Substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives, compositions thereof and pharmaceutical uses

Abstract

The substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives as shown in formula (I), their pharma- ceutically acceptable salts, solvates, stereoisomers, prodrugs, and pharmaceutical compositions have significant CDK9 selective inhibitory activity. JPEG2024503746000136.jpg5656

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical technical field, in particular to substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives, their pharma-ceutically acceptable salts, solvates, stereoisomers, prodrugs, pharmaceutical compositions and pharmaceutical uses. [Background technology]

[0002] The cyclin-dependent kinase (CDK) protein family consists of members that are major regulators of the cell division cycle (cell cycle CDKs) involved in gene transcription regulation (transcriptional CDKs) and members with other functions. CDKs require activation by binding to cell cycle protein regulatory subunits. The cell cycle CDKs CDK1 / cell cycle protein B, CDK2 / cell cycle protein A, CDK2 / cell cycle protein E, CDK4 / cell cycle protein D, and CDK6 / cell cycle protein D are activated sequentially to drive cells through the cell division cycle. The transcribed CDKs CDK9 / period protein T and CDK7 / period protein H regulate the activity of RNA polymerase II by phosphorylating the carboxyl-terminal domain (CTD).

[0003] CDK9 is a catalytic subunit in the positive transcription elongation factor b (P-TEFb) complex, which controls gene transcription elongation via the carbon-terminal domain of phosphorylated RNA complex II, and is located at chromosome 9q34.1 in the RNA transcription elongation-regulating kinase. CDK9 expression is widespread and is expressed in a variety of eukaryotic cells and human tissues, among which CDK9 kinase is highly expressed in cardiomyocytes, hepatocytes, hematopoietic tissues, adipocytes, neurons and muscle cells, and generally highly expressed in tumor cells. CDK9 is also an important factor in the progression and maintenance of tumor cells. CDK9 inhibitors suppress gene transcription elongation and promote the apoptosis of cancer cells by reducing the expression of the associated oncoprotein (MYC) and the expression of the apoptosis inhibitor protein Mcl-1. CDK9 inhibitors regulate the epigenetic factor BRG1, which reactivates silent genes, promotes the expression of interferon, including the activation of ERVs in tumor cells, and makes tumor cells more sensitive to immunotherapy.

[0004] At present, many companies are developing CDK9 inhibitors, including selective CDK9 inhibitor BAY1251152 developed by Bayer, selective CDK9 inhibitor AZD4573 developed by AstraZeneca, non-selective CDK9 inhibitor TP-1287 developed by Tolero, and non-selective CDK9 inhibitor QHRD107 developed by Changzhou Qianhong Pharmaceutical Co., Ltd. However, at present, most selective CDK9 inhibitors are in the early clinical development stage, and the selective inhibitory activity against CDK9 and the in vivo drug metabolism parameters have room to be improved. Therefore, it is of great clinical significance to develop new CDK9 inhibitors with high activity, high selectivity, and reduced in vivo toxicity. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to provide substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives having high inhibitory activity against CDK9, good selectivity and better drug metabolism parameters. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound according to formula (I), or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof: JPEG0007657943000001.jpg5064However, R 1 is C 3-8 Cycloalkyl groups (preferably C 3-6 cycloalkyl group), C 2-8 Alkenyl group (preferably C 2-6 Alkenyl groups, more preferably C 2-4 alkenyl group) or C 2-8 Alkynyl groups (preferably C 2-6 Alkynyl groups, more preferably C 2-4 alkynyl group), 3-8 Cycloalkyl groups, C 2-8 Alkenyl groups and C 2-8 The alkynyl group may be unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)C 1-3 Alkyl group, -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 is substituted by one, two or three substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, and a phenyl group, with the proviso that the phenyl group is optionally substituted by one, two or three substituents each independently selected from a substituent group S; R 2 , R 3 are independently hydrogen, C 1-8Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl group), C 1-8 Alkoxy groups (preferably C 1-6 is an alkoxy group, more preferably C 1-3 alkoxy group), cyano group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), -C(O)NR a0 R b0 , -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group) or -OC(O)C 1-8 Alkyl groups (preferably -OC(O)C 1-6 is an alkyl group, more preferably -OC(O)C 1-3 alkyl group), provided that the C 1-8 Alkyl group, C 1-8 Alkoxy group, C 3-8 The cycloalkyl groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6is substituted by one, two or three substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are each optionally substituted by one, two or three substituents independently selected from a substituent group S; R 4 , R 5 are independently hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -(C=N)-C 1-8 Alkyl group (preferably -(C=N)-C 1-6 Alkyl groups, more preferably -(C=N)-C 1-3 alkyl group) or -(C=N)-NR a0 R b0 or R 4 , R 5 form a 3- to 7-membered saturated or partially unsaturated monoheterocyclic ring together with the nitrogen atom to which it is linked, provided that the 3- to 7-membered saturated or partially unsaturated monoheterocyclic ring is unsubstituted or each independently contains a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 substituted by one, two or three substituents selected from a cycloalkyloxy group and a 3- to 6-membered heterocyclic alkyl group; Z is N or CR Z where R Z is hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 1-8 Alkoxy groups (preferably C 1-6 Alkoxy groups, more preferably C 1-3 Alkoxy group), -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), -C(O)NR a0 R b0 , a 5- to 6-membered heteroaryl group, or an 8- to 10-membered heteroaryl group, provided that 1-8 Alkyl group, C 1-8 The alkoxy groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 is substituted by one, two or three substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are each optionally substituted by one, two or three substituents independently selected from a substituent group S; R a , R b are independently hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl group), C 1-8 Alkoxy groups (preferably C 1-6 Alkoxy groups, more preferably C 1-3 alkoxy group), cyano group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), -C(O)NR a0 R b0 , -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), -OC(O)C 1-8 Alkyl groups (preferably -OC(O)C 1-6 Alkyl groups, more preferably -OC(O)C 1-3 Alkyl group), -SO 2 C 1-8 Alkyl group (preferably -SO 2 C 1-6 An alkyl group, more preferably -SO 2 C 1-3 Alkyl group), -SO 2 NR a0 R b0 or R a , R bare linked together to form a condensed 3- to 7-membered saturated or partially unsaturated monoheterocycle or a condensed 3- to 7-membered saturated or partially unsaturated monocycle, provided that 1-8 Alkyl group, C 1-8 The alkoxy group, the 3- to 7-membered saturated or partially unsaturated monoheterocycle and the 3- to 7-membered saturated or partially unsaturated monocycle are unsubstituted or each independently include a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 is substituted by one, two or three substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are each optionally substituted by one, two or three substituents independently selected from a substituent group S; Ring A is a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; (R 0 ) m R has m hydrogen atoms on ring A. 0 m is 0, 1, 2 or 3, and each R 0 may be the same or different, and each independently represents a cyano group, a hydroxyl group, a carboxyl group, a halogen (preferably fluorine or chlorine), C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 1-8 Alkoxy groups (preferably C1-6 Alkoxy groups, more preferably C 1-3 Alkoxy group), -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), -OC(O)C 1-8 Alkyl groups (preferably -OC(O)C 1-6 Alkyl groups, more preferably -OC(O)C 1-3 alkyl group) or -C(O)NR a0 R b0 or any two R 0 are linked together to form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle, provided that 1-8 Alkyl group, C 1-8 The alkoxy group, the 3- to 7-membered saturated or partially unsaturated monoheterocycle and the 3- to 7-membered saturated or partially unsaturated monocycle are unsubstituted or each independently include a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6is substituted by one, two or three substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are each optionally substituted by one, two or three substituents independently selected from a substituent group S; The substituent group S is a halogen, a cyano group, a hydroxyl group, a carboxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; R a0 , R b0 are independently hydrogen, C 1-3 is an alkyl group or an acetyl group, or R a0 , R b0 form a 4- to 6-membered saturated monoheterocycle together with the nitrogen atom to which it is linked, and the 4- to 6-membered saturated monoheterocycle may optionally and independently contain deuterium, halogen, a cyano group, a hydroxyl group, a carboxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NH 2, -C(O)NH(C 1-3 alkyl group), -C(O)N(C 1-3 (alkyl group) 2 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 substituted by one, two or three substituents selected from a cycloalkyloxy group and a 3- to 6-membered heterocyclic alkyl group; R a1 , R b1 are independently hydrogen, C 1-3 is an alkyl group or an acetyl group, or R a1 , R b1 form a 4- to 6-membered saturated monoheterocycle together with the nitrogen atom to which it is linked, and the 4- to 6-membered saturated monoheterocycle may optionally and independently include deuterium, halogen, cyano group, hydroxyl group, carboxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl group), -C(O)N(C 1-3 (alkyl group) 2 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 It is substituted by 1, 2 or 3 substituents selected from a cycloalkyloxy group and a 3- to 6-membered heterocyclic alkyl group.

[0007] In some embodiments, the compound of formula (I) has the structure of formula (II): JPEG0007657943000002.jpg5370 wherein each group is defined as above.

[0008] In some embodiments, R 1 is C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl group) or C 2-8 Alkenyl group (preferably C 2-6 Alkenyl groups, more preferably C 2-4 alkenyl group), R 2 , R 3 are independently hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group) or deuterated C 1-8 Alkyl groups (preferably deuterated C 1-6 Alkyl groups, more preferably deuterated C 1-3 alkyl group), 3-8 Cycloalkyl groups, C 2-8 The alkenyl group may be unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)C 1-3 Alkyl group, -C(O)OC 1-3 It is substituted with one, two or three substituents selected from alkyl groups.

[0009] In some embodiments, R 1 is C 3-8 Cycloalkyl groups (preferably C 3-6Cycloalkyl group) or C 2-8 Alkenyl group (preferably C 2-6 Alkenyl groups, more preferably C 2-4 alkenyl group), R 2 is hydrogen or C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 alkyl group), and R 3 is hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group) or deuterated C 1-8 Alkyl groups (preferably deuterated C 1-6 Alkyl groups, more preferably deuterated C 1-3 alkyl group), 3-8 Cycloalkyl groups, C 2-8 The alkenyl group may be unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 is substituted with one, two or three substituents selected from:

[0010] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclopentyl, 1-methylcyclohexyl, vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and R 2 , R 3are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclopentyl, 1-methylcyclohexyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuterated methyl, monodeuterated ethyl, deuterated methyl, deuterated ethyl, tritiated methyl, or tritiated ethyl.

[0011] In some embodiments, Z is CH.

[0012] In some embodiments, the 3- to 7-membered saturated or partially unsaturated monoheterocycle represented by ring A is an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrrolidine ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-ketone ring, an oxetane-2-ketone ring, a pyrrolidine-2-ketone ring, a pyrrolidine-2,5-diketone ring, a piperidine-2-ketone ring, a dihydrofuran-2(3H)-ketone ring, a dihydrofuran-2,5-diketone ring, a tetrahydro-2H-pyran-2-ketone ring, a piperazine-2-ketone ring, a morpholine-3-ketone ring, a 1H-pyran-2 ... ,2-Dihydroazetidiene ring, 1,2-dihydrooxyheterocyclic butadiene ring, 2,5-dihydro-1H-pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2,3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydro and the ring is selected from the group consisting of a 4,5-dihydro-1H-imidazole ring, a 1,4,5,6-tetrahydropyrimidine ring, a 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, a 1,6-dihydropyrimidine ring, a 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, and a 2,5,6,7-tetrahydro-1,3,5-oxadiazazepine ring.

[0013] In some embodiments, the 3- to 7-membered saturated or partially unsaturated monocyclic ring represented by Ring A is selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclopentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadiene ring, a cycloheptyl ring, a cycloheptanyl cycloheptanyl ring, a cyclopentanone ring, and a cyclopentane-1,3-diketone ring.

[0014] In some embodiments, the compound of formula (I) has a structure of formula (III-a) or (III-b): JPEG0007657943000003.jpg58126However, R 1a is hydrogen, C 1-6 Alkyl group (preferably C 1-3 Alkyl group) or deuterated C 1-6 Alkyl groups (preferably deuterated C 1-3 alkyl group), n is 1, 2, 3, 4, 5, or 6, t is 0, 1, 2, 3, or 4, and R 11 , R 12 are independently hydrogen, C 1-3 an alkyl group or a halogen, the other groups being as defined above.

[0015] In some embodiments, R 2 , R 3 are independently hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group) or deuterated C 1-8 Alkyl groups (preferably deuterated C 1-6 Alkyl groups, more preferably deuterated C 1-3 alkyl group), 3-8 The cycloalkyl groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)C 1-3 Alkyl group, -C(O)OC 1-3It is substituted with one, two or three substituents selected from alkyl groups.

[0016] In some embodiments, R 2 is hydrogen or C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 alkyl group), and R 3 is hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group) or deuterated C 1-8 Alkyl groups (preferably deuterated C 1-6 Alkyl groups, more preferably deuterated C 1-3 alkyl group), 3-8 The cycloalkyl groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 is substituted with one, two or three substituents selected from:

[0017] In some embodiments, R 2 , R 3are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclopentyl, 1-methylcyclohexyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuterated methyl, monodeuterated ethyl, deuterated methyl, deuterated ethyl, tritiated methyl, or tritiated ethyl.

[0018] In some embodiments, the compound of formula (III-a) has a structure of formula (III-a-1) or (III-a-2): JPEG0007657943000004.jpg64106However, R 3 ' is C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 1-8 Alkoxy groups (preferably C 1-6 Alkoxy groups, more preferably C 1-3 alkoxy group), cyano group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), -C(O)NR a0 R b0 , -C(O)C 1-8 Alkyl group (preferably -C(O)C 1-6 Alkyl groups, more preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-8 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group) or -OC(O)C 1-8 Alkyl groups (preferably -OC(O)C 1-6 Alkyl groups, more preferably -OC(O)C 1-3 alkyl group), provided that the C1-8 Alkyl group, C 1-8 The alkoxy groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 It is substituted by 1, 2 or 3 substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are each optionally substituted by 1, 2 or 3 substituents independently selected from the substituent group S, and the other groups are as defined above.

[0019] In some embodiments, the compound of formula (III-a) has a structure of formula (III-a-3): JPEG0007657943000005.jpg52104 where the groups are defined as above.

[0020] In some embodiments, R 3 ' is C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group) or deuterated C 1-8 Alkyl groups (preferably deuterated C1-6 Alkyl groups, more preferably deuterated C 1-3 alkyl group).

[0021] In some embodiments, R 3 ' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuteromethyl, monodeuteroethyl, deuteromethyl, deuteroethyl, tritiatedmethyl or tritiatedethyl.

[0022] In some embodiments, in the structure of Formula (III-a), Formula (III-a-1), or Formula (III-a-2), t is 1 or 2, m is 0, and R 4 is H and R 5 is H, -C(O)C 1-3 Alkyl group, -C(O)OC 1-3 Alkyl group, -(C=N)-C 1-3 Alkyl group or -(C=N)-NH 2 It is.

[0023] In some embodiments, R a , R b are independently hydrogen, C 1-6 Alkyl group (preferably C 1-3 Alkyl group), C 3-6 Cycloalkyl groups, C 1-6 Alkoxy groups (preferably C 1-3 Alkoxy group), halogenated C 1-6 Alkyl groups (preferably halogenated C 1-3 alkyl group), cyano group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), -C(O)NR a0 R b0 , -C(O)C 1-6 Alkyl group (preferably -C(O)C 1-3alkyl group), -C(O)OC 1-6 Alkyl group (preferably -C(O)OC 1-3 alkyl group), -OC(O)C 1-6 Alkyl groups (preferably -OC(O)C 1-3 Alkyl group), -SO 2 C 1-6 Alkyl group (preferably -SO 2 C 1-3 Alkyl group), -SO 2 NR a0 R b0 However, the above C 1-6 Alkyl group, C 1-6 The alkoxy groups are unsubstituted or independently substituted with deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 It is substituted by 1, 2 or 3 substituents selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclic alkyl group, a phenyl group, and a 5- to 6-membered heteroaryl group, with the proviso that the phenyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 substituents each independently selected from the substituent group S.

[0024] In some embodiments, R a , R beach independently represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monodeuterated methyl, monodeuterated ethyl, deuterated methyl, deuterated ethyl, tritiated methyl, tritiated ethyl, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)NH 2 , -C(O)NH(C 1-3 alkyl group), -C(O)N(C 1-3 (alkyl group) 2 , -C(O)C 1-6 Alkyl group (preferably -C(O)C 1-3 alkyl group), -C(O)OC 1-6 Alkyl group (preferably -C(O)OC 1-3 alkyl group), -OC(O)C 1-6 Alkyl groups (preferably -OC(O)C 1-3 Alkyl group), -SO 2 C 1-6 Alkyl group (preferably -SO 2 C 1-3 Alkyl group), -SO 2 NH 2 , -SO 2 NH(C 1-3 Alkyl group), -SO 2 N(C 1-3 (alkyl group) 2 It is.

[0025] In some embodiments, R 4 , R 5 are independently hydrogen, C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 alkyl group), -C(O)OC 1-8Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), or R 4 , R 5 form a 3- to 7-membered saturated or partially unsaturated monoheterocyclic ring together with the nitrogen atom to which it is linked, provided that the 3- to 7-membered saturated or partially unsaturated monoheterocyclic ring is unsubstituted or each independently contains a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 It is substituted by 1, 2 or 3 substituents selected from a cycloalkyloxy group and a 3- to 6-membered heterocyclic alkyl group.

[0026] In some embodiments, R 4 , R 5 and the nitrogen atom linked thereto are 4- to 6-membered saturated or partially unsaturated monoheterocycles selected from azetidine, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, 1,2-dihydroazetidiene ring, 2,5-dihydro-1H-pyrrole ring, 2,3-dihydro-1H-pyrrole ring, 1,2,3,4-tetrahydropyridine ring, and 1,2,3,6-tetrahydropyridine ring.

[0027] In some embodiments, R a , R bThe condensed 3- to 7-membered saturated or partially unsaturated monoheterocycle formed by linking the above rings includes condensed azetidine, condensed oxetane, condensed tetrahydrofuran ring, condensed tetrahydrothiophene ring, condensed tetrahydropyrrole ring, condensed piperidine ring, condensed piperazine ring, condensed morpholine ring, condensed thiomorpholine ring, condensed thiomorpholine-1,1-dioxide, condensed tetrahydropyran ring, condensed 1,2-dihydroazetidiene ring, condensed 1, It is a fused 4- to 6-membered saturated monoheterocycle selected from a 2-dihydroxyoxyheterocycle butadiene ring, a fused 2,5-dihydro-1H-pyrrole ring, a fused 2,5-dihydrofuran ring, a fused 2,3-dihydrofuran ring, a fused 2,3-dihydro-1H-pyrrole ring, a fused 3,4-dihydro-2H-pyran ring, a fused 1,2,3,4-tetrahydropyridine ring, a fused 3,6-dihydro-2H-pyran ring, or a fused 1,2,3,6-tetrahydropyridine ring.

[0028] In some embodiments, R a , R b The fused 3- to 7-membered saturated or partially unsaturated monocyclic ring formed by linking the above is a fused 3- to 6-membered saturated monocyclic ring selected from a fused cyclopropyl ring, a fused cyclobutyl ring, a fused cyclopentyl ring, a fused cyclopentenyl ring, a fused cyclohexyl ring, a fused cyclohexenyl ring, and a fused cyclohexadiene ring.

[0029] In some embodiments, any two R are attached to the same ring atom or different ring atoms. 0 The 3- to 7-membered saturated or partially unsaturated monoheterocycle formed by linking these is a 4- to 6-membered saturated monoheterocycle selected from azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, and tetrahydropyran ring.

[0030] In some embodiments, any two R are attached to the same ring atom or different ring atoms. 0The 3- to 7-membered saturated or partially unsaturated monocyclic ring formed by linking the above is a 3- to 6-membered saturated monocyclic ring selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring.

[0031] In some embodiments, R a0 , R b0 and the nitrogen atom linked thereto, the 4- to 6-membered saturated monoheterocycle is selected from an azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, and tetrahydropyran ring.

[0032] In some embodiments, R a1 , R b1 and the nitrogen atom linked thereto, the 4- to 6-membered saturated monoheterocycle is selected from an azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, and tetrahydropyran ring.

[0033] In some embodiments, in each of the above structural formulas, the 5- to 6-membered heteroaryl groups described in each group are each independently selected from a thienyl group, a furyl group, a thiazolyl group, an isothiazolyl group, an imidazole group, an oxazolyl group, a pyrrole group, a pyrazole group, a triazole group, a 1,2,3-triazole group, a 1,2,4-triazole group, a 1,2,5-triazole group, a 1,3,4-triazole group, a tetrazolyl group, a isoxazole group, a oxadiazole group, a 1,2,3-oxadiazole group, a 1,2,4-oxadiazole group, a 1,2,5-oxadiazole group, a 1,3,4-oxadiazole group, a thiadiazole group, a pyridine group, a pyridazine group, a pyrimidine group, a pyrazinyl group, a triazinyl group, and a tetraoxazine group.

[0034] In some embodiments, the 5-6 membered heteroaryl group is Selected from JPEG0007657943000006.jpg71169.

[0035] The 5- to 6-membered heteroaryl groups are unsubstituted or each independently selected from halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 Alkoxy group, NR a1 R b1 , -SO 2 C 1-3 Alkyl group, -S(O)C 1-3 Alkyl group, -C(O)NR a1 R b1 , -C(O)OC 1-3 Alkyl group, -OC(O)C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 3-6 cycloalkyloxy group, 3- to 6-membered heterocyclic alkyl group, phenyl group, and 5- to 6-membered heteroaryl group; R a1 , R b1 It is defined as above.

[0036] In some embodiments, the 8-10 membered heteroaryl group described in each group in each of the above structural formulas is an indole group, an isoindolyl group, an indazolyl group, a benzotriazole group, a benzothienyl group, an isobenzothienyl group, a benzofuryl group, a benzoisofuryl group, a benzimidazole group, a benzoxazolyl group, a benzisoxazole group, a benzoxadiazole group, a benzothiazolyl group, a benzisothiazolyl group, a benzothiadiazol group, a benzo ... It is selected from a zole group, an indolizine group, a purine group, a pyridine[3,2-d]pyrimidine group, a pyridine[2,3-d]pyrimidine group, a pyridine[3,4-d]pyrimidine group, a pyridine[4,3-d]pyrimidine group, a 1,8-naphthyridine group, a 1,7-naphthyridine group, a 1,6-naphthyridine group, a 1,5-naphthyridine group, a pteridine group, a quinoline group, an isoquinoline group, a cinnoline group, a quinoxaline group, a phthalazine group and a quinazoline group.

[0037] In some embodiments, in each of the structural formulas, the 3- to 6-membered heterocyclic alkyl groups described in each group are each independently a 4- to 6-membered heterocyclic alkyl group selected from an azetidine group, a trimethylene oxide group, a tetrahydrofuran group, a tetrahydrothiophene group, a tetrahydropyrrole group, an oxazolyl alkyl group, a dioxolane group, a piperidine group, a piperazine group, a morpholine group, a dioxane group, a thiomorpholine group, a thiomorpholine-1,1-dioxide, a tetrahydropyran group, a pyrrolidine-2-ketone group, a dihydrofuran-2(3H)-ketone group, a morpholine-3-ketone group, a piperazine-2-ketone group, and a piperidine-2-ketone group.

[0038] In some embodiments, the compound of formula (I) is JPEG0007657943000007.jpg98168 JPEG0007657943000008.jpg212169 JPEG0007657943000009.jpg222166 JPEG0007657943000010.jpg224168 JPEG0007657943000011.jpg230168 It is one of the compounds in JPEG0007657943000012.jpg242168.

[0039] In some embodiments, the compound of Formula (I) is any of the Example compounds.

[0040] A second aspect of the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, and a pharma- ceutically acceptable carrier.

[0041] A third aspect of the present invention provides the use of a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutical composition according to the second aspect of the present invention, in the manufacture of a medicament for the treatment of a disease associated with or mediated by CDK9 activity, preferably a hyperproliferative disease, a virally induced infectious disease and / or a cardiovascular disease, more preferably a hyperproliferative disease.

[0042] A fourth aspect of the invention provides a method of treating a disease associated with or mediated by CDK9 activity, said method comprising administering to a subject an effective amount of a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention. In some embodiments, the disease associated with CDK9 activity is a hyperproliferative disease, in particular a cancer, such as a solid tumor or a hematological tumor.

[0043] In the present invention, diseases associated with or mediated by CDK9 activity include diseases associated with or involving CDK9 activity (e.g., CDK9 overactivity) and pathologies associated with these diseases. CDK9 overactivity refers to increased CDK9 enzyme activity compared to normal non-diseased cells, or CDK9 activity that leads to unwanted cell proliferation or reduced or deficient programmed cell death (cell apoptosis), or mutations that lead to constitutive activation of CDK9. Hyperproliferative diseases include diseases involving undesirable or uncontrolled proliferation of cells, and also diseases involving reduced or deficient programmed cell death (cell apoptosis). The compounds of the present invention can be used to prevent, inhibit, block, reduce, decrease, control, etc., cell proliferation and / or cell division, and / or cause cell apoptosis. The method includes administering to a subject in need thereof (including a mammal, including a human) an amount of a compound of the present invention or a pharma- ceutical acceptable salt, hydrate, or solvate thereof that effectively treats or prevents the disease.

[0044] Hyperproliferative diseases in the context of the present invention include, but are not limited to, angiogenic or vascular proliferative diseases, such as breast, respiratory, brain, reproductive organs, gastrointestinal, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid cancer and their distant metastases, mesangial cell proliferative diseases and solid tumors. These diseases further include lymphomas, sarcomas and leukemias. In some embodiments, the cancer is selected from pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, and leukemia.

[0045] 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. Due to space limitations, we will not describe them in further detail here. [Brief description of the drawings]

[0046] [Figure 1]FIG. 1 shows changes in tumor volume after oral administration of compound D and compound Z-11-P1 once a day. [Diagram 2] FIG. 1 is a graph showing changes in mouse body weight after oral administration of compound D and compound Z-11-P1 once a day. [Diagram 3] FIG. 1 shows changes in tumor volume after oral administration of Compound D and Compound Z-5-2 once a day. [Figure 4] FIG. 1 is a graph showing changes in mouse body weight after oral administration of Compound D and Compound Z-5-2 once a day. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] As a result of intensive and detailed research, the present inventors have unexpectedly discovered substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives with significant CDK9 selective inhibitory activity and excellent in vivo pharmacokinetic activity. Therefore, this series of compounds is expected to be developed as drugs for treating and / or preventing diseases related to or mediated by CDK9 activity. Based on this, the inventors have completed the present invention.

[0048] Term definition

[0049] In order to make the technical content of the present invention more clearly understood, the terms used in the present invention are further explained below.

[0050] "Alkyl group" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. 1-8 The term "alkyl group" refers to an alkyl group having 1 to 8 carbon atoms, preferably C 1-6 Alkyl groups, more preferably C 1-3Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 20-methylhexyl, 21-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43- Examples of dimethylhexyl include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.

[0051] The term "alkenyl group" refers to a linear or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C). 2-8 The term "alkenyl group" refers to an alkenyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkenyl groups, more preferably C 2-4 Alkenyl groups are similar in definition, and non-limiting examples of alkenyl groups include vinyl, propenyl, isopropenyl, normal butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0052] The term "alkynyl group" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, and includes "C 2-8 The term "alkynyl group" refers to an alkynyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkynyl groups, more preferably C 2-4 For alkynyl groups, the definition is similar, and non-limiting examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutylenyl, pentonyl, hexynyl, and the like.

[0053] The terms "cycloalkyl group" and "cycloalkyl ring" are used interchangeably and refer to a saturated monocyclic, bicyclic, or polycyclic hydrocarbon group, or a group fused to an aryl or heteroaryl group, or an optionally substituted form thereof. In some embodiments, the cycloalkyl group ring contains one or more carbonyl groups, such as oxygenated groups. 3-8 "Cycloalkyl group" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-diketone, and the like. Preferably, C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 8-10 "Cycloalkyl group" refers to a fused bicyclic hydrocarbon group having 8 to 10 ring atoms, C 8-10 Non-limiting examples of cycloalkyl groups include Contains JPEG0007657943000013.jpg2274.

[0054] The terms "spirocyclic group" and "spiro ring" are used interchangeably and refer to a polycyclic hydrocarbon group in which one carbon atom (called a spiro atom) is shared between the monocyclic rings. A "7-11 membered spirocyclic group" refers to a spiro ring having 7-11 ring atoms. Depending on the number of rings, the spiro ring is divided into a double spiro ring or a multiple spiro ring, and a double spiro ring is preferred. More preferably, it is a 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered double spiro ring. For example, The image is JPEG0007657943000014.jpg23131.

[0055] The terms "cycloalkenyl group" and "cycloalkenyl ring" are used interchangeably and refer to a monocyclic, bicyclic or polycyclic hydrocarbon group having one or more carbon-carbon double bonds within the ring, which may be fused to an aryl or heteroaryl group. The cycloalkenyl ring may be optionally substituted. In some embodiments, the cycloalkenyl ring contains one or more carbonyl groups, such as oxygenated groups. "C 3-8 The term "cycloalkenyl group" refers to a monocyclic cycloalkenyl group having 3 to 8 carbon atoms. 3-6 Cycloalkenyl groups. Non-limiting examples of cycloalkenyl groups include cyclobutene, cyclopentenyl, cyclohexenyl, cyclohexadiene, cycloheptanyl, cycloheptanyl, cyclopentyl-2-ene-1-ketone, cyclohexyl-2,5-diene-1-ketone, cyclohexyl-2-ene-1-ketone, cyclohexyl-2-ene-1,4-diketone, and the like.

[0056] The terms "heterocyclic alkyl group" and "heterocyclic alkyl group ring" are used interchangeably and refer to a cycloalkyl group containing at least one heteroatom, such as nitrogen, oxygen, and sulfur, in the ring atom, which can be fused with an aryl or heteroaryl group. The heterocyclic alkyl group ring can be optionally substituted. In some embodiments, the heterocyclic alkyl group ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxygen and thio. A "3-8 membered heterocyclic alkyl group" refers to a monocyclic hydrocarbon group having 3-8 ring atoms, with one, two, or three ring atoms being selected from nitrogen, oxygen, and sulfur, and is preferably a 4-8 membered heterocyclic alkyl group. More preferably, the heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group, with three to six ring atoms, with one or two ring atoms being selected from nitrogen, oxygen, and sulfur. More preferred are 4- to 6-membered heterocyclic alkyl groups having 4 to 6 ring atoms, provided that one or two of the ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include nitrogen propyl ring groups, oxiranyl groups, azetidine groups, trimethylene oxide groups, tetrahydrofuran groups, tetrahydrothiophene groups, tetrahydropyrrole groups, oxazolylalkyl groups, dioxolane groups, piperidine groups, piperazine groups, morpholine groups, dioxane groups, thiomorpholine groups, thiomorpholine-1,1-dioxide, tetrahydropyran groups, azetidine-2-ketone groups, oxetane-2-ketone groups, dihydrofuran-2(3H)-ketone groups, pyrrolidine-2-ketone groups, pyrrolidine-2,5-diketone groups, dihydrofuran-2,5-diketone groups, piperidine-2-ketone groups, tetrahydro-2H-pyran-2-ketone groups, piperazine-2-ketone groups, morpholine-3-ketone groups, and the like. The terms "6- to 12-membered heterocyclic alkyl group" and "6- to 12-membered fused heterocyclic alkyl group" are used interchangeably and refer to a bicyclic hydrocarbon group having 6 to 12 ring atoms, provided that 1, 2, or 3 ring atoms are fused to heteroatoms selected from nitrogen, oxygen, and sulfur.The terms "8-10 membered heterocyclic alkyl group" and "8-10 membered fused heterocyclic alkyl group" are used interchangeably and refer to a fused bicyclic hydrocarbon group having 8 to 10 ring atoms, where one, two or three ring atoms are selected from nitrogen, oxygen and sulfur. Non-limiting examples include hexahydro-1H-furan[3,4-c]pyrrole, octahydro-1H-cyclopentane[c]pyridine, hexahydro-1H-pyrrole[2,1-c][1,4]oxazine, octahydropyrrole[1,2-a]pyrazinyl, hexahydropyrrole[1,2-a]pyrazinyl-4(1H)-ketone, octahydrocyclopentane[c]pyrrole, and the like. In fused bicyclic heterocyclic alkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as valence permits. Bicyclic heterocyclic alkyl groups can contain one or more heteroatoms in one or both rings.

[0057] The terms "heterospirocyclic group" and "heterospiro ring" are used interchangeably and refer to a monovalent non-aromatic ring system in which two monocyclic rings share one carbon atom, which consists of a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus, which does not contain any degree of unsaturation, and which is connected to the mother nucleus by one single bond. The heterospiro ring may be optionally substituted. In some embodiments, the heterospiro ring is one or more carbonyl or thiocarbonyl groups, such as groups containing oxygen and thio. A "7-11 membered heterospiro ring" is a heterospiro ring having 7-11 ring atoms, provided that one, two, or three ring atoms are heteroatoms. Non-limiting examples of heterospirocyclic groups include 2,6-diazabicyclo[3.4]octane-5-ketone, 2-oxo-6-azabicyclo[3.3]heptane, 6-oxaspiro[3.3]heptan-2-yl, 7-methyl-7-azaspiro[3.5]nonan-2-yl, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 9-methyl-9-phosphinecyclo[5.5]undecane-3-yl, and the like.

[0058] "Heterocyclic alkenyl" and "heterocyclic alkenyl ring" are used interchangeably and are heterocyclic alkyl groups containing one or more carbon-carbon or carbon-nitrogen double bonds in the ring backbone, but are not intended to include heteroaryl moieties as defined herein. The group can be fused with an aryl or heteroaryl group. The heterocyclic alkenyl ring can be optionally substituted. In some embodiments, the heterocyclic alkenyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxygen and thio. "5-8 membered heterocyclic alkenyl ring" refers to a heterocyclic alkenyl ring having 5-8 ring atoms, with one, two or three ring atoms being heteroatoms selected from nitrogen, oxygen and sulfur. A 5-6 membered heterocyclic alkenyl ring is preferred. Non-limiting examples of heterocyclic alkenyl rings include a 4,5-dihydro-1H-imidazole ring, a 1,4,5,6-tetrahydropyrimidine ring, a 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, a 1,6-dihydropyrimidine ring, a 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, and a 2,5,6,7-tetrahydro-1,3,5-oxadiazazepine ring.

[0059] The terms "aryl group" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which may be fused to a cycloalkyl ring, a heterocyclic alkyl ring, a cycloalkenyl ring, a heterocyclic alkenyl ring, or a heteroaryl group. 6-10 "Aryl group" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, non-limiting examples of aryl groups include phenyl, naphthyl, and the like.

[0060] The terms "heteroaryl group" and "heteroaryl ring" are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons shared in a cyclic arrangement) having cyclic carbon atoms and cyclic heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In the present invention, heteroaryl groups further include ring systems in which the heteroaryl ring is fused with one or more cycloalkyl rings, heterocyclic alkyl rings, cycloalkenyl rings, heterocyclic alkenyl rings, or aromatic rings. The heteroaryl rings may be optionally substituted. A "5-10 membered heteroaryl group" refers to a monocyclic or bicyclic heteroaryl group having 5-10 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms. The term "5- to 6-membered heteroaryl group" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, provided that 1, 2, 3, or 4 ring atoms are heteroatoms, and non-limiting examples include thienyl, furyl, thiazolyl, isothiazolyl, imidazole, oxazolyl, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolyl, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazinyl, triazinyl, and tetraoxazine.The term "8-10 membered heteroaryl group" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, provided that 1, 2, 3 or 4 ring atoms are heteroatoms. Non-limiting examples include indole, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuryl, benzoisofuryl, benzimidazole, benzoxazolyl, benzisoxazole, benzoxadiazole, benzothiazolyl, and the like. Heteroaryl, benzisothiazolyl, benzothiadiazole, indolizine, purine, pyridine[3,2-d]pyrimidine, pyridine[2,3-d]pyrimidine, pyridine[3,4-d]pyrimidine, pyridine[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pteridine, quinoline, isoquinoline, cinnoline, quinoxaline, phthalazine, and quinazoline. "Heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings.

[0061] "Fused" refers to a structure in which two or more rings share one or more bonds.

[0062] A "phenylheterocyclic alkyl group" refers to a group in which a benzene ring and a heterocyclic alkyl ring are fused to form a bicyclic, tricyclic or polycyclic system, where the heterocyclic alkyl ring is as defined above. A "7-11 membered phenylheterocyclic alkyl group" refers to a bicyclic group having 7-11 ring atoms, where 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Preferred are 8-10 membered phenylheterocyclic alkyl groups, having 8-10 ring atoms, where 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include indoline, benzo[d][1,3]bisoxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, and the like.

[0063] "Heteroaryl heterocyclic alkyl group" refers to a group in which a heteroaryl ring and a heterocyclic alkyl ring are fused to form a bicyclic, tricyclic or polycyclic ring system, where the heterocyclic alkyl ring is defined above. "7-11 membered heteroaryl heterocyclic alkyl group" refers to a bicyclic group having 7-11 ring atoms, where 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Preferably, it is an 8-10 membered heteroaryl heterocyclic alkyl group, having 8-10 ring atoms, where 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include 2,3-dihydro-1H-pyrrole[2,3-b]pyridine, [1,3]dioxolane[4,5-b]pyridine, 2,3-dihydro-1H-pyridine[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4,5,6-tetrahydropyran[2,3-c]pyrazole, 5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine, and the like.

[0064] The term "alkoxy group" refers to an -O-alkyl group, where alkyl is as defined above. 1-8 is an alkoxy group, more preferably C 1-6An alkoxy group, most preferably C 1-3 An alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy, and the like.

[0065] "Cycloalkyloxy group" refers to an -O-cycloalkyl group, where cycloalkyl is as defined above. 3-8 is a cycloalkyloxy group, more preferably C 3-6 Non-limiting examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0066] A "single bond" refers to the two groups attached thereto being linked by a single covalent bond.

[0067] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0068] "Halogenated" refers to one or more (eg, 1, 2, 3, 4 or 5) hydrogens in a group being replaced with a halogen.

[0069] For example, a "halogenated alkyl group" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, where alkyl is as defined above. Preferably, the halogenated C 1-8 is preferably an alkyl group, more preferably a halogenated C 1-6 is preferably an alkyl group, more preferably a halogenated C 1-3 Examples of halogenated alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0070] For example, a "halogenated alkoxy group" refers to an alkoxy group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, where alkoxy is as defined above. 1-8 Alkoxy groups, more preferably halogenated C 1-6 Alkoxy groups, more preferably halogenated C 1-3 Alkoxy groups. Halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0071] For example, a "halogenated cycloalkyl group" refers to a cycloalkyl group that is substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, where cycloalkyl is as defined above. Preferably, the halogenated C 3-8 Cycloalkyl groups, more preferably halogenated C 3-6 Cycloalkyl groups. Halogenated cycloalkyl groups include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

[0072] A "deuterated alkyl group" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, where alkyl is as defined above. Preferably, the deuterated C 1-8 is an alkyl group, more preferably a deuterated C 1-6 is an alkyl group, more preferably a deuterated C 1-3 Examples of deuterated alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, deuterated methyl, deuterated ethyl, tritiated methyl, tritiated ethyl, and the like.

[0073] "Amino group" is NH2 , where 'cyano group' is CN and 'nitro group' is NO 2 and the "benzyl group" is -CH 2 -phenyl group, "oxo group" is =O, "carboxyl group" is -C(O)OH, and "acetyl group" is -C(O)CH 3 and the "methylol group" is -CH 2 OH, and a "hydroxyethyl group" is -CH 2 CH 2 OH or -CHOHCH 3 , the "hydroxyl group" is -OH, the "mercaptan" is SH, and the "subcyclopropyl" structure is The file is TIFF0007657943000015.tif1013.

[0074] A "saturated or partially unsaturated monocyclic ring" refers to a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated" refers to at least one double or triple bonded ring moiety, and "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. In some embodiments, the saturated or partially unsaturated monocyclic ring contains one or more carbonyl groups, including oxygenated groups, etc. A "3-7 membered saturated or partially unsaturated monocyclic ring" is a saturated or partially unsaturated monocyclic ring having 3-7 ring carbon atoms, preferably 3-6 ring carbon atoms, and more preferably a saturated monocyclic ring having 3-6 ring carbon atoms. Non-limiting examples of saturated or partially unsaturated monocyclic rings include a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclopentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadiene ring, a cycloheptyl ring, a cycloheptanyl cycloheptanyl ring, a cyclopentanone ring, a cyclopentane-1,3-diketone ring, and the like.

[0075] A "saturated or partially unsaturated monoheterocyclic ring" is a saturated or partially unsaturated monocyclic ring in which one, two or three ring carbon atoms are nitrogen, oxygen or S(O). t(wherein t is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. A "3- to 7-membered saturated or partially unsaturated monoheterocycle" has 3 to 7 ring atoms, with 1, 2, or 3 ring atoms being the above heteroatoms. It preferably has 3 to 6 ring atoms, with 1 or 2 ring atoms being the above 3- to 6-membered saturated or partially unsaturated monoheterocycle, more preferably has 5 to 6 ring atoms, with 1 or 2 ring atoms being the above 5- to 6-membered saturated or partially unsaturated monoheterocycle, and most preferably is a 5- or 6-membered saturated monoheterocycle. Non-limiting examples of saturated monoheterocyclic rings include a propylene oxide ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrrolidine ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-ketone ring, an oxetane-2-ketone ring, a pyrrolidine-2-ketone ring, a pyrrolidine-2,5-diketone ring, a piperidine-2-ketone ring, a dihydrofuran-2(3H)-ketone ring, a dihydrofuran-2,5-diketone ring, a tetrahydro-2H-pyran-2-ketone ring, a piperazine-2-ketone ring, and a morpholine-3-ketone ring. Non-limiting examples of partially unsaturated monoheterocycles include a 1,2-dihydroazetidiene ring, a 1,2-dihydroxyheterocycle butadiene ring, a 2,5-dihydro-1H-pyrrole ring, a 2,5-dihydrofuran ring, a 2,3-dihydrofuran ring, a 2,3-dihydro-1H-pyrrole ring, a 3,4-dihydro-2H-pyran ring, a 1,2,3,4-tetrahydropyridine ring, a 3,6-dihydro-2H-pyran ring, a 1,2,3,4-tetrahydropyridine ... , 2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, 2,5,6,7-tetrahydro-1,3,5-oxadiazazepine ring, etc.

[0076] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms are substituted with a corresponding number of substituents independently of each other, more preferably 1 to 3 hydrogen atoms are substituted with a corresponding number of substituents independently of each other. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0077] Unless otherwise specified, the term "substituents each independently selected from" as used herein means that when one or more hydrogen atoms on a group are replaced with substituents, the types of the substituents may be the same or different, and each selected substituent is an independent type.

[0078] Unless otherwise specified, the phrase "may be the same or different, and each is independently ..." used in the present invention means that when one or more of the same substituents are present in the general formula, the groups may be the same or different, and each is an independent type. For example, L is (CR 01 R 02 ) s If s is 2, then L is (CR 01 R 02 )-(CR 01 R 02 ), of which two R 01 or R 02 may be the same or different and are each an independent entity, e.g., L is C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN)(CH 2 CH 3 )-C(OH)(CH 2 CH 3 ) may also be used.

[0079] Unless otherwise defined, any group herein may be substituted or unsubstituted. When the group is substituted, the substituents are independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 Alkyl group (preferably C 1-6 Alkyl groups, more preferably C 1-3 Alkyl group), C 1-8 Alkoxy groups (preferably C 1-6 Alkoxy groups, more preferably C 1-3 Alkoxy group), halogenated C 1-8 Alkyl groups (preferably halogenated C 1-6 Alkyl groups, more preferably halogenated C 1-3 Alkyl group), C 3-8 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups), halogenated C 1-8 Alkoxy groups (preferably halogenated C 1-6 Alkoxy groups, more preferably halogenated C 1-3 Alkoxy group), C 1-8 Amino groups substituted with alkyl groups, halogenated C 1-8 Amino group substituted with alkyl group, acetyl group, hydroxyl group, methylol, hydroxyethyl, carboxyl group, nitro group, C 6-10 Aryl group (preferably phenyl group), C 3-8 Cycloalkyloxy groups (preferably C 3-6 Cycloalkyloxy group), C 2-8 Alkenyl group (preferably C 2-6 Alkenyl groups, more preferably C 2-4 alkenyl group), C 2-8 Alkynyl groups (preferably C 2-6 Alkynyl groups, more preferably C 2-4 alkynyl group), -CONR a0 R b0 , -C(O)OC 1-10 Alkyl group (preferably -C(O)OC 1-6 Alkyl groups, more preferably -C(O)OC 1-3 alkyl group), -CHO, -OC(O)C 1-10 Alkyl groups (preferably -OC(O)C 1-6Alkyl groups, more preferably -OC(O)C 1-3 Alkyl group), -SO 2 C 1-10 Alkyl group (preferably -SO 2 C 1-6 An alkyl group, more preferably -SO 2 C 1-3 Alkyl group), -SO 2 C 6-10 Aryl groups (preferably -SO 2 C 6 Aryl groups, such as -SO 2 -phenyl group), -COC 6-10 Aryl groups (preferably -COC 6 R is preferably 1 to 5 groups selected from an aryl group, such as an -CO-phenyl group), a 4- to 6-membered saturated or unsaturated monoheterocycle, a 4- to 6-membered saturated or unsaturated monocycle, a 5- to 6-membered monocyclic heteroaryl ring, an 8- to 10-membered bicyclic heteroaryl ring, a spiro ring, a spiro heterocycle, a bridged ring or a bridged heterocycle, a0 , R b0 are each independently hydrogen or C 1-3 It is an alkyl group.

[0080] The various substituents as defined herein above may themselves be substituted with groups as described herein.

[0081] When the 4-6 membered saturated monoheterocycles described herein are substituted, the positions of the substituents can be located at their possible chemical positions, and representative substitution cases of the exemplary monoheterocycles are as follows: JPEG0007657943000016.jpg81169 JPEG0007657943000017.jpg78169, where "Sub" represents various substituents as described herein; JPEG0007657943000018.jpg616 shows connections to other atoms.

[0082] Drug Composition

[0083] In general, the compound of the present invention or its pharma- ceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug can be administered by forming an appropriate dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, buccal, and other non-gastrointestinal administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compound of the present invention contained in these preparations may be a solid powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, a water-in-oil or oil-in-water emulsion, etc. The above dosage forms can be prepared by a conventional pharmaceutical method by combining an active compound and one or more carriers or auxiliary materials. The above carriers must be compatible with the active compound or other auxiliary materials. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol, etc. The active compound may form a solution or suspension with the above carriers.

[0084] A "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or auxiliary formulation or auxiliary material of any type, which is compatible with the subject to which it is administered (preferably a mammal, more preferably a human) and is suitable for transporting an active agent to its intended target without terminating the activity of the agent.

[0085] The term "active substance of the present invention" or "active compound of the present invention" refers to a compound represented by formula (I) of the present invention, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has high CDK9 selective inhibitory activity.

[0086] The compositions of the present invention are formulated, quantified and administered in a manner consistent with standard medical practice. The "therapeutically effective amount" in which the compound is administered will depend on factors such as the particular disease being treated, the individual being treated, the cause of the disease, the target of the drug and the mode of administration.

[0087] "Therapeutically effective amount" refers to an amount of a compound of the present invention or a pharma- ceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, that reduces or inhibits an enzyme or protein activity, or elicits a biological or medical response in an individual, such as ameliorating symptoms, relieving a disease, slowing or retarding disease progression, or preventing a disease.

[0088] The therapeutically effective amount of the compound of the present invention or a pharma- ceutical acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof contained in the drug composition or pharmaceutical composition according to the present invention is preferably 0.1 mg / kg-5 g / kg (body weight).

[0089] "Subject" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

[0090] "Treatment" refers to relieving, slowing, attenuating, preventing the progression, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or disorder.

[0091] The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.

[0092] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, etc., and salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc. These salts can be prepared by methods known in the art.

[0093] The term "solvate" as referred to in the present invention refers to a complex formed between the compound of the present invention and a solvent. They react in the solvent or precipitate or crystallize from the solvent. For example, a complex formed with water is called a "hydrate". The solvate of the compound of formula (I) is within the scope of the present invention.

[0094] When the compound of formula (I) of the present invention contains one or more chiral centers, it can exist in different optically active forms. When the compound of formula (I) contains one chiral center, the compound includes a pair of enantiomers. The two enantiomers of the compound and the mixture of the pair of enantiomers, such as a racemic mixture, are also within the scope of protection of the present invention. The enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of formula (I) contains one or more chiral centers, the compound includes enantiomers and diastereomers. All enantiomers and diastereomers of the compound, mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers are also within the scope of protection of the present invention. The enantiomers and diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

[0095] The present invention includes prodrugs of the above compounds. The prodrugs contain known amino and carboxyl protecting groups and are hydrolyzed under physiological conditions or released by enzymatic reactions to obtain the parent compounds. For specific methods of preparing prodrugs, see (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0096] Preparation method

[0097] The present invention provides a method for preparing the compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art, or by combining methods known in the art with the methods described in the present invention. The solvents, temperatures and other reaction conditions given in the present invention may vary according to the skill of the art. The reactions can be used in sequence to provide the compounds of the present invention, or they can be used to synthesize fragments, which are added subsequently by the methods described in the present invention and / or known in the art.

[0098] The compounds described in the present invention can be synthesized using suitable selectable starting materials using methods similar to those described below or exemplary methods described in the Examples, or relevant published literature used by those skilled in the art. The starting materials for synthesizing the compounds described in the present invention can be synthesized or commercially obtained. The compounds described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The general method for preparing the compounds disclosed in the present invention can be obtained from reactions known in the art, and the reactions can be modified by suitable reagents and conditions considered by those skilled in the art to introduce various moieties in the molecules provided by the present invention.

[0099] Compared with the prior art, the main advantages of the present invention are: We have provided a series of novel substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives that have highly selective inhibitory activity against CDK9 and excellent in vivo pharmacokinetic activity, and have developed IC 50 Since the value is less than 100 nM, preferably less than 50 nM, more preferably less than 10 nM, it can be used as a drug for treating and / or preventing diseases associated with or mediated by CDK9 activity.

[0100] The present invention will be further described below with reference to specific examples. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The following examples do not show specific conditions for the experimental methods, but generally follow conventional conditions, such as those described in Molecular Cloning: A Laboratory Manual by Sambrook et al. (New York: Cold Spring Harbor Laboratory Press, 1989), or follow the manufacturer's recommended conditions. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise defined, the terms used in this specification have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.

[0101] Known starting materials may be synthesized by methods known in the art or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.) and Dali Chemicals.

[0102] Unless otherwise noted, all reactions in the examples are carried out under a nitrogen or argon atmosphere.

[0103] DMF: dimethylformamide, DMSO: dimethylsulfoxide, THF: tetrahydrofuran, DIEA: N,N-diisopropylethanamine, EA: ethyl acetate, PE: petroleum ether, BINAP: (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthalene, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, CDI: N,N'-carbonyldiimidazole, Pd 2 (dba) 3 : Tris(diphenylenemethylacetone)dipalladium, Pd(dppf)Cl 2: [1,1'-Bis(triphenylphosphine)ferrocene]palladium(II) dichloride, DPPA: diphenyl azidophosphate, DBU: 1,8-diazabicycloundecane-7-ene, TBAF: tetrabutylammonium fluoride, Na Ascorbate: sodium ascorbate, t-BuXPhosPd-G3: (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate. In this specification, room temperature refers to about 20°C-30°C.

[0104] Intermediates Preparation of intermediate V1 JPEG0007657943000019.jpg29141

[0105] Step 1: Dissolve 1,3-disulfan-2-yl(trimethyl)silane (4.23 g, 21.97 mmol) in tetrahydrofuran (20 mL), cool to -78 ° C, add n-butyl lithium (2.5 M, 8.79 mL) dropwise, react for 0.5 hours, add bicyclopropyl ketone (2.2 g, 19.97 mmol) in tetrahydrofuran (10 mL) dropwise, stir at -78 ° C for 1.5 hours, and then warm to room temperature and react for 16 hours. Add saturated sodium chloride solution (100 mL), extract with ethyl acetate (100 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate the residue by silica gel column chromatography (40 g, 100% petroleum ether) to obtain compound V1-1 (3.0 g, pale yellow liquid). Yield: 70.7%. MS m / z(ESI):213.0 [M+1]. Step 2: Compound V1-1 (3.0 g, 14.13 mmol) is dissolved in acetonitrile (50 mL) and water (12.5 mL), and trifluoroacetic acid (4.83 g, 42.38 mmol) and 30% hydrogen peroxide (20.82 g, 183.64 mmol) are added. The mixture is stirred at 80°C for 1 hour, cooled to 40°C, 2N NaOH solution (40 mL) is added to the solution, stirred for 0.5 hours, neutralized by adding 2N hydrochloric acid (40 mL), extracted with ethyl acetate (60 mL x 3), the organic phase is dried over anhydrous sodium sulfate, and the solvent is spin-dried under reduced pressure. The residue is separated by silica gel column chromatography (40 g, 0-60% ethyl acetate / petroleum ether) to obtain compound V1-2 (1.5 g, colorless oil). Yield: 75.8%. MS m / z (ESI): 139.0 [M-1] Step 3: In a reaction vial, 2,2-dicyclopropylacetic acid (1.50 g, 10.70 mmol) is dissolved in tetrahydrofuran (30 mL), CDI (2.31 g, 16.05 mmol) is added, and the mixture is reacted at room temperature for 16 hours (Solution A). In another reaction vial, (3-ethoxy-3-oxopropionyl)oxypotassium (2.73 g, 16.05 mmol) is added to magnesium chloride (1.02 g, 10.70 mmol), and the mixture is heated to 50° C. and reacted for 16 hours (Solution B). Solution A is added dropwise to solution B (about 5 minutes), and the solution is mixed and stirred at room temperature for 16 hours. Ethyl acetate (100 mL) is added, and the mixture is washed with saturated sodium chloride solution (80 mL×3), and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 g, 0-30% ethyl acetate / petroleum ether) to give compound V1 (800 mg, colorless oil). Yield: 33.6%. MS m / z (ESI): 211.1 [M+1]

[0106] Preparation of intermediate V2 JPEG0007657943000020.jpg2985

[0107] Refer to the method of step 3 of the preparation of intermediate V1. The difference is that 2-cyclopropylacetic acid (CAS.NO: 5239-82-7) is used instead of 2,2-dicyclopropylacetic acid to prepare intermediate V2 (light yellow oil, yield: 88.2%). MS m / z (ESI): 171.1 [M+1]

[0108] Preparation of intermediate V3 JPEG0007657943000021.jpg2138

[0109] Refer to the preparation method of intermediate V1. The difference is that 1-cyclopropylethylketone is used instead of bicyclopropylketone to prepare intermediate V3 (light yellow liquid, 47.50% yield). MS m / z (ESI): 185.1 [M+1].

[0110] Preparation of intermediate V4 JPEG0007657943000022.jpg20113

[0111] Add thionyl chloride (919.31 mg, 7.73 mmol) to 2,2-dimethylbutyn-3-enoic acid (588 mg, 5.15 mmol) under nitrogen protection, react at 80 ° C for 2 hours, and concentrate the reaction solution until a yellow oil is obtained. Add n-butyllithium (2.5 M, 6.42 mL) to a solution of 3-ethoxy-3-oxypropionic acid (1.14 g, 8.60 mmol) and tetrahydrofuran (15 mL) under nitrogen protection at -65 ° C, and react at -10 ° C for 1 hour. Add a solution of the above yellow oil in tetrahydrofuran (15 mL), react at -65 ° C for 1 hour, and react at room temperature for 1 hour. Pour the reaction solution into a solution of tetrahydrofuran / 1N hydrochloric acid (20 / 20 mL) and stir at room temperature for 2 hours. The organic layer was separated, washed with saturated sodium carbonate, washed with saturated sodium chloride, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=97.5%:2.5%) to give intermediate V4 (380 mg, 2.06 mmol, 71.97% yield) as a colorless oil. MS m / z(ESI): 185.2 [M+1].

[0112] Preparation of intermediate V5 JPEG0007657943000023.jpg2730

[0113] Refer to the method of step 3 of the preparation of intermediate V1, except that 2-cyclobutylpropionic acid (CAS.NO: 1082453-55-1) is used instead of 2,2-dicyclopropylacetic acid to prepare intermediate V5.

[0114] Preparation of intermediate V6 TIFF0007657943000024.tif2628

[0115] Refer to the preparation of intermediate V1, except that 1-cyclopentyl ethyl ketone is used instead of bicyclopropyl ketone to prepare intermediate V6.

[0116] Preparation of intermediate V7 JPEG0007657943000025.jpg1834

[0117] Refer to the preparation of intermediate V4, except that 2-cyclopropyl-2-methylpropionic acid is used instead of 2,2-dimethylbutyn-3-enoic acid, to prepare intermediate V7.

[0118] Preparation of intermediate V8 JPEG0007657943000026.jpg22162

[0119] Step 1: Dissolve 2,2-dicyclopropyl acetate (2.5 g, 17.83 mmol) in methanol (50 mL) and add thionyl chloride (2.6 mL, 35.67 mmol). The reaction is stirred at 70° C. for 6 hours. Remove the solvent under reduced pressure, add ethyl acetate (60 mL), wash with saturated sodium chloride solution (50 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by separation with silica gel column chromatography to give methyl 2,2-dicyclopropyl acetate (1.6 g, colorless oil). Yield: 51.2%. 1 H NMR(400MHz,DMSO-d6)δ 3.60(s,3H),1.17-1.08(m,1H),1.02-0.88(m,2H),0.53-0.43(m,2H),0.41-0.31(m,2H),0.26-0.20(m,2H),0.14-0.06(m,2H). Step 2: Dissolve methyl 2,2-dicyclopropyl acetate (1.5 g, 9.73 mmol) in tetrahydrofuran (30 mL), cool to -78°C, and add lithium diisopropylamide (2M, 14.59 mL). The reaction is stirred at -78°C for 0.5 hours, then slowly warmed to -20°C and stirred for 0.5 hours, cooled to -78°C, and methyl iodide (4.14 g, 29.18 mmol) is added dropwise, slowly warmed to room temperature, and reacted for 5 hours. Then, cool to -78°C and add lithium diisopropylamide (2M, 14.59 mL). The reaction is stirred at -78°C for 0.5 hours, then slowly warmed to -20°C and stirred for 0.5 hours, cooled to -78°C, methyl iodide (4.14g, 29.18mmol) is added dropwise, and the mixture is slowly warmed to room temperature and reacted for 16 hours. Ethyl acetate (80mL) is added, washed with saturated sodium chloride solution (80mL x 2), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product, methyl 2,2-dicyclopropylpropionate (1.5g, pale yellow oil), is obtained. Yield: 91.7%. No further purification is required and it is used directly in the next step. Step 3: Dissolve methyl 2,2-dicyclopropylpropionate (1.5 g, 8.92 mmol) in methanol (10 mL) and add sodium hydroxide (1.43 g, 35.66 mmol) dissolved in water (4 mL). Stir the reaction at room temperature for 16 hours. Stop the reaction, adjust the pH to about 2 with 2N hydrochloric acid, extract with ethyl acetate (50 mL x 2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate and purify the residue by silica gel column chromatography to give 2,2-dicyclopropylpropionic acid (900 mg, pale yellow oil). Yield: 65.5%. MS m / z (ESI): 155.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 1.01-0.89(m,2H),0.66(s,3H),0.33-0.20(m,8H). Step 4: In a reaction vial, 2,2-dicyclopropylpropionic acid (900 mg, 5.84 mmol) is dissolved in tetrahydrofuran (15 mL), and N,N'-carbonyldiimidazole (1.26 g, 8.75 mmol) is added, and the mixture is reacted at room temperature for 16 hours (Solution A). In another reaction vial, (3-ethoxy-3-oxopropionyl)oxypotassium (2.48 g, 14.59 mmol) is dissolved in tetrahydrofuran (25 mL), and magnesium chloride (1.11 g, 11.67 mmol) is added, and the mixture is heated to 50°C and reacted for 16 hours (Solution B). Then, Solution A is added dropwise to Solution B (about 5 minutes), and the solutions are mixed and stirred at 30°C for 16 hours. The reaction is stopped, ethyl acetate (50 mL) is added, and the mixture is washed with saturated sodium chloride solution (50 mL x 3), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography to obtain ethyl 4,4-dicyclopropyl-3-carbonylvalanoate (600 mg, pale yellow oil). Yield: 45.8%. MS m / z (ESI): 225.1 [M+1].

[0120] Preparation of intermediate V9 JPEG0007657943000027.jpg21170

[0121] Step 1: Dissolve 3-methylbutyl-3-en-1-ol (8.6 g, 99.85 mmol) in dichloromethane (200 mL) at -20 ° C., add diethylzinc (1 M, 299.54 mL) and diiodomethane (79.98 g, 299.54 mmol), and react at -20 ° C for 4 h. Slowly add saturated aqueous ammonium chloride solution to the reaction solution, extract with dichloromethane (2 * 200 mL), dry with anhydrous sodium sulfate, and spin dry. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 80%: 20%) to obtain a pale yellow liquid, 2-(1-methylcyclopropyl)ethanol (5.6 g, yield: 56.0%). 1 H NMR(400MHz,DMSO-d6)δ4.27(s,1H),3.46(dd,J=6.8,4.8Hz,2H),1.40-1.32(m,2H),0.97(s,3H),0.23(t,J=4.8Hz,2H),0.15(dd,J=5.2,4.0Hz,2H). Step 2: Dissolve 2-(1-methylcyclopropyl)ethanol (4.6 g, 45.93 mmol) in acetone under ice bath and add Jones reagent (2.2 M, 62.63 mL). React at room temperature for 16 h, add 70 mL of water to the reaction solution, extract with dichloromethane (2*50 mL), wash twice with saturated saline, dry with anhydrous sodium sulfate, and spin dry at low temperature. The residue is treated with column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain a pale yellow liquid, 2-(1-methylcyclopropyl)acetic acid (1.7 g, yield 32.43%). MS m / z (ESI): 113.1 [M-1]. Step 3: Add N,N'-carbonyldiimidazole (1.92g, 11.83mmol) to a solution of 2-(1-methylcyclopropyl)acetic acid (900mg, 1.67mmol) and tetrahydrofuran (30mL) under nitrogen protection at 0℃, and react at room temperature for 16 hours after addition (solution 1). Heat (3-ethoxy-3-oxopropionyl)oxypotassium (2.01g, 11.83mmol), magnesium chloride (749.07mg, 7.88mmol)) and tetrahydrofuran (30mL) under nitrogen protection and react at 50℃ for 16 hours, and then add 1 drop of the solution to the above reaction solution after cooling to 0℃, and react at room temperature for another 16 hours. Add the reaction solution to ice water, and further extract with ethyl acetate (50mL*3), and concentrate the organic layer to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=90%:10%) to give a pale yellow liquid, ethyl 4-(1-methylcyclopropyl)-3-oxobutanoate (1.2 g, 82.61% yield). MS m / z(ESI): 185.1 [M+1].

[0122] Preparation of intermediate V10 JPEG0007657943000028.jpg25106

[0123] Add N,N'-carbonyldiimidazole (404.67mg, 2.50mmol) to a solution of 2-(3,3-difluorocyclobutyl)acetic acid (250mg, 1.67mmol) and tetrahydrofuran (15mL) under nitrogen protection at 0℃, and react at room temperature for 16 hours after addition (solution 1). Heat (3-ethoxy-3-oxopropionyl)oxypotassium (425.16mg, 2.50mmol), magnesium chloride (158.20mg, 1.67mmol)) and tetrahydrofuran (15mL) under nitrogen protection and react at 50℃ for 16 hours, then cool to 0℃, add 1 drop of the solution to the above reaction solution, and react at room temperature for another 16 hours after addition. Add the reaction solution to ice water and further extract with ethyl acetate (15mL*3), and concentrate the organic layer to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=90%:10%) to give ethyl 4-(3,3-difluorocyclobutyl)-3-oxobutanoate (290 mg, 79.08% yield). MS m / z(ESI): 221.1 [M+1].

[0124] Preparation of intermediate V11 JPEG0007657943000029.jpg45128

[0125] Step 1: Dissolve 2-(1-methylcyclopropyl)acetic acid (1.7 g, 14.89 mmol) in N,N-dimethylformamide (15 mL), add potassium carbonate (6.18 g, 44.68 mmol), and benzyl bromide (3.06 g, 17.87 mmol). React at 25 °C overnight. Add 50 mL of water to the reaction solution, extract with ethyl acetate (2 * 30 mL), wash twice with saturated saline, dry with anhydrous sodium sulfate, and spin dry. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 95%: 5%) to obtain a pale yellow liquid, 2-(1-methylcyclopropyl) benzyl acetate (2.1 g, yield: 69.03%). 1H NMR(400MHz,DMSO-d6)δ 7.45-7.24(m,5H),5.10(s,2H),2.29(s,2H),1.06(s,3H),0.41(t,J=4.8 Hz,2H),0.30(dd,J=5.6,4.0 Hz,2H). Step 2: At -78°C, dissolve 2-(1-methylcyclopropyl)benzyl acetate (1.6g, 7.83mmol) in THF (20mL) and add methyl iodide (5.52g, 39.17mmol). Stir for 30min and add bis(trimethylsilyl)aminolithium (1M, 15.67mL). Slowly return to room temperature and stir for 2h. Add saturated ammonium chloride to the reaction mixture, extract with ethyl acetate (2*50mL), fuse the organic phase, wash twice with saturated saline, dry with anhydrous sodium sulfate, and spin dry. Column chromatography (petroleum ether:ethyl acetate=95%:5%) of the residue gives 2-(1-methylcyclopropyl)benzyl propionate (1.6g, yield: 93.57%) as a pale yellow liquid. Step 3: Dissolve benzyl 2-(1-methylcyclopropyl)propionate (2.1 g, 9.62 mmol) in methanol (20 mL) and add to a solution of sodium hydroxide (3.85 g, 96.20 mmol) in water (10 mL). React at 30 °C for 16 h. Spin off most of the methanol from the reaction solution, extract with methyl tert-butyl ether (2 * 30 mL), adjust the pH to about 4 with hydrochloric acid, extract with methyl tert-butyl ether (2 * 40 mL), wash twice with saturated saline, dry over anhydrous sodium sulfate, and spin dry. Obtain 2-(1-methylcyclopropyl)propionic acid (1.1 g, yield: 89.21%) as a pale yellow liquid. MS m / z (ESI): 127.1 [M-1]. Step 4: Prepared with reference to Step 4 of Intermediate V8. MS m / z(ESI): 199.1 [M+1].

[0126] Preparation of intermediate V12 JPEG0007657943000030.jpg26170

[0127] Step 1: Dissolve 2-cyclopropylacetic acid (50 g, 499.42 mmol) in N,N-dimethylformamide (500 mL), add potassium carbonate (207.07 g, 1.50 mol) and benzyl bromide (111.04 g, 649.25 mmol), and react at 30 °C for 16 h. Add 2 L of water to the reaction solution, extract with ethyl acetate (3 * 500 mL), fuse the organic phase, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, and spin dry. Treat the residue with combi-flash of petroleum ether: ethyl acetate = 10: 1 to obtain compound V12-1 (89 g, yield: 93.68%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ 7.42-7.25(m,5H),5.08(s,2H),2.27(d,J=4 Hz,2H),1.01-0.90(m,1H),0.51-0.38(m,2H),0.19-0.05(m,2H). Step 2: Add bis(trimethylsilyl)aminolithium (1M, 78.85mL) to a three-neck flask and dropwise add compound V12-1 (5g, 26.28mmol), iodoethane (41.00g, 262.83mmol) in tetrahydrofuran (70mL) under argon protection at -78℃. React at -40℃ for 2h. Add saturated ammonium chloride solution to the reaction solution, extract with 2*200mL ethyl acetate, fuse the organic phase and wash twice with saturated brine. Dry with anhydrous sodium sulfate, filter and spin dry. Treat the residue with combi-flash of petroleum ether:ethyl acetate=10:1 to obtain compound V12-2 (2.85g, yield: 49.67%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ 7.40-7.26(m,5H),5.10(s,2H),1.57-1.65(m,3H),0.90-0.79(m,4H),0.52-0.43(m,1H),0.43-0.35(m,1H),0.21-0.12(m,2H). Step 3: Compound V12-2 (22 g, 100.78 mmol) is dissolved in methanol (200 mL), and a solution of sodium hydroxide (32.25 g, 806.26 mmol) in water (100 mL) is added dropwise under ice bath. After the addition is completed, the reaction is carried out at 30 °C for 16 hours. The reaction solution is spun off methanol, 200 mL of water is added to the residue, extracted with methyl tert-butyl ether (3 * 150 mL), the aqueous phase is adjusted to pH = 4, and extracted with methyl tert-butyl ether (3 * 150 mL). The organic phase is combined, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and spin-dried at low temperature. Compound V12-3 (12 g, yield: 90.2%) is obtained as a pale yellow liquid. MS m / z (ESI): 127.2 [M-1]. Step 4: At 0°C, dissolve carbonyldiimidazole (18.96g, 117.03mmol) in tetrahydrofuran (200mL) and add compound V12-3 (10g, 78.02mmol). Stir at room temperature for 16 hours. Dissolve (3-ethoxy-3-oxopropionyl)oxypotassium (39.84g, 234.07mmol) in tetrahydrofuran (200mL) and add magnesium chloride (22.24g, 234.07mmol). Stir at 50°C for 16 hours. Then, slowly drip the liquid in the first flask into the second flask. Stir at room temperature for 16 hours. Add water to the reaction solution, extract with ethyl acetate (3*150mL), fuse the organic phase, wash twice with saturated brine, dry with anhydrous sodium sulfate, and spin dry. The residue was treated with combi-flash with petroleum ether:ethyl acetate=10:1 to give compound V12 (14.8 g, yield: 95.68%) as a yellow liquid. MS m / z (ESI): 199 [M+1].

[0128] Preparation of intermediate V13 JPEG0007657943000031.jpg19170

[0129] Step 1: Add oxaloyl chloride (1.78g, 14.02mmol, 1.20mL) dropwise to a solution of 2-cyclopropyl-2-oxoacetic acid (1g, 8.76mmol) and dichloromethane (15mL) under nitrogen protection at 0℃, add N,N-dimethylformamide (6.41mg, 87.64μmol) after the dropwise addition, warm to room temperature and react for 1 hour. Concentrate the reaction solution to dryness, add dichloromethane (15mL), add dropwise to a solution of benzyl alcohol (1.33g, 12.27mmol, 1.27mL), triethylamine (2.22g, 21.91mmol, 3.06mL) and dichloromethane (15mL) at 0℃, and react at room temperature for 1 hour after the dropwise addition. The reaction mixture is poured into ice water, and further extracted with dichloromethane (15 mL*2). The organic layers are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 90%: 10%) to obtain compound V13-1 (1.26 g, 67.56% yield), which is a colorless liquid (no ion current). Step 2: Add bis(2-methoxyethyl)aminosulfur trifluoride (3.90g, 17.63mmol) to compound V13-1 (900mg, 4.41mmol) and dichloromethane (30mL) under the protection of nitrogen at room temperature, and react at 50℃ for 16 hours after the dropwise addition is completed. Pour the reaction liquid onto ice, extract with dichloromethane (50mL*2), combine the organic layer, wash with saturated aqueous sodium bicarbonate, dry with anhydrous sodium sulfate, and then concentrate to obtain the crude product. Purify the crude product by column chromatography (petroleum ether:ethyl acetate=70%:30%) to obtain compound V13-2 (555mg, yield 55.67%), a colorless liquid (no ion current). Step 3: Compound V13-2 (555 mg, 2.45 mmol), sodium hydroxide (490.64 mg, 12.27 mmol), methanol (5 mL), and water (5 mL) are mixed and reacted at room temperature for 16 hours. Methanol is removed under reduced pressure, and the aqueous phase is washed with methyl tert-butyl ether (15 mL*2), and the aqueous phase is collected and cooled to 0°C, and concentrated to pH=2 by adding concentrated hydrochloric acid, and then extracted with dichloromethane (15 mL*2). The organic layers are combined and dried over anhydrous sodium sulfate, and then concentrated to obtain compound V13-3 (320 mg, 2.35 mmol, 95.84% yield), a yellow liquid. MS m / z (ESI): 135.1 [M-1]. Step 4: Add N,N'-carbonyldiimidazole (507.70 mg, 3.53 mmol) to a solution of compound V13-3 (320 mg, 2.35 mmol) and tetrahydrofuran (20 mL) under nitrogen protection at 0 ° C. and react at room temperature for 16 hours after addition. Heat (3-ethoxy-3-oxopropionyl)oxypotassium (1.00 g, 5.88 mmol), magnesium chloride (447.73 mg, 4.70 mmol) and tetrahydrofuran (20 mL) under nitrogen protection and react at 50 ° C. for 16 hours, and then cool to 0 ° C. and add 1 drop of the solution to the above reaction solution, and react at room temperature for another 16 hours after addition. Add the reaction solution to ethyl acetate (50 mL) and water (50 mL), separate the organic layer, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, and further dry with anhydrous sodium sulfate, and concentrate to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=80%:20%) to give compound V13 (100 mg, 20.63% yield) as a yellow oil.

[0130] Preparation of intermediate V14 JPEG0007657943000032.jpg24136

[0131] Prepare compound V14 by reference to the method for intermediate V12. MS m / z(ESI): 213.1 [M+1].

[0132] Preparation of intermediate V15 JPEG0007657943000033.jpg25166

[0133] Step 1: Dissolve 2-fluoro-2-phosphorosyl triethyl acetate (1.90 g, 7.85 mmol) in 10 mL of THF, exchange nitrogen three times, then cool to -70 °C, slowly add n-butyl lithium (2.5 M, 3.42 mL), and stir at -70 °C for 0.5 h. Warm to 0 °C and stir for 0.5 h. Then add cyclobutanone (0.5 g, 7.13 mmol) slowly at -70 °C, and stir at room temperature for 3 h. Quench with water (20 mL), extract with ethyl acetate (20 mL x 2), wash the organic phase with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography with 0-20% ethyl acetate as eluent and petroleum ether to obtain compound V15-1 (0.8 g, pale yellow liquid). The yield is 70.9%. Step 2: Dissolve compound V15-1 (0.8 g, 5.06 mmol) in methanol (15 mL), add 10% wet Pd / C (538.26 mg, 505.79 μmol), and flush with hydrogen gas three times. Stir under hydrogen (15 Psi) at 25 °C for 1 h. Remove the catalyst by filtration and concentrate under reduced pressure to give compound V15-2 (0.7 g, colorless liquid). Yield: 86.40%. No further purification is required and it is used as is in the next step reaction. Step 3: Dissolve compound V15-2 (0.7 g, 4.37 mmol) and sodium hydroxide (524.39 mg, 13.11 mmol) in methanol (5 mL) and water (2 mL). Stir at 30 °C for 2 h. Adjust the pH value to 5 with 2 M dilute hydrochloric acid, extract with dichloromethane (10 mL × 3), fuse the organic phase, and spin dry. Purify the residue by silica gel column chromatography with 0-20% ethyl acetate as eluent and petroleum ether to obtain compound V15-3 (400 mg, colorless liquid). The yield is 69.27%. MS m / z (ESI): 131.1 [M-1]. Step 4: In a reaction vial, compound V15-3 (0.4 g, 3.03 mmol) is dissolved in tetrahydrofuran (6 mL), and DCI (736.30 mg, 4.54 mmol) is added, and the mixture is reacted at room temperature for 16 hours (solution A). In another reaction vial, (3-ethoxy-3-oxopropionyl)oxypotassium (2.06 g, 12.11 mmol) is added to anhydrous magnesium chloride (864.68 mg, 9.08 mmol) and tetrahydrofuran (20 mL), and the mixture is heated under argon protection at 50°C for 16 hours (solution B). Then, solution A is slowly added dropwise to solution B, and the solution is mixed and stirred at 30°C for 16 hours. 30 mL of water is added to the reaction solution, and the mixture is extracted with ethyl acetate (30 mL x 3). After fusing the organic phase, it is washed with brine, dried over anhydrous sodium sulfate, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography with 0-10% ethyl acetate as eluent and petroleum ether to give compound V15 (230 mg, pale yellow oil). Yield: 37.57%. MS m / z (ESI): 203.2 [M+1].

[0134] Preparation of intermediate V16 JPEG0007657943000034.jpg2628

[0135] Prepared with reference to the method for intermediate V15, with the difference being that cyclobutanone is converted to cyclopentanone. MS m / z (ESI): 217.1 [M+1].

[0136] Preparation of intermediate V17 JPEG0007657943000035.jpg2628

[0137] Prepared with reference to the method for intermediate V15, with the difference being that triethyl 2-fluoro-2-phosphorosylacetate is converted to ethyl 2-(diethoxyphosphoryl)butyrate. MS m / z (ESI): 213.1 [M+1].

[0138] Preparation of intermediate V18 JPEG0007657943000036.jpg59139

[0139] Step 1: Under nitrogen protection, add triethylamine (6.06 g, 59.93 mmol, 8.36 mL) dropwise to a solution of 2-cyclopropylacetic acid (5 g, 49.94 mmol) and tetrahydrofuran (100 mL) at -78 ° C. After the addition, add trimethylacetyl chloride (6.62 g, 54.94 mmol, 6.76 mL) dropwise at -78 ° C. The reaction solution changes from a yellow transparent solution to a white suspension. After the addition, warm the reaction solution to 0 ° C. and react for 1.5 hours (Solution 1). Under the protection of nitrogen, n-butyllithium (1.6M, 37.46mL) is added dropwise to a solution of (R)-4-benzyl-2-oxazolidinone (8.85g, 49.94mmol) and tetrahydrofuran (50mL) at -78℃, the reaction solution changes from a colorless transparent solution to a white suspension, and after the addition, the reaction solution becomes a yellow suspension after heating to 0℃, and the reaction solution is reacted at 0℃ for 0.5 hours. Further, this solution is slowly added dropwise to solution 1 at 0℃, and stirred at room temperature for 2h. Quench the reaction water (200mL), extract ethyl acetate (300mL×3), fuse the organic phase, wash with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the obtained residue by silica gel column chromatography with 0-20% ethyl acetate as eluent and petroleum ether to obtain compound V18-1 (8.5g, colorless oil). Yield: 65.64%. MS m / z(ESI): 260.1 [M+1]. Step 2: Dissolve compound V18-1 (7.5 g, 28.92 mmol) in dichloromethane (200 mL), cool to 0 ° C under argon protection, slowly add anhydrous titanium tetrachloride (6.03 g, 31.82 mmol, 3.49 mL), the solution turns yellow after the addition is complete, stir at 0 ° C for 5 minutes, then add N,N-diisopropylethanamine (4.30 g, 33.26 mmol, 5.79 mL) slowly, the solution turns black after the addition is complete, keep this temperature and stir for 1 hour. Finally, add benzyl chloromethyl ether (9.06 g, 57.85 mmol, 8.05 mL) and stir at 0 ° C for 6 hours. Quench the reaction with saturated aqueous ammonium chloride (150 mL) and extract with dichloromethane (100 mL × 3), combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the resulting residue by silica gel column chromatography with 0-15% ethyl acetate as eluent in petroleum ether to obtain compound V18-2 (9 g, yield: 82%) as a white solid. MS m / z (ESI): 380.2 [M+1]. Step 3: Dissolve compound V18-2 (9 g, 23.72 mmol) in methanol (120 mL), add 10% wet Pd / C (2.37 g, 4.74 mmol), and flush with hydrogen gas three times. Stir under hydrogen (15 Psi) pressure at room temperature for 2 h. Remove the catalyst by filtration and concentrate the organic phase under reduced pressure to give compound V18-3 (6 g, white solid). Yield: 87.43%. MS m / z (ESI): 290.1 ​​[M+H] + . Step 4: Compound V18-3 (3 g, 10.37 mmol) is dissolved in dichloromethane (50 mL), cooled to 0 °C under argon protection, and 1,8-bis(dimethylamino)naphthalene (5.56 g, 25.92 mmol) and trimethyloxonium tetrafluoroboronic acid (3.07 g, 20.74 mmol) are slowly added. The mixture is slowly returned to room temperature and stirred for 16 h. The reaction is quenched with saturated aqueous ammonium chloride solution (50 mL), and dichloromethane (50 mL x 3) is extracted. The organic phase is fused and then washed with dilute hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The resulting residue is purified by silica gel column chromatography with 0-15% ethyl acetate as eluent and petroleum ether to obtain compound V18-4 (2.6 g, white solid). Yield: 66%. MS m / z (ESI): 304.2 [M+1]. Step 5: Compound V18-4 (2.6 g, 8.57 mmol) is dissolved in tetrahydrofuran (25 mL) and water (15 mL), cooled to 0°C, and 33% hydrogen peroxide (3.89 g, 34.28 mmol, 3.44 mL) and lithium hydroxide monohydrate (720.47 mg, 17.14 mmol) are added dropwise. The mixture is slowly returned to room temperature and stirred for 1 h. Slowly add aqueous sodium sulfite solution in an ice bath to quench, and then extracted with methyl tert-butyl ether (20 mL x 2) to remove impurities. The aqueous phase is adjusted to a pH value of about 5 with dilute hydrochloric acid, and extracted with methyl tert-butyl ether (20 mL x 3). The organic phase is fused, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain the crude product compound V18-5 (1.2 g, colorless oil). Yield: 97.12%. MS m / z(ESI): 143.1 [M-1]. Step 6: In a reaction vial, compound V18-5 (0.7 g, 4.86 mmol) is dissolved in tetrahydrofuran (10 mL), and CDI (1.18 g, 7.28 mmol) is added, and the mixture is reacted at room temperature for 16 hours (Solution A). In another reaction vial, (3-ethoxy-3-oxopropionyl)oxypotassium (3.31 g, 19.42 mmol) is added to anhydrous magnesium chloride (1.39 g, 14.57 mmol) and tetrahydrofuran (20 mL), and the mixture is heated under argon protection at 50°C for 16 hours (Solution B). Then, Solution A is added dropwise to Solution B (about 10 minutes), and the solution is mixed and stirred at 70°C for 16 hours. 30 mL of water is added to the reaction solution, and the mixture is extracted with ethyl acetate (30 mL x 3). The organic phase is fused, washed with brine, dried over anhydrous sodium sulfate, and then spin-dried under reduced pressure. The resulting residue is purified by silica gel column chromatography using 0-15% ethyl acetate as eluent with petroleum ether to give compound V18 (0.9 g, pale yellow oil). Yield: 86.51%. MS m / z(ESI): 215.2 [M+1].

[0140] Preparation of intermediate V19 JPEG0007657943000037.jpg46132

[0141] Step 1: Drop oxaloyl chloride (3.56g, 28.05mmol, 2.39mL) into a solution of 2-cyclopropyl-2-oxoacetic acid (2g, 17.53mmol) and dichloromethane (50mL) under nitrogen protection at 0℃, add N,N-dimethylformamide (12.81mg, 175.29μmol, 13.57μL) after dropping, warm to room temperature and react for 1 hour. Concentrate the reaction solution to dryness, dissolve in dichloromethane (50mL), drop benzyl alcohol (2.65g, 24.54mmol, 2.54mL), triethylamine (4.43g, 43.82mmol, 6.11mL) and dichloromethane (50mL) at 0℃, and react at room temperature for 1 hour after dropping. The reaction mixture is poured into ice water, and further extracted with dichloromethane (30mL*2). The organic layers are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated to obtain the crude product. The obtained residue is purified by silica gel column chromatography using 0-10% ethyl acetate as eluent and petroleum ether to obtain compound V19-1 (2.1g, colorless liquid). Yield: 58.66%. The target product does not come out from MS, but is detected on TLC plate, and the obtained product is directly used for the next reaction. Step 2: Compound V19-1 (1.9 g, 9.30 mmol) is dissolved in methanol (30 mL), cooled to -10 °C, sodium borohydride (422.38 mg, 11.16 mmol) is slowly added, and stirred at -10 °C for 30 min. Water is added to quench the reaction, and ethyl acetate (40 mL x 3) is extracted, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography with petroleum ether using 0-20% ethyl acetate as eluent to obtain compound V19-2 (1.5 g, colorless oil). Yield: 78.18%. MS m / z (ESI): 207.1 [M+1]. Step 3: Compound V19-2 (1.5 g, 7.27 mmol), methyl iodide (5.16 g, 36.37 mmol, 2.35 mL) and silver oxide (3.37 g, 14.55 mmol, 472.12 μL) are dissolved in a sealed tube of acetonitrile (15 mL), sealed by blowing argon gas for a while, and heated to 70 °C and stirred overnight. The solid is removed by filtration and spin-dried under reduced pressure to obtain the crude product. The resulting residue is purified by silica gel column chromatography with petroleum ether using 0-10% ethyl acetate as eluent to obtain compound V19-3 (1.1 g, colorless oil). Yield: 68.66%. MS m / z (ESI): 221.1 [M+1]. Step 4: Dissolve compound V19-3 (1.1 g, 4.99 mmol) and sodium hydroxide (599.24 mg, 14.98 mmol) in methanol (15 mL) and water (5 mL). Heat to 30 °C and stir for 4 h. Remove the solvent under reduced pressure, adjust the pH to 3 with 2 M dilute hydrochloric acid, extract with ethyl acetate (15 mL × 3), fuse the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography with 0-20% ethyl acetate as eluent and petroleum ether to obtain compound V19-4 (0.6 g, colorless oil). Yield: 92.32%. MS m / z (ESI): 129.1 [M-1]. Step 5: Prepare with reference to step 6 of intermediate V18 to give compound V19. MS m / z(ESI): 201.1 [M+1].

[0142] Preparation of intermediate V20 JPEG0007657943000038.jpg3032

[0143] Prepare compound V20 according to the method of intermediate V2. MS m / z(ESI): 185.1 [M+1].

[0144] Preparation of intermediate V21 JPEG0007657943000039.jpg26166

[0145] Step 1: Under the protection of nitrogen, dissolve ethyl glyoxylate (5 g, 24.49 mmol) in tetrahydrofuran (30 mL). Cool to -78 °C and slowly add cyclopropylmagnesium bromide (1.78 g, 12.24 mmol). Allow the reaction to react at -20 °C for 3 hours. Quench the reaction with ice water, extract with ethyl acetate (30 mL x 2), combine the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Separate by column chromatography (PE:EA = 4:1) to obtain compound V21-1 (620 mg, colorless liquid). Yield: 17.56%. MS m / z (ESI): 145.0 [M+1]. Step 2: Dissolve compound V21-1 (620 mg, 4.30 mmol) in 8 mL of dichloromethane. Under the protection of nitrogen, slowly add DAST (1.39 g, 8.60 mmol) at -70 °C. Allow the reaction to react at room temperature with stirring for 12 hours. Add 20 mL of water, extract with dichloromethane (20 mL x 2), fuse the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound V21-2 (448 mg, brown liquid). Yield: 78%. MS m / z (ESI): 147.2 [M+1]. Step 3: Compound V21-2 (448 mg, 3.07 mmol) is dissolved in water (3 mL) and methanol (1 mL). Lithium hydroxide (293.62 mg, 12.26 mmol) is added, and the reaction solution is stirred at room temperature under nitrogen protection for 2 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, the pH is adjusted to 1 with hydrochloric acid, and extracted with dichloromethane (20 mL x 2), the organic phase is fused, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound V21-3 (380 mg, brown liquid). Yield: 78%. MS m / z (ESI): 117.1 [M-1]. Step 4: Prepare with reference to step 6 of intermediate V18 to give compound V21. MS m / z(ESI): 189.1 [M+1].

[0146] Preparation of intermediate V22 JPEG0007657943000040.jpg3333

[0147] Prepare compound V22 by following the procedure for intermediate V4. MS m / z(ESI): 199.1 [M+H + ].

[0148] Preparation of intermediate 3-2 JPEG0007657943000041.jpg24128

[0149] Step 1: Compound V2 (1.2 g, 7.05 mmol) and 1H-pyrazol-5-amine (585.8 mg, 7.05 mmol) are dissolved in acetic acid (8 mL) and the reaction is stirred at 70° C. for 4 h. The solvent is removed under reduced pressure and ethyl acetate (15 ml) is added to precipitate a solid, which is filtered and dried to give compound 3-1 (800 mg, brown solid). Yield: 60.0%. MS m / z (ESI): 190.1 [M+1]. Step 2: Compound 3-1 (500 mg, 2.64 mmol) is dissolved in phosphorus oxychloride (6 mL) and heated to 120 °C and stirred for 3 h. The reaction is stopped, cooled to room temperature, poured into ice water (60 g), extracted with dichloromethane (80 mL), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (20 g, 0%-40% ethyl acetate / petroleum ether) to give compound 3-2 (300 mg, pale yellow oil). Yield: 54.7%. MS m / z (ESI): 208.1 [M+1].

[0150] Intermediate 4-2 to Intermediate 23-2

[0151] Intermediate 4-2 to intermediate 23-2 are prepared by referring to the method for intermediate 3-2 using the corresponding ethyl oxobutanoate as a starting material. JPEG0007657943000042.jpg252170 JPEG0007657943000043.jpg34170

[0152] Preparation of intermediate 24-2 JPEG0007657943000044.jpg2683

[0153] Prepared with reference to the method for compound 2-1. MS m / z(ESI): 256.0 [M+1].

[0154] Preparation of intermediate 27-3 JPEG0007657943000045.jpg44152

[0155] Step 1: Hydrogen peroxide (818.72 mg, 7.22 mmol, 30% purity) and iodine (1.53 g, 6.02 mmol) are added to a solution of 1H-pyrazol-5-amine (1 g, 12.03 mmol) and water (10 mL) at room temperature, and the mixture is reacted at room temperature for 1 hour after the addition is complete. 20 mL of saturated sodium sulfite solution is added to the reaction mixture, and the mixture is stirred for 10 minutes after the addition is complete, then filtered, the filter cake is washed with water and dried to obtain 4-iodine-1H-pyrazol-5-amine (1.3 g, 51.69% yield), and the crude product is used directly in the next step. MS m / z(ESI): 210.0 [M+1]. Step 2: Compound V1 (1 g, 4.76 mmol), 4-iodo-1H-pyrazol-5-amine (993.91 mg, 4.76 mmol) and acetic acid (35 mL) are mixed and reacted at 70° C. for 1 hour under nitrogen protection. The reaction solution is concentrated to dryness to obtain a crude product. The crude product is purified by column chromatography (dichloromethane:dichloromethane / tetrahydrofuran / ethyl acetate (volume ratio 2 / 1 / 1))=70%:30%) to obtain a yellow solid compound 27-1 (300 mg, yield 17.76%). MS m / z (ESI): 356.0 [M+1]. Step 3: Cuprous iodide (257.38 mg, 1.35 mmol), potassium fluoride (78.51 mg, 1.35 mmol) are added to the reaction vial, nitrogen gas is replaced, compound 27-1 (240 mg, 675.73 μmol), N,N-dimethylformamide (12 mL) and trimethyl(trifluoromethyl)silane (288.25 mg, 2.03 mmol) are added, nitrogen is further dispensed, and the reaction is carried out at 90 ° C for 16 hours (cooling tube + nitrogen ball). After cooling, cuprous iodide (257.38 mg, 1.35 mmol), potassium fluoride (78.51 mg, 1.35 mmol), trimethyl(trifluoromethyl)silane (288.25 mg, 2.03 mmol) are added, and the reaction is further heated and carried out at 90 ° C for 16 hours. The reaction vessel is replaced with a large sealed tube and reacted at 95°C for 6 hours. The reaction solution is poured into ice water, filtered to remove insoluble matter, and further extracted with ethyl acetate (20mL*2). The organic layers are combined, washed with water (10mL*3), washed with saturated saline (15mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate=70%:30%) to obtain compound 27-2 (137mg, 293.70μmol, yield 43.46%) as a brown solid. MS m / z(ESI): 298.2[M+1]. Step 4: Compound 27-2 (127 mg, 427.21 μmol) and phosphorus oxychloride (655.06 mg, 4.27 mmol) are heated to 110 °C and reacted for 3 hours. Excess phosphorus oxychloride in the reaction is steamed to dryness, and ice water is added to the residue, followed by extraction with dichloromethane (20 mL * 3). The organic layer is washed with saturated saline, then dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain a pale yellow solid, compound 27-3 (86 mg, yield 39.30%). MS m / z (ESI): 316.1 [M + 1].

[0156] Intermediate 25-2 to Intermediate 50-2 Intermediate 25-2 to intermediate 50-2 are produced by referring to the above-mentioned method using the corresponding ethyl oxobutanoate as a raw material.

[0157] JPEG0007657943000046.jpg110169 JPEG0007657943000047.jpg250166 JPEG0007657943000048.jpg110169

[0158] Example 1: Preparation of compound Z-1 JPEG0007657943000049.jpg23158

[0159] Step 1: Compound V1 (0.7 g, 3.33 mmol) and 1H-pyrazol-5-amine (276.6 mg, 3.33 mmol) were dissolved in acetic acid (6 mL) and cooled to 70°C. ℃ The mixture was stirred for 4 hours under the conditions described above. The solvent was removed under reduced pressure, and ethyl acetate (15 ml) was added to precipitate a solid, which was filtered and dried to give compound 1-1 (500 mg, brown solid), with a yield of 65.5%. MS m / z (ESI): 230.1 [M+1] Step 2: Compound 1-1 (500.0 mg, 2.18 mmol) is dissolved in phosphorus oxychloride (6 mL) and heated to 120 °C and stirred for 3 h. Cool to room temperature, put it into ice water (60 g), extract with methylene chloride (80 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (20 g, 0%-40% EA / DCM) to obtain compound 1-2 (350 mg, pale yellow oil), with a yield of 64.8%. MS m / z (ESI): 248.0 [M+1]. Step 3: Compound 1-2 (150.0 mg, 605.5 μmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (121.27 mg, 605.52 μmol) are dissolved in acetonitrile (20 mL) and potassium carbonate (251.0 mg, 1.81 mmol) is added thereto. The reaction is stirred at 90° C. for 16 hours. Dilute with ethyl acetate (80 mL), wash with saturated sodium chloride solution (80 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give compound 1-3 (180 mg, pale yellow oil), 72.2% yield. MS m / z (ESI): 412.2 [M+1]. Step 4: Compound 1-3 (180 mg, 437.38 μmol) is dissolved in 1,4-dioxane (3 mL), 4M hydrochloric acid solution (3.0 mL) is added, and the mixture is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure, water (60 mL) is added, and the mixture is extracted with ethyl acetate (50 mL). The aqueous phase is adjusted to PH=9-10 with saturated sodium carbonate solution, and extracted with ethyl acetate (60 mL×2). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound Z-1 (43.5 mg) is obtained by separation by preparative HPLC chromatography, with a yield of 31.3%. MS m / z (ESI): 312.2 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 7.96(d,J = 2.4 Hz,1H),7.39(d,J = 7.2 Hz,1H),6.27(d,J = 2.4 Hz,1H),6.00(s,1H),4.25 - 4.10(m,1H),3.42-3.35(m,1H),2.26 - 2.10(m,1H),2.04 - 1.53(m,6H),1.34 - 1.09(m,4H),0.59-0.47(m,2H),0.36 - 0.16(m,4H),0.13 - 0.02(m,2H).

[0160] Example 2: Preparation of compound Z-2 JPEG0007657943000050.jpg30170

[0161] Step 1: Compound 1-2 (100 mg, 403.68 μmol) is dissolved in acetonitrile (6 mL), NCS (53.9 mg, 403.7 μmol) is added, and the mixture is stirred at 20°C for 2 hours. Ethyl acetate (100 mL) is added, and the mixture is washed with saturated sodium chloride solution (80 mL x 3), and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (20 g, 0-30% ethyl acetate / petroleum ether) to obtain compound 2-1 (100 mg, pale yellow oil), with a yield of 87.8%. MS m / z (ESI): 282.0 [M+1] Step 2: Refer to the method of Step 3 of Example 1, except that compound 2-1 is used instead of compound 1-2, and compound 2-2 (120 mg, pale yellow oil) can be prepared with a yield of 75.9%. MS m / z (ESI): 446.1 [M+1] Step 3: Refer to the method of Step 4 of Example 1, the difference is that compound 2-2 is used instead of compound 1-3, and compound Z-2 (22.3 mg) can be prepared with a yield of 23.4%. MS m / z (ESI): 346.1 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 8.13(s,1H),7.68(bs,1H),6.12(s,1H),4.28 - 4.15(m,1H),3.45-3.30(m,1H),2.24 - 2.13(m,1H),2.13 - 1.78(m,4H),1.77-1.70(m,1H),1.68-1.58(m,1H),1.37 - 1.13(m,4H),0.58-0.49(m,2H),0.40 - 0.18(m,4H),0.12-0.02(m,2H).

[0162] Example 3: Preparation of compound Z-3 JPEG0007657943000051.jpg3239

[0163] Referring to the preparation method of compound Z-1, the difference is that compound V2 is used instead of compound V1, compound Z-3 (33.6 mg) can be prepared with a yield of 37.7%. MS m / z (ESI): 272.1 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 7.96(d,J = 2.0 Hz,1H),6.80(s,1H),6.26(d,J = 2.0 Hz,1H),6.08(s,1H),4.19 - 4.10(m,1H),3.98-3.91(m,1H),2.50(d,J = 7.2 Hz,2H),2.17-2.08(m,1H),2.05 - 1.80(m,3H),1.72-1.62(m,1H),1.50-1.38(m,1H),1.13 - 1.02(m,1H),0.49 - 0.40(m,2H),0.26 - 0.16(m,2H).

[0164] Example 4: Preparation of compound Z-4 JPEG0007657943000052.jpg3639

[0165] Referring to the preparation method of compound Z-1, the difference is that 3-amino-1H-pyrazole-4-methylnitrile is used instead of 1H-pyrazole-5-amine, compound Z-4 (9.4 mg) can be prepared with a yield of 15.2%. MS m / z (ESI): 337.1 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 8.55(s,1H),8.20(bs,1H),6.34(s,1H),4.30-4.20(m,1H),3.45-3.35(m,1H),2.26 - 2.07(m,1H),2.00 - 1.82(m,2H),1.79 - 1.58(m,2H),1.49 - 1.13(m,4H),0.67 - 0.44(m,2H),0.43 - 0.18(m,4H),0.11-0.02(m,2H).

[0166] Example 5: Preparation of compound Z-5 and its configurations, compounds Z-5-1 and Z-5-2 JPEG0007657943000053.jpg36142

[0167] By referring to the preparation method of compound Z-1, the difference is that compound V3 is used instead of compound V1, compound Z-5 (yield 41.29%) can be prepared. MS m / z (ESI): 286.1 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 7.96(d,J = 2.2 Hz,1H),7.41(s,1H),6.27(d,J = 2.2 Hz,1H),6.03(s,1H),4.24 - 4.16(m,1H),3.43 - 3.37(m,1H),2.22 - 2.13(m,1H),2.01 - 1.82(m,3H),1.78 - 1.71(m,1H),1.68 - 1.58(m,1H),1.32 - 1.22(m,4H),1.06 - 0.97(m,1H),0.51 - 0.45(m, 1H),0.35 - 0.30(m,1H),0.22 - 0.14(m,2H). Compound Z-5 (50 mg) was subjected to chiral resolution (apparatus: SFC-150 (Waters); column: IC 20*250 mm, 10 um (Daicel); auxiliary solvent: CO 2 / IPA [0.5%NH 3 (7M inMeOH)] = 60 / 40, wavelength: 214 nm) to give two single configuration products Z-5-1 (retention time 2.704 min) and Z-5-2 (retention time 3.175 min), Compound Z-5-1 (yield 21.93%), MS m / z (ESI): 286.1 [M+1]; 1 H NMR (400MHz, DMSO-d 6)δ 8.00(d,J = 2.2 Hz,1H),7.49(d,J = 7.6 Hz,1H),6.31(d,J = 2.2 Hz,1H),6.07(s,1H),4.28 - 4.19(m,1H),3.49 - 3.40(m,1H),2.26 - 2.18(m,1H),2.05 - 1.87(m, 3H),1.82- 1.75(m,1H),1.72- 1.63(m,1H),1.37 - 1.23(m,4H),1.11 - 1.00(m,1H),0.56 - 0.48(m,1H),0.40 - 0.31(m,1H),0.27 - 0.15(m,2H); Compound Z-5-2 (yield 22.62%), MS m / z (ESI): 286.1 [M+1]; 1 H NMR (400 MHz, DMSO-d 6 )δ 8.00(d,J = 2.2 Hz,1H),7.48(d,J = 7.4 Hz,1H),6.31(d,J = 2.2 Hz,1H),6.07(s,1H),4.29 - 4.18(m,1H),3.48 - 3.40(m,1H),2.25 - 2.17(m,1H),2.05 - 1.87(m,3H),1.81- 1.75(m, 1H),1.70- 1.61(m,1H),1.35 - 1.23(m,4H),1.11 - 1.01(m,1H),0.55 - 0.48(m,1H),0.40 - 0.32(m,1H),0.26- 0.17 (m, 2H).

[0168] Example 6: Preparation of compound Z-6 JPEG0007657943000054.jpg33107

[0169] Compound Z-1 (60.0 mg, 192.66 μmol) is dissolved in methylene chloride (10 mL), and triethylamine (195.0 mg, 1.93 mmol, 0.27 mL) and methyl chloroformate (91.0 mg, 963.32 μmol) are added and stirred at room temperature for 1 hour. Saturated sodium chloride solution (50 mL) is added, and the mixture is extracted with ethyl acetate (60 mL), and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is subjected to preparative HPLC chromatography to obtain compound Z-6 (40.3 mg), with a yield of 56.4%. MS m / z (ESI): 370.2 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 7.97(d,J = 2.0 Hz,1H),7.57(d,J = 8.0 Hz,1H),7.20(d,J = 6.8 Hz,1H),6.28(d,J = 2.0 Hz,1H),6.01(s,1H),4.18-4.12(m,1H),4.02-3.96(m,1H),3.48(s,3H),2.19 - 2.08(m,1H),2.06 - 1.83(m,3H),1.69-1.64(m,1H),1.52 - 1.36(m,1H),1.29 - 1.10(m,3H),0.58 - 0.45(m,2H),0.41 - 0.14(m,4H),0.13 -0.02(m,2H).

[0170] Example 7: Preparation of compound Z-7 JPEG0007657943000055.jpg26162

[0171] Step 1-2: Refer to the method of Step 1-2 of Example 1, the difference is that 3-amino-1H-pyrazole-4-methylnitrile is used instead of 1H-pyrazole-5-amine, and compound 7-1 (light yellow oil, yield 46.6%) can be prepared, MS m / z(ESI): 273.1 [M+1]. Step 3: Compound 7-1 (31 mg, 0.11 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (22.76 mg, 0.11 mmol) and potassium carbonate (22.76 mg, 0.11 mmol) are dissolved in 3 mL acetonitrile. The reaction solution is stirred at 60 °C for 3 hours. The reaction solution is concentrated under reduced pressure, 20 mL of water is added, and the mixture is extracted with methylene chloride (20 mL x 2), and the organic phase is fused, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7-2 (30 mg, yellow oil), with a yield of 60.46%. MS m / z(ESI): 437.2 [M+1]. Step 4: Compound 7-2 (30 mg, 0.068 mmol) and 5 M sodium hydroxide solution (0.5 mL) are dissolved in ethanol (1 mL) and dimethyl sulfoxide (1 mL). The reaction solution is stirred at 60 °C and reacted for 3 h. After the reaction is completed, it is extracted with methylene chloride (20 mL × 2), and the organic phase is fused, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7-3 (30 mg, yellow oil), with a yield of 91.23%. MS m / z (ESI): 455.2 [M+1]. Step 5: Compound 7-3 (30 mg, 0.07 mmol) was dissolved in 3 mL of hydrochloric acid / 1,4-dioxane solution and reacted at room temperature for 2 h under stirring. The reaction solution was concentrated under reduced pressure and subjected to preparative HPLC chromatography to obtain compound Z-7 (4.57 mg), with a yield of 19.46%. MS m / z (ESI): 355.1 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 8.34(s,1H),8.10(s,1H),7.77(s,1H),7.27(s,1H),6.28(s,1H),4.35-4.22(m,1H ),3.55-3.43(m,1H),2.30-2.18(m,1H),2.10-1.90(m,3H),1.89-1.65(m,3H),1.46 - 1.24(m,4H),0.62-0.53(m,2H),0.41-0.30(,4H),0.20 - 0.08(m,2H).

[0172] Example 8: Preparation of compound Z-8 JPEG0007657943000056.jpg3036

[0173] By referring to the preparation method of compound Z-1, the difference is that 5-methyl-1H-pyrazol-3-amine is used instead of 1H-pyrazol-5-amine, compound Z-8 (yield 33.4%) can be prepared. MS m / z (ESI): 326.2 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 7.23(s,1H),6.07(s,1H),5.95(s,1H),4.24-4.08(m,1H),3.46 - 3.36(m,1H),2.35(s,3H),2.25-2.10(m,1H),1.99 - 1.80(m,3H),1.80 - 1.55(m,3H),1.35 - 1.12(m,4H),0.56-0.48(m,2H),0.39 - 0.19(m,4H),0.15 - 0.02(m,2H).

[0174] Example 9: Preparation of compound Z-9 JPEG0007657943000057.jpg3438

[0175] By referring to the preparation method of compound Z-1, the difference is that 4-methyl-1H-pyrazol-3-amine is used instead of 1H-pyrazol-5-amine, compound Z-9 can be prepared. MS m / z(ESI): 326.2 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.30(d,J = 7.6 Hz,1H),5.98(s,1H),4.25-4.16(m,1H),3.43-3.35(m,1H),2.24 - 2.14(m,4H),1.96 - 1.83(m,2H),1.79- 1.57(m,4H),1.33 - 1.16(m,4H),0.57 - 0.48(m,2H),0.38 - 0.22(m,4H),0.13-0.03(m,2H).

[0176] Example 10: Preparation of compound Z-10 JPEG0007657943000058.jpg33168

[0177] Step 1: Compound 1-3 (200 mg, 0.485 mmol) and potassium thiocyanate (141.68 mg, 1.46 mmol) are dissolved in methanol (5 mL) and reacted at room temperature with stirring for 3 hours. Extract with methylene chloride (15 mL x 2), combine the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography separation (PE:EA=4:1), compound 10-1 (169 mg, yellow solid) is obtained with a yield of 74.21%. MS m / z (ESI): 469.2 [M+1]. Step 2: Dissolve compound 10-1 (169 mg, 0.36 mmol) in 3 mL of tetrahydrofuran. Add 3M methylmagnesium chloride solution (0.2 mL) at 0 °C. Stir the reaction solution at 0 °C for 2 hours, then add acetic acid (43.31 mg, 0.72 mmol). Concentrate the reaction solution under reduced pressure, add 20 mL of water, extract with ethyl acetate (15 mL x 3), combine the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give compound 10-2 (105 mg, yellow solid), with a yield of 63.62%. MS m / z (ESI): 458.2 [M+1]. Step 3: Dissolve compound 10-2 (105 mg, 0.229 mmol) in methylene chloride (3 mL). Add m-chloroperbenzoic acid (73.31 mg, 0.482 mmol) while stirring. The reaction solution is stirred at room temperature and reacted for 2 hours. After the reaction is completed, extract with ethyl acetate (15 mL x 3), fuse the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography separation (PE:EA = 4:1), compound 10-3 (83 mg, pale yellow solid) is obtained with a yield of 79.44%. MS m / z (ESI): 490.2 [M+1]. Step 4: Compound 10-3 (83 mg, 0.17 mmol) was dissolved in 3 mL of hydrochloric acid / 1,4-dioxane solution and reacted at room temperature for 3 h under stirring. The reaction solution was concentrated under reduced pressure and subjected to preparative HPLC chromatography to obtain compound Z-10 (24.27 mg), with a yield of 33.45%. MS m / z (ESI): 390.1 [M+1];1 H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),6.85(s,1H),6.43(s,1H),6.05(s,2H),4.31 -4.21(m,1H),4.00 -4.92(m,1H),3.28(s,3H),2.25 - 2.09(m,1H),2.06 - 1.87(m,3H),1.78 - 1.66(m,1H),1.51 - 1.34(m,2H),1.29 - 1.17(m,2H),0.62-0.50(m,2H),0.45 - 0.25(m,4H),0.16-0.06(m,2H).

[0178] Example 11: Preparation of Compound Z-11 JPEG0007657943000059.jpg4525

[0179] By referring to the preparation method of compound Z-1, the difference is that intermediate V5 is used instead of intermediate V1, compound Z-11 can be prepared. MS / z(ESI): 300.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 7.97(s,1H),7.54(s,1H),6.28(s,1H),5.99(s,1H),4.13-4.22(m,1H),3.90-3.99(m,1H),2.75-2.6.3(m,1H),2.51-2.57(m,1H),2.20 - 1.96(m,3H),1.85-1.94(m,2H),1.60-1.78(m,6H),1.40-1.49(m,1H),1.11(d,J = 6.8 Hz,3H).

[0180] Example 11a: Preparation of compound Z-11-P1 JPEG0007657943000060.jpg4328

[0181] Compound Z-11 (94.46 mg, 315.48 μmol) was subjected to chiral resolution (column type: IC-3 4.6*100mm 3um; auxiliary solvent: IPA [1%NH 3(7M inMeOH)]; Sample feed volume: 5.00ul; Wavelength: 220.0nm; Run time: 6.0Minutes; Flow rate: 3.0mL / min; Pressure: 2000psi; Column temperature: 40°C) to obtain compound Z-11-P1 (9.70mg, retention time 2.471min). Yield is 9.89% and purity is 96.34%. MS m / z(ESI): 300.2 [M+H + ]. 1 H NMR (400MHz, DMSO-d 6 )δ 7.96(d, J = 2.0 Hz,1H),7.41(d, J = 7.6 Hz,1H),6.27(d, J = 2.0 Hz,1H),5.96(s,1H),4.21(q, J = 7.2 Hz,1H),3.42(q, J =6.0Hz,1H),2.65-2.74(m,1H),2.58 - 2.50(m,1H),2.16-2.24(m,1H),2.03-2.09(m,1H),1.83-1.95(m,2H),1.80 - 1.61(m,7H),1.35 - 1.25(m,1H),1.11(d, J = 6.8 Hz,3H).

[0182] Example 11b: Preparation of compound Z-11-P2 JPEG0007657943000061.jpg4428

[0183] Compound Z-11 (94.46 mg, 315.48 μmol) was subjected to chiral resolution (column type: IC-3 4.6*100 mm 3 um; auxiliary solvent: IPA [1%NH 3 (7M inMeOH)]; Sample feed volume: 5.00ul; Wavelength: 220.0nm; Run time: 6.0Minutes; Flow rate: 3.0mL / min; Pressure: 2000psi; Column temperature: 40°C) to give compound Z-11-P2 (9.37mg, retention time 2.012min) with a yield of 9.55% and a purity of 96.24%. MS m / z(ESI): 300.2 [M+H + ]. 1 H NMR (400MHz, DMSO-d 6)δ 7.96(d, J = 2.0 Hz,1H),7.42(d, J = 7.6 Hz,1H),6.27(d, J = 2.0 Hz,1H),5.96(s,1H),4.21(q, J = 7.2 Hz,1H),3.44-3.37(m,1H),2.65-2.74(m,1H),2.58 - 2.50(m,1H),2.15-2.25(m,1H),2.02-2.08(m,1H),1.82-1.95(m,2H),1.79 - 1.60(m,7H),1.35 - 1.24(m,1H),1.10(d, J = 6.8 Hz,3H).

[0184] Example 12: Preparation of compound Z-12 JPEG0007657943000062.jpg3239

[0185] By referring to the preparation method of compound Z-1, the difference is that intermediate V7 is used instead of intermediate V1, compound Z-12 can be prepared. MS m / z (ESI): 300.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 8.01(d,J = 2.0 Hz,1H),7.43(d,J =6.0Hz,1H),6.34(d,J = 2.0 Hz,1H),6.23(s,1H),4.30 - 4.18(m,1H),3.46 -3.40(m,1H),2.26 - 2.18(m,1H),1.99 - 1.86(m,2H),1.83 - 1.74(m,1H),1.73 - 1.64(m,1H),1.37 - 1.27(m,1H),1.17 (s,6H),1.15 - 1.11(m,1H),0.39 - 0.34(m,4H).

[0186] Example 13: Preparation of compound Z-13 JPEG0007657943000063.jpg4726

[0187] By referring to the preparation method of compound Z-1, the difference is that intermediate V6 is used instead of intermediate V1, compound Z-13 can be prepared. MS m / z(ESI): 314.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 7.99(d, J = 2.4 Hz,1H),7.50(d, J = 38.8 Hz,1H),6.30(d, J = 2.4 Hz,1H),6.02(d, J = 8.0 Hz,1H),4.23(s,1H),3.50-3.38(m,1H),2.52-2.55(m,1H),2.07-2.25(m,2H),1.99 - 1.77(m,4H),1.71 - 1.29(m,7H),1.26-1.16(m,4H),1.12 - 1.01(m,1H).

[0188] Example 14: Preparation of compound Z-14 JPEG0007657943000064.jpg4041

[0189] By referring to the preparation method of compound Z-1, the difference is that 4-cyclopropyl-1H-pyrazol-3-amine is used instead of 1H-pyrazol-5-amine, compound Z-14 can be prepared. MS m / z(ESI): 352.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 7.74(s,1H),7.29(d,J = 7.2 Hz,1H),5.98(s,1H),4.24-4.12(m,1H),3.45-3.36(m,1H),2.27 - 1.79(m,6H),1.76-1.70(m,1H),1.67-1.56(m,1H),1.35-1.14(m,4H),0.89 - 0.71(m,4H),0.57- 0.48(m,2H),0.39 - 0.20(m,4H),0.15- 0.06(m,2H).

[0190] Example 15: Preparation of compound Z-15 JPEG0007657943000065.jpg33148

[0191] Step 1: Compound 1-2 (145 mg, 0.585 mmol) and acetic acid (70.24 mg, 1.17 mmol) are dissolved in acetonitrile (5 mL), Selectfluor fluorine reagent (207.36 mg, 0.584 mmol) is added while stirring, and then the mixture is reacted for 4 hours with stirring at 70 °C. Extract with ethyl acetate (15 mL × 2), and the organic phase is fused, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography separation (PE:EA = 4:1), compound 15-1 (45 mg, yellow liquid) is obtained, with a yield of 28.93%. MS m / z (ESI): 266.0 [M + 1]. Step 2-3: Refer to the preparation methods of step 3 and step 4 of compound Z-1, the difference being that compound 15-1 is used instead of compound 1-2, to prepare compound Z-15. MS m / z(ESI): 330.3 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 8.16(d,J = 3.6 Hz,1H),7.65(s,1H),6.08(s,1H),4.30-4.15(m,1H),3.48-3.42(m,1H),2.2 6-2.15(m,1H),2.00-1.85(m,2H),1.82-1.76(m,1H),1.72-1.60(m,1H),1.36 - 1.16(m,4H),0.61 - 0.50(m,2H),0.39 - 0.25(m,4H),0.15-0.05(m,2H).

[0192] Example 16: Preparation of compound Z-16 JPEG0007657943000066.jpg3939

[0193] Refer to the preparation method of compound Z-1, the difference being that 4-ethyl-1H-pyrazol-3-amine is used instead of 1H-pyrazol-5-amine, compound Z-16 can be prepared. MS m / z(ESI): 340.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6)δ 7.86(s,1H),7.30(d, J = 7.6 Hz,1H),5.99(s,1H),4.25-4.15(m,1H),3.37-3.45(m,1H),2.63(q, J = 7.6 Hz,2H),2.14-2.23(m,1H),1.98 - 1.81(m,2H),1.71-1.79(m,2H),1.69 - 1.56(m,1H),1.35 - 1.17(m,6H),0.47-0.56(m,2H),0.23-0.34(m,4H),0.15 - 0.03(m,2H).

[0194] Example 17: Preparation of compound Z-17 JPEG0007657943000067.jpg3228

[0195] By referring to the preparation method of compound Z-1, the difference is that compound V9 is used instead of compound V1, compound Z-17 can be prepared. MS m / z (ESI): 286.2 [M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 8.01(d,J = 2.4 Hz,1H),7.64(s,1H),6.90(d,J = 6.4 Hz,1H),6.32(d,J = 2.4 Hz,1H),6.07(s,2H),4.15-4.12(m,1H),4.03- 3.91(m,1H),2.57(s,2H),2.25-2.10(s,1H),2.06-1.85(m,3H),1.76- 1.63(m,1H),1.53-1.40(m,1H),1.02(s,3H),0.56(s,2H),0.31(s,2H).

[0196] Example 18: Preparation of compound Z-18 JPEG0007657943000068.jpg3439

[0197] By referring to the preparation method of compound Z-1, the difference is that compound V4 is used instead of compound V1, compound Z-18 (yield 25.40%) can be prepared. MS m / z (ESI): 286.1 [M+1]; 1H NMR(400MHz,DMSO-d6)δ 8.03(d,J = 2.2 Hz,1H),7.61 & 6.89(s,1H),6.37(d,J = 2.2 Hz,1H),6.17(dd,J = 17.2,10.6 Hz,1H),6.04(s,1H),5.11(dd,J = 17.6,1.2 Hz,1H),5.07(dd,J = 10.6,1.2 Hz,1H),4.22 - 4.14(m,1H),4.00 - 3.93(m,1H),2.20 - 2.07(m,1H),2.03 - 1.86(m,3H),1.74 - 1.62(m,1H),1.53 - 1.41(m,1H),1.41(s,6H).

[0198] Example 19: Preparation of compound Z-19 JPEG0007657943000069.jpg3337

[0199] By referring to the preparation method of compound Z-1, the difference is that compound V4 is used instead of compound V1, and 4-methyl-1H-pyrazol-3-amine is used instead of 1H-pyrazol-5-amine, compound Z-19 can be prepared. MS m / z(ESI): 300.2[M+1]; 1 H NMR (400MHz, DMSO-d 6 )δ 7.86(s,1H),7.46 - 7.34(m,1H),6.17(dd,J = 17.6,10.4 Hz,1H),5.94(d,J =6.0Hz,1H),5.07(dd,J = 21.0,14.0 Hz,2H),4.19 - 4.12(m,1H),3.43 - 3.37(m,1H),2.92(bs,2H),2.18(s,3H),2.21-1.96(m,1H),1.94 - 1.82(m,2H),1.77 - 1.66(m,1H),1.67 - 1.59(m,1H),1.49 - 1.24(m,7H).

[0200] Examples 20 to 25

[0201] Compounds Z-20 to Z-25 can be prepared with reference to the method of Example 1.

[0202] JPEG0007657943000070.jpg78166 JPEG0007657943000071.jpg250163 JPEG0007657943000072.jpg160166

[0203] Example 26: Preparation of compound Z-26 JPEG0007657943000073.jpg26122

[0204] Compound Z-26 was obtained by preparing compound 22-2 according to the method of steps 3 and 4 in Example 1. MS m / z (ESI): 314.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.85(s,1H),7.28(d,J =6.0Hz,1H),5.97(s,1H),4.26 - 4.12(m,1H),3.50 - 3.38(m,1H),2.35-2.27(m,1H),2.25-2.10(m,5H),1.97 - 1.86(m,2H),1.83 - 1.72(m,1H),1.72 - 1.56(m,2H),1.34(d,J = 7.2Hz,1H),1.29(d,J = 7.2Hz,3H),0.96(s,3H),0.75 - 0.66(m,1H),0.48 - 0.38(m,1H),0.23-0.18(m,2H).

[0205] Example 26a: Preparation of compound Z-26-P1 JPEG0007657943000074.jpg33138

[0206] Step 1: Compound Z-26-1 (650 mg) was subjected to supercritical fluid chromatography (SFC) decomposition (column type: IC-3 4.6*100 mm 3 um, auxiliary solvent: IPA / ACN=1 / 1 [0.1% DEA] flow rate: 3.0 mL / min, column temperature: 40°C) to obtain 212 mg of compound Z-26-a (retention time 2.468 minutes). Step 2: Dissolve compound Z-26-a (212 mg, 512.63 μmol) in hydrochloric acid / dioxane (4 M) (10 mL). React at room temperature for 2 h. Spin-dry the reaction solution, dissolve the residue in 20 mL of ethyl acetate, wash twice with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter, and spin-dry. Purify the residue by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 0; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain 60.12 mg of compound Z-26-P1, with a yield of 36.79%. MS m / z(ESI): 314.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.36(s,1H). 5.96(s,1H),4.25- 4.05(m,1H),3.50 - 3.38(m,1H),2.35-2.25(m,1H),2.25-2.07(m,4H),2.05-1.80(m,3H),1.75-1.60(m,1H),1.53-1.40(m,1H),1.27(d,J = 7.2 Hz,3H),0.94(s,3H),0.74 - 0.64(m,1H),0.44 - 0.37(m,1H),0.31 - 0.19(m,2H).

[0207] Example 26b: Preparation of compound Z-26-P2 JPEG0007657943000075.jpg33138

[0208] Step 1: Compound Z-26-1 (650 mg) was subjected to supercritical fluid chromatography (SFC) decomposition (method: column type: IC-3 4.6*100 mm 3 um, auxiliary solvent: IPA / ACN=1 / 1 [0.1% DEA] flow rate: 3.0 mL / min, column temperature: 40°C) to obtain 120 mg of compound Z-26-b (retention time 2.976 minutes). Step 2: Dissolve compound Z-26-b (120 mg, 290.17 μmol) in hydrochloric acid / dioxane (4 M) (10 mL). React at room temperature for 2 h. Spin-dry the reaction solution, dissolve the residue in 20 mL of ethyl acetate, wash twice with saturated sodium bicarbonate, dry with anhydrous sodium sulfate, filter, and spin-dry. Purify the residue by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO 3 H 2 0; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to give 34.2 mg of compound Z-26-P2, with a yield of 36.96%. MS m / z (ESI): 314.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.24(d,J = 7.2 Hz,1H),5.96(s,1H),4.23-4.13(m,1H),3.47 - 3.37(m,1H),2.35-2.25(m,1H), 2.25 - 2.10(m,4H),2.00 - 1.82(m,2H),1.81 -1.72(m,1H),1.70 - 1.57(m,1H),1.37 - 1.23(m,4H),0.94(s,3H),0.73 - 0.64(m,1H),0.45-0.37(m,1H),0.34 - 0.19(m,2H).

[0209] Examples 27 to 30 Compounds Z-27 to Z-30 can be prepared with reference to the method of Example 1.

[0210] JPEG0007657943000076.jpg184164 JPEG0007657943000077.jpg144165

[0211] Example 27a: Preparation of compound Z-27-P1 JPEG0007657943000078.jpg32152

[0212] Step 1: Compound 51-2 is used as the raw material, and the compound Z-27-1 is obtained by referring to the method of Step 3 in Example 1. MS m / z (ESI): 400.2 [M+1]. Step 2: 410 mg of compound Z-27-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: IG 4.6*100mm 5um, co-solvent: MeOH [0.2%NH 3 (7M inMeOH)], sample feed volume: 5.00 ul, run time: 4.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to obtain 160 mg of compound Z-27-a (retention time 1.954 minutes). Step 3: Prepare with reference to step 2 of example 26a to obtain compound Z-27-P1. MS m / z(ESI): 300.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6 )δ 8.00(d,J = 2.4 Hz,1H),7.44(s,1H),6.35(d,J = 2.0 Hz,1H),6.05(s,1H),4.28-4.15(m,1H),3.49 - 3.38(m,1H),2.38 - 2.10(m,2H),2.05 - 1.88(m,2H),1.87 - 1.61(m,2H),1.55 - 1.22(m,4H),0.94(s,3H),0.75 - 0.64(m,1H),0.47-0.38(m,1H),0.34 - 0.13(m,2H).

[0213] Example 27b: Preparation of compound Z-27-P2 JPEG0007657943000079.jpg38117

[0214] Step 1: 410 mg of compound Z-27-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: IG 4.6*100mm 5um, co-solvent: MeOH [0.2%NH 3 (7M MeOH)], sample feed volume: 1.00 ul, run time: 4.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to obtain 120 mg of compound Z-27-b (retention time 2.336 minutes). Step 2: Prepare with reference to step 2 of example 26a to obtain compound Z-27-P2. MS m / z(ESI): 300.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6 )δ 8.00(d,J = 2.4 Hz,1H),7.45(s,1H),6.35(d,J = 2.0 Hz,1H),6.04(s,1H),4.27-4.15(m,1H),3.50-3.40(m,1H),2.37 - 2.11(m,2H),2.05 - 1.87(m,2H),1.84 - 1.55(m,2H),1.54 - 1.19(m,4H),0.94(s,3H),0.77 - 0.59(m,1H),0.47-0.39(m,1H),0.35-0.22 (m,2H).

[0215] Example 28a: Preparation of compound Z-28-P1 JPEG0007657943000080.jpg30157

[0216] Step 1: Compound 23-2 (5 g, 21.21 mmol) is dissolved in acetonitrile (30 mL), and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (5.10 g, 25.45 mmol) and potassium carbonate (8.80 g, 63.64 mmol) are added. The reaction is carried out at 90°C for 16 h. The reaction solution is filtered and spin-dried. The residue is combi-flashed with petroleum ether:ethyl acetate = 3:1 to obtain compound Z-28-1 (7 g, 82.6% yield) as a yellow liquid. MS m / z (ESI): 400.2 [M+1]. Step 2: Compound Z-28-1 (6.0 g) was subjected to supercritical fluid chromatography (SFC) decomposition (method: column type: IG 4.6*100 mm 5um, auxiliary solvent: IPA / ACN=1 / 1 [0.1% DEA] flow rate: 3.0 mL / min column temperature: 40°C) to obtain 2.2 g of compound Z-28-a (retention time 1.931 minutes). Step 3: Compound Z-28-a (2.2 g, 5.51 mmol) is dissolved in hydrochloric acid / dioxane (10 mL) and reacted at 30 °C for 2 h. The reaction is also spin-dried, and the residue is dissolved in 50 mL of water and extracted twice with ethyl acetate. The aqueous phase is adjusted to pH=8 with aqueous ammonia, extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate. Filter and spin-dry. Compound Z-28-P1 (1.3 g, 79.1% yield) is obtained. MS m / z (ESI): 300.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.98(d,J = 2.0 Hz,1H),7.41(d,J = 7.6Hz,1H),6.29(d,J = 2.0 Hz,1H),6.00(s,1H),4.28-4.16(m,1H),3.50-3.40(m,1H),2.27-2.17(m,1H),2.00 - 1.57(m,7H),1.35-1.24(m,1H),1.11 - 0.97(m,1H),0.80(t,J = 7.6 Hz,3H),0.60-0.51(m,1H),0.35-0.20(m,2H),0.18-0.08(m,1H).

[0217] Example 28b: Preparation of compound Z-28-P2 JPEG0007657943000081.jpg37132

[0218] Step 1: Compound Z-28-1 (6.0 g) was subjected to supercritical fluid chromatography (SFC) decomposition (method: column type: IG 4.6*100mm 5um, auxiliary solvent: IPA / ACN=1 / 1[0.1%DEA] flow rate: 3.0mL / min column temperature: 40℃) to obtain 2.3g of compound Z-28-b (retention time 2.566 minutes). Step 2: Compound Z-28-b (220 mg, 550.6 μmol) is dissolved in hydrochloric acid / dioxane (10 mL) and reacted at 30 °C for 2 h. The reaction is also spin-dried, and the residue is dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate. Dry over anhydrous sodium sulfate. Filter and spin-dry. The residue is purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3 H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to give compound Z-28-P2 (99.58 mg, 60.10% yield). MS m / z (ESI): 300.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.98(d,J = 2.0 Hz,1H),7.42(d,J = 6.0Hz,1H),6.29(d,J = 2.4 Hz,1H),6.01(s,1H),4.26-4.16(m,1H),3.50-3.40(m,1H),2.25-2.17(m,1H),2.00 - 1.57(m,7H),1.34-1.24(m,1H),1.10- 0.97(m,1H),0.80(t,J = 7.2 Hz,3H),0.58-0.48(m,1H),0.32-0.17(m,2H),0.16-0.06(m,1H).

[0219] Example 30a: Preparation of compound Z-30-P1 JPEG0007657943000082.jpg32154

[0220] Step 1: Compound 25-2 is used as the raw material, and the compound Z-30-1 is obtained by referring to the method of Step 3 in Example 1. MS m / z (ESI): 414.2 [M+1]. Step 2: 1.1g of compound Z-30-1 is subjected to supercritical fluid chromatography (SFC) decomposition (column type: IC-3 4.6*100mm 3um, auxiliary solvent: IPA [1% NH3 (7M in MeOH)], sample feed volume: 5.00ul, run time: 6.0 minutes, flow rate: 3.0mL / min, pressure: 2000psi, column temperature: 40℃) to obtain 370mg of compound Z-30-a (retention time 2.135 minutes). Step 3: Prepare with reference to step 2 of example 26a to obtain compound Z-30-P1. MS m / z (ESI): 314.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.25(d, J = 7.6 Hz,1H),5.95(s,1H),4.26-4.16(m,1H),3.45 - 3.36(m,1H),2.26 - 2.13(m,4H),2.02 - 1.54(m,7H),1.33-1.22(m,1H),1.10 - 0.99(m,1H),0.85-0.78(m,3H),0.59 - 0.49(m,1H),0.32 - 0.17(m,2H),0.14-0.08(m,1H).

[0221] Example 30b: Preparation of compound Z-30-P2 JPEG0007657943000083.jpg35111

[0222] Step 1: 1.1g of compound Z-30-1 is subjected to supercritical fluid chromatography (SFC) decomposition (column type: IC-3 4.6*100mm 3um, cosolvent: IPA [1% NH3 (7M in MeOH)], sample feed volume: 5.00ul, run time: 6.0minutes, flow rate: 3.0mL / min, pressure: 2000 psi, column temperature: 40℃) to obtain 380mg of compound Z-30-b (retention time 2.416minutes). Step 2: Prepare with reference to step 2 of example 26a to obtain compound Z-30-P2. MS m / z (ESI): 314.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.25(d, J = 7.6 Hz,1H),5.96(s,1H),4.25-4.15(m,1H),3.48 - 3.35(m,1H),2.24 - 2.09(m,4H),2.01 - 1.70(m,6H),1.68-1.56(m,1H),1.35-1.25(m,1H),1.10-1.00(m,1H),0.86-0.79(m,3H),0.57 - 0.47(m,1H),0.35-0.19(m,2H),0.15-0.08(m,1H).

[0223] Example 31 Preparation of Compound Z-31 JPEG0007657943000084.jpg56127

[0224] Step 1: Compound 5-2 (400 mg, 1.80 mmol) and acetic acid (216.70 mg, 3.61 mmol) are dissolved in acetonitrile (20 mL). 1-Chloromethyl-4-fluoro-1,4-diazepineheterodicyclo[2.2.2]octane bis(tetrafluoroborate) (639.2 mg, 1.80 mmol) is added and then stirred at 70 °C for 4 h. The reaction is stopped, the solvent is removed under reduced pressure, and the mixture is dissolved in ethyl acetate (50 mL). The organic phase is washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-1 (200 mg, 46.3% yield) is obtained as a pale yellow oil by separation and purification using silica gel column chromatography. MS m / z (ESI): 240.1 [M+1]. Step 2: Compound 31-1 (100 mg, 417.23 μmol) and t-butyl 3-aminopyrrolidine-1-carboxylate (116.6 mg, 625.84 μmol) are dissolved in acetonitrile (20 mL) and potassium carbonate (173.00 mg, 1.25 mmol) is added. The reaction is stirred at 90° C. for 16 hours. The reaction is quenched, dissolved in ethyl acetate (50 mL), washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography to give compound 31-2 (120 mg, 73.85% yield), a pale yellow oil. MS m / z (ESI): 389.6 [M+1]. Step 3: Compound 31-2 (120 mg, 308.11 μmol) is dissolved in 4M hydrogen chloride / 1,4-dioxane solution (4M, 7.70 mL). The reaction is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure, pure water (30 mL) is added, impurities are extracted with ethyl acetate (30 mL), the aqueous phase is adjusted to PH=9-10 with saturated sodium carbonate solution, extracted with ethyl acetate (50 mL×2), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-3 (89 mg, 99.83% yield) is obtained as a pale yellow oil. MS m / z (ESI): 290 [M+1]. Step 4: Compound 31-3 (90 mg, 311.04 μmol) is dissolved in water (2 mL) and acetic acid (2 mL), and a solution of sodium nitrite (31.73 mg, 466.56 μmol) in water (2 mL) is slowly added dropwise under ice bath. The mixture is slowly returned to room temperature and stirred for 2 h. The reaction mixture is adjusted to pH=8 with saturated sodium bicarbonate, extracted with ethyl acetate (2*30 mL), dried over anhydrous sodium sulfate, and spin-dried. The residue is combi-flashed with petroleum ether:ethyl acetate=1:1 to give compound 31-4 (55 mg, 55.54% yield), a pale yellow solid. MS m / z(ESI): 319 [M+1]. Step 5: Compound 31-4 (55 mg, 172.77 μmol) was dissolved in methanol (3 mL) and acetic acid (0.3 mL), zinc (225.94 mg, 3.46 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction mixture was adjusted to pH = 9 by adding aqueous ammonia, extracted with ethyl acetate (2 * 30 mL), the organic phase was fused, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 Purify the crude product obtained by HPLC using a 5% to 95% acetonitrile gradient (O; wavelength: 254 / 214 nm; gradient: 5% to 95% acetonitrile change) to obtain compound Z-31 (4.98 mg, 9.07% yield). MS m / z (ESI): 304.6 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 8.16(dd,J = 6.0,3.6 Hz,1H),7.58(d,J = 6.8 Hz,1H),6.12(s,1H),4.28-4.16(m,1H),3.01 - 2.91(m,1H),2.91 - 2.68(m,2H),2.67 - 2.52(m,1H),2.33 - 2.18(m,1H),2.07-1.95(m,1H),1.93-1.81(m,1H),1.30(d,J = 6.8 Hz,3H),1.10-0.98(m,1H),0.55-0.47(m,1H),0.39-0.30(m,1H),0.27-0.15(m,2H).

[0225] Example 32: Preparation of compound Z-32 JPEG0007657943000085.jpg33152

[0226] Compound 26-2 was used as the starting material to prepare compound Z-32 according to the methods of steps 3 and 4 in Example 1. MS m / z (ESI): 300.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.43(s,1H),6.01(s,1H),4.25 - 4.13(m,1H),3.99 -3.91(m,1H),2.24 - 1.81(m,4H),2.16(s,3H),1.79 - 1.72(m,1H),1.67 - 1.58(m,1H),1.50 - 1.40(m,1H),1.30(d,J = 6.8 Hz,3H),1.10 - 1.01(m,1H),0.54 - 0.46(m,1H),0.38 - 0.30(m,1H),0.23 - 0.16(m,2H).

[0227] Example 32a: Preparation of compound Z-32-P1 JPEG0007657943000086.jpg41136

[0228] Step 1: 590 mg of compound Z-32-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: AD-3 4.6*100mm 3um, co-solvent: EtOH [1%NH 3 (7M inMeOH)], sample feed volume: 2.00ul, run time: 4.0 minutes, flow rate: 3.0mL / min, pressure: 2000psi, column temperature: 40°C) to give compound Z-32-a (218mg, 545.64μmol, yield 36.95%, retention time 2.592 minutes) as a yellow oil. MS m / z(ESI): 400.3[M+1]. ee%=100%. Step 2: Prepare with reference to step 2 of example 26a to obtain compound Z-32-P1. MS m / z (ESI): 300.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.26(d,J = 4.8 Hz,1H),6.00(s,1H),4.24 - 4.15(m,1H),3.44 - 3.36(m,1H),2.24 - 2.17(m,1H),2.17(s,3H), 2.05 - 1.82(m,3H),1.80 - 1.73(m,1H),1.67 - 1.58(m,1H),1.31(d,J = 7.0 Hz,3H),1.29 - 1.23(m,1H),1.11 - 1.01(m,1H),0.53 - 0.48(m,1H),0.38 - 0.31(m,1H),0.24 - 0.16(m,2H).

[0229] Example 32b: Preparation of compound Z-32-P2 JPEG0007657943000087.jpg41129

[0230] Step 1: 590 mg of compound Z-32-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: AD-3 4.6*100mm 3um, co-solvent: EtOH [1%NH 3 (7M inMeOH)], sample feed volume: 2.00 ul, run time: 4.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to give compound Z-32-b (241 mg, 603.21 μmol, 40.85% yield, retention time 3.167 minutes) as a yellow oil. MS m / z (ESI): 400.3 [M+1]. ee%=99.6%. Step 2: Prepare with reference to step 2 of example 26a to obtain compound Z-32-P2. MS m / z (ESI): 300.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.27(s,1H),6.00(s,1H),4.26 - 4.15(m,1H),3.44 - 3.38(m,1H),2.25 - 2.18(m,1H),2.17(s,3H),2.04 - 1.82(m,4H),1.79 - 1.71(m,1H),1.68 - 1.59(m,1H),1.31 - 1.30(d,J = 6.8 Hz, 4H),1.28 - 1.24(m,1H),1.10 - 1.01(m,1H),0.53 - 0.47(m,1H),0.37 - 0.32(m,1H),0.24 - 0.16(m,2H).

[0231] Examples 33 to 44

[0232] Compounds Z-33 to Z-44 can be prepared with reference to the method of Example 1.

[0233] JPEG0007657943000088.jpg218167 JPEG0007657943000089.jpg224169 JPEG0007657943000090.jpg207167 JPEG0007657943000091.jpg250164

[0234] Example 38a: Preparation of compound Z-38-P1 JPEG0007657943000092.jpg35153

[0235] Step 1: Compound 35-2 is used as the raw material to prepare compound Z-38-1 according to the method of Step 3 in Example 1. MS m / z (ESI): 414.2 [M+1]. Step 2: 850 mg of compound Z-38-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: IC-3 4.6*100mm 3um, co-solvent: IPA [1%NH 3(7M inMeOH)], sample feed volume: 2.00 ul, run time: 6.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to obtain 230 mg of compound Z-38-a (retention time 3.138 minutes). Step 3: Prepare with reference to step 2 of example 26a to obtain compound Z-38-P1. MS m / z(ESI): 314.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6 )δ 7.84(s,1H),7.29(d, J = 7.6 Hz,1H),5.90(s,1H),4.25 - 4.17(m,1H),3.45-3.38(m,1H),2.74 - 2.67(m,1H),2.61 - 2.52(m,1H),2.20(d, J = 8.0 Hz,1H),2.18(s,3H),2.12-2.05(m,1H),1.97 - 1.82(m,2H),1.81 - 1.56(m,7H),1.35 - 1.25(m,1H),1.13(d, J = 6.8 Hz,3H).

[0236] Example 38b: Preparation of compound Z-38-P2 JPEG0007657943000093.jpg37109

[0237] Step 1: 850 mg of compound Z-38-1 was subjected to supercritical fluid chromatography (SFC) digestion (column type: IC-3 4.6*100mm 3um, co-solvent: IPA [1%NH 3 (7M inMeOH)], sample feed volume: 2.00 ul, run time: 6.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to obtain 230 mg of compound Z-38-b (retention time 3.507 minutes). Step 2: Prepare with reference to step 2 of example 26a to obtain compound Z-38-P2. MS m / z(ESI): 314.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6)δ 7.84(s,1H),7.30(d, J = 7.6 Hz,1H),5.91(s,1H),4.25 - 4.17(m,1H),3.46-3.39(m,1H),2.76-2.66(m,1H),2.61 - 2.52(m,1H),2.25-2.19(m,1H),2.18(s,3H),2.12-2.05(m,1H),1.98 - 1.82(m,2H),1.81 - 1.58(m,7H),1.36 - 1.26(m,1H),1.13(d, J = 6.8Hz,3H).

[0238] Example 41a: Preparation of compound Z-41-P1 JPEG0007657943000094.jpg5428

[0239] Compound Z-41 (76 mg, 250.51 μmol) was sent to chiral resolution (column type: IC-3 4.6*100 mm 3 um; co-solvent: IPA [1% NH3 (7M in MeOH)]; sample feed volume: 5.00 ul; run time: 6.0 minutes; flow rate: 3.0 mL / min; pressure: 2000 psi; column temperature: 40°C) to obtain compound Z-41-P1 (9.76 mg, retention time 2.153 minutes), with a yield of 12.84% and a purity of 100%. MS m / z (ESI): 304.2 [M+H + ]. 1 H NMR (400MHz, DMSO-d 6 )δ 8.08(d, J = 2.4 Hz,1H),7.82(s,1H),6.39(d, J = 2.4 Hz,1H),6.15(s,1H),5.34(dd, J = 48.8,6.0 Hz,1H),4.22-4.32(m,1H),3.40-3.47(m,1H),2.86-2.99(m,1H),2.24 - 2.13(m,1H),2.12 - 1.60(m,12H),1.27-1.36(m,1H).

[0240] Example 41b: Preparation of compound Z-41-P2 JPEG0007657943000095.jpg5428

[0241] Compound Z-41 (76 mg, 250.51 μmol) was sent to chiral resolution (column type: IC-3 4.6*100 mm 3 um; co-solvent: IPA [1% NH3 (7M in MeOH)]; sample feed volume: 5.00 ul; run time: 6.0 minutes; flow rate: 3.0 mL / min; pressure: 2000 psi; column temperature: 40°C) to obtain compound Z-41-P2 (11.42 mg, retention time 1.448 minutes), with a yield of 14.98% and a purity of 99.72%. MS m / z (ESI): 304.2 [M+H + ]. 1 H NMR (400MHz, DMSO-d 6 )δ 8.08(d, J = 2.4 Hz,1H),7.83(s,1H),6.39(d, J = 2.4 Hz,1H),6.15(s,1H),5.34(dd, J = 48.8,6.0 Hz,1H),4.21-4.31(m,1H),3.48 - 3.41(m,1H),3.05 - 2.86(m,1H),2.15-2.25(m,1H),2.13 - 1.59(m,12H),1.27-1.37(m,1H).

[0242] Example 45: Preparation of compound Z-45 JPEG0007657943000096.jpg31153

[0243] Step 1: Compound 5-2 (200 mg, 902.18 μmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (201.64 mg, 1.08 mmol) and potassium carbonate (374.06 mg, 2.71 mmol) were dissolved in acetonitrile (5 mL), heated to 90 °C and stirred overnight. The reaction mixture was added with 5 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and spun dry under reduced pressure. The residue was purified by silica gel column chromatography in petroleum ether with 0-40% ethyl acetate as eluent to give compound 45-1 (0.28 g, pale yellow oil), with a yield of 83.55%. MS m / z (ESI): 372.2 [M+1]. Step 2: Compound 45-1 (0.28 g, 753.75 μmol) was dissolved in HCl-dioxane (4M) (5 mL) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give crude compound 45-2 (230 mg, pale yellow solid hydrochloride salt), with a yield of 99.13%. MS m / z (ESI): 308.2 [M+1]. Step 3: Compound 45-2 (150 mg, 487.30 μmol, HCl) is dissolved in water (1 mL) and acetic acid (2 mL), and cooled to 0°C under argon gas protection. Sodium nitrite (67.25 mg, 974.59 μmol) is dissolved in water (1 mL) and slowly added dropwise to the solution. The mixture is allowed to warm to room temperature and stirred for 1.5 h. Water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL x 3). The organic phase is fused, washed with aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product compound 45-3 (140 mg, brown oil), with a yield of 95.65%. MS m / z (ESI): 301.1 [M+1]. Step 4: Compound 45-3 (140 mg, 466.11 μmol) is dissolved in methanol (3 mL) and acetic acid (0.3 mL) and zinc powder (609.58 mg, 9.32 mmol) is added. Stir at room temperature for 1 h. Filter the zinc powder, spin-dry the solvent, dissolve in ethyl acetate (5 mL), wash with aqueous sodium bicarbonate and brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Preparative HPLC chromatography gives compound Z-45 (36.59 mg) with a yield of 23.78% and a purity of 86.74%. MS m / z(ESI): 287.1 [M+1]. 1 H NMR (400MHz, DMSO-d 6 )δ 7.99(d, J = 2.4 Hz,1H),7.40(s,1H),6.31(d, J = 2.4 Hz,1H),6.09(s,1H),4.24-4.15(m,1H),2.98-2.92(m,1H),2.84-2.77(m,1H),2 .76-2.77(m,1H),2.60-2.53(m,1H),2.31-2.19(m,1H),2.03-1.94(m,1H),1.93 - 1.80(m,1H),1.29(d, J = 6.8 Hz,3H),1.10 - 0.99(m,1H),0.54 - 0.44(m,1H),0.37-0.30(m,1H),0.25 - 0.14(m,2H).

[0244] Examples 46 to 59 and 64

[0245] Compounds Z-46 to Z-59 and Compound Z-64 can be prepared with reference to the method of Example 1.

[0246] JPEG0007657943000097.jpg251160 JPEG0007657943000098.jpg254162 JPEG0007657943000099.jpg216163 JPEG0007657943000100.jpg231164 JPEG0007657943000101.jpg41163

[0247] Example 60: Preparation of compound Z-60 JPEG0007657943000102.jpg33162

[0248] Step 1: Under the protection of nitrogen, dissolve N-bromosuccinimide (562.01 mg, 3.16 mmol) in acetonitrile (5 mL) and dropwise add to a solution of compound 5-2 (700 mg, 3.16 mmol) and acetonitrile (10 mL) at 0 °C. After the dropwise addition, react at room temperature for 0.5 hours. Put the reaction solution into water, extract with ethyl acetate (5 mL * 2), wash the organic layer with saturated saline, dry with anhydrous sodium sulfate, and then concentrate to obtain the crude product. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 49-2 (946 mg, 96.57% yield), which is a yellow oil. MS m / z (ESI): 300.0 [M + 1]. Step 2: Under nitrogen protection, compound 49-2 (300 mg, 998.06 μmol), potassium carbonate (344.84 mg, 2.50 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (239.87 mg, 1.20 mmol) and acetonitrile (10 mL) were mixed and then heated to 90 °C for 16 h. The reaction solution was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30% ~ 65%: 35%) to obtain compound Z-60-1 (433 mg, 93.42% yield), which is a colorless oil. MS m / z (ESI): 464.2 [M+1]. Step 3: Under nitrogen protection, compound Z-60-1 (383 mg, 824.72 μmol), potassium vinyltrifluoroborate (331.41 mg, 2.47 mmol), 1,1'-bisdiphenylphosphineferrocene dichloropalladium(II) dichloride (120.69 mg, 164.94 μmol), potassium carbonate (455.93 mg, 3.30 mmol), 1,4-dioxane (10 mL), and water (2.5 mL) are mixed, and then reacted at 120 ° C for 2 hours by microwave. The reaction solution is filtered, water is added to the filtrate, and the mixture is extracted with ethyl acetate (10 mL * 2), and the organic layers are combined and washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=90%:10%-70%:30%) to obtain compound Z-60-2 (320 mg, 94.28% yield), a yellow oil. MS m / z(ESI): 412.2 [M+1]. Step 4: Under nitrogen protection, add zinc bromide (1.05 g, 4.67 mmol) to a solution of compound Z-60-2 (320 mg, 777.57 μmol) and methylene chloride (18 mL), and react at room temperature for 16 hours after addition. Add zinc bromide (1.05 g, 4.67 mmol) and react at room temperature for 16 hours. Add water and a small amount of methanol to the reaction solution, extract with methylene chloride (20 mL * 2), combine the organic layers, wash with saturated saline, dry with anhydrous sodium sulfate, and then concentrate to obtain the crude product. The crude product is separated by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 3H; wavelength: 254 / 214 nm) to give compound Z-60 (24.73 mg, 9.82% yield). MS m / z(ESI): 312.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 8.18(s,1H),6.86(s,1H),6.76(dd,J = 18.0,11.6 Hz,1H),6.15(s,1H),5.93(dd,J = 17.6,2.0 Hz,1H),5.07(dd,J = 11.2,2.4 Hz,1H),4.25-4.18(m,1H),4.03 - 3.92(m,1H),2.22 - 2.12(m,1H),2.09 - 1.90(m,4H),1.75 - 1.64(m,1H),1.51 - 1.45(m,1H),1.34(d,J = 7.2 Hz,3H),1.13 - 1.04(m,1H),0.56 - 0.50(m,1H),0.42 - 0.35(m,1H),0.28 - 0.19(m,2H).

[0249] Example 61: Preparation of compound Z-61 JPEG0007657943000103.jpg38110

[0250] Compound Z-9 (150 mg, 352.47 μmol) and ethyl acetylimine hydrochloride (262.0 mg, 2.12 mmol) are dissolved in acetonitrile (10 mL) and N,N-diisopropylethanamine (0.68 mL, 3.91 mmol) is added. The reaction is stirred at 80° C. for 2 hours, cooled to room temperature, 5 mL of 7N ammonia in methanol is added, and stirred at room temperature for 1 hour. Dilute with ethyl acetate (50 mL), wash with saturated sodium chloride solution (50 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use preparative HPLC chromatography to obtain compound Z-61 (33.58 mg), 25.11% yield. MS m / z (ESI): 367.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 7.86(s,1H),7.42(s,1H),5.99(s,1H),4.24 - 4.10(m,1H),4.00 - 3.90(m,1H),2.29 - 2.12(m,4H),2.11 - 1.93(m,2H),1.90 - 1.72(m,4H),1.68-1.59(m,1H),1.48-1.40(m,1H),1.37 - 1.12(m,3H),0.58-0.51(m,2H),0.38-0.24(m,4H),0.15-0.05(m,2H).

[0251] Example 62: Preparation of Compound Z-62 JPEG0007657943000104.jpg35151

[0252] Step 1: Compound 5-2 (100 mg, 451.1 μmol) and ((1R,3R)-3-aminocyclobutyl) tert-butyl carbamate (84.0 mg, 451.1 μmol) are dissolved in acetonitrile (20 mL) and potassium carbonate (187.0 mg, 1.35 mmol) is added. The reaction is stirred at 90° C. for 16 hours. Ethyl acetate (80 mL) is added and washed with saturated sodium chloride solution (80 mL×3), the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound Z-62-1 (120 mg, pale yellow oil), 71.6% yield. MS m / z (ESI): 372.2 [M+1]. Step 2: Compound Z-62-1 (120 mg, 323.04 μmol) is dissolved in 1,4-dioxane (2 mL) and 4M hydrogen chloride / 1,4-dioxane solution (5 mL) is added. The reaction is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, water (50 mL) is added, and the mixture is extracted with ethyl acetate (50 mL×2), the aqueous phase is adjusted to PH=9-10 with saturated sodium carbonate solution, and extracted with ethyl acetate (60 mL×2), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound Z-62 (47.9 mg) is obtained by preparative HPLC chromatography, with a yield of 54.3%. MS m / z (ESI): 272.2 [M+1]. 1H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.85(s,1H),6.30(d,J = 2.0 Hz,1H),5.85(s,1H),4.26-4.17(m,1H),3.56-3.47(s,1H),2.45-2.26(m,3H),2.15 - 1.96(m,2H),1.28(d,J = 7.2 Hz,3H),1.05-0.96(m,1H),0.55-0.46(m,1H),0.37 - 0.27(m,1H),0.24-0.15(m,2H).

[0253] Example 62a: Preparation of compound Z-62-P1 JPEG0007657943000105.jpg3940

[0254] Compound Z-62 (45mg, 165.83μmol) was sent to chiral resolution (resolution conditions: column type: IC-3 4.6*100mm 3um; auxiliary solvent: IPA (0.5%DEA); wavelength: 220.0nm; flow rate: 3.0mL / min; column temperature: 40℃) to obtain compound Z-62-P1 (7.47mg, retention time 3.394minutes), with a yield of 15.4%. MS m / z(ESI): 272.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 8.00(d,J = 2.4 Hz,1H),7.85(s,1H),6.30(d,J = 2.4 Hz,1H),5.85(s,1H),4.24-4.16(m,1H),3.56-3.50(m,1H),2.49-2.5(m,2H),2.15 - 1.92(m,3H),1.35 - 1.18(m,3H),1.07 - 0.95(m,1H),0.54-0.45(m,1H),0.37-0.28(m,1H),0.22 - 0.15(m,2H).

[0255] Example 62b: Preparation of compound Z-62-P2 JPEG0007657943000106.jpg3840

[0256] Compound Z-62 (45mg, 165.83μmol) was sent to chiral resolution (resolution conditions: column type: IC-3 4.6*100mm 3um; auxiliary solvent: IPA (0.5%DEA); wavelength: 220.0nm; flow rate: 3.0mL / min; column temperature: 40℃) to obtain compound Z-62-P2 (7.74mg, retention time 2.850minutes), with a yield of 16.3%. MS m / z(ESI): 272.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 8.00(d,J = 2.4 Hz,1H),7.84(s,1H),6.30(d,J = 2.4 Hz,1H),5.85(s,1H),4.26-4.18(m,1H),3.56-3.47(m,1H),2.45 - 2.29(m,2H),2.15 - 1.89(m,3H),1.32-1.20(m,3H),1.06 - 0.96(m,1H),0.55-0.45(m,1H),0.37-0.29(m,1H),0.22-0.14(m,2H).

[0257] Example 63: Preparation of Compound Z-63 JPEG0007657943000107.jpg29157Step 1: Compound 49-2 (550 mg, 2.15 mmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (645.10 mg, 3.22 mmol) are dissolved in acetonitrile (20 mL) and potassium carbonate (890.32 mg, 6.44 mmol) is added. The reaction is stirred at 90° C. for 16 hours. The reaction is quenched, diluted with ethyl acetate (60 mL), and the organic phase is washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product Z-63-1 (850 mg, pale yellow oil), 94.3% yield. MS m / z (ESI): 420.2 [M+1]. Step 2: Compound Z-63-1 (550 mg, 1.31 mmol) is dissolved in 1,4-dioxane (2 mL) and 4M hydrogen chloride / 1,4-dioxane solution (4M, 9.82 mL) is added. The reaction is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure, pure water (50 mL) is added, impurities are extracted with ethyl acetate (50 mL), the aqueous phase ammonia solution is adjusted to PH=9-10, extracted with ethyl acetate (60 mL x 2), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound Z-63-2 (410 mg, pale yellow oil), 97.9% yield. MS m / z (ESI): 320.2 [M+1]. Step 3: Compound Z-63-2 (60 mg, 187.60 μmol) is dissolved in methylene chloride (10 mL) and acetyl chloride (73.63 mg, 937.99 μmol) is added, followed by N,N-diisopropylethanamine (0.33 mL, 1.88 mmol). The reaction is stirred at room temperature for 0.5 hours. The reaction is quenched, dissolved and diluted with ethyl acetate (50 mL), the organic phase is washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue is subjected to preparative HPLC chromatography to give compound Z-63 (47.0 mg), with a yield of 67.9%. MS m / z (ESI): 362.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 8.15(s,1H),7.90-7.83(m,2H),6.14(s,1H),4.25-4.14(m,2H),2.21 - 2.12(m,1H),2.08 - 1.95(m,3H),1.90 - 1.81(m,1H),1.72(s,3H),1.74 - 1.65(m,1H),1.47-1.36(m,1H),1.31(d,J =6.8 Hz,3H),1.11 - 1.02(m,1H),0.55-0.47(m,1H),0.39-0.31(m,1H),0.25 - 0.17(m,2H).

[0258] Example 64a: Preparation of compound Z-64-P1 JPEG0007657943000108.jpg27159

[0259] Step 1: 1.2g compound Z-63-1 was resolved by supercritical fluid chromatography (SFC) (column type: AD-3 4.6*100mm 3um, auxiliary solvent: EtOH [1%NH 3 (7M inMeOH)], sample feed volume: 1.00 ul, run time: 4.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to give 440 mg of compound Z-63-a (retention time 1.329 minutes). Step 2: Compound Z-63-a (170.00 mg, 404.81 μmol) is dissolved in 1,4-dioxane (2 mL), and hydrogen chloride / 1,4-dioxane solution (4 M, 6.07 mL) is added, and the reaction chamber is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure to obtain crude product compound Z-63-P1 (120 mg, pale yellow solid hydrochloride salt), with a yield of 92.68%. MS m / z (ESI): 320.2 [M+1]. Step 3: Compound Z-63-P1 (120 mg, 375.20 μmol) and ethyl ethyleneimine (163.44 mg, 1.88 mmol) are dissolved in acetonitrile (15 mL) and N,N-diisopropylethanamine (0.65 mL, 3.75 mmol) is added. The reaction is stirred at 80° C. for 2 hours, cooled to room temperature, and 2 mL of 7N ammonia in methanol is added. Stir at room temperature for 1 hour. The reaction is quenched, dissolved and diluted with ethyl acetate (50 mL), and the organic phase is washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative liquid chromatography (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 The crude product was purified by HPLC using a 5%-95% acetonitrile gradient (O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to give compound Z-64-P1 (63.5 mg), with a yield of 46.2%. MS m / z (ESI): 361.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6)δ 8.17(s,1H),6.17(s,1H),4.30 - 4.15(m,1H),3.99 - 3.89(m,1H),2.26 - 2.17(m,1H),2.12 - 1.93(m,3H),1.89 - 1.70(m,4H),1.70-1.60(m,1H),1.50-1.38(m,1H),1.33(d,J = 6.8 Hz,3H),1.10-1.02(m,1H),0.57-0.48(m,1H),0.42-0.31(m,1H),0.28-0.17(m,2H).

[0260] Example 64b: Preparation of compound Z-64-P2 JPEG0007657943000109.jpg27161Step 1: 1.2g of compound Z-63-1 was resolved by supercritical fluid chromatography (SFC) (column type: AD-3 4.6*100mm 3um, auxiliary solvent: EtOH [1%NH 3 (7M inMeOH)], sample feed volume: 5.00 ul, run time: 6.0 minutes, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40° C. to obtain 440 mg of compound Z-63-b (retention time 1.512 minutes). Step 2-3: Prepare with reference to the methods of Steps 2 and 3 of Example 64a to obtain compound Z-64-P2. MS m / z(ESI): 361.2 [M+1]. 1 H NMR (400MHz, DMSO-d 6 )δ 8.17(s,1H),6.16(s,1H),4.24 - 4.12(m,1H),3.98 - 3.88(m,1H),2.27 - 2.16(m,1H),2.12 - 1.92(m,3H),1.86 - 1.71(m,4H),1.70-1.60(m,1H),1.50-1.38(m,1H),1.33(d,J = 6.8 Hz,3H),1.12-1.02(m,1H),0.56-0.48(m,1H),0.41-0.30(m,1H),0.28-0.18(m,2H).

[0261] Example 65 Preparation of Compound Z-65 JPEG0007657943000110.jpg36106

[0262] Compound Z-63-2 (60 mg, 187.60 μmol) and 1H-pyrazole-1-methylamidine hydrochloride (620 mg, 4.23 mmol) are dissolved in acetonitrile (12 mL) and N,N-diisopropylethanamine (1.31 mL, 7.50 mmol) is added. The reaction is stirred at room temperature for 16 hours. The reaction is stopped, saturated sodium chloride solution (30 mL) is added, extracted with ethyl acetate (30 mL x 2), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparative HPLC chromatography gives the target product compound Z-65 (26.21 mg), with a yield of 36.68%. MS m / z (ESI): 362.1 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ 7.96(s,1H),7.60(s,1H),5.99(d,J = 2.8Hz,1H),4.10-4.00(m,1H),3.85-3.70(m,1H),2.09 - 1.77(m,4H),1.75-1.60(m,1H),1.55-1.46(m,1H),1.36-1.25(m,1H),1.07(d,J = 6.8Hz,3H),0.92 - 0.75(m,1H),0.33-0.25(m,1H),0.17-0.08(m,1H),0.05-0.01(m,2H).

[0263] Examples 66 to 74

[0264] Compounds Z-66, Z-68, Z-69, Z-72, and Z-73 can be prepared by referring to the method of Example 64a. Compounds Z-67 and Z-71 can be prepared by referring to the method of Example 65. Compounds Z-70 and Z-74 can be prepared by referring to the method of Example 1.

[0265] JPEG0007657943000111.jpg249162 JPEG0007657943000112.jpg249157 JPEG0007657943000113.jpg246164

[0266] Preparation of Comparative Compounds D and E JPEG0007657943000114.jpg52102

[0267] Compounds D and E can be prepared with reference to prior published patent literature.

[0268] Test Example 1: Activity inhibition test against CDK family kinases

[0269] In the following, in the LANCE Ultra test method, the kinase reagent is purchased from Carna Bioscience, the reaction substrate and detection reagent are purchased from PerkinElmer, and other reagents are purchased from Thermo scientific. The LANCE Ultra method measures the inhibitory effect of the test substance on the kinase activity of CDK1 / CycB (Carna bioscience, #04-102), CDK2 / CycA (Carna bioscience, #04-103), and CDK9 / CycT (Carna bioscience, #04-110).

[0270] The kinase activity test uses a 10μL system, which contains CDK kinase diluent, substrate diluent mixed with Ulight-Myelic basic protein (Perkin Elmer, #TRF-0109, hereinafter referred to as U-MBP) and ATP (Thermo scientific, #PV3227), and the compound (i.e., the object to be measured) prepared in the above examples of the present invention. In the test, each kinase includes three test groups, a blank group (Blank), a non-inhibited group (PC) and a compound test group (Test). The components contained in each test group are shown below.

[0271] TIFF0007657943000115.tif31121

[0272] The working concentrations of each component in the test group for different kinase reactions are as follows:

[0273] Compounds: Compounds to be measured dissolved at 10 mM at room temperature were gradient diluted with DMSO, and then diluted to 4x compound working solution with deionized water, with DMSO content of 2%. The highest concentration of compounds used in CDK1 and CDK2 tests was 10 μM, and CDK9 was 1 μM.

[0274] 1.33x Reaction Buffer: Ingredients: 26.7 mM MOPS, 6.67 mM MgCl 2 and 0.0133% Tween-20. After preparation, store in a refrigerator at 4° C. away from light, and add freshly prepared DTT to a final concentration of 5.33 mM before use.

[0275] TIFF0007657943000116.tif52130

[0276] The DMSO working concentration in the reaction is 0.5%.

[0277] After mixing the above components, place on a rocking bed and incubate at room temperature for 1 hour in the dark. Then add 10 μL of detection solution to all test groups (including Blank, PC and Test groups).

[0278] The components contained in 10 μL of detection solution were 16 mM EDTA (Thermo scientific, #15575), 1 nM phosphorylated U-MBP protein antibody (Perkin Elmer, #TRF-0201), and 1x detection buffer (Perkin Elmer, #CR97-100).

[0279] After adding the detection solution, it is placed on a rocking bed and incubated at room temperature for 1 hour in the dark. After incubation, the signal is read using Perkin Elmer's Victor X5 fluorescent enzyme marker, the excitation light wavelength is 320 nm, the emission light wavelength is 615 nm and 665 nm, and the inhibition rate is calculated as follows: 1. Calculate the 665nm / 615nm value (hereinafter referred to as the ratio value) for all groups, and calculate the inhibition rate using the ratio value of each group. 2, Suppression rate = (PC Ratio -Test Ratio ) / (PC Ratio -Blank Ratio )*100%, 3. The IC50 of the compound was calculated using a 4-parameter model with the logarithm of the compound concentration on the X-axis and the inhibition rate on the Y-axis, using XLFIT 5.0 software (IDBS, UK). 50 Calculate.

[0280] JPEG0007657943000117.jpg248144 JPEG0007657943000118.jpg52163

[0281] JPEG0007657943000119.jpg249154 JPEG0007657943000120.jpg96169

[0282] As can be seen from Tables 1 and 2, the compounds of the examples of the present invention have high inhibitory activity against CDK9 and high selectivity for CDK9 inhibition.

[0283] Test Example 2: Pharmacokinetics test in mice

[0284] Using LC / MS / MS, the plasma drug concentrations at different time points after intravenous injection and intragastric administration of the compounds of the present invention to mice were measured to study the pharmacokinetic behavior of the compounds of the present invention in mice and evaluate their pharmacokinetic characteristics.

[0285] Testing Procedures: Test animals: healthy adult male ICR mice (body weight 30-40g, 12 mice, mice in the intravenous injection group had free access to water and food, mice in the intragastric administration group were fasted overnight and had free access to water and food after 4h administration), provided by Beijing Vital River Laboratory Animal Co. LTD. Administration method and dose: Tail vein injection (2mg / kg, 5% DMSO, pH 4.5 20% Captisol) and intragastric injection (10mg / kg, 5% DMSO, pH 4.5 20% Captisol) into ICR mice.

[0286] Blood sample collection: Select animals that meet the experimental requirements before dosing, weigh and mark them. Before collecting blood samples, bind the mice, and each administered mouse will have approximately 100 μL of blood collected from the orbit at the designated blood collection time points (intravenous administration: blood is collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, and 24 h after dosing, for a total of nine time points; intragastric administration: blood is collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, and 24 h after dosing, for a total of nine time points). Blood is then collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, and 24 h after dosing, for a total of nine time points). 2 The blood was transferred to a 1.5 mL test tube containing EDTA, centrifuged for 4 min (8000 rpm, 4°C), and plasma was extracted. The entire process was completed within 15 min after blood collection. All samples should be stored in a refrigerator at -20°C until sample analysis. LC / MS / MS method was used to measure drug concentration, and the pharmacokinetic characteristic parameters in mice of some examples of the compounds of the present invention at the same dose and administration method are shown in Table 3.

[0287] JPEG0007657943000121.jpg62170

[0288] Test Example 3: Intra-body drug efficacy test

[0289] We subcutaneously implanted xenograft (CDX) BALB / c cells based on the human tumor cell line derived from an acute myeloid leukemia patient, MV4-11, in nude mice to conduct in vivo drug efficacy experiments.

[0290] Experimental methods: BALB / c nude mice, female, 6-10 weeks old, weighing approximately 20-23g. Mice were kept in a specific pathogen-free environment and housed in single ventilated cages (5 mice per cage, 10 mice per group in 2 cages). All cages, bedding and water were disinfected before use. All animals were allowed to eat food ad libitum in a standard certified commercial laboratory. A total of 80 mice were purchased from the Laboratory Animal Management Department of Shanghai Institute of Family Planning Science (No. 3577 Jinke Road, Pudong, Shanghai) and used in the study. Each mouse was subcutaneously inoculated with tumor cells (1 × 10 7 The mice are implanted with 0.1 ml of PBS (0.1 ml + Matrigel 0.1 ml) and used for tumor growth. When the average tumor volume reaches approximately 165 cubic millimeters, they are randomly grouped according to body weight and tumor volume and treatment is initiated. The test compound is orally administered intragastrically every day. Antitumor efficacy is determined by dividing the average tumor volume of compound-treated animals by the average tumor volume of untreated animals.

[0291] Tumor volumes are measured twice weekly with a 2D caliper and the volume is measured in cubic millimeters. Tumor volume TV = 0.5a x b 2 a is the long axis of the tumor, and b is the short axis of the tumor.

[0292] Relative tumor enhancement rate T / C (%), i.e., the percentage value of tumor volume in the treatment group and the control group at a certain time point. The calculation formula is T / C%=T RTV / C RTV ×100%(T RTV :Treatment group average RTV;C RTV : Mean RTV of the vehicle control group; RTV=V t / V 0 , V 0 is the tumor volume of the animal at the time of grouping, and Vt is the tumor volume of the animal after treatment). The weight change (%) of tumor-bearing animals was calculated as follows: (weight at time of measurement-weight at time of grouping) / weight at time of grouping×100.

[0293] JPEG0007657943000122.jpg74160

[0294] JPEG0007657943000123.jpg78159

[0295] All documents mentioned in this application are incorporated herein by reference as if each document was incorporated by reference in its entirety. It should be understood that after reading the above teachings of the present invention, a person skilled in the art may make various changes or modifications to the present invention, and the equivalents thereof are also intended to be defined in the appended claims of this application.

Claims

1. A compound represented by formula (III-a) or (III-b), or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, however, R 1a is hydrogen, C 1-6 Alkyl group or deuterated C 1-6 is an alkyl group, n is 1, 2, 3, or 4; t is 1, 2, or 3; R 11 , R 12 are each independently hydrogen; R 2 is hydrogen, C 1-6 is an alkyl group or a halogen; R 3 is hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl group, C 1-6 an alkoxy group or a halogen; 1-6 The alkyl group may be unsubstituted or C 1-3 substituted with one, two or three substituents selected from alkoxy groups; R 4 is hydrogen, -C(O)OC 1-3 Alkyl group, -(C=N)-C 1-3 An alkyl group, or -(C=N)-NR a0 R b0 and R 5 is hydrogen, R a is hydrogen, C 1-6 Alkyl group, C 3-6 is a cycloalkyl group, a cyano group, or a halogen; 1-6 The alkyl group is unsubstituted or substituted with one, two or three substituents selected from halogen; R b is hydrogen, (R 0 ) m means the number m of hydrogen atoms on the ring substituted by the substituent R 0 , m being 0; R a0 , R b0 is each independently hydrogen, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

2. The compound has the structure shown in formula (III-a):

2. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof.

3. R 2 is hydrogen, or C 1-3 is an alkyl group, R 3 is hydrogen, C 1-3 Alkyl group, or C 3-6 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, which is a cycloalkyl group.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, wherein t is 1 or 2.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, wherein n is 1 or 2.

6. R 1a is hydrogen, n is 1 or 2; t is 1 or 2; R 2 is hydrogen or C 1-3 is an alkyl group, R 3 is C 1-3 Alkyl group or C 3-6 is a cycloalkyl group, R 4 is hydrogen, R a is hydrogen, C 1-3 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, wherein R is an alkyl group or a halogen.

7. R 1a is hydrogen, n is 1 or 2; R 2 is hydrogen, R 3 is C 1-3 Alkyl group or C 3-6 is a cycloalkyl group, R 4 is hydrogen, R a is hydrogen or C 1-3 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, which is an alkyl group.

8. The compound represented by formula (III-a) has a structure represented by formula (III-a-1) or formula (III-a-2), In the formula, R 3 ' is C 1-3 is an alkyl group, R 1a is hydrogen or C 1-3 is an alkyl group, n is 1, 2, or 3; t is 1 or 2; R 4 is hydrogen, -(C=N)-C 1-3 An alkyl group, or -(C=N)-NR a0 R b0 and R a is hydrogen, C 1-3 Alkyl group, C 3-6 is a cycloalkyl group, a cyano group, or a halogen; 1-3 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or a stereoisomer, or a solvate thereof, wherein the alkyl group is unsubstituted or substituted with one, two or three substituents selected from halogen.

9. R 3 9. The compound of claim 8, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof, wherein: R is a methyl group;

10. R a is hydrogen, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof.

11. R 4 is hydrogen, or a pharma- ceutically acceptable salt, or stereoisomer, or solvate thereof.

12. The compound represented by formula (III-a) or formula (III-b) is any one of the following compounds:

2. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof.

13. The compound represented by formula (III-a) or formula (III-b) is any one of the following compounds:

2. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof.

14. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt, or a stereoisomer, or a solvate thereof, and a pharma- ceutically acceptable carrier.

15. Use of a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for treating or preventing a disease associated with or mediated by CDK9 activity.

16. 16. The use according to claim 15, wherein the disease associated with or mediated by CDK9 activity is cancer.

17. 17. The use according to claim 16, wherein the disease associated with or mediated by CDK9 activity is a solid tumor or a hematological tumor.

18. The use according to claim 16, wherein the cancer is selected from pancreatic cancer, breast cancer, ovarian cancer, cervical cancer and leukemia.

19. Use of a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a pharmaceutical composition according to claim 14, in the preparation of a CDK9 inhibitor.

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