extract with ethyl acetate, combine the organic phase, dry, spin-dry, and pass through a column to obtain 187.5g of compound 2.

[0108] (2) Synthesis of Compound 3 Under nitrogen gas protection, add 1.0Mol / L vinylmagnesium bromide solution (5.0eq) to the reaction flask, then slowly add dropwise a solution of compound 2 (1.0eq) in tetrahydrofuran (THF) under a dry ice bath, and after the dropwise addition is completed, allow to naturally warm to room temperature under nitrogen gas protection, react overnight, add aqueous ammonium chloride solution to quench the reaction, extract with ethyl acetate, combine the organic phase, dry, spin-dry, and pass through a column to obtain 132.4g of compound 3.

[0109] (3) Synthesis of intermediate 1 Compound 3 (132 g) was added to a 4.0 Mol / L hydrochloric acid / 1,4-dioxane solution at room temperature and reacted for 2 hours, the reaction system was filtered, and the filter cake was washed with methyl t-butyl ether to obtain 53.1 g of the hydrochloride salt of intermediate 1.

[0110] Synthesis of intermediate 2 The structural formula of intermediate 2 is as follows: [ka]

[0111] The experimental process is as follows. The synthetic route is as follows: [ka]

[0112] Synthesis steps: (1) Synthesis of Compound 2 At room temperature, compound 1 (5.38 g, 1.0 eq) is dissolved in methanol (60 mL), and then sodium methanol (6.4 g, 2.0 eq) is added. Then, the mixture is refluxed for 16 hours, and the reaction is monitored by TLC for completion. Then, the temperature is lowered, the methanol is rotary evaporated, and then 100 mL of ice water is added, and the pH value is adjusted to a weak acidic value (pH=4-5) with 2 Mol / L hydrochloric acid to precipitate the product, and then the mixture is filtered, the filter cake is washed with water, and the filter cake is collected and dried to obtain 6.16 g of compound 2.

[0113] (2) Synthesis of Compound 3 At room temperature, compound 2 (6.36 g, 1.0 eq) is dissolved in methanol (65 mL), then cooled to 0° C., concentrated sulfate (3.79 g, 1.2 eq) is added. Then the temperature is slowly raised to reflux, and the reaction is carried out for 12 hours, and the reaction completion is monitored by TLC. After cooling to room temperature, the methanol is rotary evaporated, 50 mL of ice water is added, the pH value is adjusted to neutral with aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride, the organic phase is dried, and the crude product of compound 3 is obtained by spin drying, which is used directly in the next step.

[0114] (3) Synthesis of compound 4 Dissolve compound 3 (5.8g, 1.0eq) in dichloromethane (100mL) at room temperature. Then cool to -78°C under nitrogen gas protection, then add boron tribromide (32.5mL, 5.0eq) dropwise, and after completion of addition, react at -78°C for 1 hour, and monitor the completion of the reaction by TLC. Add methanol (20mL) dropwise at -78°C to quench the reaction, then warm to 0°C, add 200mL of ice water, extract with dichloromethane, combine the organic phase, dry, concentrate, and pass through a column to obtain 2.6g of compound 4.

[0115] (4) Synthesis of Compound 5 Compound 4 (2.6 g, 1.0 eq) is added to acetonitrile (20 mL), then cooled to -15°C, 10% aqueous potassium hydroxide (147.8 g, 20.0 eq) is added, diethyl bromodifluoromethyl phosphate (10.6 g, 3.0 eq) is slowly added dropwise, and after the addition is complete, the reaction is continued at -10°C for 2 hours, then the reaction is continued by slowly warming to room temperature for 3 hours, and the reaction is monitored by TLC for completion. The reaction is quenched by adding aqueous ammonium chloride, extracted with ethyl acetate, the organic phases are combined, dried, spun dry, and passed through a column to obtain 0.92 g of compound 5.

[0116] (5) Synthesis of compound 6 Compound 5 (0.92 g, 1.0 eq) is added to tetrahydrofuran (20 mL), then cooled to -78°C, then vinylmagnesium bromide (11.2 mL, 1.0 mol / L, 3.0 eq) is added dropwise at this temperature, then the reaction is continued at -78°C for 1 hour, then allowed to slowly warm to room temperature and react overnight. The reaction is monitored for completion by TLC, then cooled to -10°C, and ammonium chloride aqueous solution is added dropwise to quench the reaction. Extract with ethyl acetate, combine the organic phases, dry, spin dry, and pass through a column to obtain 503 mg of compound 6.

[0117] (6) Synthesis of compound 7 Compound 6 (500 mg, 1.0 eq) is dissolved in methanol (5 mL), then sodium hydroxide (250 mg, 3.0 eq) is added, and the mixture is allowed to react at elevated temperature under reflux overnight. The reaction is monitored for completion by TLC. Then the methanol is spin-dried, 20 mL of ice water is added, and the aqueous phase is extracted once with methyl t-butyl ether. Then the aqueous phase is adjusted to a pH value of 4-5 with 2 mol / L hydrochloric acid to precipitate the solid, and the mixture is suction filtered, the filter cake is washed with water, and the filter cake is collected and dried to obtain 352 mg of compound 7.

[0118] (7) Synthesis of intermediate 2 Compound 7 (350 mg, 1.0 eq) is added to dioxane (5 mL), then triethylamine (230 mg, 1.5 eq) is added, and the temperature is raised to 90°C, then diphenylphosphoryl azide (630 mg, 1.5 eq) is slowly added dropwise, adjusting the rate of addition so as not to generate a large amount of gas and cause it to fly away. After the addition is complete, the reaction is continued at this temperature for 1 hour, then methanol (1 mL) is added dropwise, and the reaction is continued for 3 hours. The reaction is monitored for completion by TLC. Cool to 0°C, then quench the reaction by adding 2 mol / L sodium hydroxide solution, extract with ethyl acetate, combine the organic phase, spin dry, and pass through a column to obtain 230 mg of intermediate 2. LC-MS [M+1]: 257.0.

[0119] Synthesis of intermediate 3 The structural formula of intermediate 3 is as follows: [ka]

[0120] The experimental process is as follows. The synthetic route is as follows: [ka]

[0121] Synthesis steps: (1) Synthesis of compound 8 In a glove box, under nitrogen gas protection, add silver trifluoromethanesulfonate (12.85 g, 5.0 eq), selective fluorine reagent (Selectfluor) (7.1 g, 2.0 eq), N-fluorobisbenzenesulfonamide (NFSI) (6.3 g, 2.0 eq), cesium fluoride (9.1 g, 6.0 eq) and compound 4 (2.0 g, 1.0 eq) to a reaction flask, then add toluene (20 mL) and trifluorotoluene (40 mL). Then, under nitrogen gas protection, add trifluoromethyltrimethylsilane (11.36 g, 8.0 eq) and 2-fluoropyridine (4.85 g, 5.0 eq). React overnight at 35 °C, monitor the reaction completion by TLC, then filter, wash the filter cake with ethyl acetate, collect the organic phase, spin dry and pass through a column to obtain 0.15 g of compound 8.

[0122] (2) Synthesis of Compound 9 Compound 8 (0.6 g, 1.0 eq) is added to tetrahydrofuran (20 mL), then cooled to -78°C, then vinylmagnesium bromide (6.7 mL, 1.0 mol / L, 3.0 eq) is added dropwise at this temperature, then the reaction is continued at -78°C for 1 hour, then allowed to slowly warm to room temperature and react overnight. The reaction is monitored for completion by TLC, then cooled to -10°C and quenched by adding aqueous ammonium chloride solution dropwise. Extract with ethyl acetate, combine the organic phases, dry, spin dry and pass through a column to obtain 320 mg of compound 9.

[0123] (3) Synthesis of compound 10 Compound 9 (300 mg, 1.0 eq) is dissolved in methanol (5 mL), then sodium hydroxide (140 mg, 3.0 eq) is added, and the mixture is allowed to react at elevated temperature under reflux overnight. The reaction is monitored for completion by TLC. Then the methanol is spin-dried, 20 mL of ice water is added, and the aqueous phase is extracted once with methyl t-butyl ether. Then the aqueous phase is adjusted to a pH value of 4-5 with 2 mol / L hydrochloric acid to precipitate the solid, and the solid is filtered by suction, the filter cake is washed with water, and the filter cake is collected and dried to obtain 145 mg of compound 10.

[0124] (4) Synthesis of intermediate 3 Compound 10 (100 mg, 1.0 eq) is added to dioxane (3 mL), then triethylamine (62 mg, 1.5 eq) is added, and the mixture is heated to 90°C, followed by slow dropwise addition of diphenylphosphoryl azide (168 mg, 1.5 eq). After completion of the addition, the mixture is allowed to react at this temperature for 1 hour, then methanol (1 mL) is added dropwise, and the mixture is allowed to react for 3 hours. The reaction is monitored for completion by TLC. The mixture is cooled to 0°C, then aqueous ammonium chloride solution is added to quench the reaction, and the mixture is extracted with ethyl acetate, and the organic phases are combined, spin-dried, and passed through a column to obtain 54 mg of intermediate 3. LC-MS [M+1]: 275.0.

[0125] Synthesis of intermediate 4 The structural formula of intermediate 4 is as follows: [ka]

[0126] The experimental process is as follows. The synthetic route is as follows: [ka]

[0127] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 12g (1eq) of compound 1 in 200ml of anhydrous methanol, add 7.8g (0.8eq) of NaHCO3, cool to -78℃, add 12.6g (3eq) of NaBH4 in batches, control the temperature below -60℃, dissolve 36.4ml of Cbz-Cl (2.5eq) in 50ml of anhydrous methanol, slowly drip into the reaction system under -78℃, maintain the temperature for 1.5 hours, monitor the completion of the reaction by TLC, slowly add 1mol / L of NaOH(aq) to the reaction solution to quench, and extract with EA to obtain 10g.

[0128] (2) Synthesis of Compound 3 Under N2 protection, dissolve 10 g (1 eq) of compound 2 in 150 ml of DCE, slowly add 100 ml (1.5 eq) of 1M / L ZnEt2, add 26 g (1.5 eq) of CH2I2 after addition is complete, react at RT for 6 h, quench with NaHCO3(aq), extract with DCM, dry, spin-dry to give 11 g (directly used in the next step).

[0129] (3) Synthesis of compound 4 Dissolve 11g (1eq) of compound 3 in 110ml DCM, add 14.3g (2.5eq) of DIEA, add 6.1g (1.2eq) of MsCl slowly after the addition is complete, and react at rt. After the reaction is complete, quench with water, extract with DCM, dry, spin dry, and pass through a column to obtain 6g.

[0130] (4) Synthesis of Compound 5 Dissolve 6g (1eq) of compound 4 in 30ml of DMF, add 4g (1.2eq) of potassium phthalimide, and react overnight at 100°C. Add water, extract with EA, dry, spin-dry, and pass through a column to obtain 5g.

[0131] (5) Synthesis of intermediate 4 5g (1eq) of compound 5 is dissolved in 100ml of ethanol, 0.3g (2eq) of 80% hydrazine hydrate is added, and the mixture is reacted at 80°C for 15 minutes. Spin-dry, add water, extract with EA, dry, and spin-dry to obtain 1.2g. LC-MS [M+1]: 247.1.

[0132] Synthesis of intermediate 5 The structural formula of intermediate 5 is: [ka]

[0133] The experimental process is as follows. The synthetic route is as follows: [ka]

[0134] Synthesis steps: (1) Synthesis of intermediate 5 Under nitrogen gas condition, 50g compound 1, 11g sodium methyl mercaptide (1.3eq.) and 800mL 1,4-dioxane solvent were added to a 1000mL three-neck flask, heated to reflux, maintained the reaction temperature, and monitored by TLC that all the raw materials were converted, then stopped heating, cooled to room temperature, extracted and separated the liquid with EA and water, dried the organic phase with anhydrous sodium sulfate, and the solution was rotary evaporated, concentrated, and recrystallized with EA to obtain 39g of intermediate 5, the yield is 71%.

[0135] Synthesis of intermediate 6 and intermediate 7 The structural formulae of intermediates 6 and 7 are as follows: [ka]

[0136] The experimental process is as follows. The synthetic route is as follows: [ka]

[0137] Synthesis steps: (1) Synthesis of Compound 2 Add 27g (1eq) of compound 1 dissolved in 250ml of n-butanol to a 250mL three-neck flask, stir and dissolve, 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 in sequence, replace with nitrogen gas three times, and react overnight at 95℃. Monitor the completion of the reaction by TLC. Add water, extract twice with ethyl acetate, transfer the ethyl acetate phase to a 250mL single-neck bottle, add 5ml (1.5eq) of concentrated hydrochloric acid, and stir at room temperature for 3 hours. Monitor the completion of the reaction by TLC. Purify directly by column to obtain 13.4g of compound 2.

[0138] (2) Synthesis of intermediate 6 and intermediate 7 Add 50mg (1eq) of compound 1 to a 50mL single-mouth bottle, add 1ml of tetrahydrofuran, stir and dissolve, add 1.4ml (3eq) of DAST dropwise at -20℃, warm to room temperature and react for 5 hours. Monitor the completion of the reaction by TLC. Add water under ice bath, extract twice with ethyl acetate, and purify by column to obtain 10mg of intermediate 6 and 25mg of intermediate 7. Here, the NMR of intermediate 7 is as follows: 1 H NMR(400MHz,DMSO-d6)δ 10.68(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).

[0139] Example T-01 Compounds synthesized according to the present invention: [ka]

[0140] The experimental process is as follows. The synthetic route is as follows: [ka]

[0141] Synthesis steps: (1) Synthesis of Compound 2 In a 250ml three-neck 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 for 1 hour at 80°C under nitrogen gas protection, add 3.5ml (2.0eq) of methanol, and continue to react for 3 hours. Monitor the completion of the reaction by TLC. Add water, extract with EA, and purify by column to obtain 9.2g of white solid.

[0142] (2) Synthesis of Compound 3 In a 500ml three-neck flask, add 8g (1.0eq) of compound 1, 12.7g (2.0eq) of 2,4-dichloro-5-trifluoromethylpyrimidine, 6.8g (1.7eq) of aluminum trichloride, and 400ml of DCE, and react overnight at 80°C under nitrogen gas protection. Monitor the reaction completion by TLC. Add water to quench the reaction, separate the liquid, add EA to the aqueous phase to extract, combine the organic layer, spin dry, and add EA to slurry to obtain 5g of purple-red solid.

[0143] (3) Synthesis of compound 4 Add 4.4g (1.0eq) of compound 3, 4.1g (2.1eq) of (S)-1-Boc-3-aminopiperidine, and 50ml of DMF to a 100ml round bottom flask and react overnight at room temperature. Monitor the reaction completion by TLC. Add water, extract with EA, and purify by column to obtain 4.8g of white solid.

[0144] (4) Synthesis of compound T-01 Add 2.0g of compound 4, 10ml of EA, and 10ml of 4M / L hydrochloric acid in dioxane to a 25ml round bottom flask and react for 4 hours at room temperature. Monitor the completion of the reaction by TLC. Filter with suction to obtain a filter cake, wash with methyl t-butyl ether to obtain 1.1g of the hydrochloride salt of compound T-01. 1 H NMR(400MHz,DMSO-d6)δ 12.07(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).

[0145] Compound T-01 hydrochloride (50 mg) was made basic (pH=8.0) by adding aqueous NaHCO3, extracted with EA, dried and spin-dried to obtain compound T-01. HPLC purity: 98.9%. LC-MS [M+1]: 513.0, 515.0.

[0146] The following compounds are synthesized according to the method of Example T-01. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0147] Example T-07 Compounds synthesized according to the present invention: [ka]

[0148] The experimental process is as follows. The synthetic route is as follows: [ka]

[0149] Synthesis steps: (1) Synthesis of Compound 2 At -10°C, 0.28g (1.1eq) of thiocarbonyldiimidazole is dissolved in 5ml of dry THF, 0.3g (1eq) of compound 1 (dissolved in 5ml of THF) is added, and then reacted for 5 minutes while maintaining the temperature. Next, 10.17g (1.3eq) of INT-3 (dissolved in 1.5ml of THF) is added dropwise to the reaction system, and then the reaction is allowed to proceed by slowly raising the temperature to room temperature. After the reaction is completed, water is added to quench the reaction, and the reaction is extracted with EA, dried, spin-dried, and passed through a column to obtain 0.36g of compound 2.

[0150] (2) Synthesis of Compound 3 Dissolve 0.36g (1eq) of compound 2 in 15ml of THF, add 0.25g (6eq) of sodium hydroxide (NaOH), then add 0.18g (0.9eq) of p-toluenesulfonyl chloride, and react at room temperature for 3 hours. After the reaction is completed, quench by adding water, extract with EA, dry the EA phase, spin-dry, and pass through a column to obtain 0.15g of compound 3.

[0151] (3) Synthesis of compound 4 Dissolve 0.32g (3eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 10ml of 1,2-dichloroethane (DCE), add 0.1g (1.5eq) of aluminum trichloride (AlCl3), and react for 30 minutes under N2 protection at 80°C. Then add compound 3 and react overnight at 80°C. After the reaction is complete, quench by adding water, separate the DCE phase, extract the water phase with EA, combine the DCE phase and EA phase, dry, spin-dry, and slurried with EA to obtain 0.1g of compound 4.

[0152] (4) Synthesis of Compound 5 0.1g (1eq) of compound 4 is dissolved in 1mL of N,N-dimethylformamide (DMF), then 0.1g (2eq) of (S)-1-Boc-3-aminopiperidine is added, and the mixture is reacted overnight at room temperature under N2 protection. Quench with water, extract with EA, dry, spin dry, and pass through a column to obtain 0.1g of compound 5. LC-MS [M+1]: 652.1, 654.1.

[0153] (5) Synthesis of T-07 Take 0.1g (1eq) of compound 5 and add it to 1ml of hydrochloric acid dioxane (4.0Mol / L) to complete the reaction at room temperature. Add aqueous NaHCO3 to make it basic, extract with EA, dry, spin-dry, and separate by preparative plate to obtain 0.02g of compound T-07. HPLC: 89.8%. 1 H NMR(400MHz,DMSO-d6)δ 11.59(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).

[0154] Examples T-08 and T-11 Compounds synthesized according to the present invention: [ka]

[0155] The experimental process is as follows. The synthetic route is as follows: [ka]

[0156] Synthesis steps: (1) Synthesis of Compound 2 1.0g (1.0eq) of cyclopropane carboxylic acid is taken in a 50mL round bottom flask, 10mL of N,N-dimethylformamide (DMF) is added, and the mixture is stirred at room temperature. Then, 2.7g (1.5eq) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 1.2g (2.0eq) of diisopropylethylamine (DIPEA) are added, and the mixture is reacted at room temperature for 5 minutes, after which compound 1 (1.0eq) is added and the mixture is allowed to react at room temperature. After the reaction is completed, 100mL of water is slowly added, and the solid is precipitated, and the mixture is suction filtered to obtain 1.1g of compound 2, with a yield of 85%.

[0157] (2) Synthesis of Compound 3 In a 50mL round bottom flask, add 1.4g (3eq) of 2,4-dichloro-5-trifluoromethylpyrimidine, 30mL of dichloroethane (DCE) and 0.5g (1.7eq) of AlCl3 and heat to 80℃. After reacting for 30 minutes under N2 protection, add 0.6g (1eq) of compound 2 and react under N2 protection at 80℃. After the reaction is completed, add water, extract with EA, evaporate the organic layer to dryness, add EA to make a slurry and obtain 200mg of compound 3.

[0158] (3) Synthesis of compound 4 Dissolve 0.2g (1eq) of compound 3 in 6mL of DMF, add 0.18g of (S)-1-Boc-3-aminopiperidine (2eq), and react overnight at room temperature with stirring. After completion of the reaction, add water, extract with EA, dry, and spin-dry to obtain 0.24g of compound 4.

[0159] (4) Synthesis of Compound 5 Dissolve 110 mg (1 eq) of compound 4 in 4 mL of methanol (MeOH), add 30 mg of Pd / C (2 eq), 2 drops of Et3N, and react overnight under H2 protection at rt with stirring. After completion of the reaction, filter the solution and spin-dry the filtrate to obtain 92 mg of compound 5.

[0160] (5) Synthesis of compound T-08: 100mg (1eq) of compound 4 is taken up in 3mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After the reaction is complete, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and refine to obtain 47mg. HPLC: 96.4%. 1 H NMR(400MHz,DMSO-d6)δ 11.94(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,1H),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).

[0161] (6) Synthesis of T-11: 80mg (1eq) of compound 5 is taken up in 3mL of 2M / L hydrochloric acid in dioxane and reacted at room temperature. After the reaction is complete, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and refine to obtain 35mg of compound T-11. HPLC: 96.7%. 1H NMR(400MHz,DMSO-d6)δ 11.84(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).

[0162] The following compounds are synthesized with reference to the methods of Examples T-08 and T-11. [Table 2]

[0163] Example T-12 Compounds synthesized according to the present invention: [ka]

[0164] The experimental process is as follows. The synthetic route is as follows: [ka]

[0165] Synthesis steps: (1) Synthesis of Compound 2 At 0°C, 2g (1eq) of compound 1 is dissolved in 40mL of THF, 2.4g (2.5eq) of triethylamine (TEA) is added, and then chloroethyl chloroformate is added dropwise to the reaction system. After the reaction of compound 1 is completed by TLC, 1.2g (5eq) of sodium hydride (NaH) is added in batches at 0°C, and then the reaction is carried out at room temperature. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with EA, dried, spin-dried, and passed through a column to obtain 1.2g of compound 2. LC-MS [M+1]: 280.9, 282.9.

[0166] (2) Synthesis of Compound 3 Dissolve 2.78g (3eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 60mL of 1,2-dichloroethane (DCE), add 0.85g (1.5eq) of aluminum trichloride (AlCl3), and react for 30 minutes at 80°C under N2 protection. Then add compound 2 and react overnight at 80°C. After the reaction is complete, add water, separate the DCE phase, extract the aqueous phase with EA, combine the DCE phase and EA phase, dry, spin-dry, and slurried with EA to obtain 1.3g of compound 3. LC-MS [M+1]: 460.9, 462.9.

[0167] (3) Synthesis of compound 4 0.3 g (1 eq) of compound 3 is dissolved in 3 mL of N,N-dimethylformamide (DMF), then 0.24 g (2 eq) of (S)-1-Boc-3-aminopiperidine is added, and the mixture is reacted overnight at room temperature under N2 protection. Quench with water, extract with EA, dry, spin dry, and pass through a column to obtain 0.3 g of compound 4. LC-MS [M+1]: 625.1, 627.1.

[0168] (4) Synthesis of Compound T-12 Hydrochloride Take 0.1g (1eq) of compound 4, add it to 2mL of ethyl acetate (EA) and 1mL of hydrochloric acid in dioxane (4Mol / L), and complete the reaction at room temperature. Filter to obtain 0.06g of hydrochloride salt of compound T-12. HPLC purity: 96.4%.

[0169] (5) Synthesis of compound T-12 Take 0.1g (1eq) of compound 4 and add it to 2mL of hydrochloric acid dioxane (4Mol / L) to complete the reaction at room temperature. Add aqueous NaHCO3 to make it basic (pH=8.0), extract with EA, dry, spin-dry, and separate by preparative plate to obtain 0.03g of compound T-12. HPLC purity: 93.4%. 1H NMR(400MHz,DMSO-d6)δ 12.28(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).

[0170] (6) Synthesis of compound T-49 Dissolve 0.15 g (1 eq) of compound 4 in 10 mL of methanol (CHOH), add 0.01 g of palladium on carbon (Pd / C) and 3 drops of TEA, react overnight under H2, and complete the reaction at room temperature. Filter, dry, and spin-dry to obtain 0.1 g of compound T-49.

[0171] Following the procedure of Example T-12, the following compounds are synthesized. [Table 3-1] [Table 3-2]

[0172] Example T-14 Compounds synthesized according to the present invention: [ka]

[0173] The experimental process is as follows. The synthetic route is as follows: [ka]

[0174] Synthesis steps: (1) Synthesis of Compound 2 230mg (1eq) of compound 1 is dissolved in 6mL of dry DMF, 16mg (0.2eq) of palladium acetate, 84mg (0.4eq) of Xantphos and 226mg (8eq) of dimethylphosphine oxide are added, and the mixture is reacted under N2 protection at 140°C. After completion of the reaction, water is added, extracted with EA, dried and spin-dried to obtain 40mg of crude product of compound 5.

[0175] (2) Synthesis of Compound 3 Dissolve 50mg (1eq) of compound 4 in 3ml of methyl chloroformate, add 100mg of Na2CO3, and react at room temperature. After completion of the reaction, add water, extract with EA, dry, and spin-dry to obtain 40mg of crude product of compound 5.

[0176] (3) Synthesis of compound T-14 40mg (1eq) of compound 3 is taken up in 2mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After the reaction is complete, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and scrape to obtain 10mg of compound TY-2652. HPLC: 88%. 1 H NMR(400MHz,DMSO-d6)δ 11.75(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).

[0177] Following the method of Example T-14, the following compounds are synthesized. [Table 4]

[0178] Example T-15 Compounds synthesized according to the present invention: [ka]

[0179] The experimental process is as follows. The synthetic route is as follows: [ka]

[0180] Synthesis steps: (1) Synthesis of Compound 2 250mg (1eq) of compound 1 is dissolved in 6ml of dry DMF, 19mg (0.2eq) of palladium acetate, 97mg (0.4eq) of Xantphos and 262mg (8eq) of dimethylphosphine oxide are added, and the mixture is reacted under N2 protection at 140°C for 1.5 hours. Water is added, and the mixture is extracted with EA, dried and spin-dried to obtain 150mg of crude product of compound 6.

[0181] (2) Synthesis of compound T-15: 150mg (1eq) of compound 2 is taken up in 4mL of 4M / L HCl dioxane and reacted at rt. After the reaction is complete, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and refine to obtain 10mg of compound T-15. HPLC: 96.7%. 1 H NMR(400MHz,DMSO-d6)δ 11.73(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),7.2 7-7.03(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).

[0182] Example T-16 Compounds synthesized according to the present invention: [ka]

[0183] The experimental process is as follows. The synthetic route is as follows: [ka]

[0184] Synthesis steps: (1) Synthesis of Compound 2 220 mg (1 eq) of compound 1 is dissolved in 6 mL of MeOH, 50 mg of Pd / C, 3 drops of Et3N are added, and the mixture is reacted overnight under H2 protection at room temperature with stirring. After the reaction is complete, the solution is filtered and the filtrate is spin-dried to obtain 200 mg of compound 5.

[0185] (2) Synthesis of compound T-16 200mg (1eq) of compound 2 is taken up in 3mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After the reaction is complete, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and refine to obtain 10mg of compound T-16. HPLC: 92.6%. 1 H NMR(400MHz,DMSO-d6)δ 11.78(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),3.90 (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).

[0186] Example T-17 Compounds synthesized according to the present invention: [ka]

[0187] The experimental process is as follows. The synthetic route is as follows: [ka]

[0188] Synthesis steps: (1) Synthesis of Compound 2 0.5g (1.0eq) of compound 1 is dissolved in 10mL of dioxane and 1mL of water, and 0.34g (3eq) of K2CO3, 0.35g (5eq) of cyclopropaneboronic acid and 0.12g (0.2eq) of Pd(dppf)Cl2 are added and reacted under N2 protection at 100°C. After the reaction is completed, water is added, extracted with EA, dried, spin-dried and passed through a column to obtain 0.40g of compound 3.

[0189] (2) Synthesis of compound T-17 Take 200mg (1eq) of compound 3, add 4mL of 4M / L hydrochloric acid in dioxane and 3mL of EA at room temperature, and react at room temperature. After the reaction is completed, suction filter and wash the filter cake with methyl t-butyl ether to obtain 175mg of hydrochloride of compound T-17. HPLC: 93.9%. 1 H NMR (400MHz, DMSO-d6) δ 11.47(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).

[0190] Following the method of Example T-17, the following compounds are synthesized. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0191] Example T-20 Compounds synthesized according to the present invention: [ka]

[0192] The experimental process is as follows. The synthetic route is as follows: [ka]

[0193] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 0.25g (1eq) of compound 1 in 3mL of (N,N-dimethylformamide) DMF, add 0.14g (1.1eq) of (1S,3S)-3-aminocyclohexylcarbamate (CAS: 1788036-28-1), and react overnight at room temperature. Add water, extract with EA, dry, spin-dry, and pass through a column to obtain 0.2g of compound 2. LC-MS [M+1]: 627.1, 629.1.

[0194] (2) Synthesis of T-20 Hydrochloride and T-20 Dissolve 0.2g (1eq) of compound 2 in 5mL of ethyl acetate (EA), add 2mL of hydrochloric acid dioxane (4.0Mol / L), and complete the reaction at room temperature. Filtrate to obtain 0.13g of compound T-20 hydrochloride. HPLC: 98.7%. 1H NMR(400MHz,Methanol-d4)δ 8.63(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).

[0195] Compound T-20 hydrochloride (50 mg) is added to aqueous NaHCO3 to make it basic (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.

[0196] Following the method of Example T-20, the following compounds are synthesized. [Table 6-1] [Table 6-2] [Table 6-3]

[0197] Example T-27 Compounds synthesized according to the present invention: [ka]

[0198] The experimental process is as follows. The synthetic route is as follows: [ka]

[0199] Synthesis steps: (1) Synthesis of Compound 2 0.5g (1.0eq) of compound 1 is dissolved in 6mL of DMF, 0.22g (3eq) of CuCN is added, and the mixture is reacted at 100°C overnight. After the reaction is completed, ammonia water and water are added, and the mixture is extracted with EA, dried, and spin-dried to obtain 0.13g of crude product of compound 2. LC-MS [M+1]: 560.2.

[0200] (2) Synthesis of compound T-27 130mg (1eq) of compound 2 is taken in 4mL of 4M / L hydrochloric acid dioxane and 4mL of EA and reacted at room temperature. After the reaction is complete, NaHCO3 aqueous solution is added to adjust the solution to basic, extracted with EA, dried, spun dry, and separated by preparative plate to obtain 40mg of compound T-27. HPLC: 95.1%. LC-MS [M+1]: 460.1. 1 H NMR(400MHz,DMSO-d6)δ 9.81(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).

[0201] Example T-28 Compounds synthesized according to the present invention: [ka]

[0202] The experimental process is as follows. The synthetic route is as follows: [ka]

[0203] Synthesis steps: (1) Synthesis of Compound 2 In a 100mL three-neck flask, add 200mg of compound 1, INT-1 (2.0eq), and 15mL of DMF as solvent, and react under nitrogen gas conditions at room temperature. After the reaction is completed, remove the DMF solvent by rotary evaporation, and separate and purify by silica gel column chromatography to obtain 220mg of compound 2, the yield is 77.5%, and the LC-MS [M+1] is 639.1, 641.1.

[0204] (2) Synthesis of T-28 Hydrochloride and T-28 In a 50mL three-neck flask, add 220mg of compound 2, dissolve in 10mL of ethyl acetate, add 3mL of 1M hydrochloric acid dioxane solution, react at room temperature under nitrogen gas with stirring for 1 hour, after the reaction is completed, suction filter, wash the solid with an appropriate amount of ethyl acetate and ether successively to obtain 100mg of yellow solid T-28 hydrochloride, the yield is 50.5%, LC-MS [M+1]: 539.1, 541.1, HPLC purity is 99.0%.

[0205] Compound T-28 hydrochloride (50 mg) is added to aqueous NaHCO3 to make it basic (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.

[0206] Following the procedure of Example T-28, the following compounds are synthesized. [Table 7]

[0207] Examples T-32 and T-33 Compounds synthesized according to the present invention: [ka]

[0208] The experimental process is as follows. The synthetic route is as follows: [ka]

[0209] Synthesis steps: (1) Synthesis of Compound 2 0.2g (300mg, 1eq) of compound 1 is dissolved in 5ml of DMF, then INT-4 (146mg, 1.1eq) and DIPEA (118.3mg, 1.5eq) are added, and the mixture is reacted at rt overnight under N2 protection. After the reaction is completed, water is added to the system, and the mixture is extracted with EA, dried, spin-dried, and passed through a column to obtain compound 2 (470mg).

[0210] (2) Synthesis of Compound 3 Dissolve compound 2 (200 mg, 1.0 eq) in DCM (5 ml) and cool to -45°C under nitrogen gas protection, then add boron tribromide (151.4 mg, 1.5 eq) in DCM (1.0 ml) dropwise, and after the addition is complete, warm to -30°C and react for 10 minutes, then naturally warm to room temperature and react for 2 hours. After the reaction is complete, add aqueous sodium bicarbonate to quench, extract with DCM, separate the liquid, and dry to obtain compound 3 (130 mg).

[0211] (3) Synthesis of compound 4 Compound 3 (130 mg, 1.0 eq) is added to DCM (5 ml) to dissolve, then phenyl chloroformate (42 mg, 1.0 eq) is added to dissolve, then TEA (27 mg, 1.0 eq) is added and reacted at room temperature for 2 hours. After the reaction is completed, water is added to the system, then DCM is added to extract, the liquid is separated, dried, filtered and scraped to obtain compound 4 (112 mg).

[0212] (4) Synthesis of Compound 5 and Compound 6: Compound 4 (112 mg, 1.0 eq) is dissolved in THF (5 ml), then dimethylamine aqueous solution (6 ml) is added, and the mixture is left overnight. After the reaction is completed, water is added to the system, then EA is added for extraction, the liquid is separated, dried, and scraped to give compound 5 (23 mg) and compound 6 (31 mg).

[0213] (5) Synthesis of Compounds T-32 and T-33 Compound 5 (23 mg) and compound 6 (31 mg) are dissolved in methanol respectively, then Pd / C is added respectively, H2 is passed through overnight, and after the reaction is completed, the mixture is filtered and spin-dried to obtain the final product compound T-32 (12 mg), HPLC purity is 95.6%, LC-MS [M+1]: 477.2. Compound T-33 (8 mg) is obtained, HPLC purity is 94.2%. LC-MS [M+1]: 477.2.

[0214] Example T-34 Compounds synthesized according to the present invention: [ka]

[0215] The experimental process is as follows. The synthetic route is as follows: [ka]

[0216] Synthesis steps: (1) Synthesis of Compound 2 Under anhydrous and oxygen-free conditions, 300 mg of compound 1, methyl fluorosulfonyldifluoroacetate (5.0 eq), and CuI (5.0 eq) were added to a 10 mL reaction tube, and the mixture was heated to 100°C and reacted while maintaining the temperature. After the reaction was completed, the mixture was cooled to room temperature, and several mL of 1M dilute hydrochloric acid was added, and the mixture was extracted with water and EA. The liquid was separated, and the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 110 mg of compound 2, with a yield of 37.3%, and LC-MS [M+1]: 603.2.

[0217] (2) Synthesis of compound T-34 In a 50mL three-neck flask, add 110mg of compound 2, add 6mL of dichloromethane, add 2mL of trifluoroacetic acid after dissolving, and react at room temperature with stirring for 30 minutes. After the reaction is completed, remove excess solvent by concentration, then adjust pH value to basic, extract with EA, spin-dry, and separate and purify by medium pressure preparative reverse column to obtain 60mg of compound T-34, yield is 65.2%, HPLC purity is 95.0%, LC-MS [M+1]: 503.1.

[0218] Following the procedure of Example T-34, the following compounds are synthesized. [Table 8-1] [Table 8-2] [Table 8-3]

[0219] Example T-37 Compounds synthesized according to the present invention: [ka]

[0220] The experimental process is as follows. The synthetic route is as follows: [ka]

[0221] Synthesis steps: (1) Synthesis of Compound 2 At 0°C, compound 1 (10.0g, 1.0eq) is dissolved in methanol (100ml), then sodium methanol (6.9g, 2.0eq) is added, and after the dropwise addition is completed, the temperature is raised to 65°C and the reaction is carried out for 3 hours. The reaction is monitored by TLC until completion, and after cooling, the solvent is spin-dried, and then a small amount of methanol is added to make a slurry, filtered, and the filter cake is collected to obtain compound 2 (10.06g).

[0222] (2) Synthesis of Compound 3 Compound 2 (3.0 g, 1.0 eq) was dissolved in t-butanol (15 ml), then diphenylphosphoryl azide (DPPA) (5.86 g, 1.4 eq) and triethylamine (2.77 g, 1.8 eq) were added, and the mixture was reacted for 2 hours at 80° C. under nitrogen gas protection. After monitoring the completion of the reaction by TLC, water was added to the system after cooling, and then EA was added for extraction. The EA phase was collected, dried by adding anhydrous sodium sulfate, filtered, spin-dried, and passed through a column to obtain compound 3 (2.2 g).

[0223] (3) Synthesis of compound 4 Compound 3 (2.2 g) was added with HCl / dioxane (10 ml) and stirred at room temperature for 1.5 hours. The reaction of the raw materials was monitored by TLC to determine whether the reaction was complete. The solvent was then spin-dried, and petroleum ether was added to form a slurry, which was then filtered to obtain compound 4 (1.2 g).

[0224] (4) Synthesis of Compound 5 Compound 4 (1.2 g, 1.0 eq) is added with methyl chloroformate (10 ml), cooled to 0° C., sodium carbonate (3.0 g, 4.0 eq) is added in batches, and after the dropwise addition is completed, the mixture is allowed to warm to room temperature and react overnight. The reaction is monitored by TLC to confirm completion, and water is added to the system, followed by extraction with EA. The EA phase is collected, dried with anhydrous sodium sulfate, filtered, spin-dried, and passed through a column to obtain compound 5 (1.3 g).

[0225] (5) Synthesis of compound 6 Compound 5 (1.0g, 1.0eq) is dissolved in dry THF (10ml), degassed and replaced with nitrogen, then cooled to -78℃, 1Mol / L vinylmagnesium bromide (26.5ml, 6.0eq) is added dropwise, and after the addition is complete, the temperature is naturally raised to room temperature and stirred overnight. The reaction completion of the raw materials is monitored by TLC, the temperature is lowered, an aqueous ammonium chloride solution (20ml) is added to the system, and the system is stirred for 30 minutes, and then EA is added for extraction, the liquid is separated, and the EA phase is collected and added to anhydrous sodium sulfate to dry, filtered, spin-dried, and passed through a column to obtain compound 6 (0.3g).

[0226] (6) Synthesis of compound 7 Dissolve 0.58g (3.0eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 6mL of dichloroethane (DCE), add 0.18g (1.5eq) of aluminum trichloride (AlCl3), and react for 30 minutes under N2 protection at 80°C. Then add compound 6 (0.2g, 1.0eq) and react overnight at 80°C. After the reaction is complete, add water, separate the DCE phase, extract the aqueous phase with EA, combine the DCE phase and EA phase, dry, spin-dry, slurried with EA, and filter to obtain compound 7 (60mg).

[0227] (7) Synthesis of compound 8 Dissolve 60mg (1.0eq) of compound 7 in 1mL DMF, then add (S)-1-Boc-3-aminopiperidine (60mg, 2eq) and react overnight at room temperature under N2 protection. After the reaction is complete, add water to the system, extract with EA, dry, spin dry, and pass through a column to obtain compound 8 (70mg).

[0228] (8) Synthesis of compound T-37 hydrochloride: Compound 8 (70 mg) is added with HCl / dioxane (5 ml) and stirred at room temperature for 1.5 hours. The reaction of the raw materials is monitored by TLC to determine whether the reaction is complete. The solvent is spin-dried, and then petroleum ether is added to form a slurry, followed by filtration to obtain T-37 (43 mg, purity 97.2%). 1H NMR(400MHz,DMSO-d6)δ 12.12-11.93(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),3.87 (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).

[0229] Following the procedure of Example T-37, the following compounds are synthesized. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0230] Example T-40 Compounds synthesized according to the present invention: [ka]

[0231] The experimental process is as follows. The synthetic route is as follows: [ka]

[0232] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 350mg (1eq) of compound 1 in 4mL of DMF, add 200mg (2.5eq) of K2CO3 and 410mg (5eq) of iodomethane (CHI) and react at room temperature. After completion of the reaction, add 40mL of water, extract with EA, dry and spin-dry to obtain 250mg of crude product of compound 2.

[0233] (2) Synthesis of compound T-40 250mg (1eq) of compound 5 (crude product) from the above step is taken up in 4mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After completion of the reaction, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry and separate by preparative chromatography to obtain 40mg of compound T-40. HPLC: 96.2%. LC-MS [M+1]: 527.0, 529.0. 1 H NMR(400MHz,DMSO-d6)δ 9.10(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).

[0234] Example T-41 Compounds synthesized according to the present invention: [ka]

[0235] The experimental process is as follows. The synthetic route is as follows: [ka]

[0236] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 500mg (1eq) of compound 1 in 6mL of THF, add 267mg (6eq) of NaH under salt-ice bath, stir for 5 minutes, then add 1.39g (5eq) of CH3I and react at room temperature. After the reaction is complete, add 40mL of water, extract with EA, dry, spin-dry to obtain 500mg of crude product of compound 2. LC-MS [M+1]: 477.0, 479.0.

[0237] (2) Synthesis of Compound 3 Dissolve 0.5g (1.0eq) of compound 2 in 6mL of DMF, add 0.46g (2.2eq) of (S)-1-Boc-3-aminopiperidine, and react overnight at room temperature with stirring. After completion of the reaction, add water, extract with EA, dry, spin dry, and pass through a column to obtain 0.21g of compound 3. LC-MS [M+1]: 641.1, 643.1.

[0238] (3) Synthesis of compound T-41 150mg (1eq) of compound 5 is taken up in 3mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After completion of the reaction, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry, separate and separate to obtain 25mg of compound T-41. HPLC: 94.1%. LC-MS [M+1]: 541.1, 543.1. 1 H NMR(400MHz,DMSO-d6)δ 8.65-8.52(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).

[0239] Example T-42 Compounds synthesized according to the present invention: [ka]

[0240] The experimental process is as follows. The synthetic route is as follows: [ka]

[0241] Synthesis steps: (1) Synthesis of Compound 2 Under nitrogen gas conditions, 250mg of compound 1 and 5mL of anhydrous ethanol were added to a 10mL reaction tube in sequence. After dissolving, DPPA (10.0eq) and Et3N (5.0eq) were added, respectively, and the mixture was heated to reflux and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched by adding water, extracted with EA and water, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain 116mg of compound 2, the yield was 43.2%, and the HPLC purity was 95.1%.

[0242] (2) Synthesis of Compound T-42 Hydrochloride and T-42 In a 50mL three-neck flask, add 156mg of compound 2, dissolve in 5mL of ethyl acetate, add 2mL of 1M hydrochloric acid dioxane solution, react at room temperature under nitrogen gas with stirring for 1 hour, after the reaction is completed, suction filter, wash the solid with an appropriate amount of ethyl acetate and ether successively to obtain 116mg of yellow solid T-42 hydrochloride, the yield is 82.8%, LC-MS [M+1]: 527.1, 529.1, HPLC purity is 95.3%.

[0243] Compound T-42 hydrochloride (40 mg) was added to aqueous NaHCO3 to make it basic (pH=8.0), extracted with EA, dried and spin-dried to give compound T-42. HPLC purity: 95.3%. LC-MS [M+1]: 527.1, 529.1.

[0244] Following the procedure of Example T-42, the following compounds are synthesized. [Table 10]

[0245] Example T-52 Compounds synthesized according to the present invention: [ka]

[0246] The experimental process is as follows. The synthetic route is as follows: [ka]

[0247] Synthesis steps: (1) Synthesis of Compound 2 Add 274 mg (1.0 eq) of compound 1 to a mixed solvent of dioxane (4 ml) and water (0.4 ml), then add 150 mg (5.0 eq) of methylboronic acid, 207 mg of Pd(dppf)Cl2 (0.2 eq) and 207 mg (3.0 eq) of potassium carbonate, and react under N2 protection at 100°C until the reaction is complete. Add water, extract with EA, dry, spin dry, and pass through a column to obtain compound 2 (121 mg).

[0248] (2) Synthesis of compound T-52: 100mg of compound 3, 1ml of TFA, 4ml of DCM were added to the reaction system, and the reaction was completed after 5 hours at room temperature by TLC. The reaction was purified by preparative liquid phase to obtain a total of 58mg of T-52, with a purity of 98.7%. LC-MS [M+1]: 449.1, 1H NMR(400MHz,DMSO-d6)δ 11.76(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=2.2H z,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).

[0249] Example T-57 Compounds synthesized according to the present invention: [ka]

[0250] The experimental process is as follows. The synthetic route is as follows: [ka]

[0251] Synthesis steps: (1) Synthesis of Compound 2 In a 100mL three-neck flask, add 379mg of compound 1, INT-2 (2.0eq.), and 15mL of DMF as a solvent, and react at room temperature under nitrogen gas conditions. After the reaction is completed, remove the DMF solvent by rotary evaporation, and separate and purify by silica gel column chromatography to obtain 386mg of compound 2, the yield is 74.7%, and the LC-MS [M+1] is 613.1, 615.1.

[0252] (2) Synthesis of T-57 Hydrochloride and T-57 In a 50mL three-neck flask, add 253mg of compound 2, dissolve in 10mL of ethyl acetate, add 3mL of 4M hydrochloric acid dioxane solution, react at room temperature under nitrogen gas with stirring for 1 hour, after the reaction is completed, suction filter, wash the solid with an appropriate amount of ethyl acetate and ether successively to obtain 190mg of yellow solid T-57 hydrochloride, the yield is 83.7%, LC-MS [M+1]: 513.1, 515.1, HPLC purity is 95.7%.

[0253] Compound T-57 hydrochloride (60 mg) is added to aqueous NaHCO3 to make it basic (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.

[0254] Following the procedure of Example T-57, the following compounds are synthesized. [Table 11-1] [Table 11-2]

[0255] Example T-60 Compounds synthesized according to the present invention: [ka]

[0256] The experimental process is as follows. The synthetic route is as follows: [ka]

[0257] Synthesis steps: (1) Synthesis of Compound 2 Add 0.2g (1eq) of compound 1 to a mixture of 4ml of dioxane and 0.4ml of water, then add 0.2g (5eq) of phenylboronic acid, 0.05g (0.2eq) of Pd(dppf)Cl2 and 0.14g (3eq) of potassium carbonate, and react under N2 protection at 100°C until the reaction is complete. Quench with water, extract with EA, dry, spin dry, and pass through a column to obtain 0.2g of compound 2.

[0258] (2) Synthesis of T-60 Dissolve 0.2g (1eq) of compound 2 in 5mL of EA, add 2ml of hydrochloric acid dioxane, and complete the reaction at room temperature. Filtrate to obtain 0.17g of compound T-60 hydrochloride. HPLC: 95.4%. 1 H NMR(400MHz,Methanol-d4)δ 8.60(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).

[0259] Example T-62 Compounds synthesized according to the present invention: [ka]

[0260] The experimental process is as follows. The synthetic route is as follows: [ka]

[0261] Synthesis steps: (1) Synthesis of Compound 2 Under anhydrous and oxygen-free ice-water bath conditions, add 5mL of 2-methoxyethyl chloroformate and sodium carbonate (2.0eq) in a 25mL three-neck flask in sequence, and stir and react for 30 minutes while maintaining the temperature. Add 500mg of compound 1, slowly warm to room temperature and continue to react. After the reaction is completed, add water to quench, extract with water and EA, separate the liquid, dry the organic layer with anhydrous sodium sulfate, and concentrate. After separation and purification by silica gel column chromatography, obtain 597mg of compound 2, with a yield of 80.5%.

[0262] (2) Synthesis of Compound 3 Under nitrogen gas condition, add 2,4-dichloro-5-trifluoromethylpyrimidine (1.5eq) and aluminum trichloride (2.0eq) to a three-neck flask containing 150mL of dichloroethane, heat to reflux, and react for 30 minutes to obtain 2.34g of compound 2. The temperature is maintained while reacting overnight. After the reaction is completed, add ice water to quench, extract with DCM and water, separate the liquid, remove most of the DCM by concentration, recrystallize with EA, and suction filter to obtain 1.5g of solid compound 3, the yield is 40.8%.

[0263] (3) Synthesis of compound 4 In a 100mL three-neck flask, add 500mg of compound 3, (S)-1-Boc-3-aminopiperidine (2.0eq), and 15mL of DMF as solvent, and react at room temperature under nitrogen gas conditions. After the reaction is completed, remove the DMF solvent by rotary evaporation, and separate and purify by silica gel column chromatography to obtain 430mg of compound 4, the yield is 64.6%. LC-MS [M+1]: 657.1, 659.1.

[0264] (4) Synthesis of Compound T-62 Hydrochloride and T-62 In a 50mL three-neck flask, dissolve 420mg of compound 4 in 10mL of ethyl acetate, add 3mL of 1M hydrochloric acid dioxane solution, react at room temperature under nitrogen gas with stirring for 1 hour, after the reaction is completed, suction filter, wash the solid with appropriate amount of ethyl acetate and ether in succession to obtain 320mg of yellow solid compound T-62 hydrochloride, the yield is 84.4%, LC-MS [M+1]: 557.1, 559.1, HPLC purity is 97.9%.

[0265] Compound T-62 hydrochloride (100 mg) is added to aqueous NaHCO3 to make it basic (pH=8.0), extracted with EA, dried and spin-dried to give compound T-62. HPLC purity: 97.7%. LC-MS [M+1]: 557.1, 559.1.

[0266] Examples T-63, T-65 and T-66 Compounds synthesized according to the present invention: [ka]

[0267] The experimental process is as follows. The synthetic route is as follows: [ka]

[0268] Synthesis steps: (1) Synthesis of Compound 2 Compound 1 (7.4 g, 1.0 eq) is dissolved in N,N-dimethylformamide (80 mL), then sodium isopropylthiolate (8.0 g, 2.5 eq) is added, then the temperature is raised to 50° C. and the reaction is allowed to proceed for 2 hours. The reaction is monitored for completion by TLC, cooled to room temperature, then 80 mL of ice water is added, the pH is adjusted to 5 with 2 mol / L hydrochloric acid, then extracted with ethyl acetate, the organic phases are combined, dried and spin-dried to obtain 11.5 g of crude compound 2.

[0269] (2) Synthesis of Compound 3 Under nitrogen gas condition, compound 2 (9.64 g, 1.0 eq) is dissolved in t-butanol (100 mL), then triethylamine (10 mL, 1.8 eq) and diphenylphosphoryl azide (13.2 g, 1.2 eq) are added. Then it is slowly heated to 80°C (the rate of temperature increase is controlled to prevent a large amount of gas from being released and scattering) and reacted for 12 hours. The reaction is monitored for completion by TLC. The reaction solution is cooled to room temperature, then 100 mL of water is added, extracted with ethyl acetate, the organic phase is dried, spin-dried, and passed through a column to obtain 8.5 g of compound 3, the yield is 68%.

[0270] (3) Synthesis of compound 4 Compound 3 (8.5 g, 1.0 eq) was added to 120 mL of 4 mol / L hydrochloric acid in dioxane, and reacted overnight at room temperature. The reaction was monitored by TLC for completion, filtered, and the filter cake was collected and dried to obtain 6.7 g of compound 4, with a yield of 100%.

[0271] (4) Synthesis of Compound 5 Compound 4 (6.7 g, 1.0 eq) is added to methyl chloroformate (90 mL), then sodium carbonate (17.4 g, 4.0 eq) is added in batches at 0° C., and after the addition is complete, the mixture is allowed to warm to room temperature and react overnight. The reaction is monitored for completion by TLC, filtered, the filter cake is washed with 120 mL of ethyl acetate, the organic phase is collected and directly spin-dried to obtain 8 g of crude compound 5. The yield is 94%.

[0272] (5) Synthesis of compound 6 Under nitrogen gas, compound 5 (4.0g, 1.0eq) is added to 80mL of tetrahydrofuran, then cooled to -78℃, vinylmagnesium bromide (113mL, 6.0eq) is slowly added dropwise, after the addition is completed, the reaction is carried out at this temperature for 1 hour, then the temperature is slowly raised to room temperature and the reaction is carried out for 1 hour, and the reaction is monitored by TLC for completion. The system is cooled to -10℃, then the reaction is quenched by adding aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase is combined, spin-dried, and passed through a column to obtain 1.2g of compound 6, the yield is 30%.

[0273] (6) Synthesis of compound 7 Under nitrogen gas condition, 2,4-dichloro-5-trifluoromethylpyrimidine (1.72g, 3.0eq) and aluminum trichloride (0.706g, 2.0eq) were added to a three-neck flask containing 50mL of dichloroethane, and the mixture was heated to reflux and reacted for 30 minutes. Then, 0.7g of compound 6 was added, and the temperature was maintained while reacting overnight. After the reaction was completed, the mixture was quenched by adding ice water, extracted with DCM and water, and the liquid was separated, concentrated, and passed through a column to obtain 0.4g of compound 7, with a yield of 34%.

[0274] (7) Synthesis of compound 8 In a 50mL three-neck flask, add 175mg of compound 7, (S)-1-Boc-3-aminopiperidine (158mg, 2.0eq), 2mL of DMF and 2mL of acetonitrile as solvent, react at room temperature under nitrogen gas condition for 14 hours, after the reaction is completed, remove the acetonitrile solvent by rotary evaporation, then pour the remaining reaction liquid into 10mL of water, collect the filter cake, then pass the filter cake through a column to obtain 72mg of compound 8, the yield is 30%.

[0275] (8) Synthesis of Compound 9 Compound 8 (100 mg, 1.0 eq) was added to dichloromethane (2 mL), followed by m-chloroperoxybenzoic acid (45.2 mg, 0.99 eq) at -10°C, reacted at this temperature for 2 hours, then warmed to room temperature and reacted overnight. Completion of the reaction was monitored by TLC. Filtration was performed, the filtrate was washed with 10% sodium hydroxide solution, and the organic phase was then spun dry and passed through a column to obtain 80 mg of compound 9, with a yield of 77%.

[0276] (9) Synthesis of compound 10 Compound 8 (100 mg, 1.0 eq) was dissolved in 2 mL of dichloromethane, and then m-chloroperoxybenzoic acid (114 mg, 2.5 eq) was added at room temperature and reacted overnight. The reaction was monitored for completion by TLC. After filtration, the filtrate was washed with 10% aqueous sodium hydroxide solution, and the organic phase was spun dry and passed through a column to obtain 90 mg of compound 10, with a yield of 86%.

[0277] (10) Synthesis of Compounds T-63, 65 and 66 Hydrochloride Into three 25mL three-neck flasks, add 100mg of compound 8, compound 9 and compound 10, respectively, then add 3mL of hydrochloric acid dioxane solution to each, react at room temperature under nitrogen gas with stirring for 1 hour, after the reaction is completed, suction filter, wash the solid with an appropriate amount of ether to obtain 50mg of compound T-63 hydrochloride, 69mg of compound T-65 hydrochloride and 48mg of compound T-66 hydrochloride.

[0278] Following the procedure of Example T-63, the following compounds are synthesized. [Table 12]

[0279] Examples T-69 and T-70 Compounds synthesized according to the present invention: [ka]

[0280] The experimental process is as follows. The synthetic route is as follows: [ka]

[0281] Synthesis steps: (1) Synthesis of Compound 2 1.0g (1.0eq) of raw material compound 1, 1.37g (5.0eq) of isopropenylboronic acid pinacol ester, 0.24g (0.2eq) of Pd(dppf)Cl2, 0.67g (3.0eq) of potassium carbonate, 20ml of solvent dioxane, 2ml of water were mixed evenly, and after replacing with nitrogen gas three times, the oil bath was heated to 100°C under nitrogen gas protection and reacted for 18 hours. TLC showed that no raw material remained, and water and EA were added for extraction, dried, the sample was stirred, and passed through a column to obtain 0.7g. The yield was 75%.

[0282] (2) Synthesis of Compound 3 200mg (1eq) of compound 2, 3ml of methanol and 10mg of Pd / C are added to the reaction system in sequence, and the air is replaced with H2, and then the reaction is carried out overnight under sealed pressure with a hydrogen balloon. After the reaction is completed for 36 hours, the excess palladium carbon is removed by celite filtration, and the mother liquor is spin-dried to obtain 150mg of crude product 3.

[0283] (3) Synthesis of compound T-69 Add 150mg of compound 3, 2ml of 4M HCl / dioxane solution and 4mL of EA to the reaction system, detect the completion of the reaction by TLC after 5 hours at room temperature, suction filter to obtain the crude product of interest, HPLC purity is 84%, release with saturated sodium bicarbonate solution, extract with EA, and then purify by prep TLC to obtain 38mg of T-69, purity is 93.8%. 1H NMR(400MHz,DMSO-d6)δ 11.50(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),4.2 0(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).

[0284] (4) Synthesis of compound T-70 400mg (1eq) of compound 2, 3mL of 4M hydrochloric acid / dioxane solution and 5mL of EA are added to the reaction system in sequence and reacted at room temperature overnight. After completion of the reaction, it is liberated with saturated sodium bicarbonate solution, extracted and spin-dried. Separation by liquid phase separation gives 53mg of T-70. 1 H NMR(400MHz,DMSO-d6)δ 11.51(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).

[0285] Example T-71 Compounds synthesized according to the present invention: [ka]

[0286] The experimental process is as follows. The synthetic route is as follows: [ka]

[0287] Synthesis steps: (1) Synthesis of Compound 2 Under nitrogen gas condition, add 2,4,5-trichloropyrimidine (1.5eq) and aluminum trichloride (2.0eq) to a three-neck flask containing 100mL of dichloroethane, heat to reflux, react for 30 minutes, add 2.78g of compound 1, maintain the temperature and react overnight, after the reaction is completed, add ice water to quench, extract with DCM and water, separate the liquid, remove most of the DCM by concentration, recrystallize with EA, and suction filter to obtain 1.16g of solid compound 2, the yield is 27.2%.

[0288] (2) Synthesis of Compound 3 In a 100mL three-neck flask, add 400mg of compound 2, (S)-1-Boc-3-aminopiperidine (2.0eq), DIPEA (5.0eq), 15mL of NMP as solvent, react at room temperature under nitrogen gas condition, after completion of reaction, extract with EA and water, separate liquid, dry the organic phase with anhydrous sodium sulfate, separate and purify by silica gel column chromatography to obtain 230mg of compound 3, the yield is 41.3%.

[0289] (3) Synthesis of compound T-71 In a 50mL three-neck flask, add 100mg of compound 3, add 5mL of dichloromethane, dissolve, add 2mL of trifluoroacetic acid, and react at room temperature for 30 minutes with stirring. After the reaction is completed, remove excess solvent by concentration, adjust pH value to basic, extract spin-dry, and separate and purify by medium pressure preparative reverse column to obtain 40mg of compound 4, yield 48.4%, HPLC purity 96.6%, LC-MS [M+1]: 479.0, 481.0.

[0290] The following compounds are synthesized with reference to the methods of Examples T-01 and T-71. [Table 13]

[0291] Example T-79 Compounds synthesized according to the present invention: [ka]

[0292] The experimental process is as follows. The synthetic route is as follows: [ka]

[0293] Synthesis steps: (1) Synthesis of Compound 2 Under nitrogen gas condition, add 20g of compound 1 and 200mL of anhydrous tetrahydrofuran to a 500mL three-neck flask, cool to -78℃, add vinylmagnesium bromide (10e.q.) in THF dropwise, react while controlling the temperature, add water to quench after the reaction is completed, extract with EA and water, dry the organic phase with anhydrous sodium sulfate, concentrate, and separate and purify by silica gel column chromatography to obtain 3.56g of compound 2.

[0294] (2) Synthesis of Compound 3 In a 150mL three-neck flask, add 3.56g of compound 2 and 35mL of absolute ethanol, use concentrated sulfate (1.0eq) as a catalyst, and react overnight under nitrogen gas reflux. After the reaction is completed, cool to room temperature, remove excess solvent by concentration, and separate and purify by silica gel column chromatography to obtain 1.6g of compound 3.

[0295] (3) Synthesis of compound 4 Under nitrogen gas condition, add 2,4-dichloro-5-trifluoromethylpyrimidine (2.0eq) and aluminum trichloride (3.0eq) to 50mL of dichloroethane in a three-neck flask, heat to reflux, react for 30 minutes, add 1.7g of compound 3, maintain the temperature and react overnight, after the reaction is completed, add ice water to quench, extract with DCM and water, separate the liquid, remove most of DCM by concentration, recrystallize with EA, and suction filter to obtain 500mg of solid compound 4, yield is 16.3%, LC-MS [M+1]: 404.0, 406.0.

[0296] (4) Synthesis of Compound 5 In a 100mL three-neck flask, add 500mg of compound 4, (S)-1-Boc-3-aminopiperidine (2.0eq), and 10mL of DMF as solvent, and react under nitrogen gas conditions at room temperature. After the reaction is completed, remove the DMF solvent by rotary evaporation, and separate and purify by silica gel column chromatography to obtain 384mg of compound 5, the yield is 54.6%, and LC-MS [M+1]: 568.1, 570.1.

[0297] (5) Synthesis of compound 6 In a 50mL three-neck flask, 384mg of compound 5 was added and dissolved in 10mL of ethanol, then 5M aqueous sodium hydroxide solution (5.0eq) was added dropwise, and the reaction was carried out overnight while maintaining the temperature at 50°C to obtain 353.1mg of hydrolysis product 6, the yield being 97.0%.

[0298] (6) Synthesis of compound 7 Under nitrogen gas condition, 150mg of compound 6 and 5mL of anhydrous methanol are added to a 10mL reaction tube in sequence. After dissolving, DPPA (10.0eq) and Et3N (5.0eq) are added respectively, and the mixture is heated to reflux and reacted for 2 hours. After the reaction is completed, the mixture is cooled to room temperature, quenched by adding water, extracted with EA and water, the liquid is separated, the organic phase is dried with anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain 100mg of compound 7, the yield is 63.3%, and LC-MS [M+1]: 569.2, 571.2.

[0299] (7) Synthesis of compound T-79 Under nitrogen gas condition, add 100mg compound 7, 6mL dichloromethane and 2mL trifluoroacetic acid into 50mL three-neck flask, react under stirring at room temperature, after reaction is completed, concentrate, adjust pH value to 8, then extract, dry, spin-dry, pass through column to obtain 40mg compound T-79, yield is 48.8%, HPLC purity is 93%, LC-MS [M+1]: 469.1, 471.1.

[0300] Example T-80 Compounds synthesized according to the present invention: [ka]

[0301] The experimental process is as follows. The synthetic route is as follows: [ka]

[0302] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 20g of compound 1 in t-butanol (300mL) and stir at room temperature. Add triethylamine (20.2g, 0.2mol) to the reaction solution until the solution changes from transparent yellow to transparent reddish brown. Under nitrogen gas protection, slowly add DPPA (41.3g, 0.15mol) dropwise and control the reaction temperature sufficiently to prevent scattering. Monitor the temperature stabilized at 80°C with a thermometer and react for 3-5 hours. Add aqueous ammonium chloride solution to quench the reaction, then extract with EA. After extraction is completed, combine the organic phase, wash once with saturated sodium chloride, dry with anhydrous sodium sulfate, spin dry, pass through a column, and purify by EA / PE=10:1 to obtain 26g of compound 2.

[0303] (2) Synthesis of Compound 3 Under nitrogen gas protection, vinyl magnesium bromide (670mL, 1mol / L, 0.67moL) is added to the reaction flask, and the mixture is stirred under a liquid nitrogen bath until the temperature cools to -70℃~-80℃. Then, compound 2 (26g) is dissolved in THF (100mL) and slowly added dropwise to the reaction solution under nitrogen gas protection. After the addition is complete, the mixture is allowed to naturally warm to room temperature and react overnight. Quench with saturated ammonium chloride under an ice bath. At the start, a large amount of bubbles are generated, the temperature rises sharply, and attention should be paid to the rate of addition so as not to splash. After quenching with saturated ammonium chloride, a large amount of solid is precipitated, and then EA is added to extract. The insoluble solid can be dissolved with water. After the extraction is complete, the organic phase is combined, washed once with saturated sodium chloride, dried with anhydrous sodium sulfate, spin-dried, and passed through a column PE:EA=5:1 to obtain 13g of compound 3.

[0304] (3) Synthesis of compound 4 Compound 3 (13 g) is added to the reaction flask under ice bath, then 50 mL of 1,4-dioxane is added, then 4 mol / L hydrochloric acid / 1,4-dioxane solution (80 mL) is added dropwise with stirring, then reacted for 5 hours. After the reaction is completed, a large amount of solid is produced, which is filtered to obtain 12 g of compound 4.

[0305] (4) Synthesis of Compound 5 Under nitrogen gas protection, compound 4 (12g) is added to the reaction flask under ice bath, then 100mL of dichloromethane is added, then sodium carbonate (40.7g, 0.3mol) is added, and finally, methyl chloroformate (11.3g, 0.12mol) is slowly added dropwise, and after the addition is completed, the mixture is kept under ice bath for 3 hours. Then ice water is added to quench the reaction, and then it is extracted with EA, and after the extraction is completed, the organic phase is washed once with saturated sodium chloride, dried with anhydrous sodium sulfate, spin-dried, and passed through a column with PE:EA=2:1 to obtain 4g of compound 5.

[0306] (5) Synthesis of compound 6 Under nitrogen gas condition, aluminum trichloride (0.03 mol) is added to 2,4-dichloro-5-trifluoromethylpyrimidine (0.034 mol) in a solution of DCE (150 mL), then the temperature is raised to 80° C. and the reaction is continued for 30 minutes, after which 4 g of compound 5 is slowly added and the reaction is continued at 80° C. overnight. The reaction is quenched with water, then extracted with dichloromethane, after the extraction is completed, the organic phase is washed once with saturated sodium chloride, dried with anhydrous sodium sulfate, after the rotary evaporation is completed, the solid is slurried with EA (50 mL) to obtain 3 g of compound 6.

[0307] (6) Synthesis of compound T-80 In a 100mL three-neck flask, add 400mg of compound 2, (S)-6,6-dimethyl-3-aminopiperidine hydrochloride (2.0eq), DIPEA (5.0eq), 15mL of NMP as solvent, react at room temperature under nitrogen gas condition, after the reaction is completed, extract with EA and water, separate the liquid, dry the organic phase with anhydrous sodium sulfate, and separate and purify by silica gel column chromatography to obtain 130mg of compound T-80, the yield is 26.1%.

[0308] Following the procedures of Examples T-79 and T-80, the following compounds are synthesized. [Table 14-1] [Table 14-2] [Table 14-3]

[0309] Example T-98 Compounds synthesized according to the present invention: [ka]

[0310] The experimental process is as follows. The synthetic route is as follows: [ka]

[0311] Synthesis steps: (1) Synthesis of Compound 2 In a 250mL three-neck flask, add 17g (1eq) of intermediate 5 dissolved in 170mL of n-butanol and dissolve under stirring. Add 10.1g (2eq) of potassium carbonate, 7.4g (2.0eq) of vinyl butyl ether, 3.3g (0.4eq) of Xantphos, and 1.6g (0.2eq) of palladium acetate in sequence, replace with nitrogen gas three times, and react overnight at 95°C. Monitor the completion of the reaction by TLC. Add water, extract twice with ethyl acetate, transfer the ethyl acetate phase to a 250mL single-neck bottle, add 5ml (1.5eq) of concentrated hydrochloric acid, and stir at room temperature for 3 hours. Monitor the completion of the reaction by TLC. Purify directly by column to obtain 13.4g of compound 2.

[0312] (2) Synthesis of Compound 3 In a 250mL single-mouth bottle, dissolve 8g of compound 2 in 160mL of DCM, cool to 0℃ under ice bath, add 9.7g (3eq) of m-CPBA with stirring, react at room temperature for 3 hours, a large amount of solid precipitates, and monitor the completion of the reaction by TLC. Directly suction filter, wash with DCM, and dry to obtain 5.4g of compound 3.

[0313] (3) Synthesis of compound 4 In a 50mL single-mouth bottle, 500mg of compound 3 is dissolved in 5ml of DMF, 440mg (2eq) of (S)-1-Boc-3-aminopiperidine and 0.28g (2eq) of diisopropylethylamine are added, and the mixture is reacted at room temperature for 5 hours, and the reaction completion is monitored by TLC. Water is added, and the mixture is extracted with ethyl acetate, washed with saturated saline, dried with anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 300mg of compound 4.

[0314] (4) Synthesis of T-98 In a 50mL round bottom flask, add 300mg of compound 4 and 10ml of 4M / L hydrochloric acid dioxane, react at room temperature for 3 hours, and monitor the reaction completion by TLC. Add saturated sodium bicarbonate solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and spin dry. Purify by prep TLC to obtain 100mg of compound T-98. 1 H NMR(400MHz,DMSO-d6)δ 11.59(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).

[0315] Example T-99 Compounds synthesized according to the present invention: [ka]

[0316] The experimental process is as follows. The synthetic route is as follows: [ka]

[0317] Synthesis steps: (1) Synthesis of Compound 2 Add 1g (1eq) of compound 1 to a 50mL single-mouth bottle, add 20ml of tetrahydrofuran and dissolve under stirring, add 3ml (3eq) of DAST dropwise under ice bath, and react overnight at room temperature. Monitor the completion of the reaction by TLC. Add water under ice bath, extract twice with ethyl acetate, and purify by column to obtain 150mg of compound 2.

[0318] (2) Synthesis of compound 3: In a 25mL single-mouth bottle, 150mg of compound 2 is dissolved in 2ml of tetrahydrofuran, 125mg (2eq) of (S)-1-Boc-3-aminopiperidine and 81mg (2eq) of diisopropylethylamine are added, and the mixture is reacted at room temperature for 3 hours, and the reaction completion is monitored by TLC. Water is added, and the mixture is extracted with ethyl acetate, washed with saturated saline, dried with anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 100mg of compound 3.

[0319] (3) Synthesis of T-99: In a 25mL round bottom flask, add 100mg of compound 3 and 3ml of 4M / L hydrochloric acid dioxane, react at room temperature for 3 hours, and monitor the reaction completion by TLC. Add saturated sodium bicarbonate solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and spin dry. Purify by prep TLC to obtain 40mg of compound T-99. 1H NMR(400MHz,DMSO-d6)δ 11.54(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).

[0320] Following the procedures of Example T-98 and Example T-99, the following compounds are synthesized. [Table 15-1] [Table 15-2]

[0321] Example T-102 Compounds synthesized according to the present invention: [ka]

[0322] The experimental process is as follows. The synthetic route is as follows: [ka]

[0323] Synthesis steps: (1) Synthesis of Compound 2 Dissolve 4.7g (1eq) of compound 1 in 10mL THF, add 1.8g (6eq) of NaH under salt-ice bath, stir for 5 minutes, then add 1.6g (5eq) of CH3I and react at room temperature. After the reaction is completed, add 50mL of water, extract with EA, dry, and spin-dry to obtain 4.9g of crude product of compound 2.

[0324] (2) Synthesis of Compound 3 4.9g (1eq) of compound 1 is dissolved in 40mL of THF, and slowly added dropwise to vinylmagnesium bromide (6eq) under conditions of -78℃ and N2 protection, and the mixture is allowed to warm to room temperature after the addition is complete. After the reaction is complete, 50mL of water is added, extracted with EA, dried, spin-dried, and passed through a column to obtain 1.5g of compound 3.

[0325] (3) Synthesis of compound 4 1.5g (1eq) of compound 5 is taken up in 10mL of 4M / L hydrochloric acid in dioxane and reacted at room temperature. After completion of the reaction, add aqueous NaHCO3 to adjust the solution to basic, extract with EA, dry, spin-dry, separate and separate to obtain 1.0g of compound 4. LC-MS [M+1]: 224.9, 226.9.

[0326] (4) Synthesis of Compound 5 Dissolve 1.0g (1eq) of compound 4 in 6ml of methyl chloroformate, add 300mg of Na2CO3, and react at room temperature. After the reaction is complete, add water, extract with EA, dry, and spin-dry to obtain 0.86g of crude product of compound 5.

[0327] (5) Synthesis of compound 6 In a 50mL round bottom flask, add 1.5g (3eq) of 2,4-dichloro-5-trifluoromethylpyrimidine, 25mL of DCE and 0.5g (1.7eq) of AlCl3 and warm to 80°C. After reacting for 30 minutes under N2 protection, add 0.5g (1eq) of compound 2 and continue to react under N2 protection at 80°C. After completion of the reaction, add water, extract with EA, evaporate the organic layer to dryness, add EA to slurry to obtain 0.3g of compound 6. LC-MS [M+1]: 462.9, 464.9.

[0328] (6) Synthesis of compound 7 Dissolve 0.3g (1.0eq) of compound 3 in 6mL of DMF, add 0.3g (2.2eq) of (S)-1-Boc-3-aminopiperidine, and react overnight at room temperature with stirring. After the reaction is complete, add water, extract with EA, dry, spin-dry, and pass through a column to obtain 0.3g of compound 7.

[0329] (7) Synthesis of compound T-102 250mg (1eq) of compound 7 is taken up in 6mL of 4M / L hydrochloric acid dioxane and 4mL of EA and reacted at room temperature. After completion of the reaction, it is suction filtered and the filter cake is washed with methyl t-butyl ether to obtain 200mg of compound T-102. HPLC: 97.4%. LC-MS [M+1]: 527.0, 529.0. 1 H NMR(400MHz,DMSO-d6)δ 12.40-12.06(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).

[0330] The following compounds are synthesized according to the method of Example T-102. [Table 16-1] [Table 16-2]

[0331] With reference to patent WO2020093006A1, the compound compound101 in the patent was synthesized and used as a comparative example of the present invention. The structural formula is as follows: [ka]

[0332] Test Example 1. Enzyme activity test Hereinafter, biological activity test experiments will be carried out on some of the compounds in the above examples and comparative examples. The experimental process of the biological activity test is as follows: Detection of CDK7 kinase IC50 value of test compound (detected by Wuxi Bioortus Biosciences Co., Ltd.).

[0333] 1. Preparation of compounds: Compound powder was dissolved in 100% DMSO to prepare a stock solution of 10 mM, which was further diluted to 0.5 mM as the initial concentration, and serially diluted 3-fold to obtain 10 different concentrations of compound solutions, which were detected using duplicate wells, and the pre-incubation times of compound and enzyme were 0 and 60 minutes, respectively. Staurosporine compound (structural formula: [ka] ) is used as a positive control, and the Mobility shift assay method is used to detect the activity of the compound against CDK kinases such as CDK7, CDK9, CDK12 and CDK2.

[0334] 2.Kinase reaction process: 1) Compound solutions and positive controls were diluted 8.3 times with double distilled water and then added to a 384-well plate, with each concentration being 2 uL / well; (2) Add 6 nM of CDK7 / Cyclin H / MAT1 kinase solution to the compound wells and the positive control wells, (3) Incubate at room temperature for 0 and 60 minutes. (4) 2 mM ATP and 2 pM 5-FAM-CDK7 peptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) solution (CDK9 inhibition reaction uses 8 nM CDK9 / Cyclin Tl polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate, CDK12 inhibition reaction uses 50 nM CDK12(aa686-l082) / Cyclin K polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate, CDK2 inhibition reaction uses 0.5 nM CDK2 / Cyclin El polymer and 2 pM 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK peptide substrate), (5) Incubate the 384-well plate at 25°C for 30 minutes. (6) Add 4uL of 120mM EDTA to stop the kinase reaction. (7) Read the conversion rate using the Caliper / LabChip EZ Reader (Perkin Elmer). (8) IC was calculated by curve fitting using GraphPad Prism8 software. 50 Get the value.

[0335] The above detection results in the IC inhibitory activity of the test sample against CDK7 kinase. 50 (nM) values ​​are as shown in Table 1, where A≦50 nM, 50 nM <B<500nM、C≧500nM。 [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5]

[0336] As can be seen from the above table, in vitro bioactivity screening using Staurosporine as a control showed that the compounds synthesized by the present application have better inhibitory ability against CDK7 kinase and better selectivity, and are expected to be used for the development of drugs for controlling CDK7 kinase activity or treating CDK7-related diseases.

[0337] Test Example 2. Cell Antiproliferation Experiment 1. Experimental materials and equipment: Human breast cancer cells MDA-MB231, MDA-MB453, ovarian cancer cells OVCAR3 and A2780, colorectal cancer cells HCT-116 and WiDr, and lung cancer cells Calu-6 are 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, PH7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme immunoassay device (Tecan Spark).

[0338] 2. Experimental preparation: 1. Cell Plating A) Tumor cells are cultured in DMEM (containing high glucose, 10% FBS and 100 U / mL penicillin-G / streptomycin) under conditions of 37 °C, 5% CO2 and saturated humidity to a density of 80-90%. B) Removal of medium in a 10 cm culture dish. C) Wash the cells once with 10 mL of 1xPBS. D) Add 4 mL of 0.25% EDTA-Tripsin, place in a 37°C, 5% CO2 incubator for 5 minutes to perform trypsin digestion, transfer to a 15 mL centrifuge tube, centrifuge at 200 g for 5 minutes, discard the supernatant, and obtain a cell pellet. E) Resuspend in 4 mL of DMEM medium, count and adjust to 50,000 cells / mL. F) The cell suspension is added to a 96-well plate at a volume of 100 μL per well and incubated overnight in a 37° C., 5% CO2 incubator.

[0339] 2. Compound Treatment Compound Dilution A) Preparation of test compound gradient dilution solution: Prepare test compounds into 10mM and 1mM stock solutions, respectively. First, dissolve 1μl and 0.5μl of 10mM stock solution into 1ml of DMSO-free medium, respectively, to obtain diluted compounds with concentrations of 10 and 5μM. Then, dissolve 1.5μl of 1mM stock solution into 1.5ml of DMSO-free medium to obtain diluted compounds with concentrations of 1μM, and use 0.025% DMSO medium to perform 3-fold serial gradient dilution to obtain a total of seven concentrations. The concentrations of the 10 compounds after all the above dilutions are as follows: 10μM, 5μM, 1μM, 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM. B) After thorough mixing, 100 μL of each culture compound solution was taken to replace the culture medium in the cell culture plate, and each concentration was in 4 duplicate wells. C) The cells are transferred to an incubator and incubated for three days.

[0340] 3.MTT detection A) Remove the cell culture plate and add 10 μL of 5 mg / ml MTT in a biological safety cabinet. B) Place the cell culture plate back into the incubator and continue to incubate for 3 hours. C) The cell culture plate is taken out, the culture medium is removed, 100 μL of isopropanol (containing 0.4 mM HCl and 0.1% NP-40) is added, and the plate is shaken at room temperature for 30 minutes. D) Measure the absorbance value by selecting a wavelength of 570 nm using a TECAN enzyme immunoassay device.

[0341] 4. Data Analysis Calculate % Cell Viability using the following formula: %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC) Lum_HC: Readings from 0.1% DMSO control cells Lum_Sample: Readings from cells spiked with compound Lum_LC: Blank medium reading Curve fitting using GraphPad Prism8 software yielded IC 50 Get the value.

[0342] As shown in Table 2. [Table 18]

[0343] As can be seen from Table 2, the compounds of the present invention have very good inhibitory effects on human breast cancer cells MDA-MB231, MDA-MB453, ovarian cancer OVCAR3 and A2780, colorectal cancer cells HCT-116 and WiDr, and lung cancer cells Calu-6, and are superior to the activity of the best compound compound101 in patent WO2020093006A1.

[0344] Test Example 3. Compound Pharmacokinetics Experiment Comparison of the direct pharmacokinetics of oral administration of compound T-01 of the present invention and a control compound (compound 101 in patent WO2020093006A1).

[0345] Pharmacokinetics Experimental Scheme in Rat (1) Animals required: 3 healthy adult SD rats, male, 6-8 weeks old, weighing 200-300g. (2) Equipment required: analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0346] (3) Required reagents: EDTA-Na2 anticoagulant, etc. Weigh out 11.2g of EDTA-Na2, place it in a reagent bottle, add 100mL of saline, and shake until completely dissolved. After preparation is complete, divide 20uL into 1.5mL centrifuge tubes and use them to collect whole blood samples.

[0347] (4) Accurately weigh out approximately 10 mg of the sample to be tested, dissolve in 5% DMSO after conversion, add 30% PEG400 and 65% (10% Hp-β-CD in PBS), sonicate, and mix evenly with a vortex to obtain a solution with a concentration of 1 mg / mL. Prepare fresh before use.

[0348] (5) A 0.1 mL sample is absorbed into a 1.5 mL centrifuge tube and stored at -80°C for use in concentration analysis of the administered solution. (6) The animals are kept in rat cages, fasted (for at least 10 hours) on the day before the test, but water is not prohibited, and weighed and tail-marked on the day of the test. Blank blood is collected before each administration. Blood is collected from the tail vein.

[0349] (7) Route of administration: oral gavage (po), dosage: 10 mg / kg, dosage volume: 10 mL / kg. (8) Operation procedure: Capture the rat with the left hand wearing an anti-bite glove, hold it upright, extend the 16-cage gavage needle from the throat of the mouth, insert the needle when no obvious resistance is felt, and inject the drug into the stomach.

[0350] (9) Before administration, and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, 0.2 mL of whole blood is collected from each test animal into an EDTA-Na2 anticoagulant tube, which is then mixed evenly by inverting the tube 3-4 times, centrifuged at 10,000 g at 4°C for 5 minutes to separate the plasma, and stored at -80°C until testing. Blood is collected from the tail vein.

[0351] (10) An LC-MS / MS method was developed to measure the initial drug concentration in plasma, plot the plasma drug concentration-time curves, and calculate the main pharmacokinetic parameters using a noncompartmental model. (11) The pharmacokinetic parameters of T-01 and the reference compounds are specifically shown in Figure 1 (where the vertical axis is the concentration of drug in plasma).

[0352] As can be seen from FIG. 1, the compounds of the present invention have significantly better pharmacokinetic parameters than the reference compound (compound 101), which are approximately 5-fold better than the reference compound in terms of plasma drug concentration Cmax and AUC.

[0353] Preparation Example 1 Compounds synthesized according to the present invention: [ka]

[0354] The experimental process is as follows. 1. Synthesis of intermediate SM1 The synthetic route is as follows: [ka]

[0355] 1. Synthesis of Compound 2 Under nitrogen gas protection, add 730mL (6eq) of vinylmagnesium bromide to a 2L three-neck flask, cool to 78℃ with liquid nitrogen-ethanol, dissolve 30g of compound 1 in 700mL of anhydrous tetrahydrofuran, slowly add dropwise to the reaction flask while stirring, maintain the temperature below -70℃, slowly warm to room temperature after the dropwise addition is completed, and stir overnight. TLC shows no raw material, and the target product spot is the main spot. Quench by adding aqueous ammonium chloride solution, adjust pH to 2 with dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, rotate under reduced pressure until a large amount of solid precipitates, and suction filter under reduced pressure to obtain 16g of compound 2 as a filter cake. LC-MS [M+1]: 240, 242.

[0356] 2. Synthesis of Compound 3 In a 100mL three-neck flask, dissolve 8g of compound 2 in 15mL of DMF, cool to 0℃ under ice bath, slowly add 11g (2eq) of CDI while stirring, react for 1 hour under stirring, then slowly add 50mL of aqueous ammonia (10eq) under ice bath, and monitor the reaction completion by TLC. Add water, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin-dry, and obtain 6g of compound 3 by column chromatography. LC-MS [M+1]: 239, 241.

[0357] 3. Synthesis of intermediate SM1 In a 100mL three-neck flask, 6g of compound 3 and 25.5g (10eq) of triethylamine are dissolved in DCM, cooled to 0°C under ice bath, 23g (8eq) of methanesulfonyl chloride are added under stirring, reacted at room temperature overnight, and monitored for completion by TLC. Extract with ethyl acetate, dry with anhydrous sodium sulfate, spin-dry, and separate by column chromatography to obtain 3.3g of compound 4. LC-MS [M+1]: 221, 223.

[0358] 2. Synthesis of Compound 01 The synthetic route is as follows: [ka]

[0359] 1. Synthesis of Compound 5 In a 100mL round-bottom flask, dissolve 9g (3eq) of 2,4-dichloro-5-trifluoromethylpyrimidine in 150mL of DCE, add 3g (1.5eq) of anhydrous aluminum trichloride while stirring, heat to 80°C under nitrogen gas protection, and stir for 30 minutes. Cool to room temperature, add 3g of compound SM1, heat to 80°C, and monitor the reaction completion by TLC. The reaction product has two positional isomers, and the content ratio is close to 3:1. Add water, extract with ethyl acetate, rotate under reduced pressure until a large amount of solid is precipitated, and suction filter under reduced pressure to obtain 1.2g of a filter cake of single structure compound 5, and separate the filtrate by column chromatography to obtain 1.6g of a mixture of two structures compound 5. LC-MS [M+1]: 401, 403.

[0360] 2. Synthesis of Compound 6 In a 100mL round bottom flask, add 1.2g of compound 5, 1g (1.2eq) of (S)-6,6-dimethylpiperidin-3-amine, 1.5g (4eq) of DIPEA, and 6mL of N-methylpyrrolidone, and react under nitrogen gas protection at 130°C with stirring for 3 hours, monitoring the completion of the reaction by TLC. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 1.2g of compound 6. LC-MS [M+1]: 493, 495.

[0361] 3. Synthesis of Compound 01 In a 100mL three-neck 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. Under nitrogen gas protection, heat to 140°C and monitor the reaction completion by TLC. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 5mg of compound 01. LC-MS [M+1]: 517.

[0362] According to the method 1 or method 2 of Preparation Example 1, the following compounds are synthesized. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0363] Test Example 1. Enzyme activity test Hereinafter, biological activity test experiments will be carried out on some of the compounds in the above examples and comparative examples. The biological activity test experimental process is as follows: Detection of CDK7 kinase IC50 value of test compound (detected by Wuxi Bioortus Biosciences Co., Ltd.).

[0364] 1. Preparation of compounds: Compound powder was dissolved in 100% DMSO to prepare a stock solution of 10 mM, which was further diluted to 0.5 mM as the initial concentration, and serially diluted 3-fold to obtain 10 different concentrations of compound solutions, which were detected using duplicate wells, and the pre-incubation times of compound and enzyme were 0 and 60 minutes, respectively. Staurosporine compound (structural formula: [ka] ) is used as a positive control, and the Mobility shift assay method is used to detect the activity of the compound against CDK kinases such as CDK7, CDK9, CDK12 and CDK2.

[0365] 2.Kinase reaction process: 1) Compound solutions and positive controls were diluted 8.3 times with double distilled water and then added to a 384-well plate, with each concentration being 2 uL / well; (2) Add 6 nM of CDK7 / Cyclin H / MAT1 kinase solution to the compound wells and the positive control wells, (3) Incubate at room temperature for 0 and 60 minutes. (4) 2 mM ATP and 2 pM 5-FAM-CDK7 peptide substrate (5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK) solution (CDK9 inhibition reaction uses 8 nM CDK9 / Cyclin Tl polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate, CDK12 inhibition reaction uses 50 nM CDK12(aa686-l082) / Cyclin K polymer and 2 pM 5-FAM GSRTPMY-NH2 peptide substrate, CDK2 inhibition reaction uses 0.5 nM CDK2 / Cyclin El polymer and 2 pM 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK peptide substrate), (5) Incubate the 384-well plate at 25°C for 30 minutes. (6) Add 4uL of 120mM EDTA to stop the kinase reaction. (7) Read the conversion rate using the Caliper / LabChip EZ Reader (Perkin Elmer). (8) IC50 values ​​are obtained by curve fitting using GraphPad Prism8 software.

[0366] The above detection results in the IC inhibitory activity of the test sample against CDK7 kinase. 50 (nM) values ​​are as shown in Table 3, where A≦10 nM, 10 nM <B<500nM、C≧500nM。 [Table 20]

[0367] As can be seen from the above table, in vitro bioactivity screening using Staurosporine as a control showed that the compounds synthesized by the present application have superior inhibitory ability against CDK7 kinase, and are expected to be used for the development of drugs for controlling CDK7 kinase activity or treating CDK7-related diseases.

[0368] Test Example 2. Cell Antiproliferation Experiment 1. Experimental materials and equipment: Human breast cancer cells MDA-MB231, MDA-MB453, ovarian cancer cells OVCAR3, colorectal cancer cells HCT-116 and lung cancer cells NCI-H209 are 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, PH7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF5810R), enzyme immunoassay device (Tecan Spark).

[0369] 2. Experimental preparation: 1. Cell Plating A) Tumor cells are cultured in DMEM (containing high glucose, 10% FBS and 100 U / mL penicillin-G / streptomycin) under conditions of 37 °C, 5% CO2 and saturated humidity to a density of 80-90%. B) Removal of medium in a 10 cm culture dish. C) Wash the cells once with 10 mL of 1xPBS.

[0370] D) Add 4 mL of 0.25% EDTA-Tripsin, place in a 37°C, 5% CO2 incubator for 5 minutes to perform trypsin digestion, transfer to a 15 mL centrifuge tube, centrifuge at 200 g for 5 minutes, discard the supernatant, and obtain a cell pellet. E) Resuspend in 4 mL of DMEM medium, count and adjust to 50,000 cells / mL. F) The cell suspension is added to a 96-well plate at a volume of 100 μL per well and incubated overnight in a 37° C., 5% CO2 incubator.

[0371] 2. Compound Treatment Compound Dilution A) Preparation of gradient dilution solution of test compound: TY2600 1mM, TY2601 1mM, TY-2648a 1mM, TY-2648b 1mM and TY-2650 1mM stock solution. Then, 1.5μl of stock solution is dissolved in 1.5ml of DMSO-free medium, and diluted 3-fold with 0.1% DMSO medium to obtain a total of nine concentrations, and the concentration of the compound after dilution is as follows: 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM.

[0372] B) After thorough mixing, 100 μL of each culture compound solution was taken to replace the culture medium in the cell culture plate, and each concentration was in 4 duplicate wells. C) The cells are transferred to an incubator and incubated for three days.

[0373] 3.MTT detection A) Remove the cell culture plate and add 10 μL of 5 mg / ml MTT in a biological safety cabinet. B) Place the cell culture plate back into the incubator and continue to incubate for 3 hours.

[0374] C) The cell culture plate is taken out, the culture medium is removed, 100 μL of isopropanol (containing 0.4 mM HCl and 0.1% NP-40) is added, and the plate is shaken at room temperature for 30 minutes. D) Measure the absorbance value by selecting a wavelength of 570 nm using a TECAN enzyme immunoassay device.

[0375] 4. Data Analysis Calculate % Cell Viability using the following formula: %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC) Lum_HC: Readings from 0.1% DMSO control cells Lum_Sample: Readings from cells spiked with compound Lum_LC: Blank medium reading Curve fitting using GraphPad Prism8 software yielded IC 50 Get the value.

[0376] As shown in Table 4, where A≦10 nM, 10 nM <B<500nM、C≧500nM。 [Table 21]

[0377] As can be seen from Table 4, the compounds of the present invention have very good inhibitory effects on human breast cancer cells MDA-MB231, MDA-MB453, ovarian cancer OVCAR3, and colorectal cancer cells HCT-116.

[0378] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound comprising: The compound is a compound of formula I, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopomer thereof, 【Chemistry 1】 Where: Ring A is 【Chemistry 2】 where R ２ is selected from the group consisting of halogen, C1-C6 alkyl group, and halogenated C1-C6 alkyl group; Ring B is a substituted or unsubstituted N, O, S, S(O) or S(O) ２ a 4- to 7-membered heterocyclic group containing 1 to 3 selected from N, O, S, S(O) or S(O) ２ a 5- to 9-membered hetero bridged cycloalkyl group, a 5- to 9-membered bridged cycloalkyl group, N, O, S, S(O) or S(O) ２ a 6- to 10-membered heterospirocycloalkyl group, a 6- to 10-membered spirocycloalkyl group, N, O, S, S(O) or S(O) ２ a 6- to 10-membered fused heterocycloalkyl group, a 6- to 10-membered fused cycloalkyl group, N, O, S, S(O) or S(O) ２ and a C6-C10 aryl group, L is O, NR １ , -NR １ -(C1-C6 alkylene)-; Ring C is 【Chemistry 3】 where: X １ is selected from the group consisting of N, CH; X ２ is CR ２ ' and R ２ ' is independently -NR １ -C(=O)-O-(C1-C6 alkyl), -NR １ -C(=O)-R ５ , -NR １ -C(=O)-O-C1-C6 alkylene-X ８ -C1-C6 alkyl group, -O-C(=O)-NR １ R ５ , 【Chemistry 4】 is selected from R ４ is H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 3- to 8-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, group), 【Chemistry 5】 -NR １ -C(=O)-O-(C1-C6 alkyl), -O-C(=O)-R ５ , -C(=O)-R ５ , 【Chemistry 6】 a cyano group; R １ are independently hydrogen, an amino group, -C(=O)-O-(C1-C6 alkyl), a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 3- to 8-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, -C(=O)-NR ８ R ９ is selected from Each R ５ , R ６ , R ７ are independently hydrogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkylamino group, a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, NR ８ R ９ is selected from the group consisting of Each R ８ , R ９ is independently selected from the group consisting of hydrogen, a C1-C6 alkyl group; each X ６ and X ７ are independently O, CR ５ R ６ , N.R. １ is selected from the group consisting of each X ８ is independently selected from the group consisting of N, O, and S; m is selected from the group consisting of 0, 1, 2, and 3; each n is independently selected from the group consisting of 0, 1, 2, 3, 4, or 5; The compound, characterized in that the substitution refers to being substituted independently by a group selected from the group consisting of -NH-C(=O)-O-(C1-C6 alkyl), an amino group, a halogenated or unsubstituted C1-C6 alkyl group, =O, a hydroxyl group, and -NH(C1-C6 alkyl).

2. The compound is a compound of formula II, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopomer thereof, 【Chemistry 7】 R ２ is selected from a trifluoromethyl group, a chlorine, a bromine, a methyl group, an ethyl group, or an isopropyl group; Ring B is a substituted or unsubstituted N, O, S, S(O) or S(O) ２ a 4- to 7-membered heterocyclic group containing 1 to 3 selected from N, O, S, S(O) or S(O) ２ a 5- to 9-membered hetero bridged cycloalkyl group, a 5- to 9-membered bridged cycloalkyl group, N, O, S, S(O) or S(O) ２ a 6- to 10-membered heterospirocycloalkyl group, a 6- to 10-membered spirocycloalkyl group, N, O, S, S(O) or S(O) ２ a 6- to 10-membered fused heterocycloalkyl group, a 6- to 10-membered fused cycloalkyl group, N, O, S, S(O) or S(O) ２ a 5- to 6-membered heteroaryl group, a 5- to 6-membered aryl group, L is O, NR １ , -NR １ -(C1-C6 alkylene)-; Ring C is 【Chemistry 8】 and Here, R １ , R ４ , X １ , X ２ is characterized in that it is as defined in claim 1 The compound of claim 1.

3. Ring B is 【Chemistry 9】 is selected from the group consisting of Ring C is 【Chemistry 10】 is selected from the group consisting of Here, R １ , R ４ , R ５ , R ６ , X １ , X ２ , X ６ , m is as defined in claim 1, and Q1 is a 3- to 7-membered ring. The compound of claim 1.

4. Ring A is 【Chemistry 11】 is selected from the group consisting of Ring C is 【Chemistry 12】 is selected from the group consisting of R ４ is H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a 3- to 8-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, 【Chemistry 13】 is selected from the group consisting of Here, R １ , R ５ , R ６ , R ７ , X １ , X ６ , X ７ , m, n are as defined in claim 1. The compound of claim 1.

5. The compound is selected from the group consisting of: Ring A is 【Chemistry 14】 is selected from the group consisting of Ring C is 【Chemistry 15】 is selected from the group consisting of R ４ represents H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, a 3- to 8-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, 【Chemistry 16】 is selected from the group consisting of L is O, NR １ is selected from the group consisting of Here, R １ , R ５ , R ６ , R ７ , X １ , X ６ , m are as defined in claim 1 The compound of claim 1.

6. R ４ is selected from the group consisting of H, halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, and a 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S; L is NH The compound according to claim 5.

7. A compound selected from the group consisting of: 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】

8. The pharma- ceutically acceptable salt is an inorganic or 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 salts include formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonic acid salt (methanesulfonate), ethanesulfonate (ethanesulfonate), benzenesulfonate (benzenesulfonate), p-toluenesulfonate (p-toluenesulfonate), salicylate (salicylate), picrate (picrate), glutamate (glutamate), ascorbate (ascorbate), camphorate (camphorate), camphorsulfonate (camphorsulfonate) The compound of claim 1.

9. 1. A pharmaceutical composition comprising:

13. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound according to claim 1 and a pharma- ceutically acceptable carrier.

10. 1) for modulating CDK7 kinase activity, or 2) for preventing and / or treating CDK7-related diseases; 10. A compound according to claim 1 for use in the preparation of a medicament.

11. The CDK7-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immune disease, and metabolic disease. The compound of claim 10.

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