Compounds as RET kinase inhibitors and their uses

Abstract

The present invention belongs to the technical field of medicine, and specifically discloses a compound represented by formula I' or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein each symbol is as defined in the claims. The compound of the present invention is useful as a drug for regulating the activity of RET kinase or treating RET-related diseases, and has good pharmacokinetic properties.

Description

[Technical field]

[0001] The present invention relates to the technical field of medicine, specifically to compounds as RET kinase inhibitors and their use in modulating the activity of RET kinase or in treating RET-related diseases. [Background technology]

[0002] The RET (rearranged during transfection) gene is located on chromosome 10, and the RET protein it encodes is a receptor tyrosine kinase (RTK) present in the cell membrane. Its mutant forms mainly include fusion mutations with genes such as KIF5B, TRIM33, CCDC6 and NCOA4, as well as point mutations at sites such as M918T. Common RET mutations in humans occur mainly in many types of cancer, including thyroid cancer and non-small cell lung cancer. The incidence of RET gene fusions is about 1%-2% in NSCLC patients and 10%-20% in papillary thyroid cancer (accounting for about 85% of all thyroid cancers), and RET fusions are more common in young patients, especially in young non-smoking lung adenocarcinoma patients, where the incidence is as high as 7%-17%. Currently, treatment proposals for RET gene alterations mainly include multiple kinase inhibitor drugs, such as cabozantinib and vandetanib, but due to their poor targeting, they often result in high toxicity associated with VEGFR inhibition due to off-target.

[0003] Blueprint Medicines, Inc. (Blueprint) and Loxo Oncology, Inc. (Loxo Oncology) announced the development of BLU-667 and LOXO-292, two potent and selective orally administered RET inhibitors. Results from Blueprint's Phase I clinical data showed that BLU-667 has broad antitumor activity, with an overall response rate (ORR) of 45% in patients with tumors harboring RET fusions and mutations, including ORRs of 50% and 40% in patients with non-small cell lung cancer and medullary thyroid cancer, respectively. Recently, Loxo Oncology's investigational LOXO-292 was granted Breakthrough Therapy Designation by the US FDA for the treatment of patients with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) harboring RET gene mutations.

[0004] Whether BLU-667 or LOXO-292, both are currently in the clinical trial stage. Therefore, the development of new compounds with RET kinase inhibitory activity and better pharmacological and pharmacokinetic performances has become an important research topic for the development of new antitumor drugs, and will eventually be used to treat human tumors and other diseases. Summary of the Invention

[0005] The present invention provides novel compounds that have RET kinase inhibitory activity and have superior pharmacological and pharmacokinetic properties.

[0006] In a first aspect of the present invention there is provided a compound as a RET kinase inhibitor, the compound being of formula I' or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof. [ka]

[0007] (however, R1 is a substituted or unsubstituted 5- to 6-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, said substitution being optionally substituted with one or more R2 groups. X3 is O, NR8, CR9R 10 , [ka] where R8 and R 11 are each independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, and a C3-C6 heterocycloalkyl group; R9 and R 10 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group.

[0008] Ring W is a substituted or unsubstituted heterocyclylene group or heteroarylene group, the substitution meaning that it is optionally substituted with 0 to 2 R5. Ring Q1 is optionally selected from a 3- to 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring, or bridged ring, and may contain 0 to 3 heteroatoms, which are optionally selected from N, O, and S. Any hydrogen atom in ring Q1 may be substituted with a substituent selected from deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group, or a heteroaryl group.

[0009] X5 is C(O), S(O), S(O)2, [ka] Selected from. X6 is selected from CR9, N, and O.

[0010] R2 is optionally selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, alkylamino group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with.

[0011] A is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in the A ring may be substituted with a substituent selected from deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0012] R3 is optionally selected from hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, alkylamino group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with.

[0013] R4 is independently any of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, a cyano group, -C(O)R6, -OC(O)R6, -C(O)OR6, -(C1-C6 alkylene)- It is selected from C(O)R6, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N(R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7). Here, each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group, and heterocycloalkyl group independently represents 0 to 5 R a has been replaced with.

[0014] R5 is independently any of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, an oxo group, a cyano group, -C(O)R6, -OC(O)R6, -C(O)OR6, -(C1-C6 alkylene )-C(O)R6, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N(R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7). Here, each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group, and heterocycloalkyl group independently represents 0 to 5 R a has been replaced with. R6 and R7 are each independently selected from H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group.

[0015] R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group. m is 0, 1, 2, 3, 4, 5 or 6. n is 0 or 1.

[0016] The limitation is that when ring W is a substituted or unsubstituted 6-membered heteroaryl group, ring W is substituted with X4, where X4 is CN, [ka] Selected from And Q1 is linked to ring W only through carbon atoms in the Q1 ring.

[0017] In another preferred embodiment, the W ring is selected from the group consisting of a substituted or unsubstituted 5-6 membered monocyclic heterocyclylene group, an 8-10 membered bicyclic heterocyclylene group, a 5-6 membered monocyclic heteroarylene group, or an 8-10 membered bicyclic heteroarylene group, and the substitution is optionally substituted with 0 to 2 R5, and each R5 is independently optionally selected from hydrogen, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a halogen, a C1 to C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, an oxo group, a cyano group, -C(O)R6, -OC(O)R6, -C(O)OR6, -(C1 to C6 alkylene)-C(O)R6, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N( R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7), wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group and heterocycloalkyl group are each independently selected from 0 to 5 R a is replaced by R ais arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0018] In another preferred embodiment, in the compound represented by formula I' or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the W ring is [ka] wherein X1, X2, X7, and X8 are each independently selected from N or CR5, and at least one of X7 and X8 is N;

[0019] R5 is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, a nitro group, a cyano group, and an amino group, wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group are independently selected from 0 to 5 R a is replaced by R ais optionally selected from a C1-C6 alkyl group, a halogen, a hydroxy group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group; ring Q2 is optionally selected from a 5-, 6-, or 7-membered saturated ring, an unsaturated ring, an aromatic ring, a heteroaromatic ring, a spiro ring, or a bridged ring, and may contain 0 to 3 heteroatoms, the heteroatoms being optionally selected from N, O, and S; any hydrogen atom in Q2 may be substituted with a substituent selected from a deuterium atom, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group, or a heteroaryl group.

[0020] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (II), formula (III) or formula (IV). [ka] [ka]

[0021] (however, A is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, optionally selected from N, O and S. Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in ring Q1 may be substituted with a substituent selected from deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketone group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 thioalkyl group, C1-C6 alkoxy group, C1-C6 heteroalkyl group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C3-C8 cycloalkylamino group, aryl group or heteroaryl group. In formula (II), Q1 is linked to ring B only through a carbon atom in ring Q1.

[0022] R 1 is optionally one of the following structures: [ka] [ka]

[0023] R2 is optionally selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with. R3 is optionally selected from hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with. R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0024] X1 and X2 are each independently selected from N or CR5. X3 is O, NR8, CR9R 10 , [ka] where R8 and R 11 are each independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, and a C3-C6 heterocycloalkyl group; R9 and R 10 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group.

[0025] X4 is CN, [ka] Selected from. X5 is C(O), S(O), S(O)2, [ka] Selected from.

[0026] X6 is selected from CR9, N, and O. R4 and R5 each independently represent any of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, a cyano group, -C(O)R6, -OC(O)R6, -C(O)OR6, -(C1-C6 alkylene)-C(O)R6, It is selected from -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N(R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7). Here, each alkyl group, alkenyl group, alkynyl group, alkoxy group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group, and heterocycloalkyl group independently represents 0 to 5 R a R6 and R7 are each independently selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group.

[0027] Ring Q2 is optionally selected from a 5-, 6- or 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in ring Q2 may be substituted with a substituent selected from deuterium, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0028] m is 0, 1, 2, 3, 4, 5 or 6. n is 0 or 1.) In another preferred embodiment, X3 is NR8, wherein R8 is H.

[0029] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (2), formula (3) or formula (4). [ka]

[0030] (however, A is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, optionally selected from N, O and S.

[0031] Ring Q1 is optionally selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in ring Q1 may be substituted with a substituent selected from deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketone group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 thioalkyl group, C1-C6 alkoxy group, C1-C6 heteroalkyl group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C3-C8 cycloalkylamino group, aryl group or heteroaryl group. In formula (2), Q1 is linked to ring B only through a carbon atom in ring Q1.

[0032] R 1 is optionally one of the following structures: [ka]

[0033] R2 is optionally selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with. R3 is optionally selected from hydrogen, deuterium, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a has been replaced with. R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0034] X1 and X2 are each independently selected from N or CR5. R4 and R5 each independently represent any of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, a cyano group, -C(O)R6, -OC(O)R6, -C(O)OR6, -(C1-C6 alkylene)-C(O)R6, It is selected from -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N(R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7). Here, each alkyl group, alkenyl group, alkynyl group, alkoxy group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group, and heterocycloalkyl group independently represents 0 to 5 R a R6 and R7 are each independently selected from a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group.

[0035] Ring Q2 is optionally selected from a 5-, 6- or 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in ring Q2 may be substituted with a substituent selected from deuterium, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group. m is 0, 1, 2, 3, 4, 5 or 6.

[0036] In another preferred embodiment, in the compound of formula I' above, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the W ring is [ka] [ka] [ka] is selected from the group consisting of:

[0037] (however, [ka] It may be a single bond or a double bond. R a are independently selected from H, halogen, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a nitro group, a cyano group, and an amino group. Each Y1, Y2, and Y3 is independently O, N, or NR 17 , C.R. 13 , C.R. 13 R 14 Selected from.

[0038] R13 , R 14 , R 15 , R 16 are each independently selected from H, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a nitro group, a cyano group, and an amino group, or R 13 and R 14 forms a carbonyl group (C=O) together with the C atom attached to it, or R 15 and R 16 forms a carbonyl group (C=O) together with the C atom attached to it. R 17 is selected from H and C1 to C6 alkyl groups.

[0039] In another preferred embodiment, the W ring is [ka] Selected from.

[0040] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 2'. [ka]

[0041] (however, [ka] It may be a single bond or a double bond.

[0042] Each R 17 are independently selected from deuterium, halogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, and a C3-C6 cycloalkyl group. f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9. X1, X2, R1, R2, R3, R4, A and m are defined as above.

[0043] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 2''. [ka]

[0044] (however, R1, R2, R3, R4, A, m, X1, X2 and R 17 is defined above.) In another preferred embodiment, [ka] Selected from R 12 The definition is as above.

[0045] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 3'. [ka]

[0046] (however, [ka] is a single bond or a double bond. [ka] When Y4 is a single bond, Y4 is N or CR 17 Selected from [ka] When it is a double bond, Y4 is C.

[0047] Each R 17 are independently selected from deuterium, halogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, and a C3-C6 cycloalkyl group. f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9. p is 0, 1, 2, and 3. X2, Q2, R1, R2, R3, R4, A and m are defined as above.

[0048] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 3''. [ka] (R1, X2, R2, R3, R4, A, Q2, m and R 17 is defined above.)

[0049] In another preferred embodiment, [ka] [ka] Selected from.

[0050] (however, [ka] It may be a single bond or a double bond. Y1, Y2, Y3, R 12 , R 13 , R 14 , R 15 and R 16 is defined above.)

[0051] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 4'. [ka]

[0052] (however, [ka] It may be a single bond or a double bond. [ka] When Y4 is a single bond, Y4 is N or CR 17 Selected from [ka] When it is a double bond, Y4 is C.

[0053] Each R 17 are independently selected from deuterium, halogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, and a C3-C6 cycloalkyl group. f is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9. p is 0, 1, 2, and 3. X2, Q2, R1, R2, R3, R4, A and m are defined as above.

[0054] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 4''. [ka] (R1, X2, R2, R3, R4, A, Q2, m and R 17 is defined above.)

[0055] In another preferred embodiment, [ka] Here, Q2 is defined as above.

[0056] In another preferred embodiment, the compound of formula I′, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 5 or 6. [ka] (However, R1, X7, X8, X2, Q2, R2, R3, R4, R 17 , A and m are defined as above, and at least one of X7 and X8 is N.

[0057] In another preferred embodiment, in the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, A is an aromatic ring or a heteroaromatic ring, the heteroaromatic ring containing 0 to 3 heteroatoms, the heteroatoms being optionally selected from N, O and S, and any hydrogen atom in ring A may be substituted with a substituent selected from deuterium, a hydroxyl group, a halogen atom, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0058] In another preferable example, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazyl group, and any hydrogen atom in the A ring may be substituted with a substituent selected from deuterium, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group. In another preferred embodiment, in the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, each R4 is independently selected from an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, and a heterocyclyl group, wherein each aryl group, heteroaryl group, aroxyl group, aralkyl group, and heterocyclyl group is independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0059] In another preferred embodiment, R4 is a 5-membered heteroaryl group, and the heteroaryl group is independently selected from 0 to 5 R a may be substituted with R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0060] In another preferred embodiment, R4 is [ka] where R 18 is selected from halogen (preferably F) and C1 to C6 alkyl groups.

[0061] In another preferred embodiment, m is 1. In another preferred embodiment, R3 is H, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group. In another preferred embodiment, R2 is H. In another preferred embodiment, R1, X3, W, Q1, X5, X6, R2, R3, R4, A, m and n are specific groups corresponding to each specific compound in the examples. In another preferred embodiment, R1, X1, X2, X3, Q1, Q2, X5, X6, R2, R3, R4, A, m and n are specific groups corresponding to each specific compound in the examples.

[0062] In another preferred embodiment, [ka] Here, X9, X 10 are each independently selected from N or CR5, where R5 is each independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, a nitro group, a cyano group, and an amino group, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group are each independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0063] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 5' or 6'. [ka] (However, X2, X7, X8, X9, X 10 are each independently selected from N or CR5, and at least one of X7 and X8 is N.

[0064] R5 are each independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, a nitro group, a cyano group, and an amino group, wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group are each independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group. Ring Q2 is optionally selected from a 5-, 6- or 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaromatic ring, spiro ring or bridged ring, and may contain 0 to 3 heteroatoms, which are optionally selected from N, O and S. Any hydrogen atom in ring Q2 may be substituted with a substituent selected from deuterium, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0065] In another preferred embodiment, [ka] [ka] Selected from Y2, Y3, R 12 The definition is as above.

[0066] In another preferred embodiment, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, may optionally be selected from compounds represented by the following structure: [ka]

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] In another preferred embodiment, the compound is selected from the compounds set forth in the Examples. In another preferred embodiment, in the compound or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the pharma- ceutically acceptable salt is preferably an inorganic acid salt or an organic acid salt, the inorganic acid salt being selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate and acid phosphate, and the organic acid salt being selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate and camphorsulfonate.

[0071] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I' as described in the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0072] In another preferred embodiment, the pharmaceutical composition may further include one or more other therapeutic agents, and the other therapeutic agents may be PD-1 inhibitors (e.g., nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biosimilars of the above drugs), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, tositumomab, ibritumomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alpha-lactamase inhibitors, etc.), rectinib, brigutinib, lorlatinib, alcotinib), PI3K inhibitors (e.g. idelalisib, dactolisib, taselisib, buparisib, etc.), BTK inhibitors (e.g. ibrutinib, tirabrutinib, acalabrutinib, etc.), EGFR inhibitors (e.g. afatinib, gefitinib, lapatinib, lapatinib, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (e.g. sorafenib, pazopanib, lenvatinib, cabozantinib, etc.), tinib, sunitinib, donafenib, etc.), HDAC inhibitors (e.g. gibinostat, droxinostat, entinostat, dacinostat, tacedinaline, etc.), CDK inhibitors (e.g. palbociclib, ribociclib, abemaciclib, relociclib, etc.), MEK inhibitors (e.g. selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI -1040), Akt inhibitors (e.g., MK-2206, ipatasertib, capivasertib, afuresertib, uprosertib, etc.), mTOR inhibitors (e.g., vistusertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (e.g., ceritinib, alcotinib, linsitinib, BMS-754807, GSK1838705A, etc.), or combinations thereof.

[0073] In a third aspect of the invention there is provided the use of a compound of formula I' as defined in the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in the manufacture of a medicament for a RET kinase inhibitor. In a fourth aspect of the invention there is provided the use of a compound of formula I' as defined in the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in the manufacture of a medicament for modulating the activity of RET kinase or for treating a RET associated disease. In another preferred embodiment, the RET-associated disease comprises cancer. In another preferred embodiment, the cancer is thyroid cancer or lung cancer. In another preferred embodiment, the cancer is medullary thyroid cancer or non-small cell lung cancer.

[0074] Specific embodiments Through extensive and in-depth research, the present inventors have unexpectedly found a compound with good RET kinase inhibitory activity. Moreover, the compound has excellent inhibitory activity against RET kinase and has better pharmacological / pharmacokinetic performance. Based on this, the present invention has been completed.

[0075] term Unless otherwise stated, the following terms used in this application (including the specification and claims) have the meanings set forth below. When a substituent is depicted by a conventional chemical formula written from left to right, the substituent includes the chemically equivalent substituent that would result if the structural formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0076] An "alkyl group (alone or as part of another group)" is a monovalent linear or branched saturated hydrocarbon group consisting solely of carbon and hydrogen atoms, containing 1 to 12 carbon atoms. The alkyl group is preferably a C1-C6 alkyl group (i.e., containing 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl groups also include substituted alkyl groups, i.e., substituted at one or more positions on the alkyl group, and may be substituted at any position, particularly with 1 to 4 substituents. A "haloalkyl group" is an alkyl group as defined herein having one or more hydrogens replaced with the same or different halogen. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

[0077] An "alkylene group" is a divalent radical of an alkyl group, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-. An "alkoxy group (alone or as part of another group)" is an alkyl group having an oxy group attached thereto, and has the structure alkyl-O-, where the alkyl group is as defined above. The definition Preferably, the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, t-butoxy, and the like. A "haloalkoxy group" is a group of formula -OR, where R is a haloalkyl group as defined herein. Illustrative examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0078] A "thioalkyl group" is an alkyl group in which a carbon is replaced with S, S(O), or S(O)2. An "alkenyl group (alone or as part of another group)" is an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, a "C2-C6 alkenyl group" refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl groups, propenyl groups, butenyl groups, 1-methyl-2-buten-1-yl groups, and the like. In the present invention, an alkenyl group includes a substituted alkenyl group.

[0079] An "alkenylene group" is an alkenyl group that has two binding sites. For example, a "vinylene group" refers to the group -CH=CH-. Alkenylene groups can be unsubstituted or substituted with one or more substituents. An "alkynyl group (alone or as part of another group)" is a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, typically having from 2 to 20 carbon atoms. In the present invention, a "C2-6 alkynyl group" refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl and 3-hexynyl groups. One of the carbons of the triple bond may optionally be the site of attachment of a substituent of the alkynyl group. In the present invention, alkynyl groups further include substituted alkynyl groups. An "alkynylene group" is an alkynyl group that has two binding sites. For example, an "ethynylene group" refers to -C≡C-. Alkynylene groups can be unsubstituted or substituted with one or more substituents.

[0080] An "aliphatic group" is a straight-chain, branched-chain or cyclic hydrocarbon group, including saturated and unsaturated groups, such as alkyl, alkenyl and alkynyl groups. An "aromatic ring system" is a monocyclic, bicyclic or polycyclic hydrocarbon ring system, at least one of which is aromatic. An "aryl group (alone or as part of another group)" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include all aromatic ring systems, such as phenyl, naphthyl and anthracenyl groups, as well as ring systems in which the aromatic carbocyclic ring is fused with one or more non-aromatic carbocyclic rings, such as indanyl, phthalimido, naphthylimino or tetrahydronaphthyl groups. In the present invention, the aryl group is preferably a C6-C12 aryl group. In the present invention, the aryl group further includes substituted aryl groups.

[0081] An "arylalkyl group" or "aralkyl group" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by an aryl group. Aralkyl groups include groups in which one or more hydrogen atoms have been replaced by an aryl group, and the aryl and alkyl groups are as defined above. The definition Examples of "arylalkyl groups" or "aralkyl groups" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl groups. An "aroxyl group" is an -O-(aryl) group, wherein the aryl portion is as defined herein.

[0082] A "heteroalkyl group" is a substituted alkyl group having one or more atoms in the skeletal chain selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. A range of values ​​may be indicated, for example, a C1-C6 heteroalkyl group refers to the number of carbons in the chain, from 1 to 6 carbon atoms. For example, the group -CH2OCH2CH3 would be referred to as a "C3" heteroalkyl group. Connection to the rest of the molecule may be through a heteroatom or carbon in the heteroalkyl chain. A "heteroalkylene group" is an optionally substituted divalent alkyl group having one or more atoms in the skeletal chain selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof.

[0083] "Carbocyclic ring system" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but none of the rings is aromatic. A "carbocyclic group" refers to a monovalent group of a carbon ring system, including, for example, cycloalkyl groups (such as cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl) and cycloalkenyl groups (such as cyclopentenyl, cyclohexadienyl, cyclopentadienyl).

[0084] A "cycloalkyl group" is a monovalent, monocyclic or bicyclic saturated carbocyclic group having 3 to 12, preferably 3 to 10, and more preferably 3 to 6 ring atoms. A cycloalkyl group may be optionally substituted with one or more substituents, each of which is independently a hydroxyl group, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, an amino group, a monoalkylamino group, or a dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0085] A "haloalkoxy group" is a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. A "cycloalkylalkyl group" is a -(cycloalkyl)-alkyl group, wherein the cycloalkyl and alkyl groups are as disclosed herein. A "cycloalkylalkyl group" is attached to the parent molecular structure via a cycloalkyl group.

[0086] A "heteroaromatic ring system" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (6-12 membered) or polycyclic ring system in which at least one ring is aromatic and contains at least one heteroatom (e.g., N, O or S), and none of the other rings is a heterocyclyl group (as defined below). In some cases, an aromatic heteroatom-containing ring contains 1, 2, 3 or 4 ring heteroatoms in the ring. At least one of the rings may be heteroaromatic and the other rings may be saturated, partially unsaturated or fully unsaturated.

[0087] A "heteroaryl group" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10-membered), or tricyclic group of 5-12 ring atoms containing at least one, two, or three ring heteroatoms selected from N, O, or S, with the remaining ring atoms containing aromatic rings of C, provided that the attachment site of the heteroaryl group is located on the aromatic ring. Illustrative examples of heteroaryl groups include imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuryl, benzofuryl, benzothienyl, benzothiopyranyl, benzimidazolyl, Groups that may be used include, but are not limited to, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazyl, quinoxalinyl, purinyl, quinazolinyl, quinolizidinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, azetidinyl, and the like. A "heteroarylene group" is a heteroaryl group having two linkage sites.

[0088] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (non-aromatic) and contains at least one heteroatom. The heterocyclic ring system may be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted.

[0089] A "heterocyclyl group" refers to a monovalent radical of a heterocyclic ring system, typically having stable monocyclic (e.g., 3-8 membered, i.e., 3, 4, 5, 6, 7, or 8 membered) or bicyclic (e.g., 5-12 membered, i.e., 5, 6, 7, 8, 9, 10, 11, or 12 membered) or polycyclic (e.g., 7-14 membered, i.e., 7, 8, 9, 10, 11, 12, 13, or 14 membered) rings, including fused, spiro and / or bridged ring structures, which may be saturated, partially unsaturated, and contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O and S. Representative heterocyclyl groups include the following ring systems: (1) those in which each ring is non-aromatic and at least one ring contains a heteroatom, such as tetrahydrofuryl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidyl, pyrrolidonyl, piperidyl, pyrrolinyl, decahydroquinolinyl, thiazolidinyl, piperazyl, pyrrolidonyl, piperidyl, pyrrolinyl, decahydroquinolinyl, thiazolidinyl, piperazyl, dioxolanyl, diazepinyl, oxoazepinyl, thiazepinyl, morpholyl, and quinucinyl. (2) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic carbocyclic, e.g., 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, e.g., 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-diazanaphthalene.

[0090] A "heterocyclylene group" refers to a heterocyclyl group having two linking sites. In the present invention, the heterocyclylene group is preferably a bicyclic ring, one of which is a heteroaryl group and is linked to other moieties in the general formula via the heteroaryl group. In the present invention, the heterocyclylene group is preferably a 5-6 membered monocyclic heterocyclylene group or an 8-10 membered bicyclic heterocyclylene group. A "heterocyclylalkyl group" is an alkyl group substituted with a heterocyclyl group, where the heterocyclyl group and the alkyl group are defined above.

[0091] An "alkylamino group" is a group having the structure alkyl-NR-, where R is H or any of the above. No.A Examples of the alkyl group include alkyl groups, cycloalkyl groups, aryl groups, and heteroaryl groups. A "cycloalkylamino group" is a group of the formula -NRaRb, where Ra is H, an alkyl group as defined herein or a cycloalkyl group as defined herein, Rb is a cycloalkyl group as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclyl group, such as a tetrahydropyrrolyl group. As used herein, a C3-C8 cycloalkylamino group is an amino group containing 3 to 8 carbon atoms.

[0092] As used herein, an "ester group" is an ester having the structure -C(O)-OR or -RC(O)-O-, where R independently represents a hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclyl group, as defined above. As used herein, the term "amide group" refers to a group having the structure -CONRR', where R and R' independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above, and R and R' may be the same or different in the dialkylamine fragment.

[0093] As used herein, the term "sulfonamide group" refers to a group having the structure -SONRR', where R and R' independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above, and R and R' may be the same or different in the dialkylamine fragment. A "ketone group" is R—C═O—, where R is as defined above. No.A alkyl groups, cycloalkyl groups, etc. When the substituent is a non-terminal substituent, it is a divalent radical of the corresponding group, for example, an alkylene group for an alkyl group, a cycloalkylene group for a cycloalkyl group, a heterocyclylene group for a heterocyclyl group, an alkoxylene group for an alkoxy group, etc.

[0094] In the present invention, each group in the above alkyl group, alkoxy group, cycloalkyl group, heteroalkyl group, aryl group, heteroaryl group, heterocycloalkyl group, alkenyl group, alkyne, heterocycle, heterocyclyl group, etc. may be substituted or unsubstituted.

[0095] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms in a particular group with a particular substituent. The particular substituents are the corresponding substituents described above or in each example. Unless otherwise stated, a substituted group may have one substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position. As will be appreciated by those skilled in the art, the combination of substituents contemplated by the present invention is any stable combination or chemically feasible combination. Exemplary substitutions include, for example, hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents, the latter being, for example, trifluoromethyl or alkyl groups containing Cl), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR, aryl ...a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e ,P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a ,OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or N.R. b P(=O)2R e

[0046] In one embodiment, R a each independently represents hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocycle, or an aromatic ring; R b , R c and R d each independently represents hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring, or an aromatic ring, or R b and R c may form a heterocycle together with the N atom, R eindependently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocycle, or an aromatic ring. The above-mentioned typical substituents, such as an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring, may be optionally substituted. The above-mentioned substituents include, but are not limited to, halogen, a cyano group, a hydroxy group, a cyano group, a carboxy group (-COOH), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-12 membered heterocycle, an aryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, an amino group, a C1-C6 alkoxy group, a C1-C10 sulfonyl group, and a C1-C6 urea group.

[0096] A "cyano group" refers to the group -CN. "Nitro group" refers to --NO2. A "hydroxy group" refers to --OH. An "amino group" is -NH2 or RNH-, where R is a ketone group, a sulfonyl group, a sulfonamide group, or R a -C(=O)-, R a R b NC(=O)-, etc., where R a and R b is an alkyl group, a cycloalkyl group, an aryl group, or a heteroaryl group, for example. "Halogen (halo)" refers to any halogen radical, for example, -F, -Cl, -Br, or -I. A "deuterium-substituted compound" is a compound in which one hydrogen atom (H) or multiple hydrogen atoms (H) are replaced with deuterium atoms (D). In the present invention, the term "plurality" refers independently to 2, 3, 4, 5.

[0097] active ingredient As used herein, the terms "compound of the invention" or "active ingredient of the invention" refer interchangeably to a compound of Formula I', or a pharma-ceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound), or prodrug thereof. The terms further include racemic forms, optical isomers.

[0098] The compound of formula I' above has the structure: [ka]

[0099] (R1, X3, W, Q1, X5, X6, R2, R3, R4, A, m and n are as defined above. Preferably, the W ring is selected from the group consisting of a substituted or unsubstituted 5-6 membered monocyclic heterocyclylene group, an 8-10 membered bicyclic heterocyclylene group, a 5-6 membered monocyclic heteroarylene group or an 8-10 membered bicyclic heteroarylene group, and the substitution is optionally substituted with 0 to 2 R5, and R5 is each independently optionally selected from hydrogen, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a halogen, a C1 to C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, a heterocyclyl group, a heterocycloalkyl group, a nitro group, an oxo group, a cyano group, -C(O)R6, -OC(O) R6, -C(O)OR6, -(C1-C6 alkylene)-C(O)R6, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 alkylene)-S(O)2-N(R6)(R7), -N(R6)(R7), -C(O)-N(R6)(R7), -N(R6)-C(O)R7, -N(R6)-C(O)OR7, -(C1-C6 alkylene)-N(R6)-C(O)R7, -N(R6)S(O)2R7 and -P(O)(R6)(R7), wherein each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group and heterocycloalkyl group each independently represents 0 to 5 R a is replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0100] More preferably, the W ring is [ka] wherein X1, X2, X7, X8, and Q2 are defined as above, and at least one of X7 and X8 is N.

[0101] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (II), formula (III) or formula (IV). [ka] (wherein R1, X1, X2, X3, Q1, Q2, X5, X6, R2, R3, R4, A, m and n are defined as above.)

[0102] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula (2), formula (3), or formula (4). [ka] [ka] (wherein R1, X1, X2, Q1, Q2, R2, R3, R4, A and m are defined as above.)

[0103] Preferably, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 2': [ka] (however, [ka] It may be a single bond or a double bond. X1, X2, R1, R2, R3, R4, A, R 17 , f and m are defined as above.)

[0104] Preferably, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 2''. [ka] (however, X1, X2, R1, R2, R3, R4, A, m and R 17 is defined above.)

[0105] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, has the structure represented by formula 3': [ka] (however, [ka] It may be a single bond or a double bond. [ka] When Y4 is a single bond, Y4 is N or CR 17 Selected from [ka] When it is a double bond, Y4 is C. R1, X2, R2, R3, R4, R 17 , A, m, f, p and Q2 are defined as above.)

[0106] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 3''. [ka] (R1, X2, R2, R3, R4, A, Q2, m and R 17 is defined above.)

[0107] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, has the structure represented by formula 4': [ka] (however, [ka] It may be a single bond or a double bond. [ka] When Y4 is a single bond, Y4 is N or CR 17 Selected from [ka] When it is a double bond, Y4 is C. R1, X2, R2, R3, R4, R 17 , A, m, f, p and Q2 are defined as above.)

[0108] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure represented by formula 4''. [ka] (R1, X2, R2, R3, R4, A, Q2, m and R 17 is defined above.)

[0109] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure represented by formula 5, formula 6. [ka] (However, R1, X7, X8, X2, Q2, R2, R3, R4, R 17 , A and m are defined as above, and at least one of X7 and X8 is N.

[0110] Preferably, in each of the above formulas, R 1 is optionally selected from one of the following structures: [ka] [ka]

[0111] More preferably, R1 is [ka] R2 is optionally selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, wherein each alkyl group, alkoxy group, cycloalkyl group, and heteroalkyl group is optionally and independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0112] Preferably, in each of the above formulas, the W ring is [ka] [ka]

[0113] [ka]

[0114] [ka]

[0115] however, [ka] Single or double bonds, R 12 are independently selected from H, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, and an amino group; Each of Y1, Y2, and Y3 is independently O, N, or NR 17 , C.R. 13 , C.R. 13 R 14 Selected from R 13 , R 14 , R 15 , R 16 are each independently selected from H, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a nitro group, a cyano group, and an amino group, or R 13 and R 14 forms a carbonyl group (C=O) together with the C atom attached to it, or R 15 and R 16 forms a carbonyl group (C=O) together with the C atom connected to it, R 17 is selected from H and C1 to C6 alkyl groups.

[0116] Preferably, in each of the above formulas, A is an aromatic ring or a heteroaromatic ring, more preferably, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazyl group, the heteroaromatic ring contains 0 to 3 heteroatoms, the heteroatoms being optionally selected from N, O and S, and any hydrogen atom in the A ring may be substituted with a substituent selected from deuterium, a hydroxy group, a halogen, a cyano group, an ester group, an amide group, a ketone group, an amino group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 thioalkyl group, a C1-C6 alkoxy group, a C1-C6 heteroalkyl group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C3-C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0117] Preferably, in each of the above formulae, R4 is independently selected from an aryl group, a heteroaryl group, an aroxyl group, an aralkyl group, and a heterocyclyl group, and more preferably, R4 is a 5-membered heteroaryl group, wherein each aryl group, heteroaryl group, aroxyl group, aralkyl group, heterocyclyl group, and heterocycloalkyl group is independently selected from 0 to 5 R a is replaced by R a is optionally selected from a C1-C6 alkyl group, a halogen, a hydroxy group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group, and more preferably, R4 is [ka] where R 18 is selected from halogen (preferably F) and C1 to C6 alkyl groups.

[0118] Preferably, in each of the above formulas, m is 1. Preferably, in each of the above formulas, R3 is H, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group. Preferably, in each of the above formulas, R2 is H.

[0119] Preferably, in each of the above formulas, [ka] Here, X9, X 10 are each independently selected from N or CR5, where R5 is each independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, a nitro group, a cyano group, and an amino group, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group are each independently selected from 0 to 5 R a is replaced by R ais arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylamino group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0120] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, has the structure represented by formula 5' or 6'. [ka] [ka] (However, X2, X7, X8, X9, X 10 and the definition of Q2 is as above, and at least one of X7 and X8 is N.

[0121] The compounds of the present invention may also be formed into salts within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to the formation of acidic or basic salts with inorganic or organic acids and bases. In addition, when the compounds of the present invention contain a basic moiety, including but not limited to pyrimidines or imidazoles, and when the compounds of the present invention contain an acidic moiety, including but not limited to carboxylic acids, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, separation or purification steps during the manufacturing process may be used. The compounds of the present invention may be formed into salts, for example, by reacting compound I' with a predetermined amount, for example, an equivalent amount, of an acid or base, and salting out from the medium or freeze-drying in an aqueous solution.

[0122] The basic moieties contained in the compounds of the present invention include, but are not limited to, amine or pyridine or imidazole rings, and may form salts with organic or inorganic acids. Exemplary acids capable of forming salts include acetate (e.g., using acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. Examples of suitable salts include phosphates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate (e.g., p-toluenesulfonate), dodecanoate, and the like.

[0123] Acidic moieties contained in some of the compounds of the present invention may form salts with a variety of organic or inorganic bases, including, but not limited to, carboxylic acids. Exemplary salts formed with bases include ammonium salts, alkali metal salts, such as sodium, lithium, potassium salts, alkaline earth metal salts, such as calcium, magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (salts formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucamide, t-butylamine, and amino acids, such as arginine, lysine, and the like. The basic nitrogen-containing groups may be quaternary ammonium halides, small alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

[0124] Prodrugs and solvates of the compounds of the present invention are also included within the scope of the present invention. The term "prodrug" herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce the compounds, salts, or solvates of the compounds of the present invention when used to treat a related disease. The compounds of the present invention include solvates, such as hydrates.

[0125] The compounds, salts, or solvates of the present invention may exist in tautomeric forms (for example amides, imine ethers) and all such tautomeric forms are part of the present invention. All stereoisomers of the compounds (e.g., asymmetric carbon atoms that may be present due to various substitutions), including their enantiomeric and diastereomeric forms, are within the scope of the present invention. The individual stereoisomers of the compounds of the present invention may be present alone (e.g., with specific activity as a single or substantially single optical isomer) or in mixtures, e.g., racemates, or mixtures with all or a portion of the other stereoisomers. The chiral centers of the present invention are of two configurations, S or R, as defined by the International Union of Pure and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, e.g., fractional crystallization, or by separating crystals by inducing diastereomers, or by resolution by chiral column chromatography. Single optical isomers can be obtained from the racemates by suitable methods, including, but not limited to, conventional methods, e.g., by forming a salt with an optically active acid and recrystallizing. The compounds of the present invention are described herein as having a weight content of 90% or more, for example, 95% or more, 99% or more, which are obtained by sequentially producing, isolating and purifying the compounds ("highly pure" compounds), and such "highly pure" compounds of the present invention are also part of the present invention.

[0126] All configurational isomers of the compounds of the present invention, whether in admixture or in pure or highly purified form, are included within the scope of the present invention. The definition of the compounds of the present invention includes the two olefin isomers, cis (Z) and trans (E), and the cis and trans isomers of carbocyclic and heterocyclic rings. Throughout the specification, groups and substituents are chosen to provide stable fragments and compounds.

[0127] For details on the definition of specific functional groups and chemical terms, see: In the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thThis definition is consistent with the definitions in "Organic Chemistry", Ed. Definitions of specific functional groups are also provided therein. Fundamental principles of organic chemistry and specific functional groups and their reactivities are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.

[0128] Some compounds of the present invention may exist in particular geometric or stereoisomeric forms. All compounds included in the present invention include their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are included in the present invention. In the present invention, the isomer mixture may have a variety of ratios of isomers, for example, mixtures of only two isomers such as 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention, as are similar ratios that would be obvious to one skilled in the art, as well as ratios of more complex isomer mixtures.

[0129] Furthermore, the present invention includes isotopically labeled compounds, which are disclosed herein as the original compounds. In practice, this often occurs when one or more atoms are replaced by atoms whose atomic mass or mass number differs. Examples of isotopes of the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, each of which is, for example, 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharma- ceutically acceptable salts or solvates thereof, which contain isotopes of the above compounds or other isotopes, are also within the scope of the present invention. Some isotopically labeled compounds of the present invention, e.g. 3 H and 14 Radioisotopes, including C, are useful in drug and substrate tissue distribution studies. Tritium, i.e., 3 H and carbon-14, i.e. 14 C is the isotope of choice because it is easy to produce and detect. Also, heavier isotopes, such as deuterium, i.e. 2 Substitution with H may be advantageous in some therapies due to better metabolic stability, e.g., increased half-life in the body or reduced dosage, and may be considered preferred in some cases. Isotopically labeled compounds can be prepared in the manner disclosed in the examples by substituting readily available isotopically labeled reagents for nonisotopic reagents in a conventional manner.

[0130] If a synthesis of a particular enantiomer of a compound of the invention is designed, it may be prepared by asymmetric synthesis or it may be derivatized with a chiral auxiliary, resolved the resulting mixture of diastereomers, and then removed to yield a single enantiomer. If the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxy group, formation of a diastereomeric salt with an appropriate optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography, will yield the single enantiomers.

[0131] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their coverage. In general, the term "substituted", whether before or after the term "optionally", refers to the general formula containing the substituents in the context of the present invention, which is to use a substituent of a given structure in place of a hydrogen radical. When a particular structure is substituted with multiple specific substituents at multiple positions, the positions of the substituents may be the same or different. As used herein, the term "substituted" includes all permissible substitutions of organic compounds. In a broad sense, permissible substitutions include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the nitrogen of a heteroatom may be supplemented with a hydrogen substituent or any of the permissible valence states of the organic compounds described above. In addition, the present invention does not impose any restrictions on the substitution of organic compounds. In the present invention, the combination of substituents and variable groups is advantageous for the treatment of diseases in the form of a stable compound. The term "stable" as used herein refers to a compound that is stable, that is capable of maintaining the integrity of the compound's structure for a sufficiently long period of time to be detectable, and preferably remains effective for a sufficiently long period of time, for the purposes set forth herein above. Metabolites of the compounds according to the present application and their pharma- ceutically acceptable salts, as well as prodrugs whose structures are converted in the body to the compounds according to the present application and their pharma- ceutically acceptable salts, are also included within the scope of the claims of the present application.

[0132] Manufacturing method The following schemes and examples describe methods for preparing compounds of formula I'. Starting materials and intermediates are commercially available, prepared by known processes, or obtained by other described methods. In some cases, the order of steps in the reaction schemes is altered to facilitate the reaction or to avoid unwanted side reaction products. The method for preparing the compound of the formula I' of the present invention will be described in detail below, but these specific methods are not intended to limit the present invention. The compound of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs. In general, in the preparation process, each reaction is usually carried out under the protection of an inert gas in a suitable solvent at 0 to 90° C., and the reaction time is usually 2 to 24 hours.

[0133] A preferred method of preparation is as follows. Method 1: [ka]

[0134] Step 1: In a solvent (e.g. DMF / H2O, dioxane, toluene) under basic conditions (e.g. potassium carbonate, sodium carbonate, etc.) in the presence of a catalyst and a ligand (e.g. Pd(PPh3)4), [ka]

[0135] Step 2: In an inert solvent (e.g., DMF, dioxane, ethylene glycol dimethyl ether, etc.), under basic conditions (e.g., diisopropylethylamine, potassium acetate, DBU, etc.) or in the presence of a catalyst and a ligand (e.g., Pd(PPh3)4, Pd2(dba)3 / t-BuXphos, etc.), [ka]

[0136] Step 3: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka]

[0137] Method 2: [ka]

[0138] Step 1: In an inert solvent (e.g., DMF, dioxane, ethylene glycol dimethyl ether, etc.), under basic conditions (e.g., diisopropylethylamine, potassium acetate, DBU, etc.) or in the presence of a catalyst and a ligand (e.g., Pd(PPh3)4, Pd2(dba)3 / t-BuXphos, etc.), [ka]

[0139] Step 2: In an inert solvent (e.g. DMF / H2O) under basic (e.g. K2CO3) conditions in the presence of a catalyst and a ligand (e.g. Pd(PPh3)4), [ka]

[0140] Step 3: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka]

[0141] (In each of the above formulas, G and G' are each independently a halogen (e.g., F, Cl, Br). G'' is a borate ester group [ka] X3' is OH, -NHR8, -CHR9R 10 , [ka] X5' is -C(O)-OH, -S(O)-OH, -S(O)2-OH, [ka] Selected from. R1, X3, W, Q1, X5, X6, R2, R3, R4, A, Q2, m and n are defined as above.) Unless otherwise specified, all of the above starting materials can be purchased commercially or synthesized according to reported literature.

[0142] Drug Compositions and Methods of Application The pharmaceutical compositions according to the present invention are used for the prevention and / or treatment of inflammation, cancer, cardiovascular diseases, infections, immune diseases, metabolic diseases. The compound of general formula I' may be used in combination with other drugs known to treat or improve similar pathologies. In the case of combination, the compound of formula I' is administered simultaneously or subsequently, while maintaining the dosage form and dosage of the original drug. When the compound of formula I' is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I'. The combination of drugs also includes administering the compound of formula I' and one or more other known drugs at overlapping times. When the compound of formula I' is combined with one or more other drugs, the dosage of the compound of formula I' or the known drug may be lower than the dosage when administered alone.

[0143] Drugs or active ingredients that can be used in combination with the compounds according to general formula I' include PD-1 inhibitors (e.g. nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs), PD-L1 inhibitors (e.g. durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, tositumomab, ibritumomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alkenebulizer, tinib, brigutinib, lorlatinib, alcotinib), PI3K inhibitors (e.g. idelalisib, dactolisib, taselisib, buparisib, etc.), BTK inhibitors (e.g. ibrutinib, tirabrutinib, acalabrutinib, etc.), EGFR inhibitors (e.g. afatinib, gefitinib, lapatinib, lapatinib, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (e.g. sorafenib, pazopanib, lenvatinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (e.g. gibinostat, droxinostat, entinostat, dacinostat, tacedinaline, etc.), CDK inhibitors (e.g. palbociclib, ribociclib, abemaciclib, relociclib, etc.), MEK inhibitors (e.g. selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc. and the like), Akt inhibitors (e.g., MK-2206, ipatasertib, capivasertib, afuresertib, uprosertib, and the like), mTOR inhibitors (e.g., vistusertib, and the like), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, and the like), IGF-1R inhibitors (e.g., ceritinib, alcotinib, linsitinib, BMS-754807, GSK1838705A, and the like), or combinations thereof.

[0144] The dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, membranes, drop pills, external pour-ons, controlled or sustained release forms or nano formulations. The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharma- ceutically acceptable salt in a safe effective amount range and a pharma- ceutically acceptable excipient or carrier. Here, the "safe effective amount" refers to the amount of the compound that is sufficient to significantly improve the disease condition and does not cause severe side effects. Usually, the pharmaceutical composition contains the compound of the present invention in an amount of 1-2000 mg / formulation, preferably 10-1000 mg / formulation. Preferably, the "formulation" is a capsule or tablet.

[0145] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be applicable to humans and have sufficient purity and sufficiently low toxicity. "Compatible" refers to the ability of each component in the composition to be blended with and among the compounds of the present invention without significantly reducing the effectiveness of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tallow, glyceryl ... R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water. The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, but representative modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral gastrointestinal administration (intravenous, intramuscular, or subcutaneous administration), and topical administration.

[0146] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is usually mixed with at least one inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or may contain (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; and (d) a disintegrant, such as agar, calcium carbonate, or the like. The pharmaceutical composition may be mixed with ingredients such as calcium, potato starch or tapioca starch, alginic acid, certain complex silicates or sodium carbonate, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol or glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0147] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active or compound may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used include polymeric and wax-based materials. If necessary, the activator may also be formed into a microcapsule with one or more of the above excipients. Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, or sesame oil, or mixtures of these substances.

[0148] Besides these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxyl or agar, or mixtures of these substances. Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms of the compounds of the present invention for topical administration include ointments, powders, poultices, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0149] The treatment methods of the present invention may be administered alone or in combination with other therapeutic procedures or agents. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, and the dosage is a pharmacologically effective dosage, and for a human weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage should further consider factors such as the mode of administration and the health condition of the patient, all of which are within the skill of a skilled doctor. The present invention further provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharma- ceutically acceptable carrier with a compound of general formula I' according to the present invention or a crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof to form a pharmaceutical composition. Furthermore, the present invention provides a method of treatment comprising the step of inhibiting RET by administering to a subject in need of treatment a compound of formula I' according to the present invention, or a crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the present invention.

[0150] The present invention has the following main advantages: (1) The compound of the present invention has excellent inhibitory activity against RET kinase. (2) The compounds of the present invention have lower toxicity and side effects. (3) The compounds of the present invention have better pharmacological and pharmacokinetic properties.

[0151] Working Example The technical solutions of the present invention are further described below, but the protection scope of the present invention is not limited thereto. Example 1 Compounds synthesized in the present invention: [ka] [ka]

[0152] The experimental process is as follows. 1. Synthesis of intermediate C1-7 The synthetic route is as follows: [ka]

[0153] 1.Synthesis of C1-9 C1-8 (6.98 g, 34.9 mmol), 4-fluoro-1H-pyrazole (3.3 g, 35 mmol), potassium carbonate (11.1 g, 73.6 mmol) and DMF (30 mL) were placed in a 100 mL single-neck flask and reacted at 100 °C for 15 h, cooled to room temperature, poured into water, filtered and dried to obtain 5.93 g of compound C1-9. Nuclear magnetic resonance analysis data of compound C1-9: 1 H NMR (400 MHz, CDCl3):δ 8.96-8.95(d,J=1.8 Hz,1H), 8.47-8.45(dd,1H),8.37-8.34(dd,1H),8.05-8.03(dd,1H),7.66-7.65(d,J=3.96,1H),2.65(s,3H).

[0154] 2.Synthesis of C1-10 In a 100 mL three-neck flask, C1-9 (4.2 g, 0.02 mol), Rt-butylsulfinamide (2.48 g, 0.02 mol), tetraethyl titanate (9.34 g, 0.041 mol) and THF (50 mL) were added and reacted at 75 °C for 15 h, cooled to room temperature, poured into water, filtered, the cake was washed with ethyl acetate, the organic phases were combined, dried and concentrated, and 5.35 g of compound C1-10 was obtained by chromatography. Nuclear magnetic resonance analysis data for compound C1-10: 1 H NMR (400 MHz, CDCl3):δ 8.96-8.95(d,J=1.8 Hz,1H), 8.47-8.45(dd,1H),8.37-8.34(dd,1H),8.05-8.03(dd,1H),7.66-7.65(d,J=3.96,1H),2.65(s,3H).

[0155] 3.Synthesis of C1-11 C1-10 (3.5 g) and THF (50 mL) were placed in a 100 mL three-neck flask, cooled to -70°C, lithium tri-sec-butylborohydride in THF solution (1M, 34.1 mL) was added dropwise, stirred at the same temperature for half an hour, and allowed to warm to room temperature. When TLC showed complete reaction, 5 mL of methanol was added to quench the reaction, water was added, filtered, and the cake was washed with ethyl acetate. The organic phases were combined, dried, concentrated, and chromatographed to obtain 3.1 g of compound C1-11. Nuclear magnetic resonance analysis data of compound C1-11: 1 H NMR (400 MHz, CDCl3):δ 8.40-8.39(d,J=4.6Hz,1H),8.36-8.35(d,J=2.08Hz,1H),7.94-7.91(d,J=8.48Hz,1H),7.79-7.76(m,1H) ,7.59-7.58(d,J=4.28,1H),4.68-4.63(m,1H),3.37-3.36(m,1H),1.59-1.57(d,J=6.72,3H),1.21(s,9H).

[0156] 4. Synthesis of C1-7 C1-11 (3.1 g) was placed in a 100 mL three-neck flask, methanol (10 mL) and 1,4-dioxane (10 mL) were added, and the mixture was stirred to dissolve. Then, HCl / 1,4-dioxane (4 M, 25 mL) was added and stirred at room temperature for 2 h. The reaction solution was concentrated, and the resulting crude product was mixed with ethyl ether to obtain 2.27 g of compound C1-7. Nuclear magnetic resonance analysis data for compound C1-7: 1 H NMR (400 MHz,DMSO-D6):δ 8.79(br,3H),8.74-8.72(m,1H),8.64-8.63(d,J=2.08Hz,1H),8.23-8.20( m,1H),7.97-7.95(m,2H),4.52-4.52(m,1H),1.60-1.58(d,J=6.84Hz,3H).

[0157] 2. Synthesis of intermediate C1-3 The synthetic route is as follows: [ka] 1. Synthesis of Compound C1-13 Bromoform (125 mL) and C1-12 (128 mmol, 20 g) were placed in a 250 mL three-neck flask, stirred to dissolve, cooled to 0 °C, and slowly added dropwise to a solution of KOH (1 mol, 57.4 g) in methanol (300 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 16 h. When TLC showed the reaction was complete, the mother liquor was concentrated, diluted with water (50 mL), extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried the organic phase, and concentrated under reduced pressure to give the product C1-13, 25 g, which was used directly in the next step.

[0158] 2. Synthesis of Compound C1-14 In a 500 mL single-neck flask, add C1-13 (86 mmol, 20 g) and methanol (200 mL), add concentrated hydrochloric acid (100 mL) while stirring at room temperature, and stir at room temperature for 16 h. When TLC showed that the reaction was complete, concentrate the mother liquor, add saturated NaHCO3 aqueous solution to adjust the pH to 6-7, extract with ethyl acetate three times, wash the organic phase with saturated saline, dry the organic phase, and concentrate under reduced pressure to obtain a crude product, which was purified by column chromatography (vehicle: ethyl acetate / petroleum ether=1:30-1:5) to obtain the product 10 g C1-14.

[0159] 3. Synthesis of Compound C1-15 In a 250 mL three-neck flask, 50 mL of anhydrous toluene and anhydrous pyridine (4.5 mL, 53 mmol) were added and cooled to -10 ° C. Under the protection of nitrogen gas, a solution of trifluoromethanesulfonic anhydride (10.8 mL, 60 mmol) in anhydrous toluene (60 mL) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature, and a solution of C1-14 (9 g, 48 mmol) in anhydrous toluene (30 mL) was added. The reaction solution was heated to 40 ° C and stirred for 16 h. When the reaction was complete as shown by TLC, the mixture was diluted with 10 mL of water, extracted three times with ethyl acetate, washed with saturated saline, dried, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (vehicle: ethyl acetate / petroleum ether = 1:40-1:20) to obtain the product C1-15, 9 g.

[0160] 4. Synthesis of Compound C1-3 Under the protection of nitrogen gas, C1-15 (9 g, 28 mmol), bis(pinacolato)diboron (8.7 g, 34 mmol), dppf (1.5 g, 3 mmol), palladium acetate (350 mg, 1.5 mmol), potassium acetate (8.25 g, 88 mmol) and dioxane (120 mL) were placed in a 250 mL three-neck flask in that order, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was stirred at 95 ° C for 16 hours, and when TLC showed that the reaction was complete, it was filtered and concentrated under reduced pressure, diluted with 20 mL of water, extracted three times with ethyl acetate, washed the organic phase with saturated saline, dried the organic phase, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (vehicle: ethyl acetate / petroleum ether = 1: 20-1: 10) to obtain the product C1-3 (light yellow solid, 8 g).

[0161] 3. Synthesis of Compounds C1 and C2 The synthetic route is as follows: [ka]

[0162] 1.Synthesis of C1-2 C1-1 (3.46 g, 20 mmol), 3-amino-5-methylpyrazole (2.14 g, 22 mmol), DMF (50 mL), and diisopropylethylamine (3.88 g, 30 mmol) were placed in a 250 mL single-neck flask and reacted at 90 °C overnight. When LC-MS showed the reaction was complete, the reaction solution was poured into 200 mL water while stirring, a solid precipitated, filtered, the cake was washed with water, the cake was dried, mixed with methanol (100 mL), and filtered. The operation was repeated 3 to 5 times to obtain 2.82 g. [M+H]: 234.1.

[0163] 2.Synthesis of C1-4 C1-2 (2.1 g, 9 mmol), C1-3 (2.66 g, 9 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (1.86 g, 13.5 mmol), and DMF / H2O (30 mL / 12 mL) were placed in a 250 mL single-neck flask and reacted at 110 °C overnight under N2 protection. When LC-MS showed the reaction was complete, the reaction solution was poured into water (300 mL) with stirring, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, rotovapped, and purified by column chromatography DCM:MeOH=50:1-10:1 to give 1.87 g. [M+H]: 368.2.

[0164] 3.Synthesis of C1-5 A 250 mL single-neck flask was charged with C1-4 (720 mg, 1.96 mmol), Pd(OH)2 / C (10%, 300 mg), and EtOH (100 mL) and reacted overnight at 80 °C under H2 atmosphere. When LC-MS showed the reaction was complete, it was filtered, spun dry, and purified by column chromatography DCM:MeOH=100:1-50:1 to give 502 mg of a white solid. [M+H]: 370.3.

[0165] 4. Synthesis of C1-6 A 25 mL single-neck flask was charged with C1-5 (240 mg, 0.65 mmol), LiOH·HO (55 mg, 1.3 mmol), and MeOH / HO (5 mL / 1 mL) and reacted at 50 °C overnight. When LC-MS showed the reaction was complete, it was concentrated to give 241 mg of crude product. [M+H]: 356.2.

[0166] 5. Synthesis of C1 and C2 C1-6 (249 mg, 0.69 mmol), C1-7 (212 mg, 0.76 mmol), and DMF (2 mL) were placed in a 25 mL single-neck flask, and DMAP (337 mg, 2.76 mmol) and HATU (393 mg, 1.04 mmol) were added while stirring at room temperature, and the reaction was allowed to proceed at 25 °C for 1 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (20 mL), extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, rotovapped, and purified by column chromatography DCM:MeOH = 100:1-30:1, and the obtained crude product was separated to give C2 (12 mg, purity: 96.7%); [M+H]: 544.3; C1 (11 mg; purity: 97.6%), [M+H]: 544.3.

[0167] Separation of C1 and C2 was performed using a Waters high performance liquid chromatograph under the following separation conditions: Equipment: waters Chromatography column: innoval ODS-2 / C18 (30 x 100 mm, 5 μm) Mobile phase: Phase A: Water (containing 0.1% trifluoroacetic acid) Phase B: Methanol Flow rate: 15.0 ml / min, detection wavelength: 254 nm Solvent: methanol-water (1:1) Preparation concentration: approx. 15 mg / mL Amount to be prepared: 2mL Peak time: 14.7 min

[0168] Gradient Program: [Table 1]

[0169] Example 2 Compounds synthesized in the present invention: [ka]

[0170] The synthetic route and experimental steps are as follows. [ka]

[0171] Synthesis of C3-2 31 mL of hydrobromic acid in acetic acid was added to a 100 mL single-neck flask, and 5 g of compound C3-1 was added to the solution while stirring, and the temperature was controlled to 30°C or less. After the addition was completed, the mixture was reacted at room temperature for 2 h. The mixture was cooled to 0°C, 30 mL of ethyl acetate was added, filtered, and the cake was washed with ethyl acetate. The cake was added to methanol (50 mL), stirred, filtered, and the cake was washed with methanol (20 mL). The cake was added to water and stirred, sodium carbonate was added to adjust the pH value to 9, filtered, the cake was washed with water, and dried to obtain 4.7 g of compound C3-2. Nuclear magnetic resonance analysis data for compound C3-2: 1 H NMR (400 MHz, DMSO): δ 8.61-8.60 (dd, 1H), 8.04-8.02 (dd, 1H), 7.51-7.48 (dd, 1H), 6.61 (s, 1H), 6.49 (br, 2H).

[0172] 2. Synthesis of C3-4 Compound C3-2 (3 g, 0.013 mol), compound C1-3 (4.56 g, 0.0154 mol), tricyclohexylphosphine (0.36 g, 0.0013 mol), potassium carbonate (2.7 g, 0.0195 mol), palladium acetate (146 mg, 0.65 mmol), dioxane (60 mL) and water (7 mL) were added to a 250 mL three-neck flask and stirred at 100 °C for 15 h. The mixture was cooled, filtered, concentrated, and the residue was poured into water, extracted with dichloromethane, dried and concentrated. Ethyl ether was added to the residue, stirred, filtered, and the cake was dried to obtain 3 g of compound C3-4. Nuclear magnetic resonance analysis data for compound C3-4: 1 H NMR (400 MHz,DMSO):δ 8.52-8.51(dd,1H),7.95-7.92(dd,1H),7.39-7.36(dd,1H),6.54-6.53(m,1H),6.49(s,H),6.03(br,2H) ),3.73(s,3H),3.21(s,3H),2.75-2.67(m,3H),2.5-2.45(m,1H),2.18-2.12(m,1H),2.04-2.00(m,1H).

[0173] 3. Synthesis of C3-5 6 g of compound C3-4 was placed in a 500 mL single-neck flask, and palladium hydroxide on carbon (2 g) and ethyl acetate (200 mL) were added. The mixture was reacted at 60° C. in a hydrogen gas atmosphere for 3 days, filtered, and the filtrate was concentrated to obtain a crude product, which was subjected to column chromatography to obtain 2.5 g of compound C3-5, which was used as is in the next reaction step.

[0174] 4. Synthesis of C3-6 Compound C3-5 (2.5 g) was placed in a single-neck flask, and 5% palladium on carbon (2 g) and toluene (90 mL) were added. The mixture was heated to reflux in air and reacted for 4 days. The mixture was then filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 2.3 g of compound C3-6. Magnetic resonance analysis data for compound C3-6: 1H NMR (400 MHz, CDCl3):δ 8.65-8.63(dd,1H),7.82-7.79(dd,1H),7.35-7.32(dd,1H),6.50-6.49(dd,1H),4.57-4.50(m,2H),4.20-4.10(m,1H),3.83-3 .78(m,3H),3.34-3.30(m,3H),2.75-2.67(m,3H),2.56-2.52(m,1H),2.20-2.17(m,1H),2.13-1.97(m,3H),1.93-1.70(m,3H).

[0175] 5. Synthesis of C3-16 1.24 g of compound C3-6 was dissolved in concentrated hydrochloric acid (30 mL) and the temperature was maintained at -5°C to 5°C. Sodium nitrite (1.36 g) was dissolved in water (8 mL) and the solution was added dropwise to the reaction and stirred for 1 h while maintaining the temperature. A mixture of cuprous chloride (1.96 g) and hydrochloric acid (8 mL) was added dropwise to the reaction and stirred for 1 h while maintaining the temperature, and then stirred at room temperature for another 1 h. The reaction was slowly poured into aqueous ammonia to keep it basic, extracted with dichloromethane, and concentrated to obtain the crude product. The crude product was taken up in toluene (80 mL) and phosphoryl chloride (4.25 mL) and heated to 100°C and stirred for 3 hours. After concentration, the residue was taken up in aqueous sodium bicarbonate, extracted with dichloromethane, dried, concentrated, and subjected to column chromatography to obtain 0.55 g of compound C3-16. Nuclear magnetic resonance analysis data for compound C3-16: 1 H NMR (400 MHz, CDCl3):δ 8.98-8.96(dd,1H),8.06-8.03(dd,1H),7.59-7.53(m,2H),4.24-4.14(m,1H),3.84-3. 79(m,3H),3.33-3.30(m,3H),2.58-2.55(m,1H),2.24-1.85(m,6H),1.78-1.70(m,1H).

[0176] 6. Synthesis of C3-18 Compound C3-16 (487 mg), compound C1-17 (430 mg), tris(dibenzylideneacetone)dipalladium (133 mg), 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl (123 mg), DBU (443 mg) and ethylene glycol dimethyl ether (7.5 mL) were placed in a 50 mL single-neck flask and reacted for 15 hours under argon gas protection at 60°C. The reaction solution was concentrated and subjected to column chromatography to obtain 626 mg of compound C3-18. Nuclear magnetic resonance analysis data for compound C3-18: 1H NMR (400 MHz, CDCl3): δ 8.73-8.72(dd,1H),8.00-7.96(m,1H),7.71-7.65(d,1H),7.43-7.40( m,1H),7.12-7.08(d,1H),6.19-6.18(d,1H),4.25-4.17(m,1H),3.84- 3.79(d,3H),3.35-3.30(d,3H),2.57-2.53(m,4H),2.22-2.18(m,1H), 2.11-1.99(m, 3H), 1.93-1.83(m, 2H), 1.79-1.72(m, 1H), 1.68(s, 9H).

[0177] 7. Synthesis of C3-19 Compound C3-18 (576 mg), LiOH·HO (153 mg), and tetrahydrofuran / methanol / water (17:1:1, 21 mL) were placed in a 50 mL single-neck flask and stirred at 60 °C for 15 h. LC-MS showed that the raw material was not completely reacted, so LiOH·HO (50 mg) was added and stirred for another 15 h. Methyl-t-butyl ether and water were added, and the aqueous phase was evaporated to dryness to give crude product C3-19, which was used directly in the next step reaction.

[0178] 8. Synthesis of C3 and C4 Compound C3-19 (387 mg), compound C1-7 (279 mg), diisopropylethylamine (1 g) and DMF (6 mL) were placed in a 50 mL single-neck flask, HATU (570 mg) was added while stirring, and the mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was washed with water, dried, concentrated, and subjected to column chromatography to obtain the crude product, which was then separated to obtain compounds C3 and C4.

[0179] Separation of C3 and C4 was performed using a Waters high performance liquid chromatograph under the following separation conditions: Equipment: waters Chromatography column: innoval ODS-2 / C18 (30 x 100 mm, 5 μm) Mobile phase: Phase A: Water (containing 0.1% trifluoroacetic acid) Phase B: Methanol Flow rate: 15.0 ml / min, detection wavelength: 254 nm Solvent: methanol-water (1:1) Preparation concentration: approx. 15 mg / mL Amount to be prepared: 2mL Peak time: 15.8 min / 17.8 min

[0180] Gradient Program: [Table 2]

[0181] Magnetic resonance analysis data for compound C4: 1H NMR (400 MHz, CDCl3): δ 8.70-8.68(dd,1H),8.39-8.38(m,2H),7.93-7.90(d,2H),7.90-7.76( dd,1H),7.59-7.58(d,1H),7.40-7.37(dd,1H),7.32(s,1H),6.86-6.84 (d,1H),6.01(s,1H),5.24-5.16(m,1H),4.25-4.20(m,1H),3.31(s,3H) ,2.34(s,3H),2.22-1.96(m,6H),1.91-1.86(m,2H),1.59-1.57(d,3H).

[0182] Example 3 Compounds synthesized in the present invention: [ka]

[0183] The synthetic route and experimental steps are as follows. [ka]

[0184] 1. Synthesis of C5-1 A 250 mL single-neck flask was charged with compound C3-18 (0.91 g), palladium hydroxide on carbon (600 mg), ethyl acetate (20 mL), and methanol (20 mL) and stirred at room temperature under an atmosphere of H2 for 48 h, after which TLC showed complete reaction. Filtration and concentration gave the crude product, which was used directly in the next step.

[0185] 2. Synthesis of C5-2 Compound C5-1 (0.87 g), aqueous formaldehyde solution (37%, 565 mg), acetic acid (418 mg), and tetrahydrofuran (16 mL) were added to a 50 mL single-neck flask. After stirring for 10 minutes, sodium triacetoxyborohydride (1.84 g) was added and stirred at room temperature overnight. TLC showed the reaction was complete, and the mixture was added with water, extracted with ethyl acetate, dried, concentrated, and subjected to column chromatography to obtain 0.84 g of compound C5-2. Nuclear magnetic resonance analysis data of compound C5-2: 1H NMR (400 MHz, CDCl3): δ 6.90-6.89(d,1H),6.67-6.64(d,1H),6.57-6.49(d,1H),3.83-3.78(d,3H),3.56-3.28(d,3H),3.17-3.05(m,4H),2.76-2.7 2(m,2H),2.65-2.64(d,3H),2.59-2.52(d,3H),2.50-2.48(m,1H),2.16-2.07(m,2H),1.91-1.75(m,6H),1.61-1.59(m,2H).

[0186] 3. Synthesis of C5-3 Compound C5-2 (0.8 g), lithium hydroxide monohydrate (261 mg), and THF / MeOH / H2O (15:1:1, 26 mL) were placed in a 50 mL single-neck flask and reacted at 60 °C for 14 h. The mixture was concentrated and water was removed with toluene to obtain the crude product of compound C5-3, which was used as it was in the next step.

[0187] 4. Synthesis of C5 and C6 In a 50 mL single-neck flask, the crude product of compound C5-3 (399 mg), compound C1-7 (279 mg), diisopropylethylamine (1 g) and DMF (6 mL) were added, and HATU (570 mg) was added while stirring. The mixture was stirred at room temperature overnight, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, dried, concentrated and subjected to column chromatography to obtain the crude product, which was then separated to obtain compounds C5 and C6. Nuclear magnetic resonance analysis data of compound C6: 1H NMR (400 MHz, CDCl3): δ 8.38-8.37(m,2H),7.91-7.90(d,1H),7.78-7.75(dd,1H),7.58-7.57(d,1H),6.89-6.87(d,1H),6.32(br,1H),5.20-5.13(m,1H),3. 34(s,3H),3.20-3.18(m,1H),3.05-3.03(m,2H),2.75-2.71(m,2H),2.64(s,3H),2.30(s,3H),2.05-1.81(m,8H),1.62-1.56(m,8H).

[0188] Example 4 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0189] 1.Synthesis of C7-1 Compound C1-4 (186 mg, 0.51 mmol), LiOH·HO (43 mg, 1 mmol), and MeOH / HO (5 mL / 1 mL) were added to a 50 mL single-neck flask and the reaction mixture was allowed to react overnight at 50 °C. When LC-MS showed the reaction was complete, it was concentrated to give 100 mg of crude product.

[0190] 2. Synthesis of C7 Compound C7-1 (83 mg, 0.24 mmol), DMF (2 mL), and HATU (134 mg, 0.35 mmol) were placed in a 50 mL single-neck flask, and diisopropylethylamine (243 mg, 1.88 mmol) and compound C1-7 (72 mg, 0.26 mmol) were added while stirring at room temperature, and the reaction system was reacted at 50 °C. When LC-MS showed the reaction was complete, the reaction solution was poured into 20 mL of water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, rotovapped, and isolated to give compound C7 (17 mg, purity: 89.9%), [M+H]: 542.3. Nuclear magnetic resonance analysis data of compound C7: 1H NMR (400 MHz, DMSO) δ 11.99 (s, 1H), 9.91 (s, 1H), 8.66 (dd, J = 22.0, 5.9 Hz, 2H), 8.45 (s, 1H), 8.01 (t, J = 5.9 Hz, 1H), 7.88 (ddd, J = 18.7, 12.7, 6.6 Hz, 3H), 7.18 (s, 1H), 6.30 (s, 1H), 6.14 (s, 1H), 5.10 (s, 1H), 3.16 (s, 3H), 2.76 - 2.55 (m, 2H), 2.33 (s, 1H), 2.19 (d, J = 11.9 Hz, 3H), 2.14 - 1.65 (m, 3H), 1.49 (d, J = 6.7 Hz, 3H).

[0191] Example 5 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0192] 1.Synthesis of C8-1 Compound C3-4 (4.0 g, 12.8 mmol) and concentrated hydrochloric acid (60 mL) were placed in a 250 mL single-neck flask, cooled to -10 °C in an ice-salt bath, slowly added an aqueous solution of NaNO2 (4.4 g, 63.9 mmol), stirred for 30 min while maintaining the temperature below 0 °C, added a suspension of CuCl (6.3 g, 63.9 mmol) in concentrated hydrochloric acid dropwise, and reacted at room temperature for 1 h. When LC-MS showed the reaction was complete, the reaction solution was slowly poured into aqueous ammonia, extracted three times with DCM, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, rotary evaporated, and subjected to column chromatography to obtain 2.3 g of product.

[0193] 2.Synthesis of C8-2 A 50 mL single-neck flask was charged with compound C8-1 (487 mg, 1.5 mmol), compound C1-17 (433 mg, 2.2), Pd2(dba)3 (137 mg, 0.15 mmol), t-BuXPhos (127 mg, 0.3 mmol), DBU (456 mg, 3 mmol), and (CHOCH)2 (8 mL), and the reaction was allowed to react overnight at 60 °C under N2. When LC-MS showed the reaction was complete, it was concentrated and subjected to column chromatography to give 525 mg of product.

[0194] 3.Synthesis of C8-3 A 50 mL single-neck flask was charged with compound C8-2 (475 mg, 0.963 mmol), LiOH·HO (121 mg, 2.89 mmol), and THF / MeOH / HO (7 mL / 7 mL / 4 mL), and the reaction was allowed to react overnight at 60 °C. When LC-MS showed the reaction was complete, it was concentrated to give 481 mg of crude product.

[0195] 4. Synthesis of C8 Compound C8-3 (390 mg, 1 mmol), compound C1-7 (280 mg, 1 mmol), DMF (6 mL), and diisopropylethylamine (1.03 g, 8 mmol) were added to a 50 mL single-neck flask, and HATU (570 mg, 1.5 mmol) was added while stirring at room temperature, and the reaction system was reacted at 25 °C for 1 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (60 mL), extracted three times with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, rotovapped, and subjected to column chromatography to obtain the crude product, which was then separated to obtain compound C8 (291 mg, purity: 95.3%), [M+H]: 568.3. Nuclear magnetic resonance analysis data of compound C8: 1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 9.16 (d, J = 3.9 Hz, 1H), 8.70 (ddd, J = 4.5, 1.7, 0.8 Hz, 1H), 8.66 - 8.55 (m, 2H), 8.47 (t, J = 2.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.03 (ddd, J = 8.0, 5.5, 2.3 Hz, 1H), 7.91 (ddd, J = 13.5, 6.4, 2.8 Hz, 2H), 7.74 (s, 1H), 7.47 (ddd, J = 8.4, 4.0, 2.3 Hz, 1H), 6.66 (s, 1H), 5.86 (d, J = 5.6 Hz, 1H), 5.19 - 5.04 (m, 1H), 3.19 (d, J = 3.3 Hz, 3H), 2.84 - 2.52 (m, 4H), 2.21 (d, J = 3.8 Hz, 3H), 2.19 - 1.90 (m, 2H), 1.51 (dd, J = 7.0, 2.2 Hz, 3H).

[0196] Example 6 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0197] 1.Synthesis of C9-2 A 250 mL single-neck flask was charged with 3-amino-5-methylpyrazole (427 mg, 4.4 mmol), compound C9-1 (764 mg, 4 mmol), DMSO (8 mL), and diisopropylethylamine (581 mg, 4.5 mmol), and the reaction was allowed to react at 90 °C for 4 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (100 mL) with stirring, and a solid precipitated. The solid was filtered, the cake was washed with water, and the cake was dried to give 1.14 g of product.

[0198] 2.Synthesis of C9-3 Compound C9-2 (796 mg, 3.16 mmol), compound C1-3 (935 mg, 3.16 mmol), Pd(PPh3)4 (365 mg, 0.32 mmol), K2CO3 (654 mg, 4.74 mmol), and dioxane / H2O (9 mL / 1.5 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to react overnight at 100 °C under N2 protection. When LC-MS showed the reaction was complete, the reaction was poured into water (100 mL) with stirring, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 775 mg of product.

[0199] 3.Synthesis of C9-4 Compound C12-3 (700 mg, 1.8 mmol), Pd(OH)2 / C (10%, 350 mg), and MeOH (15 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to react overnight at 50 °C under an atmosphere of H2 (60 psi). When LC-MS showed that most of the raw materials had reacted to completion, the mixture was filtered, concentrated, and subjected to column chromatography to obtain a mixture of compounds C9-3 and C9-4 (242 mg), which was used directly in the next step reaction.

[0200] 4. Synthesis of C9-5 and C9-6 A mixture of compounds C9-3 and C9-4 (230 mg, 0.59 mmol), LiOH·HO (100 mg, 2.4 mmol), and MeOH / HO (3 mL / 1.5 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to react overnight at 50 °C. When LC-MS showed the reaction was complete, it was concentrated to give 250 mg of the crude product, which was used directly in the next step reaction.

[0201] 5. Synthesis of Compounds C9, C10, and C11 A mixture of compounds C9-5 and C9-6 (114 mg, 0.3 mmol), compound C1-7 (66 mg, 0.24 mmol), and DMF (3 mL) were placed in a 50 mL single-neck flask, and diisopropylethylamine (397 mg, 3 mmol), PyBop (234 mg, 0.45 mmol), and HOBT (84 mg, 0.4 mmol) were added with stirring at room temperature. The reaction system was reacted at room temperature for 30 minutes. When LC-MS showed the reaction was complete, the reaction solution was poured into water (30 mL) and extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was then separated to give compound C11 (10 mg, purity: 96.7%), [M+H]: 560.2; compound C10 (19 mg, purity: 97.5%), [M+H]: 562.3; compound C9 (17 mg, purity: 97.1%), [M+H]: 562.3.

[0202] Example 7 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0203] 1.Synthesis of C12-2 A 250 mL single-neck flask was charged with 3-amino-5-methylpyrazole (426 mg, 4.4 mmol), compound C12-1 (696 mg, 4 mmol), DMSO (4 mL), and diisopropylethylamine (1.032 g, 8 mmol), and the reaction was allowed to react at 90° C. for 5 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (40 mL) with stirring, and a solid precipitated. The solid was filtered, the cake was washed with water, and the cake was dried to give 910 mg of product.

[0204] 2.Synthesis of C12-3 Compound C12-2 (585 mg, 2.5 mmol), compound C1-3 (814 mg, 2.75 mmol), Pd(PPh3)4 (289 mg, 0.25 mmol), K2CO3 (690 mg, 5 mmol), and dioxane / H2O (30 mL / 4 mL) were placed in a 50 mL single-neck flask and reacted overnight at 100 °C under N2 protection. When LC-MS showed the reaction was complete, the reaction was poured into water (100 mL) with stirring and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 747 mg of product.

[0205] 3.Synthesis of C12-4 A 150 mL single-neck flask was charged with C12-3 (747 mg, 2 mmol), Pd(OH)2 / C (10%, 700 mg), and EtOH (100 mL) and reacted overnight at 80 °C under H2 atmosphere. When LC-MS showed that most of the raw materials had reacted to completion, it was filtered, concentrated, and subjected to column chromatography to obtain 291 mg of a mixture of compounds C12-4 and C12-3, which was used directly in the next step reaction.

[0206] 4. Synthesis of C12-5 and C12-6 A mixture of compounds C12-4 and C12-3 (291 mg, 0.79 mmol), LiOH·HO (132 mg, 3.15 mmol), and MeOH / HO (15 mL / 3 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to react overnight at 50 °C. When LC-MS showed the reaction was complete, it was concentrated to give 393 mg of the crude product, which was used directly in the next step reaction.

[0207] 5. Synthesis of C12 and C13 A mixture of compounds C12-5 and C12-6 (197 mg, 0.55 mmol), compound C1-7 (122 mg, 0.44 mmol), and DMF (10 mL) were placed in a 50 mL single-neck flask, and diisopropylethylamine (705 mg, 5.5 mmol), PyBop (426 mg, 0.81 mmol), and HOBT (150 mg, 1.08 mmol) were added with stirring at room temperature. The reaction system was reacted at room temperature for 30 minutes. When LC-MS showed the reaction was complete, the reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the crude product, which was then separated to obtain compound C13 (26 mg, purity: 96.5%) and compound C12 (13 mg, purity: 97.5%).

[0208] Example 8 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0209] 1.Synthesis of C14-2 A 250 mL single-neck flask was charged with 3-amino-5-methylpyrazole (540 mg, 5.5 mmol), compound C14-1 (1.04 g, 5 mmol), DMSO (10 mL), and diisopropylethylamine (1.29 g, 10 mmol), and the reaction was allowed to react at 90° C. for 5 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (40 mL) with stirring, and a solid precipitated. The solid was filtered, the cake was washed with water, and the cake was dried to give 1.2 g of product.

[0210] 2.Synthesis of C14-3 Compound C14-2 (774 mg, 2.88 mmol), compound C1-3 (1.7 g, 5.75 mmol), Pd(PPh3)4 (999 mg, 0.864 mmol), K2CO3 (1.19 g, 8.64 mmol), and dioxane / H2O (40 mL / 10 mL) were added to a 100 mL single-neck flask, and the reaction was allowed to react overnight at 90 °C under N2 protection. When LC-MS showed the reaction was complete, the reaction was poured into water (100 mL) with stirring and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 1.16 g of product.

[0211] 3.Synthesis of C14-4 Compound C14-3 (302 mg, 0.74 mmol), Pd(OH)2 / C (10%, 30 mg), and MeOH (20 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to proceed at 50° C. under an atmosphere of H2. When LC-MS showed the reaction was complete, it was filtered, concentrated, and subjected to column chromatography to give 90 mg of product.

[0212] 4.Synthesis of C14-5 Compound C14-4 (374 mg, 1 mmol), glyoxal (174 mg, 1.2 mmol), and ethanol (10 mL) were placed in a 50 mL single-neck flask and reacted at room temperature overnight. When LC-MS showed the reaction was complete, it was concentrated and subjected to column chromatography to obtain 94 mg of product.

[0213] 5.Synthesis of C14-6 Compound C14-5 (94 mg, 0.24 mmol), LiOH·HO (20 mg, 0.48 mmol), and MeOH / HO (2 mL / 0.5 mL) were added to a 50 mL single-neck flask and the reaction mixture was allowed to react at 50 °C for 48 h. When LC-MS showed the reaction was complete, it was concentrated to give 106 mg of crude product, which was used directly in the next step reaction.

[0214] 6. Synthesis of C14 In a 50 mL single-neck flask, the crude product of compound C14-6 (106 mg, 0.17 mmol), compound C1-7 (52 mg, 1.97 mmol), DMF (1 mL), and diisopropylethylamine (176 mg, 1.36 mmol) were added and stirred at room temperature for 10 min, and PyBop (133 mg, 0.26 mmol) was added and the reaction system was reacted at room temperature for 30 min. When the reaction was shown to be complete by LC-MS, the reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the crude product, which was then separated to obtain compound C14 (37 mg, purity: 98%).

[0215] Example 9 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0216] 1.Synthesis of C15-2 Compound C15-1 (1 g), triethylamine (1.45 mL), ethanol (20 mL) and tetrahydrofuran (5 mL) were placed in a 100 mL single-neck flask, and 3-amino-5-methylpyrazole (530 mg) was added in portions with stirring and stirred at room temperature overnight. When TLC showed complete reaction, it was concentrated, the residue was taken up in water, stirred for 15 minutes, filtered, and the cake was washed with ethyl ether and dried to give compound C18-2.

[0217] 2.Synthesis of C15-3 Compound C15-2 (973 mg, 3.75 mmol), compound C1-3 (1.66 g, 5.62 mmol), Pd(PPh3)4 (2.17 g, 1.875 mmol), Cs2CO3 (3.67 g, 11.25 mmol), and dioxane / H2O (15 mL / 3 mL) were added to a 100 mL single-neck flask, and the reaction was allowed to react overnight at 110 °C under N2 protection. When LC-MS showed the reaction was complete, the reaction was poured into water (100 mL) with stirring, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 895 mg of product.

[0218] 3.Synthesis of C15-4 Compound C15-3 (875 mg, 2.23 mmol), Pd(OH)2 / C (10%, 170 mg), and MeOH (50 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to proceed at 50 °C under an atmosphere of H2. After completion of the reaction as monitored by LC-MS, it was filtered and concentrated to give 724 mg of crude product.

[0219] 4.Synthesis of C15-5 Compound C15-4 (675 mg, 1.7 mmol), LiOH·HO (145 mg, 3.4 mmol), and MeOH / HO (5 mL / 1 mL) were added to a 50 mL single-neck flask, and the reaction was allowed to react overnight at 50 °C. When LC-MS showed the reaction was complete, it was concentrated to give 210 mg of crude product, which was used directly in the next step reaction.

[0220] 5. Synthesis of C15 Compound C15-5 (148 mg, 0.39 mmol), compound C1-7 (119 mg, 0.43 mmol), DMF (2 mL), and diisopropylethylamine (401 mg, 3.1 mmol) were added to a 50 mL single-neck flask and stirred at room temperature for 10 min. PyBop (304 mg, 0.58 mmol) was added and the reaction system was allowed to react at room temperature for 30 min. When LC-MS showed the reaction was complete, the reaction solution was poured into water (30 mL), extracted three times with ethyl acetate, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to obtain the crude product, which was then separated to obtain compound C15 (10 mg, purity: 91%).

[0221] Example 10 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0222] 1.Synthesis of C16-2 Compound C16-1 (20 mmol, 3.8 g), 3-amino-5-methylpyrazole (24 mmol, 2.4 g), diisopropylethylamine (40 mmol, 5.2 g) and DMSO (30 mL) were added to a 50 mL reaction flask in this order, and the reaction system was reacted at 90 °C for 16 h under the protection of argon gas. When TLC showed the reaction was complete, water and ethyl acetate were added, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried, concentrated and recrystallized from tetrahydrofuran / methyl-t-butyl ether to obtain 3 g of product.

[0223] 2.Synthesis of C16-3 Under the protection of nitrogen gas, compound C16-2 (1 g, 4 mmol), compound C1-3 (1.3 g, 4.4 mmol), Pd(PPh3)4 (400 mg, 0.4 mmol), potassium carbonate (1 g, 6 mmol), dioxane (12 mL) and water (3 mL) were added to a 100 mL three-neck flask in this order, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was stirred at 100 °C for 16 h, and when TLC and LC-MS showed that the reaction was complete, the solution was filtered and concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate three times, washed with saturated saline, dried the organic phase, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (vehicle: dichloromethane / methanol = 30:1) to obtain 700 mg of the product.

[0224] 3.Synthesis of C16-4 Compound C16-3 (690 mg, 1.6 mmol) and ethanol (10 mL) were placed in a 50 mL single-neck flask, and 10% Pd(OH)2 / C (300 mg) was carefully added. The reaction vessel was replaced with hydrogen gas three times, and then the reaction was carried out under hydrogen gas protection at 50°C for 100 h. When the reaction was complete as detected by LC-MS, it was slowly filtered through diatomaceous earth, the cake was washed with methanol, and the filtrate was concentrated to give 650 mg of product.

[0225] 4.Synthesis of C16-5 Compound C16-4 (540 mg, 1.1 mmol), methanol (3 mL), THF (3 mL), HO (2 mL), and LiOH (140 mg, 3.5 mmol) were sequentially charged into a 50 mL single-neck flask, and the reaction was stirred at 65 °C for 16 h. When the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure, diluted with water (1 mL), impurities were extracted with ethyl ether, and the aqueous phase was adjusted to pH = 4-5 with 2 M HCl. The aqueous phase was concentrated and dried to give 500 mg of product, which was used directly in the next step.

[0226] 5. Synthesis of C16 and C17 Compound C16-5 (307 mg, 0.83 mmol), HATU (253 mg, 1 mmol), diisopropylethylamine (0.7 mL, 5 mmol) and DMF (6 mL) were added to a 10 mL reaction tube and stirred at room temperature for 10 min, then compound C1-7 (242 mg, 1 mmol) was added and stirred at room temperature for 3 h. When TLC and LC-MS showed the reaction was complete, it was diluted with water (3 mL), extracted three times with ethyl acetate, washed with saturated brine, dried the organic phase and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM / MeOH=10 / 1) to obtain the cis-trans isomers, which were then separated to obtain the isomeric compounds C16 (14 mg) and C17 (6 mg).

[0227] C16 (LC:T=16.17 min; purity:97.21%) Nuclear magnetic resonance analysis data of compound C16: 1H NMR (400 MHz, chloroform-d) δ 8.40 (d, J = 2.4 Hz,1H), 8.36 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.91 (s,1H), 6.74 (d, J = 7.9 Hz, 1H), 5.26 - 5.16 (m, 1H), 3.75 (m, 1H), 3.24 (m, 3H), 3.15(m,1H),2.42 (s, 3H), 2.30 (s, 3H), 1.98 - 1.62 (m, 8H), 1.54 (d, J = 7.0 Hz, 3H). C17 (LC:T=22.57 min; purity:97.47%) Nuclear magnetic resonance analysis data of compound C17: 1H NMR (400 MHz, chloroform-d) δ 8.49 - 8.28 (m, 1H), 7.92 (d, J = 8.5 Hz, 0H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.58 (d, J = 4.3 Hz, 0H), 6.90 - 6.64 (m, 1H), 6.12 (s, 1H), 5.19 (p, J = 7.3 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.28 (s, 3H), 3.14 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 1.94 - 1.70 (m, 8H), 1.57 (d, J = 7.0 Hz, 2H).

[0228] Example 11 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0229] 1.Synthesis of C18-1 Under the protection of nitrogen gas, compound C16-1 (25 g, 133 mmol), N,N-dimethylformamide diethyl acetal (24 g, 200 mmol) and isopropanol (300 mL) were placed in a 1 L three-neck flask in that order, and the reaction solution was stirred at 65°C for 16 h. When TLC and LC-MS showed that the reaction was complete, the solution was cooled to room temperature and filtered. The cake was washed with a small amount of ethyl acetate, filtered and concentrated under reduced pressure to obtain 30 g of the product.

[0230] 2.Synthesis of C18-2 Compound C18-1 (25 g, 91 mmol) and concentrated hydrochloric acid (100 mL) were placed in a 250 mL three-neck flask, and the reaction solution was stirred at 45° C. for 16 h. The temperature was then lowered to room temperature, and ice water was added to the reaction system. The reaction system was filtered, and the cake was washed with ice water and methyl-t-butyl ether. The crude product obtained was purified by silica gel column chromatography (vehicle: dichloromethane / methanol / aqueous ammonia=50:10:1) to obtain 10 g of the product.

[0231] 3.Synthesis of C18-3 Compound C18-2 (2.4 g, 12 mmol) and DMA (15 mL) were added to a 50 mL three-neck flask, and NaH (0.576 g, 14.4 mmol) was added separately in an ice bath. After the addition was completed, the reaction solution was stirred at 0 ° C. to room temperature for 30 minutes, p-methoxybenzyl chloride (1.8 g, 15 mmol) was added, the reaction solution was stirred at room temperature for 16 h, water (5 mL) was slowly added dropwise in an ice bath, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated saline to remove DMA, the organic phase was dried, and the crude product obtained by concentrating under reduced pressure was purified by silica gel column chromatography (vehicle: ethyl acetate / petroleum ether = 1:10-1:1) to obtain 2.5 g of the product.

[0232] 4.Synthesis of C18-4 Under the protection of nitrogen gas, the raw material compound C18-3 (1.8 g, 5.4 mmol), compound C1-3 (1.5 g, 5mmol), Pd(PPh3)4 (600 mg, 0.54 mmol), potassium carbonate (1.8 g, 13 mmol), dioxane (20 mL) and water (4 mL) were placed in a 100 mL three-neck flask in that order, and the atmosphere was replaced with nitrogen gas three times. The reaction solution was stirred at 90 °C for 16 h, and when TLC and LC-MS showed that the reaction was complete, the solution was concentrated under reduced pressure after filtration, diluted with water (20 mL), extracted with ethyl acetate three times, washed with saturated saline, dried the organic phase, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (vehicle: ethyl acetate / petroleum ether = 1:10-1:3) to obtain 1.5 g of the product.

[0233] 5.Synthesis of C18-5 Under the protection of nitrogen gas, compound C18-4 (1.1 g, 2.4 mmol), compound C1-17 (700 mg, 3.6 mmol), Pd2(dba)3 (210 mg, 0.24 mmol), DBU (727 mg, 4.8 mmol), t-BuXphos (210 mg, 0.25 mmol) and ethylene glycol dimethyl ether (10 mL) were added to a 50 mL three-neck flask in this order, and the atmosphere was replaced with nitrogen gas three times, and the reaction solution was stirred at 60 °C for 16 h. When TLC showed the reaction was complete, after filtration, the solution was concentrated under reduced pressure, diluted with water (5 mL), extracted with ethyl acetate three times, washed the organic phase with saturated saline, dried the organic phase, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (vehicle: ethyl acetate / petroleum ether = 1:10-1:3) to obtain 900 mg of the product.

[0234] 6.Synthesis of C18-6 Compound C18-5 (500 mg, 0.8 mmol) and ethanol (10 mL) were placed in a 50 mL single-neck flask, and 10% Pd(OH)2 / C (300 mg) was carefully added. The reaction vessel was replaced with hydrogen gas three times, and then the reaction was carried out under hydrogen gas protection at 65 °C for 100 h. When the reaction was complete as detected by LC-MS, it was slowly filtered through diatomaceous earth, the cake was washed with methanol, and the filtrate was concentrated to obtain 500 mg of crude product.

[0235] 7.Synthesis of C18-7 Compound C18-6 (400 mg, 0.58 mmol) and trifluoroacetic acid (10 mL) were added in sequence to a 50 mL single-neck flask, and the reaction was stirred at 80° C. for 16 h. When the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure to give the trifluoroacetate salt of the product, which was used directly in the next step.

[0236] 8.Synthesis of C18-8 A 50 mL single-neck flask was charged with compound C18-7 (410 mg, 0.55 mmol), methanol (3 mL), THF (3 mL), HO (2 mL), and LiOH (230 mg, 5.5 mmol) in that order, and the reaction was stirred at 65 °C for 16 h. When the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure, diluted with water (5 mL), extracted with ethyl ether, and the aqueous phase was adjusted to pH = 4-5 with 2 M HCl. The aqueous phase was concentrated and dried to give 400 mg of crude product, which was used directly in the next step.

[0237] 9. Synthesis of C18 and C19 Compound C18-8 (400 mg, 1.0 mmol), HATU (760 mg, 2 mmol), diisopropylethylamine (650 mg, 5 mmol) and DMF (5 mL) were added to a 10 mL reaction tube and stirred at room temperature for 10 min, then compound C1-7 (320 mg, 1.2 mmol) was added and stirred at room temperature for 16 h. When TLC and LC-MS showed the reaction was complete, it was diluted with water (3 mL), extracted three times with ethyl acetate, washed with saturated saline, dried the organic phase, concentrated under reduced pressure and the obtained crude product was purified by column chromatography (DCM / MeOH=20 / 1) to give 190 mg of cis-trans isomers, which were separated to give 100 mg of compound C18 and 23 mg of compound C19.

[0238] Compound C18 (LC:T=30.51 min; purity:98.18%) Nuclear magnetic resonance analysis data of compound C18: 1H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 8.35 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.82 - 7.64 (m, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.09 (td, J = 9.1, 8.3, 2.5 Hz, 1H), 6.75 (d, J = 11.8 Hz, 1H), 6.09 (s, 1H), 5.07 - 4.75 (m, 1H), 4.13 (s, 1H), 3.49 (s, 2H), 3.23 (s, 3H), 2.85 (d, J = 7.7 Hz, 2H), 2.68 - 2.46 (m, 1H), 2.30 (s, 3H), 2.04 (m, 4H), 1.86 (m, 4H), 1.56 (d, J = 7.0 Hz, 3H). Compound C19 (LC: T = 32.26 min; Purity: 94.58%) Nuclear magnetic resonance analysis data of compound C19: 1H NMR (400 MHz, chloroform-d) δ 8.38 (t, J = 4.3 Hz, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5, 2.3 Hz, 1H), 7.58 (d, J = 4.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 6.08 (s, 1H), 5.17 (q, J = 7.3 Hz, 1H), 4.15 (m, 1H), 3.41 (m, 2H), 3.30 (s, 3H), 2.84 (m, 2H), 2.31 (s, 3H), 1.98 - 1.68 (m, 8H), 1.55 (d, J = 7.0 Hz, 3H).

[0239] Example 12 Compounds synthesized in the present invention: [Chemical formula] The synthetic route and experimental steps are as follows. [ka]

[0240] 1.Synthesis of C20-1 Compound C18-5 (630 mg, 1 mmol) and trifluoroacetic acid (10 mL) were added to a 50 mL single-neck flask in that order, and the reaction was stirred at 20° C. for 16 h. When the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure to remove trifluoroacetic acid, charged with dichloromethane (20 mL), and the organic phase was washed with saturated sodium carbonate (5 mL), and the organic phase was separated and concentrated to give 420 mg of crude product, which was used directly in the next step.

[0241] 2.Synthesis of C20-2 Compound C20-2 (400 mg, 0.8 mmol) and methanol (10 mL) were placed in a 50 mL single-neck flask, and 10% Pd(OH)2 / C (100 mg) was carefully added in a nitrogen gas atmosphere. The reaction vessel was replaced with hydrogen gas three times, and then the reaction was carried out at 50°C for 16 h under the protection of hydrogen gas. The temperature was lowered to room temperature, and the mixture was slowly filtered through diatomaceous earth. The cake was washed with methanol, and the filtrate was concentrated to obtain 400 mg of the product.

[0242] 3.Synthesis of C20-3 Compound C20-2 (400 mg, 0.8 mmol) and trifluoroacetic acid (3 mL) were added to a microwave tube in order, and then the reaction was carried out for 15 minutes in a microwave at 140° C. When the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure to give 300 mg of the trifluoroacetate salt of the product, but the crude product was used directly in the next step.

[0243] 4.Synthesis of C20-4 A 50 mL single-neck flask was charged with compound C20-3 (300 mg, 0.58 mmol), methanol (3 mL), THF (3 mL), HO (2 mL), and LiOH·HO (170 mg, 4 mmol), in that order. The reaction was stirred at 65 °C for 16 h, and when the reaction was complete as detected by LC-MS, it was concentrated under reduced pressure, diluted with water (1 mL), extracted with ethyl ether, and the aqueous phase was adjusted to pH = 4-5 with 2 M HCl. The aqueous phase was concentrated and dried to give 310 mg, which was used directly in the next step.

[0244] 5. Synthesis of Compounds C20 and C21 Crude product compound C20-4 (200 mg, 0.5 mmol), HATU (380 mg, 1 mmol), diisopropylethylamine (330 mg, 2.5 mmol) and DMF (2 mL) were added to a 10 mL reaction tube and stirred at room temperature for 10 min, then compound C1-7 (160 mg, 0.6 mmol) was added and stirred at room temperature for 16 h. When TLC and LC-MS showed the reaction was complete, it was diluted with water (3 mL), extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried the organic phase and concentrated under reduced pressure to give 180 mg of crude product. The crude product was isolated to give 13 mg of compound C20 and 8 mg of compound C21.

[0245] Example 13 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0246] 1.Synthesis of C22-2 Compound C22-1 (5.0 g, 30.1 mmol), NCS (9.3 g, 70.4 mmol), and DMF (100 mL) were placed in a 250 mL single-neck flask and reacted at 25 °C for 15 h, poured into water, extracted with ethyl acetate three times, and the organic phases were combined, dried, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 7.12 g of compound C22-2, with a yield of 98% and [M + H]: 221.1. Nuclear magnetic resonance analysis data for compound C22-2: 1H NMR: (CDCl3, 400Hz) δ7.65 (s, 1H), 6.17 (s, 1H), 3.93(s,3H).

[0247] 2.Synthesis of C22-3 Compound C22-2 (6.7 g, 30.1 mmol), aqueous ammonia (wt%: 20%) (50 mL), and EtOH (30 mL) were placed in a 100 mL small autoclave and reacted at 80 °C for 15 h. The mixture was then cooled to room temperature, rotary dried, saturated with sodium chloride, extracted three times with ethyl acetate, and the organic phases were combined, dried, concentrated, and subjected to column chromatography (PE: ethyl acetate = 5: 1) to obtain 4.25 g of compound C22-3. The yield was 68%, and [M + H]: 206.1. Nuclear magnetic resonance analysis data of compound C22-3: 1H NMR: (MeOD, 400Hz) δ7.52 (s, 1H).

[0248] 3.Synthesis of C22-4 Compound C22-3 (3.8 g, 18.5 mmol) and triethyl orthoformate (80 mL) were placed in a 250 mL small autoclave and reacted at 160 °C for 7 h. The mixture was then cooled to room temperature, rotary dried, saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and precipitated by mixing with methyl-t-butyl ether to obtain 2.5 g of compound C22-4. The yield was 64%, and [M+H] was 215.9. Nuclear magnetic resonance analysis data for compound C22-4: 1HNMR: (DMSO-d6, 400Hz) δ 8.25 (s, 1H), 7.92 (s, 1H)

[0249] 4.Synthesis of C22-5 Compound C22-4 (300 mg, 1.40 mmol) and DMA (1 mL) were added to a 50 mL single-neck flask, sodium hydride (2.80 mmol) was added at 0 ° C, and the mixture was replaced with nitrogen gas. PMBCl (1.68 mmol) was added dropwise and reacted at 25 ° C for 12 h. When the reaction was completed by TLC, the reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined, dried, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 347 mg of compound C22-5, with a yield of 75% and [M + H]: 336.0. Nuclear magnetic resonance analysis data of compound C22-5: 1HNMR: (CDCl3, 400Hz) δ8.23 (s, 1H), 8.06 (s, 1H), 7.29(d,J=8.8 Hz,2H), 6.89(d,J=8.4 Hz,2H), 5.12 (s, 2H), 3.79 (s, 3H).

[0250] 5.Synthesis of C22-6 Compound C22-5 (347 mg, 1.04 mmol), 1,4-dioxane / H2O (1 mL / 0.5 mL) were added to a 50 mL single-neck flask, and compound C1-3 (1.25 mmol), K2CO3 (2.08 mmol), and Pd(PPh3)4 (0.052 mmol) were added. The mixture was reacted at 100 °C for 12 h and monitored by TLC. When the reaction was completed, the reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, dried, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 366 mg of compound C22-6. The yield was 75%, and [M + H]: 470.0. Nuclear magnetic resonance analysis data of compound C22-6: 1HNMR: (CDCl3, 400Hz) δ8.08 (s, 1H), 7.97 (s, 1H), 7.30(d,J=8.8 Hz,2H), 6.88(d,J=8.8 Hz,2H), 6.85(t,J=2.4 Hz,1H), 5.11 (s, 2H), 3.79 (s, 6H), 3.32 (s, 3H), 2.86(d,J=2.0 Hz,2H), 2.86-2.79 (m, 2H), 2.71-2.57 (m, 2H).

[0251] 6.Synthesis of C22-7 Compound C22-6 (1.01 g, 2.15 mmol) and 1,4-dioxane (10 mL) were placed in a 50 mL single-neck flask, and compound C1-17 (2.58 mmol), AcOK (4.30 mmol), Pd2(dba)3 (0.11 mmol), and t-Buxphos (0.11 mmol) were placed under the protection of nitrogen gas. The mixture was reacted at 90 ° C for 12 h and monitored by TLC. When the reaction was completed, the reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, dried, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 761 mg of compound C22-7. The yield was 56%, and [M + H]: 631.3. Nuclear magnetic resonance analysis data of compound C22-7: 1HNMR: (CDCl3, 400Hz) δ7.89 (s, 1H), 7.77 (s, 1H), 7.31(d,J=4.0 Hz,2H), 7.28 (s, 1H), 6.86 (d,J=8.8 Hz,2H), 6.72 (s, 1H), 6.41 (s, 1H), 5.09 (s, 2H), 3.80 (s, 6H), 3.34 (s, 3H), 2.86(d,J=2.0 Hz,2H), 2.81-2.60 (m, 2H), 2.54 (s, 3H), 2.44-2.14 (m, 2H), 1.67 (s, 9H).

[0252] 7.Synthesis of C22-8 Compound C22-7 (751 mg, 1.19 mmol) and ethyl acetate (10 mL) were placed in a 50 mL single-neck flask, and Pd / C (0.12 mmol) was placed under nitrogen gas protection. The mixture was then replaced with nitrogen gas and reacted at room temperature for 12 h under hydrogen gas conditions. When the reaction was completed by TLC, the reaction solution was filtered, the organic phase was combined, dried and concentrated to obtain 638 mg of compound C22-8, with a yield of 85% and [M+H]: 533.3.

[0253] 8.Synthesis of C22-9 Compound C22-8 (217 mg, 0.34 mmol) and trifluoroacetic acid (5 mL) were placed in a 50 mL single-neck flask and reacted at 90°C for 18 h. The reaction was monitored by TLC. When the reaction was completed, the reaction solution was concentrated to obtain 143 mg of compound C22-9, with a yield of 100% and [M+H]: 413.1.

[0254] 9.Synthesis of C22-10 A 25 mL single-neck flask was charged with C22-9 (139 mg, 0.34 mmol), LiOH·HO (1.3 mmol), and MeOH / HO (2 mL / 0.4 mL) and reacted at 60 °C for 18 h. When LC-MS showed the reaction was complete, the reaction was concentrated to give 229 mg of crude product, [M+H]: 399.1.

[0255] 10. Synthesis of C22 and C23 Compound C22-10 (320 mg, 0.80 mmol), compound C1-7 (0.88 mmol), DMF (2 mL), triethylamine (1.60 mmol) and PyBOP (1.20 mmol) were placed in a 25 mL single-neck flask and reacted at room temperature for 18 h. When LC-MS showed the reaction was complete, the reaction solution was poured into 10 mL of water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the resulting crude product was isolated to give 15 mg of compound C22, [M+H]: 587.3 and 8 mg of compound C23, [M+H]: 587.3.

[0256] Example 14 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0257] 1.Synthesis of C24-2 Compound C1-8 (1.0 g, 5.03 mmol) and compound C24-1 (0.62 g, 6.03 mmol) were dissolved in DMF (10 ml), potassium carbonate (1.6 g, 11.57 mmol) was added, the temperature was raised to 120 ° C, and the mixture was stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent DMF, and then diluted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 0.5 g of compound C24-2. Nuclear magnetic resonance analysis data of compound C24-2: 1H NMR (400 MHz, DMSO-d6) δ9.57(s, 1H), 9.09(s, 1H), 8.57-8.55(t, 1H), 7.97-7.95(d, 1H, J=8.58Hz), 2.68(s, 3H).

[0258] 2.Synthesis of C24-3 Compound C24-2 (397 mg, 1.79 mmol) and R-(+)-t-butylsulfinamide (260 mg, 2.15 mmol) were dissolved in dry tetrahydrofuran (20 mL), and then tetraethyl titanate (898 mg, 3.94 mmol) was added. Under the protection of nitrogen gas, the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, 1 mL of water was added, and the mixture was filtered under reduced pressure. The filtrate was extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 429 mg of compound C24-3. Nuclear magnetic resonance analysis data for compound C24-3: 1 H NMR (400 MHz, DMSO-d6) δ9.54(s, 1H), 9.02-9.01(d, 1H, J=1.93Hz), 8.55-8.52(dd, 1H, J=8.60Hz, 2.68Hz), 7.94-7.92(d, 1H, J=8.35Hz), 2.80(s, 3H), 1.25(s, 9H).

[0259] 3.Synthesis of C24-4 Compound C24-3 (429 mg, 1.32 mmol) was dissolved in dry tetrahydrofuran (5 mL), and under the protection of nitrogen gas, the temperature was lowered to -78 ° C., and 1M lithium tri-sec-butylborohydride tetrahydrofuran solution (3.96 ml, 3.96 mmol) was added dropwise, and the mixture was stirred for 1 h while maintaining the temperature at -78 ° C. When the reaction was completed by TLC, methanol was added dropwise to quench the reaction, the temperature was raised to room temperature, and the mixture was diluted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 362 mg of compound C24-4. Nuclear magnetic resonance analysis data for compound C24-4: 1 H NMR (400 MHz, DMSO-d6) δ9.50(s, 1H), 8.59-8.58(d, 1H, J=1.93Hz), 8.13-8.11(dd, 1H, J=8.65Hz, 2.34Hz), 7.88-7.85(d, 1H, J=8.65Hz), 5.69-5.68(d, 1H, J=5.67Hz), 4.68-4.61(m, 1H), 1.58-1.57(d, 3H, J=6.80Hz), 1.17(s, 9H).

[0260] 4.Synthesis of C24-5 Compound C24-4 (362 mg, 1.11 mmol) was dissolved in a mixture of dioxane (1.4 ml) and anhydrous methanol (1.4 ml), and then 4 M hydrogen chloride in dioxane (2.8 ml) was added and stirred at room temperature for 2 hours. Then, methyl t-butyl ether was added, filtered, and dried to obtain 258 mg of compound C24-5. Nuclear magnetic resonance analysis data for compound C24-5: 1 H NMR (400 MHz, DMSO-d6) δ9.50(s, 1H), 8.73-8.71(m, 4H), 8.29-8.26 (dd, 1H, J=8.55Hz, 2.39Hz), 7.93-7.91(d, 1H, J=8.30Hz), 4.61(br, 1H), 1.60-1.58(d, 3H, J=7.14Hz).

[0261] 5. Synthesis of C24 and C25 Compound C24-5 (40 mg, 0.16 mmol) and compound C3-19 (60 mg, 0.16 mmol) were dissolved in DMF (1.2 ml), DIPEA (160 mg, 1.24 mmol) was added, and the mixture was stirred at room temperature for 5 min., HATU (88 mg, 0.23 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 31 mg of compound C24 and 27 mg of compound C25.

[0262] Nuclear magnetic resonance analysis data for compound C24: 1H NMR (400 MHz, CDCl3) δ9.05(s, 1H), 8.67-8.66(d, 1H, J=3.99Hz, 1.54Hz), 8.44-8.43 (d, 1H, J=1.94Hz), 7.91-7.89(dd, 1H, J=8.45Hz, 1.41Hz), 7.86-7.79(m, 2H), 7.38-7.35(m, 2H), 7.06(s, 1H),6.93-6.91(d, 1H, J=7.75Hz), 5.88(s, 1H),5.22-5.18(m, 1H), 4.24-4.18(m, 1H), 3.31(s, 3H), 2.32(s, 3H), 2.18-2.10(m, 2H), 2.07-1.94(m, 5H), 1.91-1.86(m, 2H), 1.59-1.57(d, 3H, J=7.04Hz). Nuclear magnetic resonance analysis data for compound C25: 1 H NMR (400 MHz, CDCl3) δ8.99(s, 1H), 8.59-8.58(dd, 1H, J=3.88Hz, 1.55Hz), 8.43-8.42 (d, 1H, J=2.07Hz), 7.85-7.79(m, 1H), 7.74-7.72(m, 1H), 7.30-7.27(m, 3H), 6.75-6.73(d, 1H, J=7.49Hz), 5.79(s, 1H),5.19-5.14(m, 1H), 4.19-4.14(m, 1H), 3.21(s, 3H), 2.34-2.30(m, 1H), 2.24(s, 1H), 2.22-2.11(m, 3H), 1.98-1.92(m, 3H), 1.78-1.71 (m, 2H), 1.53-1.51(d, 3H, J=7.23Hz).

[0263] Example 15 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0264] 1.Synthesis of C26-2 Compound C26-1 (1.57 g, 10 mmol), 4-fluoro-1H-pyrazole (860 mg, 10 mmol), N,N-dimethylformamide (10 mL), and potassium carbonate (2.76 g, 20 mmol) were added to a 50 mL single-neck flask, and the reaction system was reacted at 100 °C for 8 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (200 mL) with stirring, and a solid precipitated. The solid was filtered, the cake was washed with water, and the cake was dried to obtain 1.08 g of solid. [M+1]: 207.03.

[0265] 2.Synthesis of C26-3 Compound C26-2 (870 mg, 4.2 mmol), Rt-butylsulfinamide (560 mg, 4.63 mmol), tetraethyl titanate (1.92 g, 8.4 mmol), and dry tetrahydrofuran (10 mL) were added to a 100 mL single-neck flask in this order, and the reaction system was reacted at 75 ° C overnight. The reaction system was cooled, diluted with water (30 mL), suction filtered, and the filtrate was extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and subjected to column chromatography to obtain 500 mg of the product.

[0266] 3.Synthesis of C26-4 Compound C26-3 (100 mg, 0.32 mmol) and dry tetrahydrofuran (2 mL) were placed in a 50 mL single-neck flask, cooled to -78°C, lithium tri-sec-butylborohydride (0.7 mL, 0.7 mmol, 1.0M) was added dropwise, and the reaction was allowed to proceed at -78°C for 1 h. The reaction was quenched by adding methanol (1 mL) at -60°C, diluted with water (5 mL), extracted three times with ethyl acetate (5 mL), the organic phase was dried, evaporated to dryness under reduced pressure, and subjected to column chromatography to obtain 113 mg of the product. Nuclear magnetic resonance analysis data of compound C26-4: 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 4.6 Hz, 1H), 7.66 (d, J = 4.3 Hz, 1H), 4.77 (p, J = 6.6 Hz, 1H), 3.74 (d, J = 5.9 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H).

[0267] 4.Synthesis of C26-5 Compound C26-4 (100 mg, 0.32 mmol), dichloromethane (3 mL), methanol (0.5 mL), and HCl / dioxane (4M, 1.5 mL) were added to a 50 mL single-neck flask in that order, and the reaction was allowed to react at room temperature for 3 h. When complete reaction was detected by LC-MS, the reaction was diluted with dichloromethane, filtered, and the cake was washed with ethyl acetate and dried to give 67 mg of product. [M+1]: 208.06.

[0268] 5.Synthesis of C26 Compound C26-5 (47 mg, 0.17 mmol), compound C3-19 (65 mg, 0.17 mmol), N,N-dimethylformamide (1 mL), and diisopropylethylamine (175 mg, 1.36 mmol) were added to a 25 mL single-neck flask and stirred at room temperature for 5 min, then HATU (97 mg, 0.26 mmol) was added and the reaction system was reacted at room temperature for 30 min. When LC-MS showed the reaction was complete, the reaction solution was poured into 10 mL of water and filtered to obtain the crude product, which was then separated to obtain compound C26 (37.6 mg, purity: 91%), [M+H]: 571.3. Nuclear magnetic resonance analysis data of compound C26: 1H NMR (400 MHz, DMSO-d6) δ 11.76 (d, J = 5.3 Hz, 1H), 9.14 (dd, J = 6.8, 3.1 Hz, 2H), 8.79 - 8.68 (m, 1H), 8.63 (tt, J = 4.2, 2.0 Hz, 1H), 8.54 (d, J = 5.3 Hz, 1H), 8.45 (t, J = 6.4 Hz, 1H), 8.12 - 7.97 (m, 2H), 7.73 - 7.43 (m, 2H), 6.08 - 5.93 (m, 1H), 5.16 (q, J = 7.1 Hz, 1H), 3.27 - 3.16 (m, 3H), 2.28 - 2.17 (m, 3H), 2.12 - 1.64 (m, 9H), 1.51 (d, J = 6.8 Hz, 3H).

[0269] Example 16 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0270] 1.Synthesis of C27-3 Compound C27-1 (1.49 g, 10 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol) were dissolved in toluene (50 mL), and then compound C27-2 (4.33 g, 12 mmol) was added, heated to 120 ° C, and stirred for 5 h. After the reaction was completed, the mixture was cooled to room temperature, 1M HCl (20 mL) was added, heated to 60 ° C, stirred for 1 h, concentrated, and diluted with ethyl acetate after adding water. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.2 g of compound C27-3. Nuclear magnetic resonance analysis data of compound C27-3: 1H NMR (400 MHz, CDCl3) δ 8.12-8.10 (d, 1H, J=9.04Hz), 7.69-7.67 (d, 1H, J=9.04Hz), 2.88 (s, J=3H).

[0271] 2.Synthesis of C27-4 Compound C27-3 (500 mg, 3.2 mmol) and 4-fluoro-1H-pyrazole (303 mg, 3.5 mmol) were dissolved in DMF (10 mL), potassium carbonate (1020 mg, 7.4 mmol) was added, and the mixture was heated to 100° C. and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and water was added, followed by extraction with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 440 mg of compound C27-4. Nuclear magnetic resonance analysis data of compound C27-4: 1H NMR (400 MHz, DMSO-d6) δ 9.08-9.07 (dd, 1H, J=4.60Hz,0.62Hz), 8.36-8.34 (d, 1H, J=9.04Hz), 8.31-8.28(d, 1H, J=9.04Hz), 8.20-8.18 (dd, 1H, J=4.10Hz, 0.75Hz), 2.79 (s, 3H).

[0272] 3.Synthesis of C27-5 Compound C27-4 (350 mg, 1.7 mmol) and Rt-butylsulfinamide (247 mg, 2.0 mmol) were dissolved in dry tetrahydrofuran (40 mL), tetraethyl titanate (775 mg, 3.4 mmol) was added, and the mixture was heated to 80° C. under nitrogen gas protection and stirred overnight. 1 mL of water was added, filtered, the cake was washed with ethyl acetate, the filtrate was concentrated, and purified by column chromatography to obtain 342 mg of compound C27-5. Nuclear magnetic resonance analysis data of compound C27-5: 1H NMR (400 MHz, CDCl3) δ 8.66-8.65 (d, 1H J=4.53Hz), 8.35-8.33(d, 1H, J=9.04Hz), 8.24-8.22(d, 1H, J=9.04Hz), 7.73-7.72 (d, 1H, J=4.21Hz), 3.02 (s, 3H), 1.35 (s, 9H).

[0273] 4.Synthesis of C27-6 Compound C27-5 (292 mg, 0.94 mmol) was dissolved in dry tetrahydrofuran (3 mL), cooled to -78°C, lithium tri-sec-butylborohydride (2.83 mL, 2.83 mmol, 1.0M) was added dropwise, and the reaction was allowed to proceed at -78°C for 1 h. The reaction was quenched by adding methanol (3 mL) at -60°C, diluted with water, extracted with ethyl acetate, the organic phase was dried, evaporated to dryness under reduced pressure, and subjected to column chromatography to obtain 200 mg of the product. Nuclear magnetic resonance analysis data of compound C27-6: 1H NMR (400 MHz, CDCl3) δ 8.55-8.54 (dd, 1H J=4.61Hz,0.55Hz), 8.12-8.09 (d, 1H, J=9.04Hz), 7.62-7.60 (m, 2H), 4.88-4.85 (m,1H), 1.66-1.64 (d, 3H, J=6.95Hz),1.16 (s, 9H).

[0274] 5.Synthesis of C27-7 Compound C27-6 (200 mg, 0.71 mmol) was dissolved in dioxane (1.8 mL) and methanol (1.8 mL), and 4M hydrochloric acid / dioxane (1.8 mL, 7.2 mmol) was added and reacted at room temperature for 3 h. When complete reaction was detected by LC-MS, the mixture was diluted with ethyl acetate, filtered, the cake was washed with ethyl acetate, and the cake was dried to obtain 47 mg of product. Nuclear magnetic resonance analysis data of compound C27-7: 1H NMR (400 MHz, DMSO-d6) δ 8.98-8.97 (dd, 1H, J=4.54Hz,0.62Hz), 8.81 (br,3H), 8.34-8.32 (d, 1H, J=9.25Hz), 8.14-8.10 (m, 2H), 4.83-4.77 (m,1H), 1.62-1.60 (d, 3H, J=7.66Hz).

[0275] 5. Synthesis of C27 and C28 Compound C27-7 (30 mg, 0.12 mmol) and compound C3-19 (48 mg, 0.12 mmol) were dissolved in 1 mL of DMF, diisopropylethylamine (0.3 mL, 0.96 mmol) was added, and the mixture was stirred at room temperature for 5 min. HATU (71 mg, 0.18 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by preparative liquid chromatography to obtain 20 mg of compound C27 and 10 mg of compound C28. Nuclear magnetic resonance analysis data of compound C27: 1H NMR (400 MHz, CDCl3) δ 8.58-8.56 (dd, 1H, J=4.06Hz, 1.72Hz), 8.53-8.52 (d, 1H, J=4.84Hz), 8.09-8.07 (d, 1H, J=9.37Hz), 7.86-7.84 (d, 1H, J=8.12Hz), 7.81-7.88 (dd, 1H, J=8.74Hz, 1.56Hz), 7.61-7.57 (m, 2H), 7.33 (br,1H), 7.28-7.25 (m, 1H), 7.22 (s, 1H), 5.89 (br,1H), 5.34-5.28 (m, 1H), 4.13-4.09 (m, 1H), 3.27 (s, 3H), 2.27(s, 3H), 2.15-1.76 (m, 8H), 1.62-1.59 (d, 3H, J=6.87Hz). Nuclear magnetic resonance analysis data of compound C28: 1H NMR (400 MHz, CDCl3) δ 8.59-8.58 (dd, 1H, J=4.06Hz, 1.72Hz), 8.52-8.50 (dd, 1H, J=4.53Hz, 0.70Hz), 8.08-8.06 (d, 1H, J=9.07Hz), 7.83-7.80 (dd, 1H, J=8.27Hz, 1.56Hz), 7.61-7.58 (d, 1H, J=9.21Hz), 7.58-7.57 (d, 1H, J=4.53Hz), 7.48 (br,1H), 7.44-7.42 (d, 1H, J=8.43Hz) 7.29-7.26 (m, 1H), 7.23 (s, 1H), 5.83 (br,1H), 5.38-5.31 (m, 1H), 4.22-4.15 (m, 1H), 3.22 (s, 3H), 2.27(s, 3H), 2.35-1.70 (m, 8H), 1.61-1.59 (d, 3H, J=7.49Hz).

[0276] Example 17 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0277] 1.Synthesis of C29-3 Compound C29-1 (500 mg, 3.6 mmol) and compound C29-2 (420 mg, 5 mmol) were dissolved in DMF (10 mL), potassium carbonate (1150 mg, 8.3 mmol) was added, the temperature was raised to 100 ° C, and the mixture was stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and water was added, followed by extraction with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 565 mg of compound C29-3. Nuclear magnetic resonance analysis data of compound C29-3: 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.06-9.05 (d, 1H, J=2.03Hz), 8.53-8.50 (dd, 1H, J=8.59Hz, 2.34Hz), 7.93-7.91 (dd, 1H, J=8.62Hz, 0.59Hz), 2.66 (s, 3H), 2.41 (s, 3H).

[0278] 2.Synthesis of C29-4 Compound C29-3 (565 mg, 2.8 mmol) and Rt-butylsulfinamide (406 mg, 3.4 mmol) were dissolved in 50 mL of dry tetrahydrofuran, tetraethyl titanate (1275 mg, 5.6 mmol) was added, and the mixture was heated to 80° C. under nitrogen gas protection and stirred overnight. 2 mL of water was added, filtered, the cake was washed with ethyl acetate, and the filtrate was concentrated and purified by chromatography to obtain 852 mg of compound C29-4. Nuclear magnetic resonance analysis data of compound C29-4: 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.85-8.84 (d, 1H, J=2.03Hz), 8.27-8.24(dd, 1H, J=8.82Hz, 2.67Hz), 7.82-7.80 (d, 1H, J=4.21Hz), 2.74 (s, 3H), 2.43 (s, 3H), 1.27 (s, 9H).

[0279] 3.Synthesis of C29-5 Compound C29-4 (752 mg, 2.47 mmol) was dissolved in dry tetrahydrofuran (8 mL), cooled to -78°C, lithium tri-sec-butylborohydride (0.7 mL, 7.4 mmol, 1.0M) was added dropwise, and the reaction was allowed to proceed at -78°C for 1 h. The reaction was quenched by adding methanol (8 mL) at -60°C, diluted with water, extracted with ethyl acetate, the organic phase was dried, evaporated to dryness under reduced pressure, and subjected to column chromatography to obtain 578 mg of the product. Nuclear magnetic resonance analysis data of compound C29-5: 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.33 (s, 1H), 7.79-7.72(m, 2H), 4.62-4.58 (m, 1H), 2.42 (s, 3H), 1.53-1.51 (d, 3H, J=7.77Hz), 1.14 (s, 9H).

[0280] 4.Synthesis of C29-6 Compound C29-5 (200 mg, 0.65 mmol) was dissolved in DCM (1.6 mL) and methanol (0.5 mL), and 4M hydrochloric acid / dioxane (1.6 mL, 6.5 mmol) was added and reacted at room temperature for 3 h. When complete reaction was detected by LC-MS, the mixture was diluted with ethyl acetate, filtered, the cake was washed with ethyl acetate, and the cake was dried to obtain 129 mg of product. Nuclear magnetic resonance analysis data of compound C29-6: 1H NMR (400 MHz, MeOD-d4) δ 10.48 (s, 1H), 8.73 (s, 1H), 8.36-8.33 (dd, 1H, J=8.58Hz, 2.27Hz), 8.06-8.04 (d, 1H, J=8.58Hz), 4.72-4.68 (m, 1H), 2.63 (s, 3H), 1.71-1.69 (d, 3H, J=6.76Hz).

[0281] 5. Synthesis of C29 and C30 Compound C29-6 (100 mg, 0.42 mmol) and compound C3-19 (162 mg, 0.42 mmol) were dissolved in DMF (3 mL), diisopropylethylamine (0.55 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 5 min. HATU (238.5 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated to obtain 9 mg of compound C29 and 5 mg of compound C30. Nuclear magnetic resonance analysis data of compound C29: 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.61-8.59 (dd, 1H, J=4.26Hz, 1.72Hz), 8.36 (br, 1H), 7.84-7.82 (dd, 1H, J=8.88Hz, 1.86Hz), 7.75-7.73 (m, 2H), 7.31-7.27 (m, 2H), 7.06 (br, 1H), 6.84-6.82 (d,1H, J=8.52Hz), 5.83 (br,1H), 5.17-5.10 (m, 1H), 4.17-4.11 (m, 1H), 3.24 (s, 3H), 2.43(s, 3H), 2.25 (s, 3H), 2.15-1.79 (m, 8H), 1.52-1.50 (d, 3H, J=7.46Hz). Nuclear magnetic resonance analysis data of compound C30: 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.58-8.57 (dd, 1H, J=4.26Hz, 1.72Hz), 8.40-8.39 (d, 1H, J=2.13Hz), 7.83-7.70 (m, 3H), 7.37 (br, 1H), 7.29-7.26 (m, 2H), 6.74-6.72 (d,1H, J=7.81Hz), 5.80 (br,1H), 5.22-5.14 (m, 1H), 4.20-4.13 (m, 1H), 3.20 (s, 3H), 2.41(s, 3H), 2.33-2.25 (m, 2H), 2.23 (s, 3H), 2.16-2.13 (m, 2H), 1.95-1.90 (m, 2H), 1.78-1.70 (m, 2H), 1.52-1.50 (d, 3H, J=6.75Hz).

[0282] Example 18 Compounds synthesized in the present invention: [ka] The synthetic route and experimental steps are as follows. [ka]

[0283] 1.Synthesis of C31-2 Compound C31-8 (2.0g, 10 mmol) and trimethylsilylacetylene (1.7 mL, 12 mmol) were dissolved in dry THF (20 mL) and triethylamine (20 mL), followed by the addition of CuI (190 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium (580 mg, 0.5 mmol), and the mixture was heated to 30°C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2.1 g of compound C31-2. Nuclear magnetic resonance analysis data for compound C31-2: 1 H NMR (400 MHz, DMSO-d6) δ9.10-9.09(d, 1H, J=1.54Hz), 8.19-8.17(dd, 1H, J=8.29Hz, 2.14Hz), 7.56-7.53(dd, 1H, J=8.12Hz, 0.55Hz), 2.63(s, 3H), 0.28(s, 9H).

[0284] 2.Synthesis of C31-3 Compound C31-2 (1.0 g, 4.61 mmol) was dissolved in 20 mL of anhydrous methanol, and then anhydrous potassium carbonate (1.27 g, 9.21 mmol) was added and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed, the solution was diluted with ethyl acetate and filtered to remove potassium carbonate. The filtrate was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 605 mg of compound C31-3. Nuclear magnetic resonance analysis data for compound C31-3: 1 H NMR (400 MHz, DMSO-d6) δ9.13(s, 1H), 8.23-8.20(dd, 1H, J=7.79Hz, 1.56Hz), 7.60-7.58(d, 1H, J=8.18Hz), 3.34(s, 1H), 2.65(s, 3H).

[0285] 3.Synthesis of C31-5 CuI (63 mg, 0.33 mmol) was suspended in a mixed solvent of DMF (2 mL) and diisopropylethylamine (3 mL), and compound C31-3 (237 mg, 1.64 mmol) and compound C31-4 (422 mg, 3.27 mmol) were added in that order, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, it was diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 313 mg of compound C31-5. Nuclear magnetic resonance analysis data for compound C31-5: 1 H NMR (400 MHz, DMSO-d6) δ9.11-9.10(d, 1H, J=1.08Hz), 8.31-8.25(m, 2H), 8.08(s, 1H), 3.99(s, 2H), 2.64(s, 3H), 0.18(s, 9H).

[0286] 4.Synthesis of C31-6 Compound C31-5 (625 mg, 2.28 mmol) was dissolved in tetrahydrofuran (150 ml), and then 1M tetrabutylammonium fluoride in tetrahydrofuran solution (2.74 ml, 2.74 mmol) was added dropwise while cooling in an ice-water bath, and the mixture was stirred for 1 h while cooling in an ice-water bath. After the reaction was completed, the mixture was washed with saturated saline and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 363 mg of compound C31-6. Nuclear magnetic resonance analysis data for compound C31-6: 1 H NMR (400 MHz, DMSO-d6) δ9.13-9.12(d, 1H, J=0.89Hz), 8.33-8.27(m, 2H), 8.21(s, 1H), 4.20(s, 2H), 2.66 (s, 3H).

[0287] 5.Synthesis of C31-7 Compound C31-6 (490 mg, 2.43 mmol) and Rt-butylsulfinamide (309 mg, 3.64 mmol) were dissolved in dry tetrahydrofuran (20 mL), and then tetraethyl titanate (2.22 g, 9.72 mmol) was added. Under the protection of nitrogen gas, the mixture was heated to 80°C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, 2 mL of water was added, and filtered under reduced pressure. The filtrate was extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 575 mg of compound C31-7. Nuclear magnetic resonance analysis data for compound C31-7: 1 H NMR (400 MHz, DMSO-d6)δ9.06(s, 1H), 8.23-8.22(d, 2H, J=1.47Hz), 8.16(s, 1H), 4.18(s, 3H), 2.80(s, 3H), 1.33(s, 9H).

[0288] 6.Synthesis of C31-8 Compound C31-7 (575 mg, 1.89 mmol) was dissolved in dry tetrahydrofuran (30 mL), and under the protection of nitrogen gas, the temperature was lowered to -78 ° C, and 1M L-selectride in tetrahydrofuran solution (5.7 mL, 5.66 mmol) was added dropwise, and the mixture was stirred for 1 h while maintaining the temperature at -78 ° C. When the reaction was completed by TLC, methanol was added dropwise to quench the reaction, the mixture was warmed to room temperature, and diluted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 558 mg of compound C31-8. Nuclear magnetic resonance analysis data for compound C31-8: 1 H NMR (400 MHz, DMSO-d6) δ8.48(s, 1H), 8.09-8.04(m, 2H), 7.69-7.66(dd, 1H, J=8.12Hz, 1.48Hz), 4.60-4.57(q, 1H), 4.10(s, 3H), 1.53 (s, 3H), 1.15(s, 9H).

[0289] 7.Synthesis of C31-9 Compound C31-8 (498 mg, 1.62 mmol) was dissolved in a mixture of dioxane (3 mL) and anhydrous methanol (3 mL), and then a 4M solution of hydrochloric acid in dioxane (4.1 mL) was added. The mixture was stirred at room temperature for 2 h, and then methyl-t-butyl ether was added. The mixture was filtered and dried to obtain 295 mg of compound C31-9.

[0290] 8.Synthesis of C31 Compound C31-9 (10 mg, 0.04 mmol) and compound C3-19 (16 mg, 0.04 mmol) were dissolved in DMF (0.5 mL), diisopropylethylamine (44 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 5 min. HATU (24 mg, 0.06 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by high performance liquid chromatography to obtain 4 mg of compound C31. MS [M+H] 567.4.

[0291] Comparative Example 1 [ka] The synthetic route and experimental steps are as follows. [ka]

[0292] 1. Synthesis of C32-1 and C32-1A Compound C1-1 (6.92 g, 40 mmol), p-methoxybenzyl alcohol (6.07 g, 44 mmol), and THF (100 mL) were added to a 250 mL single-neck flask, and NaH (2.4 g, 60 mmol) was added separately at 0 °C, and the reaction was allowed to react at room temperature for 4 h. When LC-MS showed the reaction was complete, the reaction solution was poured into water (200 mL) with stirring, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 10.7 g of a mixture of compounds C32-1 and C32-1A.

[0293] 2. Synthesis of C32-2 and C32-2A A mixture of compounds C32-1 and C32-1A (8.22 g, 30 mmol), compound C1-3 (9.77 g, 33 mmol), Pd(PPh3)4 (3.47 g, 3 mmol), K2CO3 (8.28 g, 60 mmol), and dioxane / H2O (120 mL / 30 mL) were placed in a 250 mL single-neck flask, and the reaction was allowed to react overnight at 90 °C under N2 protection. When LC-MS showed the reaction was complete, the reaction solution was poured into water (300 mL) with stirring, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to give compound C32-2A (4.78 g) and compound C32-2 (7.54 g). Nuclear magnetic resonance analysis data of compound C32-2A: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.94 - 6.86 (m, 2H), 6.67 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 5.35 (s, 2H), 3.81 (s, 6H), 3.34 (s, 3H), 2.90 - 2.56 (m, 4H), 2.28 - 2.06 (m, 2H); Nuclear magnetic resonance analysis data of compound C32-2: 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.94 - 6.87 (m, 2H), 6.85 (dd, J = 4.6, 3.3 Hz, 1H), 5.46 (s, 2H), 3.81 (d, J = 1.4 Hz, 6H), 3.31 (s, 3H), 2.87 - 2.75 (m, 1H), 2.67 - 2.50 (m, 3H), 2.32 - 2.03 (m, 2H).

[0294] 3.Synthesis of C32-3 Compound C32-2 (1.0 g, 2.45 mmol), dichloromethane (6 mL), and trifluoroacetic acid (4 mL) were placed in a 10 mL reaction vessel and reacted at room temperature for 10 h. The vessel was then rotovapped, K2CO3(aq) was added, and the mixture was extracted three times with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (583 mg).

[0295] 4.Synthesis of C32-4 Compound C32-3 (703 mg, 2.4 mmol), toluene (5 mL), and POCl3 (10 mL) were placed in a 10 mL reactor and reacted at 110°C for 10 h. The mixture was then concentrated, a saturated aqueous solution of K2CO3 was added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (430 mg).

[0296] 5.Synthesis of C32-5 A 100 mL single-neck flask was charged with compound C32-4 (320 mg, 1.05 mmol), compound C1-17 (227 mg, 1.15 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), t-BuXPhos (89 mg, 0.21 mmol), KOAc (206 mg, 2.1 mmol), and dioxane (10 mL), and the reaction was allowed to react overnight at 90 °C under N2. When LC-MS showed the reaction was complete, it was concentrated under reduced pressure, the residue was taken up in ethyl acetate, the organic phase was washed with brine, and the organic phase was dried and concentrated to give the crude product. The crude product was subjected to column chromatography to give 290 mg of product.

[0297] 6.Synthesis of C32-6 A 50 mL single-neck flask was charged with compound C32-5 (1.81 g, 3.86 mmol), LiOH·HO (648 mg, 15.44 mmol), and THF / MeOH / HO (10 mL / 2 mL / 5 mL), and the reaction was allowed to react at 50 °C for 2 h. When LC-MS showed the reaction was complete, it was concentrated under reduced pressure to give 1.58 g of crude product.

[0298] 7. Synthesis of C32 Compound C32-6 (108 mg, 0.3 mmol), compound C1-7 (92 mg, 0.33 mmol), DMF (7 mL), and diisopropylethylamine (310 mg, 2.4 mmol) were added to a 50 mL single-neck flask and stirred at room temperature for 5 min. HATU (134 mg, 0.35 mmol) was added and reacted at room temperature for 30 min. When LC-MS showed the reaction was complete, the reaction solution was poured into water (20 mL), extracted three times with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, rotovapped, and subjected to column chromatography to obtain the crude product, which was then separated to obtain compound C32 (123 mg, purity: 95.7%), with [M+H]: 542.3. Nuclear magnetic resonance analysis data of compound C32: 1H NMR (400 MHz, CDCl3) δ 8.47 (t, J = 8.3 Hz, 1H), 8.38 (d, J = 4.6 Hz, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.5, 2.1 Hz, 1H), 7.59 (d, J = 4.3 Hz, 1H), 7.25 - 7.15 (m, 1H), 6.91 (dd, J = 7.9, 5.2 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 4.3 Hz, 1H), 5.19 (dd, J = 9.8, 4.8 Hz, 1H), 3.26 (d, J = 5.7 Hz, 3H), 3.08 - 2.44 (m, 4H), 2.40 (d, J = 2.1 Hz, 3H), 2.19 - 2.01 (m, 2H), 1.60 (d, J = 7.0 Hz, 3H).

[0299] Test Example 1 Enzyme activity test Hereinafter, biological activity measurement experiments were carried out on some of the compounds in the above Examples and Comparative Examples. The process of the biological activity measurement experiment is as follows. The compounds prepared in the examples were screened for their activity against wild-type RET kinase at ATP Km concentration using the kinase activity measurement method, and the biological activity of the compounds was repeatedly measured at 10 concentrations using Staurosporine as a control.

[0300] 1. Test sample Each sample was made into a solution with a concentration of 10 mM. 2. Experimental Method 1. Preparation of base and quenching buffer solutions for experimental kinase 20mM Hepes (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.02% Brij35, 0.02mg / ml BSA, 0.1mM Na3VO4, 2mM DTT, 1% DMSO. 2. Preparation of compounds for experimental kinases Test compounds were dissolved in 100% dimethylsulfoxide to the specified concentrations and (serial) dilutions were performed with DMSO in an Integra Viaflo Assist.

[0301] 3. Reaction process The kinase was placed in freshly prepared basal reaction buffer. The substrate solution contained any necessary cofactors. Wild-type RET kinase was added to the substrate solution and mixed gently. Compounds in 100% dimethylsulfoxide were delivered to the kinase reaction mixture using Acoustic technology (Echo550; nanoliter range) and incubated for 20 min at room temperature. The reaction was initiated by adding 33P-ATP (specific activity 10 Ci / l) to the reaction mixture. Incubated at room temperature for 2 hours. Radioactivity was detected by the filter-binding method. Kinase activity data are expressed as the percentage of remaining enzyme activity in the test samples compared to the vehicle (dimethylsulfoxide) reaction. IC50 values ​​and curve fitting were performed by Prism (GRAPHPAD software).

[0302] The obtained IC50 (nM) values ​​of the inhibitory activity of the test samples against wild-type RET are shown in Table 1. [Table 3]

[0303] From the above table, it can be seen that the in vitro bioactivity screening shows that the compounds synthesized in this application have excellent inhibitory ability against wild-type RET kinase, and are promising for development into drugs for regulating RET kinase activity or treating RET-related diseases, using Staurosporine as a control. And from the activity data of compound C7 and comparative example C32, it can be seen that the compound at the cyano group position has a large effect on the inhibitory activity against wild-type RET.

[0304] Test Example 2 Cell Antiproliferation Experiment 1. Experimental materials RPMI-1640 was purchased from BI. Fetal bovine serum was purchased from BI. CellTiter-GloR was purchased from Promega. Dimethyl sulfoxide (DMSO) was purchased from TCI. BaF3 cells were purchased from RIKEN BRC CELL BANK. Ba / F3-KIF5B-RET, Ba / F3-KIF5B-RET-V804L and Ba / F3-KIF5B-RET-V804M cells were constructed by Hefei Zhongke Pu Ruisheng Biopharmaceutical Technology Co., Ltd. Culture medium for Ba / F3-KIF5B-RET, Ba / F3-KIF5B-RET-V804L and Ba / F3-KIF5B-RET-V804M: RPMI-1640 + 10% FBS + 1% P / S. Microplate Reader: Molecular Devices

[0305] II. Experimental Method 1. Compound Dilution Prepare 1000x compound solutions in DMSO and dilute compounds to 20x final concentration in growth medium and add 2μl of 1000x cpd, 98μln growth medium. 2. Cell Inoculation The suspended cells were spun down and regenerated in growth medium before being counted in a cell counter. The cell suspension was diluted to the required concentration in growth medium. 95 μL of the cell suspension was transferred to a 96-well plate. 5 μL of 20× compound was added to the 95-well plate, resulting in a final DMSO concentration of 0.1% in each well. Incubated at 37°C, 5% CO2 for 72 h. 3. Measurement Prior to measurement, the measurement plate was equilibrated to room temperature and 50 μl of CellTiter-GloR reagent was added to each well, mixed on a shaker for 2 minutes, incubated at room temperature for 10 minutes, and recorded on a Paradigm.

[0306] 3. Data Analysis The cell activity was calculated by the formula: Cell activity (CV%)=(RLU compound-RLU blank) / (RLU control-RLU blank)×100% and analyzed by Graphpad 7.0 software, and the corresponding IC50 data was calculated and shown in Table 2. [Table 4] From Table 2, it can be seen that the compounds of the present invention, especially compounds C15 and C26, have good inhibitory effects on Ba / F3 (WT-RET, RET-V804L and RET-V804M).

[0307] Test Example 3 Drug metabolism test Four small molecule compounds, BLU-667, Compound C2, Compound C4 and Compound C8, were administered to SD rats via a single intravenous and intragastric administration, and blood samples were taken at different time points to measure the plasma drug concentrations of the rats administered the test substances and calculate the relevant pharmacokinetic parameters. 1. Preparation of test sample solutions The preparation of the test substance administration solution was completed by the School of Pharmacy of Soochow University. The preparation method is as follows: The solvent for the compounds numbered BLU-667, C2, C4, and C8 is 10% NMP + 49% PEG400 + 1% Tween80 + 40% water. The specific preparation method is to weigh out an appropriate amount of each test substance, dissolve it in 10% NMP + 49% PEG400 + 1% Tween80 + 40% water, and mix uniformly with a vortex to prepare for use.

[0308] 2. Analysis of the test product solution The prepared test sample solutions were detected and analyzed by the analytical department of this experimental facility using LC-MS / MS. 3. Animal Receipt and Acclimatization Healthy male SD rats were used in the study, with the animals weighing 150-200 g. All animals were fasted before dosing and were allowed to resume food intake 4 hours after dosing.

[0309] 4. Animal Drug Administration Dosing information is shown in Table 3. [Table 5]

[0310] 5. Sample Collection and Processing Blood collection time: Intravenous administration (groups 1, 3, and 5): 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. (The time points ≦2 hours are ±2 minutes, and the other time points are ±15 minutes.) Oral administration: (Groups 2, 4, 6, 7): 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. (The time points ≦2 hours are ±2 minutes, and the other time points are ±15 minutes.) Approximately 0.1 mL of blood was collected from each animal via the jugular vein each time and anticoagulated with EDTA or sodium heparin. After blood samples were collected, they were placed on ice and centrifuged to separate plasma (centrifugation conditions: 5000 rpm, 6 min, 4°C). Rat plasma samples were analyzed by LC-MS / MS by the analytical department of the experimental institution.

[0311] 6. Pharmacokinetic Analysis The pharmacokinetic parameters AUC of each test product were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin from the data of the drug's blood drug concentration. 0→t , AUC 0→∞ , MRT 0→∞ , C max , T max , Vss, F, CL and T 1 / 2 The average value and standard deviation were also calculated.

[0312] 7. Experimental Results The main pharmacokinetic parameters of BLU-667, Compound C2, Compound C4 and Compound C8 in plasma after administration of BLU-667, Compound C2, Compound C4 and Compound C8 by intravenous injection and single intragastric administration in SD rats are shown in Table 3. [Table 6]

[0313] From Table 3, it can be seen that the compounds of the present application have good drug metabolism, and in particular, compound C4 has a maximum blood drug concentration (Cmax) and a plasma exposure AUC that are increased by 3 to 4 times and 2 to 3 times compared to the control compound, so that the compounds of the present invention have better bioavailability and may be further developed as drugs for regulating RET kinase activity or treating RET-related diseases.

[0314] The above description is merely an embodiment of the present invention, which does not limit the scope of the patent of the present invention. Any equivalent transformation in the content of the specification of the present invention, or direct or indirect application in other related technical fields, is included in the scope of protection of the patent of the present invention.

Claims

1. A compound of formula I' or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 1】 (however, R 1 is a substituted or unsubstituted 5-6 membered heteroaryl group, the substitution being one or more R 2 is replaced by X 3 is NR 8 where R 8 is hydrogen, The W ring may be substituted or unsubstituted. 【Chemistry 2】 The substitution is 0 to 2 R 5 where X is replaced by 2 , X 7 , and X 8 are each independently N or CR 5 Selected from; Ring Q1 is selected from 3- to 7-membered saturated and unsaturated rings, and any hydrogen atom in ring Q1 may be substituted with a C1-C6 alkoxy group. Ring Q2 is selected from a 6-membered saturated, unsaturated, aromatic, or heteroaromatic ring, and may optionally contain 0 to 3 heteroatoms selected from N; X 5 is selected from C(O). X 6 CR 9 where R 9 is hydrogen R 2 is selected from hydrogen, C1 to C6 alkyl groups A is selected from a 6-membered heteroaromatic ring and may contain 1 to 3 heteroatoms, the heteroatoms being selected from N. R3 is a C1-C6 alkyl group R4 is a 5-membered heteroaryl group, said heteroaryl group independently having 0 to 5 R a can be substituted with R a is selected from a C1 to C6 alkyl group and a halogen. R 5 are each independently selected from hydrogen, a C1 to C6 alkyl group, and an oxo group. m is 1. n is 1.)

2. A compound having a structure represented by formula (3) or formula (4), or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 3】 (However, R 1 has the following structure: 【Chemistry 4】 R 2 , R 3 , R 4 , A, X 2 The definitions of ring Q1, ring Q2, and m are as defined in claim 1.

3. The W ring is 【Chemistry 5】 【Chemistry 6】 2. The compound of claim 1, wherein said compound of formula I' is selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. (however, 【Chemistry 7】 It may be a single bond or a double bond. R 12 is independently selected from H, a C1-C6 alkyl group. Each Y 1 , Y2 is independently N, CR 13 , N.R. 17 , C.R. 13 R 14 Selected from. R 13 , R 14 , R 15 , R 16 are each independently selected from H, a C1-C6 alkyl group, or R 13 and R 14 forms a carbonyl group (C=O) together with the C atom attached to it, or R 15 and R 16 forms a carbonyl group (C=O) together with the C atom attached to it. R 17 is selected from H and C1 to C6 alkyl groups.

4. 13. The compound of claim 1, having the structure represented by Formula 3', or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 8】 (however, 【Chemistry 9】 It may be a single bond or a double bond. 【Chemistry 10】 If it is a single bond, Y 4 is CR 17 and 【Chemistry 11】 If it is a double bond, Y 4 is C. Each R 17 is independently a C1 to C6 alkoxy group. f is 1. p is 2. R 1 , R 2 , R 3 , R 4 , A, m, X 2 , and Q2 are defined as in claim 1.)

5. 13. The compound of claim 1, having the structure represented by formula 4', or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 12】 (however, Y4 is C. Each R 17 is independently selected from a C1 to C6 alkoxy group. f is 1. p is 2. R 1 , R 2 , R 3 , R 4 , A, m, X 2 , and Q2 are defined as in claim 1.)

6. 2. The compound of claim 1, having a structure represented by formula 5' or 6', or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. 【Chemistry 13】 (However, X 2 , X 7 , X 8 , X 9 , X 10 are each independently N or CR 5 Selected from The definitions of R5 and ring Q2 are as defined in claim 1.

7. 2. The compound of claim 1 having a structure represented by Formula 4'', or a pharma- ceutically acceptable salt, or stereoisomer thereof. 【Chemistry 14】 (R 17 is a C1 to C6 alkoxy group. R 1 , X 2 , R 2 , R 3 , R 4 The definitions of A, Q2, and m are as set forth in claim 1.

8. 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. (However, R 4 teeth, 【Chemistry 15】 where R 18 is selected from halogen or a C1 to C6 alkyl group.

9. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof. (however, 【Chemistry 16】 where X 9 , X 10 are each independently N or CR 5 where R 5 are each independently selected from hydrogen and a C1 to C6 alkyl group.

10. A compound selected from the compounds represented by the following structure, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof: 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】

11. 11. The compound according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, wherein the pharma- ceutically acceptable salt is preferably an inorganic or organic acid salt, the inorganic acid salt being selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate, and the organic acid salt being selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, and a pharma- ceutically acceptable carrier.

13. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, in the manufacture of a medicament for a RET kinase inhibitor.

14. 13. Use of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, in the manufacture of a medicament for modulating the activity of RET kinase or for treating a RET-associated disease.

15. The use according to claim 14, characterized in that the RET-related disease is selected from cancer.

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