Compounds as RET kinase inhibitors and their applications

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically discloses a compound represented by Formula I', or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, wherein each symbol is as defined in the claims. The compound of the present invention can be used as a drug for regulating RET kinase activity or treating RET-related diseases, and has better pharmacokinetic properties. [Formula 1] JPEG2023525933000236.jpg75141

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical technology, specifically to compounds as RET kinase inhibitors and their application in modulating RET kinase activity or 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, and 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. RET mutations, which are common in people, mainly occur in various types of cancers such as thyroid cancer and non-small cell lung cancer. The incidence of RET gene fusions in NSCLC patients is 1%-2%, while the incidence of papillary thyroid cancer (accounting for about 85% of all thyroid cancers) is 10%-20%, and RET fusions are more prevalent in young patients, especially young non-smoking lung adenocarcinoma patients, with an incidence rate of 7%-17%. Current treatment plans for RET mutations primarily involve the use of multikinase inhibitor drugs such as cabozantinib and vandetanib, but these drugs are not highly targeted and typically suffer from severe toxicities associated with VEGFR inhibition due to off-target effects.

[0003] Blueprint and Loxo Oncology announced their in-house developed effective and selective oral RET inhibitors BLU-667 and LOXO-292. Blueprint Phase I clinical data results showed that BLU-667 demonstrated broad-spectrum antitumor activity with an overall response rate (ORR) of 45% in patients with RET fusion and mutation tumors, whereas ORR in non-small cell lung cancer and medullary thyroid cancer patients was 50% and 40%, respectively. Recently, the US FDA granted breakthrough therapy designation to Loxo Oncology's investigational drug LOXO-292 for the treatment of patients with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) harboring RET gene mutations.

[0004] Therefore, the development of new compounds with RET kinase inhibitory activity and better pharmacodynamic and pharmacokinetic performances has become an important research project for the development of new antitumor drugs, which will eventually be used to treat human tumors and other diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides new compounds with RET kinase inhibitory activity, better pharmacodynamics and pharmacokinetic performance. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound as a RET kinase inhibitor, said compound being of formula I' or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof: [ka] Where: R1 is a substituted or unsubstituted 5- to 6-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, the substitution being optionally substituted by one or more R2; X3 is O, NR8, CR9R10 , [ka] wherein R 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 halogenated alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halogenated cycloalkyl 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 halogenated 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, a C3-C6 halogenated cycloalkyl group, an aryl group, a heteroaryl group, an aryloxy group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group; W ring is a substituted or unsubstituted heterocyclylene group or heteroarylene group, the substitution optionally referring to substitution with 0 to 2 R5; Ring Q1 is arbitrarily selected from a 3-7 membered saturated ring, an unsaturated ring, an aromatic ring, a heteroaryl ring, a spiro ring or a bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S; any hydrogen atom on ring Q1 may be substituted by a substituent such as deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl 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; X5 is C(O), S(O), S(O)2, [ka] is selected from X6 is selected from CR9, N, and O; R2 is arbitrarily 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, each of which, independently, is optionally selected from 0 to 5 R a is replaced by A is arbitrarily selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S; any hydrogen atom on the A ring may be substituted by a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, C1-C6 halogenated alkyl 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; R3 is arbitrarily 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, each of which, independently, is optionally selected from 0 to 5 R a is replaced by R4 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, halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aryloxy 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, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C6 each of the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylamino group, the heteroalkyl group, the cycloalkyl group, the aryl group, the heteroaryl group, the aryloxy group, the aralkyl group, the heterocyclyl group and the heterocycloalkyl group is independently selected from 0 to 5 R a is replaced by R5 are each independently selected from hydrogen, deuterium, 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 aryloxy 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, -(C and each of the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylamino group, the heteroalkyl group, the cycloalkyl group, the aryl group, the heteroaryl group, the aryloxy group, the aralkyl group, the heterocyclyl group, and the heterocycloalkyl group is independently selected from 0 to 5 R a is replaced by 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 aryloxy group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group; R a is arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl 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; m is 0, 1, 2, 3, 4, 5 or 6; n is 0 or 1, The limitation is that when ring W is a substituted or unsubstituted 6-membered heteroaryl group, ring W is substituted by X4, where X4 is CN, [ka] is selected from Q1 is bonded to ring W only via carbon atoms on the Q1 ring.

[0007] In another preferred example, the W ring is a substituted or unsubstituted group such as a 5- to 6-membered monocyclic heterocyclylene group, an 8- to 10-membered bicyclic heterocyclylene group, a 5- to 6-membered monocyclic heteroarylene group, or an 8- to 10-membered bicyclic heteroarylene group, and the substitution refers to optional substitution with 0 to 2 R5, and R5 is each independently hydrogen, deuterium, 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 aryloxy 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), each of which, independently, is selected from alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocycloalkyl groups, each of which is selected from 0 to 5 R a is replaced by R ais arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl 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.

[0008] 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; R5 is independently selected from hydrogen, deuterium, 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, and each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group is independently selected from 0 to 5 R a is replaced by R ais arbitrarily selected from a C1-C6 alkyl group, a halogen, a hydroxyl 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 arbitrarily selected from a five-, six-, or seven-membered saturated ring, an unsaturated ring, an aromatic ring, a heteroaryl ring, a spiro ring, or a bridged ring, and may contain 0 to 3 heteroatoms, the heteroatoms being arbitrarily selected from N, O, and S; any hydrogen atom on ring Q2 may be deuterium, hydrochloride, or aryl; It can be substituted by a substituent such as an xyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 alkyl hydroxyl group, a C1-C6 halogenated alkyl 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] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure as shown in formula (II), formula (III) or formula (IV): [ka] Where: A is optionally selected from a 3-7 membered saturated, unsaturated, aromatic, heteroaryl, spiro or bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being selected from N, O and S; Ring Q1 is arbitrarily selected from 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S; any hydrogen atom on ring Q1 may be replaced by a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, C1-C6 halogenated alkyl 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 bonded to ring B only through the carbon atom on ring Q1; R1 is selected from one of the following structures: [ka] R2 is arbitrarily selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, each of which is optionally and independently selected from 0 to 5 R a is replaced by R3 is arbitrarily 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, each of which is optionally and independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group; X1 and X2 are each independently selected from N or CR5; X3 is O, NR8, CR9R 10 , [ka] wherein R 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 halogenated alkyl group, a C1-C6 heteroalkyl group, a C3-C6 cycloalkyl group, a C3-C6 halogenated cycloalkyl 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 halogenated 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, a C3-C6 halogenated cycloalkyl group, an aryl group, a heteroaryl group, an aryloxy group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group; X4 is CN, [ka] is selected from X5 is C(O), S(O), S(O)2, [ka] is selected from X6 is selected from CR9, N, and O; R4 and R5 each independently represent hydrogen, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aryloxy 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, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C and each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocycloalkyl groups is independently selected from 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 aryloxy group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group; Ring Q2 is optionally selected from a 5-, 6- or 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, and the heteroatoms are optionally selected from N, O and S. Any hydrogen atom on ring Q2 may be substituted by a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, C1-C6 deuterated alkyl group, C1-C6 alkylhydroxyl group, C1-C6 halogenated alkyl 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; m is 0, 1, 2, 3, 4, 5 or 6; n is 0 or 1.

[0010] In another preferred example, X3 is NR8, wherein R8 is H.

[0011] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has a structure as shown in formula (2), formula (3) or formula (4): [ka] Where: A is optionally selected from a 3-7 membered saturated, unsaturated, aromatic, heteroaryl, spiro or bridged ring and may contain 0-3 heteroatoms, the heteroatoms being optionally selected from N, O and S; Ring Q1 is arbitrarily selected from a 3-7 membered saturated ring, an unsaturated ring, an aromatic ring, a heteroaryl ring, a spiro ring or a bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S; any hydrogen atom on ring Q1 may be replaced by a substituent such as deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl 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 formula (2), Q1 is bonded to ring B only via the carbon atom on ring Q1; R1 is selected from one of the following structures: [ka] R2 is arbitrarily selected from hydrogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a C1-C6 heteroalkyl group, each of which is optionally and independently selected from 0 to 5 R a is replaced by R3 is arbitrarily 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, each of which is optionally and independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group; X1 and X2 are each independently selected from N or CR5; R4 and R5 each independently represent hydrogen, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a halogen, a C1-C6 heteroalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aryloxy 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, -SR6, -S(O)2R6, -S(O)2-N(R6)(R7), -(C1-C6 alkylene)-S(O)2R6, -(C1-C and each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocycloalkyl groups is independently selected from 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 aryloxy group, an aralkyl group, a C3-C6 heterocycloalkyl group, a C1-C6 alkylamino group, and a C3-C6 cycloalkylamino group; Ring Q2 is optionally selected from a 5-, 6- or 7-membered saturated ring, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, and the heteroatoms are optionally selected from N, O and S. Any hydrogen atom on ring Q2 may be substituted by a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, C1-C6 deuterated alkyl group, C1-C6 alkylhydroxyl group, C1-C6 halogenated alkyl 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; m is 0, 1, 2, 3, 4, 5 or 6.

[0012] In another preferred embodiment, in the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the W ring is [ka] is selected from the group consisting of Where: [ka] is a single or double bond, R 12 are independently selected from H, deuterium, 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; Each Y1, Y2, and Y3 is independently O, N, or NR 17 , C.R. 13 , C.R. 13 R 14 is selected from R 13 , R 14 , R 15 , R 16are each independently selected from H, halogen, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, a halogenated 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 to which it is attached, or R 15 and R 16 forms a carbonyl group (C=O) together with the C atom to which it is attached, R 17 is selected from H, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, and a halogenated C1-C6 alkyl group.

[0013] In another preferred embodiment, the W ring is [ka] is selected from.

[0014] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2': [ka] Where: [ka] is a single or double bond, Each R 17 are independently selected from deuterium, halogen, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl 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 as defined above.

[0015] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 2'', [ka] Where: R1, R2, R3, R4, A, m, X1, X2 and R 17 is as defined above. In another preferred embodiment, [ka] Selected from R 12 is as defined above. In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3': [ka] Where: [ka] is a single or double bond, [ka] is a single bond, Y4 is N or CR 17 is selected from [ka] is a double bond, Y4 is C; Each R 17are independently selected from deuterium, halogen, a hydroxyl group, an amino group, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, a C1-C6 halogenated alkyl 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, 3; X2, Q2, R1, R2, R3, R4, A and m are as defined above.

[0016] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'', [ka] R1, X2, R2, R3, R4, A, Q2, m and R 17 is as defined above.

[0017] In another preferred embodiment, [ka] part is, [ka] is selected from Where: [ka] is a single or double bond, Y1, Y2, Y3, R 12 , R 13 , R 14 , R 15 and R 16 is as defined above.

[0018] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4': [ka] Where: [ka] is a single or double bond, [ka] is a single bond, Y4 is N or CR 17 is selected from [ka] is a double bond, Y4 is C; Each R 17 are independently selected from deuterium, halogen, a hydroxyl group, an amino group, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, a C1-C6 halogenated alkyl 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, 3; X2, Q2, R1, R2, R3, R4, A and m are as defined above.

[0019] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4'', [ka] R1, X2, R2, R3, R4, A, Q2, m and R 17 is as defined above.

[0020] In another preferred embodiment, [ka] part is, [ka] where Q2 is as defined above.

[0021] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5 or formula 6: [ka] Here, R1, X7, X8, X2, Q2, R2, R3, R4, R 17 , A and m are as defined above, and at least one of X7 and X8 is N.

[0022] In another preferred example, in the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, A is an aromatic ring, a heteroaryl ring, the heteroaryl ring contains 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S, and any hydrogen atom on the A ring can be substituted by a substituent such as deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl 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.

[0023] In another preferred example, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group, and any hydrogen atom on the A ring can be substituted with a substituent such as deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl 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.

[0024] In another preferred embodiment, in the compound of formula I′, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, R4 is independently selected from an aryl group, a heteroaryl group, an aryloxy group, an aralkyl group, and a heterocyclyl group, wherein each aryl group, heteroaryl group, aryloxy 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 hydroxyl 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.

[0025] In another preferred example, R4 is a 5-membered heteroaryl group, and the heteroaryl group independently comprises 0 to 5 R a can be replaced by R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxyl 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.

[0026] In another preferred embodiment, R4 is [ka] where R 18 is selected from halogen (preferably F), and C1 to C6 alkyl groups.

[0027] In another preferred embodiment, m is 1. In another preferred example, R3 is H, a C1-C6 alkyl group, or a C1-C6 alkoxy group. In another preferred embodiment, R2 is H.

[0028] 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 example, 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.

[0029] In another preferred embodiment, [ka] part is, [ka] where X9, X 10 are each independently selected from N or CR5, where R5 is each independently arbitrarily 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, among which 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 hydroxyl 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.

[0030] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5' or 6': [ka] Here, X2, X7, X8, X9, X 10 are each independently selected from N or CR5, and at least one of X7 and X8 is N; R5 is independently selected from hydrogen, deuterium, 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, and each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group is independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl 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, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, and the heteroatoms are optionally selected from N, O and S. Any hydrogen atom on ring Q2 may be substituted with a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, deuterated C1-C6 alkyl group, C1-C6 alkylhydroxyl group, C1-C6 halogenated alkyl 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.

[0031] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5': [ka] Where: [ka] part is, [ka] where: [ka] is a double bond, and each of Y1, Y2, and Y3 is independently N, NR 17 , C.R. 13 is selected from R 12 are independently selected from H, deuterium, 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; R 17are independently selected from deuterium, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, and a C1-C6 halogenated alkyl group; R 13 is selected from H, halogen, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a nitro group, a cyano group, and an amino group; X9, X 10 are each independently CR5; R5 is selected from hydrogen, deuterium, 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, a nitro group, a cyano group, and an amino group, and each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group is independently selected from 0 to 5 R a is replaced by R a is selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl 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.

[0032] In another preferred embodiment, [ka] part is, [ka] are selected from Y1, Y2, Y3, R 12 is as defined above.

[0033] In another preferred embodiment, in formula 5′, X 10 are all CH.

[0034] In another preferred example, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be any compound selected from those shown in the following structure: [ka] [ka] [ka] [ka] [ka]

[0035] In another preferred embodiment, the compound has the structure shown in formula I: [ka] Where: R'1 is arbitrarily selected from hydrogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a C1-C6 heteroalkyl group, and a 3-6 membered heterocyclyl group, wherein the alkyl group, the deuterated alkyl group, the alkoxy group, the alkylamino group, the cycloalkyl group, the heteroalkyl group, and the heterocyclyl group are optionally and independently selected from 0 to 5 R a is replaced by A is arbitrarily selected from a 3-7 membered saturated ring, unsaturated ring, aromatic ring, heteroaryl ring, spiro ring or bridged ring, and may contain 0-3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S; any hydrogen atom on the A ring may be substituted by a substituent such as deuterium, hydroxyl group, halogen, cyano group, ester group, amide group, ketocarbonyl group, amino group, C1-C6 alkyl group, C1-C6 halogenated alkyl 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; R a is arbitrarily selected from a C1 to C6 alkyl group, a halogen, a hydroxyl group, an amino 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.

[0036] In another preferred example, the A ring is selected from a substituted or unsubstituted 5- to 6-membered heteroaryl group, wherein any hydrogen atom on the A ring can be independently substituted by a substituent selected from a C1-C6 alkyl group, a halogen, a hydroxyl group, an amino 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.

[0037] In another preferred example, the A ring is selected from a substituted or unsubstituted imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group, wherein any hydrogen atom on the A ring can be independently substituted by a C1-C6 alkyl group, a halogen, a hydroxyl group, an amino 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.

[0038] In another preferred embodiment, the compound has the structure shown in formula II-1 or formula III-1: [ka] Where: [ka] represents a single or double bond, X'1 and X'2 are each independently selected from N or CR5; X'3 and X'4 are each independently selected from N or S; 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, and each of the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylamino group, heteroalkyl group, and cycloalkyl group is independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from a C1-C6 alkyl group, a halogen, a hydroxyl group, an amino 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; R'1 is as defined above.

[0039] In another preferred example, X'1 is N and X'2 is CH. In another preferred example, X'1 and X'2 are all CH. In another preferred embodiment, the A ring is [ka] is a substituted or unsubstituted group from the group consisting of Here, the substitution refers to substitution with one or more groups selected from the group consisting of a C1 to C6 alkyl group, a halogen, a hydroxyl group, an amino 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.

[0040] In another preferred embodiment, the A ring is [ka] and the like, Here, the substitution refers to substitution with one or more groups selected from the group consisting of a C1 to C6 alkyl group, a halogen, a hydroxyl group, an amino 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.

[0041] In another preferred embodiment, [ka] teeth, [ka] It is.

[0042] In another preferred example, R'1 is selected from H, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 halogenated alkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclyl group, a C1-C6 heteroalkyl group, a C1-C6 alkyl hydroxyl group, a C3-C6 halogenated cycloalkyl group, Me3SiCH2CH2OCH2-, a C3-C6 cycloalkylCH2-, and a 3-6 membered heterocycleCH2-.

[0043] In another preferred embodiment, the compound may be selected from the compounds shown in the following structures: [ka] [ka]

[0044] In another preferred embodiment, the compound may be selected from the compounds shown in the following structures: [ka] [ka]

[0045] In another preferred embodiment, R'1 and the A ring are specific groups corresponding to each specific compound in the Examples. In another preferred embodiment, the compound is selected from the compounds shown in the examples.

[0046] In another preferred embodiment, the compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the pharma- ceutically acceptable salt is an inorganic acid salt or an organic acid salt, and the inorganic acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a bisulfate, a nitrate, a phosphate, an acid phosphate, or an aryl phosphate. phosphate, and the organic acid salt is 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.

[0047] A second aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharma- ceutically acceptable vector.

[0048] 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, HLX 10 , BAT1306, AK105, LZM009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR 1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (e.g., Rituximab, Obinutuzumab, Ofatumumab, Tosilimumab, Tilimumab, etc.), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors agents (e.g., ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (e.g., Aidelaris, dactolisib, taselisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, alabrutinib, etc.), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, etc.), VEGFR inhibitors (e.g., sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib, etc.), sunitinib, donafenib, etc.), HDAC inhibitors (e.g., givinostat, droxinostat, entinostat, dasilast, tecdinaline, etc.), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib, lerociclib, etc.), MEK inhibitors (e.g.,Selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (e.g., MK-2206, Ipatasertib, Capivasertib, Afuresertib, Up The inhibitor is selected from among an mTOR inhibitor (e.g., Vistusertib, etc.), an SHP2 inhibitor (e.g., RMC-4630, JAB-3068, TNO155, etc.), an IGF-1R inhibitor (e.g., Ceritinib, Okatinib, Linsitinib, BMS-754807, GSK1838705A, etc.), or a combination thereof.

[0049] A third aspect of the present invention provides the use of a compound according to the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in the preparation of a RET kinase inhibitor medicament.

[0050] A fourth aspect of the present invention provides the use of a compound according to the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in the preparation of a medicament for modulating RET kinase activity or treating a RET-related disease.

[0051] In another preferred embodiment, there is provided a use of a compound according to the first aspect, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, for use in the preparation of i) a medicament which is a RET kinase inhibitor, or ii) a medicament for modulating RET kinase activity or treating a RET-related disease.

[0052] 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.

[0053] A fifth aspect of the present invention provides a method of treating a RET-associated disease, said method comprising administering to a subject identified or diagnosed as having a RET-associated disease a therapeutically effective amount of a compound according to the first aspect or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the second aspect.

[0054] In a sixth aspect of the invention, the present invention provides a method for inhibiting RET kinase activity in a cell or a subject, said method comprising contacting said cell or administering to said subject a compound or pharmaceutical composition as described above. In another preferred embodiment, the cell is a mammalian cell. In another preferred embodiment, the subject is a mammal, preferably a human.

[0055] A seventh aspect of the invention provides a method for preparing a compound of formula I, comprising: [ka] s3) In an inert solvent, in the presence of a condensing agent, [ka] of [ka] to obtain a compound of formula I, In the formula, R'1 and A are as defined above.

[0056] In another preferred embodiment, the method further comprises: Method one: [ka] s'1) In an inert solvent, in the presence of a base, a catalyst and a ligand, [ka] and [ka] By reacting with [ka] and s'2) Under hydrogen gas atmosphere [ka] is reduced and then reacted with a halogenated or trifluoromethanesulfonic anhydride to give an intermediate, which is reacted in the presence of a base [ka] React with [ka] and Method two: [ka] s''1) in an inert solvent, in the presence of a base, [ka] React with [ka] and s''2) In an inert solvent, in the presence of a base, a catalyst and a ligand, [ka] and [ka] By reacting with [ka] Then, under a hydrogen gas atmosphere, [ka] By reducing [ka] and obtaining the In the formula, G and G' are each independently a halogen (e.g., Cl, Br), R'1 is as defined above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] After extensive and thorough research, the present inventors have unexpectedly discovered a compound with better RET kinase inhibitory activity. Moreover, the compound has a better inhibitory activity against RET kinase and also has better pharmacodynamics / pharmacokinetic performance. Based on this, the present invention has been completed.

[0058] term Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. Where a substituent is depicted by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0059] "Alkyl group (alone or as part of another group)" refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms, composed exclusively of carbon and hydrogen 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 group, ethyl group, propyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, n-hexyl group, octyl group, dodecyl group, and the like. In this application, alkyl group is further intended to include substituted alkyl groups, i.e., one or more positions of the alkyl group are substituted, and in particular, 1 to 4 substituents can be substituted at any position. "Halogenated alkyl group" refers to an alkyl group, as defined herein, in which one or more hydrogens are replaced by the same or different halogens. Examples of halogenated alkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

[0060] An "alkylene group" refers to a divalent radical of an alkyl group, such as -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0061] An "alkoxy group (alone or as part of another group)" refers to an alkyl group having an alkylO- structure with an oxy group attached thereto, where the alkyl group has the definition set forth above, and preferably the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy groups, and the like. A "halogenated alkoxy group" refers to a group of the formula -OR, where R is a halogenated alkyl group as defined herein. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy groups, and the like.

[0062] A "thioalkyl group" refers to an alkyl group in which carbon is substituted with S, S(O), or S(O)2.

[0063] "Alkenyl group (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl group" refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl group, propenyl group, butenyl group, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl groups include substituted alkenyl groups.

[0064] An "alkenylene group" refers to an alkenyl group that has two points of attachment. For example, a "vinylidene group" refers to the group -CH=CH-. An alkenylene group can also be unsubstituted or substituted with one or more substituents.

[0065] An "alkynyl group (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, usually 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 groups, propargyl groups, and 3-hexynyl groups. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent. In the present invention, alkynyl groups further include substituted alkynyl groups.

[0066] An "alkynylene group" refers to an alkynyl group that has two points of attachment. For example, an "ethynylene group" refers to the group -C≡C-. Alkynylene groups can also be unsubstituted or substituted with one or more substituents.

[0067] "Aliphatic group" refers to a straight-chain, branched-chain, or cyclic hydrocarbon group, including saturated and unsaturated groups, such as alkyl, alkenyl, and alkynyl groups. "Aromatic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0068] "Aryl group (alone or as part of another group)" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems such as phenyl, naphthyl and anthracenyl groups, as well as ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, 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 is further intended to include substituted aryl groups.

[0069] An "arylalkyl group" or "aralkyl group" refers to an alkyl moiety in which one or more of the alkyl hydrogen atoms have been replaced by an aryl group. Aralkyl groups include groups in which one or more of the hydrogen atoms have been replaced by an aryl group, with the aryl and alkyl groups having the definitions given above. Examples of "arylalkyl groups" or "aralkyl groups" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

[0070] An "aryloxy group" refers to an --O-(aryl) group, where the aryl portion is as defined herein.

[0071] "Heteroalkyl group" refers to a substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, Si, or combinations thereof. Numerical ranges may be given, e.g., C1-C6 heteroalkyl group refers to the number of carbons in the chain containing 1 to 6 carbon atoms. For example, the group -CH2OCH2CH3 is referred to as a "C3" heteroalkyl group. Bonding to the remainder of the molecule can be through a heteroatom or carbon in the heteroalkyl group chain. Examples of "heteroalkyl groups" include, but are not limited to, CHOCH3, CH2CHOCH3, CH2NHCH3, CH2CH2NHCH3, Me3Si, Me3SiCH2CH2O-, Me3SiCH2CH2OCH2- (SEM). "Heteroalkylene group" refers to an optionally substituted divalent alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, Si, or combinations thereof.

[0072] "Carbocyclic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but none of the rings is aromatic.

[0073] The term "carbocyclyl group" refers to a monovalent group of a carbon ring system, including, for example, cycloalkyl groups (such as cyclopentyl group, cyclobutyl group, cyclopropyl group, cyclohexyl group, etc.) and cycloalkenyl groups (such as cyclopentenyl group, cyclohexenyl group, cyclopentadienyl group, etc.).

[0074] "Cycloalkyl group" refers to a monovalent saturated carbocyclyl group consisting of a monocyclic or bicyclic ring having 3 to 12, preferably 3 to 10, more preferably 3 to 6 ring atoms. The cycloalkyl group can be optionally substituted with one or more substituents, where each substituent is independently a hydroxyl group, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, an amino group, a monoalkylamino group, or a dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0075] "Cycloalkoxy group" refers to a group of formula -OR, where R is a cycloalkyl group, as defined herein. Exemplary cycloalkyloxy groups include cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, and the like. "Cycloalkylalkyl group" refers to a -(cycloalkyl)-alkyl group, where the cycloalkyl group and alkyl group are as disclosed herein. A "cycloalkylalkyl group" is attached to the parent molecular structure through a cycloalkyl group.

[0076] "Heteroaryl ring system" refers to a monocyclic (e.g., 5 or 6 membered), bicyclic (6-12 membered) or polycyclic system in which at least one ring is aromatic and contains at least one heteroatom (e.g., N, O or S), and in which none of the other rings are heterocyclyl groups (as defined below). In certain cases, a ring that is aromatic and contains a heteroatom contains 1, 2, 3 or 4 ring heteroatoms in the ring, at least one of which is heteroaromatic, and the remaining rings can be saturated, partially unsaturated or fully unsaturated.

[0077] 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 ring heteroatom, including 1, 2, or 3 selected from N, O, or S, and in which the main ring atom is a C aromatic ring, it is understood that the point of attachment of the heteroaryl group is located on the aromatic ring. Examples of heteroaryl groups include an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyrazinyl group, a thienyl group, a furyl group, a pyranyl group, a pyridyl group, a pyrrolyl group, a pyrazolyl group, a pyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a benzofuranyl group, a benzofuryl group, a benzothienyl group, a benzothiopyranyl group, a benzimidazolyl group, group, benzoxazolyl group, benzoxadiazolyl group, benzothiazolyl group, benzothiadiazolyl group, benzopyranyl group, indolyl group, isoindolyl group, triazolyl group, triazinyl group, quinoxalinyl group, purinyl group, quinazolinyl group, quinazinyl groupThese include, but are not limited to, a heteroaryl group, a naphthyridinyl group, a pteridinyl group, a carbazolyl group, an azalidene group, a diazepinyl group, an acridinyl group, etc. A heteroarylene group refers to a heteroaryl group having two binding sites.

[0078] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom. The heterocyclic ring system can be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted.

[0079] "Heterocyclyl group" refers to a monovalent radical of a stable monocyclic (e.g., 3-8 membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered) or bicyclic (e.g., 5-12 membered, i.e., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) or polycyclic (e.g., 7-14 membered, i.e., 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) heterocyclic ring system, usually containing fused, spiro, and / or bridged ring structures, which is saturated, partially unsaturated, and which contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.Representative heterocyclyl groups include: (1) ring systems in which each ring is non-aromatic and at least one ring contains a heteroatom, such as, for example, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothienyl group, pyrrolidinyl group, pyrrolidinyl group, piperidinyl group, pyrrolinyl group, decahydroquinolinyl group, oxazolidinyl group, piperazinyl group, dioxanyl group, dioxanyl oxolane group, diazepine group, oxazepine group, thiazepine group, and the like. (2) ring systems in which at least one ring is non-aromatic and contains a heteroatom and at least one other ring is an aromatic carbocyclic ring, such as the 1,2,3,4-tetrahydroquinolinyl group, the 1,2,3,4-tetrahydroiso ... (3) ring systems in which at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, such as ring systems such as 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthalene. A heterocyclylene group refers to a heterocyclyl group having two binding sites.In the present invention, the heterocyclylene group is preferably a bicyclic group, one of which is a heteroaryl group and is bonded to another part of the general formula via the heteroaryl group. In the present invention, the heterocyclylene group is preferably a 5- to 6-membered monocyclic heterocyclylene group or an 8- to 10-membered bicyclic heterocyclylene group.

[0080] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, where the heterocyclyl and alkyl groups are defined above. An "alkylamino group" refers to a group having the structure alkyl-NR-, where R is H or an alkyl, cycloalkyl, aryl, heteroaryl, or other group as described above.

[0081] "Cycloalkylamino group" refers to a group of formula -NRaRb, where Ra is H, an alkyl group as defined herein or a cycloalkyl group as defined herein, Rb is a cycloalkyl group as defined herein, or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclyl group, such as a tetrahydropyrrolyl group. As used herein, a C3-C8 cycloalkylamino group refers to an amino group containing 3 to 8 carbon atoms.

[0082] As used herein, an "ester group" refers to 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.

[0083] In the present invention, the term "amide group" refers to a group having the structure -CONRR', where R and R' can independently represent hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, an aryl group or a substituted aryl group, a heterocycle or a substituted heterocycle, as defined above. R and R' can be the same or different in a dialkylamine moiety.

[0084] In the present invention, the term "sulfonamide group" refers to a group having the structure -SONRR', where R and R' can independently represent hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, an aryl group or a substituted aryl group, a heterocycle or a substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0085] A "ketocarbonyl group" refers to RC(=O)--, where R is an alkyl group, cycloalkyl group, etc. as defined above. When a substituent is a non-terminal substituent, it is the corresponding subunit, e.g., an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclyl group corresponds to a heterocyclylene group, and an alkoxy group corresponds to an alkyleneoxy.

[0086] In the present invention, each of the above-mentioned alkyl groups, alkoxy groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, cycloheteroalkyl groups, alkenyl groups, alkynes, heterocycles, heterocyclyl groups, etc. may be substituted or unsubstituted.

[0087] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituents are the corresponding substituents described above or the substituents appearing in each example. Unless otherwise specified, a substituted group can have one substituent selected from the specific groups at any substitutable position of the group, and the substituents can be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are those stable or chemically feasible combinations. Exemplary substitutions include hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents such as trifluoromethyl or alkyl groups including Cl), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc , NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, where R acan independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring, Rb, Rc, and Rd can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring, or an aromatic ring, or Rb and Rc can form a heterocyclic ring together with the N atom, and Re can independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring. The above typical substituents such as alkyl groups, cycloalkyl groups, alkenyl groups, cycloalkenyl groups, alkynyl groups, heterocyclic rings, or aromatic rings can be optionally substituted. The substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3-12 membered heterocyclyl groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amine groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureido groups.

[0088] "Cyano" refers to the radical -CN. A "nitro group" refers to --NO.sub.2. "Hydroxyl group" refers to -OH. An "amino group" refers to -NH2 or RNH-, where R is a ketocarbonyl group, a sulfonyl group, a sulfonamide group, R a -C(=O)-, R a R b NC(=O)-, etc., where R a and R b is an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like.

[0089] "Halogen (halogenated)" refers to any halogen radical, such as -F, -Cl, -Br, or -I. "Deuterated" refers to the compound obtained after a hydrogen atom (H) or multiple hydrogen atoms (H) in a compound are replaced by a deuterium atom (D). In the present invention, the term "plurality" refers independently to 2, 3, 4, 5.

[0090] Active ingredient As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably and refer to a compound of Formula I', or a pharma- ceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound), or prodrug thereof. The terms further include isomers, such as chiral isomers.

[0091] The compound of formula I' has the following structure: [ka] R1, X3, W, Q1, X5, X6, R2, R3, R4, A, m and n are as defined above. Preferably, the W ring is a substituted or unsubstituted group such as a 5-6 membered monocyclic heterocyclylene group, an 8-10 membered bicyclic heterocyclylene group, or a 5-6 membered monocyclic heteroarylene group or an 8-10 membered bicyclic heteroarylene group, the substitution referring to optional substitution by 0-2 R5, each R5 being independently hydrogen, deuterium, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, halogen, C1-C6 heteroalkyl group, cycloalkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, heterocyclyl group, heterocycloalkyl group, nitro group, oxo group, cyano group, -C(O)R6, -O C(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)-S(O)2-N(R6)(R7), each of the alkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocycloalkyl groups independently represents 0 to 5 R a is replaced by R a is arbitrarily selected from deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl 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, the W ring is [ka] wherein X1, X2, X7, X8, and Q2 are as defined above, and at least one of X7 and X8 is N.

[0092] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula (II), formula (III) or formula (IV): [ka] where R1, X1, X2, X3, Q1, Q2, X5, X6, R2, R3, R4, A, m and n are as defined above. Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula (2), formula (3) or formula (4): [ka] Here, R1, X1, X2, Q1, Q2, R2, R3, R4, A and m are as defined above.

[0093] Preferably, in the above compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, it has the structure shown in formula 2': [ka] Where: [ka] is a single or double bond, X1, X2, R1, R2, R3, R4, A, R 17 , f and m are as defined above.

[0094] Preferably, in the above compound, or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, it has the structure shown in formula 2″: [ka] Where: X1, X2, R1, R2, R3, R4, A, m and R 17 is as defined above.

[0095] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3': [ka] Where: [ka] is a single or double bond, [ka] is a single bond, Y4 is N or CR 17 is selected from [ka] is a double bond, Y4 is C; R1, X2, R2, R3, R4, R 17 , A, m, f, p and Q2 are as defined above.

[0096] In another preferred embodiment, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 3'', [ka] R1, X2, R2, R3, R4, A, Q2, m and R 17 is as defined above. Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4': [ka] Where: [ka] is a single or double bond, [ka] is a single bond, Y4 is N or CR 17 is selected from [ka] is a double bond, Y4 is C; R1, X2, R2, R3, R4, R 17 , A, m, f, p and Q2 are as defined above.

[0097] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 4'', [ka] R1, X2, R2, R3, R4, A, Q2, m and R 17 is as defined above.

[0098] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5, formula 6: [ka] Here, R1, X7, X8, X2, Q2, R2, R3, R4, R 17 , A and m are as defined above, and at least one of X7 and X8 is N.

[0099] Preferably, in each of the above formulas, R1 is arbitrarily selected from any of the following structures: [ka] More preferably, R1 is [ka] and R2 is arbitrarily 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, each of which is optionally and independently selected from 0 to 5 R a is replaced by R a is arbitrarily selected from deuterium, a C1 to C6 alkyl group, a halogen, a hydroxyl group, a C1 to C6 heteroalkyl group, a C1 to C6 alkoxy group, a cycloalkyl group, a heterocycloalkyl group, or a cyano group.

[0100] Preferably, in each of the above formulas, the W ring is [ka] where: [ka] teeth, [ka] is selected from [ka] teeth, [ka] is selected from, preferably [ka] teeth, [ka] is selected from [ka] part is, [ka] is selected from Where: [ka] is a single or double bond, 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 Y1, Y2, and Y3 is independently O, N, or NR 17 , C.R. 13 , C.R. 13 R 14 is selected from R 13 , R 14 , R 15 , R 16 are each independently selected from H, halogen, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, a C1-C6 halogenated 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 to which it is attached, or R 15 and R 16 forms a carbonyl group (C=O) together with the C atom to which it is attached, R 17 is selected from H, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 alkyl hydroxyl group, and a C1-C6 halogenated alkyl group.

[0101] Preferably, in each of the above formulas, A is an aromatic ring or a heteroaryl ring, more preferably, A is a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group, the heteroaryl ring contains 0 to 3 heteroatoms, the heteroatoms being arbitrarily selected from N, O and S, and any hydrogen atom on the A ring can be substituted by a substituent such as deuterium, a hydroxyl group, a halogen, a cyano group, an ester group, an amide group, a ketocarbonyl group, an amino group, a C1 to C6 alkyl group, a C1 to C6 halogenated alkyl group, a C1 to C6 thioalkyl group, a C1 to C6 alkoxy group, a C1 to C6 heteroalkyl group, a C1 to C6 alkylamino group, a C3 to C6 cycloalkyl group, a C3 to C8 cycloalkylamino group, an aryl group or a heteroaryl group.

[0102] Preferably, in each of the above formulae, R4 is independently selected from an aryl group, a heteroaryl group, an aryloxy group, an aralkyl group, and a heterocyclyl group, and more preferably, R4 is a 5-membered heteroaryl group, wherein each aryl group, heteroaryl group, aryloxy group, aralkyl group, heterocyclyl group, and heterocycloalkyl 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 hydroxyl 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, and more preferably, R4 is [ka] where R 18 is selected from halogen (preferably F), and C1 to C6 alkyl groups.

[0103] Preferably, in each of the above formulas, m is 1. Preferably, in each of the above formulas, R3 is H, a C1-C6 alkyl group, a C1-C6 alkoxy group. Preferably, in each of the above formulas, R2 is H.

[0104] Preferably, in each of the above formulas: [ka] part is, [ka] where X9, X 10 are each independently selected from N or CR5, where R5 is each independently arbitrarily 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, among which 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 hydroxyl 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.

[0105] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5' or 6': [ka] X2, X7, X8, X9, X 10 and Q2 ring is as defined above, and at least one of X7, X8 is N.

[0106] Preferably, the compound of formula I', or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, has the structure shown in formula 5': [ka] Where: [ka] part is, [ka] where: [ka] is a double bond, and each of Y1, Y2, and Y3 is independently N, NR 17 , C.R. 13 is selected from R 12 are independently selected from H, deuterium, 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; R 17 are independently selected from deuterium, a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, a propyl group), a deuterated C1-C6 alkyl group (e.g., a deuterated methyl group), a C1-C6 alkyl hydroxyl group, and a C1-C6 halogenated alkyl group (e.g., a fluoromethyl group, a fluoroethyl group); R 13 is selected from H, halogen, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a nitro group, a cyano group, and an amino group; X9, X 10 are each independently CH.

[0107] Preferably, [ka] part is, [ka] where: [ka] is a double bond, and Y1 is NR 17 Y2 is N, Y3 is CH, and R 17 is as defined above.

[0108] Preferably, [ka] teeth, [ka] and R'1 is as defined above.

[0109] Preferably, the compound has the structure shown in formula I: [ka] R'1 and A are as defined above. Preferably, the A ring is selected from a substituted or unsubstituted 5- to 6-membered heteroaryl group, more preferably, the A ring is selected from a substituted or unsubstituted imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, or the like, and more preferably, the A ring is [ka] wherein any hydrogen atom on ring A can be independently substituted by a substituent selected from the group consisting of a C1-C6 alkyl group, a halogen atom, a hydroxyl group, an amino 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; R'1 is selected from H, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 halogenated alkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclyl group, a C1-C6 heteroalkyl group, a C1-C6 alkyl hydroxyl group, a C3-C6 halogenated cycloalkyl group, Me3SiCH2CH2OCH2-, a C3-C6 cycloalkylCH2-, and a 3-6 membered heterocycleCH2-.

[0110] Salts that may be formed by the compounds of the present invention are also within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to the formation of salts in acidic or basic form using inorganic or organic acids and bases. Furthermore, when the compounds of the present invention contain one basic fragment, including but not limited to pyridine or imidazole, and when they contain one acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Although pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts are also useful and may be used, for example, in the separation or purification steps in the preparation process. The compounds of the present invention may form salts, for example, compound I' may be reacted with a certain amount of acid or base, such as an equivalent amount, and then salted out by mediation or lyophilized in an aqueous solution.

[0111] The basic fragments contained in the compounds of the present invention include, but are not limited to, amines or pyridine or imidazole rings, and can form salts with organic or inorganic acids. Exemplary acids that can form salts include acetates (e.g., acetic acid or halogenated acetates such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentane propionates, diglycolates, lauryl sulfates, ethanesulfonates, and the like. sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalene sulfonate (e.g., 2-naphthalenesulfonate),sulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., salts formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, and the like.

[0112] Acidic fragments that some compounds of the present invention may contain include, but are not limited to, carboxylic acids, which can form salts with various organic or inorganic bases. Exemplary salts formed with bases include ammonium salts, alkali metal salts, e.g., sodium, lithium, potassium salts, alkaline earth metal salts, e.g., calcium, magnesium salts, and the like, salts formed with organic bases (e.g., organic amines), e.g., benzathine, dicyclohexylamine, hydrabamine (salts formed with N,N-bis(didehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucamide, tert-butylamine, and the like, and salts formed with amino acids, e.g., arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with quaternary ammonium salts of halides, such as small molecule alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl groups), aralkyl halides (e.g., bromides of benzyl and phenyl groups), and the like.

[0113] Prodrugs and solvates of the compounds of the present invention are also included within the scope. The term "prodrug" as used herein refers to a compound that, when treating a related disease, produces the compounds, salts, or solvates of the present invention by chemical conversion through metabolic or chemical processes. The compounds of the present invention include solvates such as hydrates. The compounds, salts or solvates of the present invention may exist in tautomeric forms (e.g. amides and imine ethers). All these tautomeric forms are part of the present invention.

[0114] All stereoisomers of the compounds, including enantiomeric and diastereomeric forms (e.g., asymmetric carbon atoms that may exist due to various substitutions), are within the scope of the present invention. The independent stereoisomers of the compounds of the present invention may not coexist with other isomers (e.g., have a particular activity as one pure or substantially pure optical isomer) or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the International Union of Theoretical and Applied Sciences (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, or separation of crystals by induction into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by suitable methods, including, but not limited to, conventional methods, such as salt formation with optically active acids followed by recrystallization.

[0115] In the compounds of the present invention, the weight content of the compounds obtained by successive preparation, separation and purification is ≧90%, for example ≧95%, ≧99% ("highly pure" compounds) as described herein. Here, such "highly pure" compounds of the present invention are also used as part of the present invention. All configurational isomers of the compounds of the present invention are within the scope, whether in admixture or in pure or highly pure form. The definition of the compounds of the present invention includes the two olefin isomers, cis (Z) and trans (E), as well as the cis and trans isomers of carbocyclic and heterocyclic rings.

[0116] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds. Definitions of specific functional groups and chemical terms are described in detail below. For the present invention, the chemical elements are consistent with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also provided. In addition, basic principles of organic chemistry and specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, the entire contents of which are incorporated by reference.

[0117] Some compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention includes all compounds, such as cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers and mixtures thereof are included in the present invention.

[0118] According to the present invention, the ratio of the mixture of isomers containing isomers can be varied. For example, a mixture of only two isomers can have a combination of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios and ratios that are more complex mixtures of isomers that are easily understood by those skilled in the art are also within the scope of the present invention.

[0119] The present invention further includes compounds that are isotopically labeled equivalent to the original compounds disclosed herein. However, in practice, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of compounds that can be classified as isotopes of the compounds of the present invention include, for example, 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as Cl. All isotopes or other isotopic atoms of the compounds of the invention, or enantiomers, diastereomers, isomers, or pharma- ceutically acceptable salts or solvates thereof, including the compounds described above, are within the scope of the invention. 3 H and 14 Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of C, are also useful in drug and substrate tissue distribution studies. Tritium, i.e. 3 H and 14 C, that is 14 C is relatively easy to prepare and detect. It is the best choice of isotope. Furthermore, deuterium, i.e. 2Heavier isotope substitution, such as H, may be advantageous in certain therapeutic procedures due to better metabolic stability, such as increased half-life in the body or reduced dosage, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared by general methods by substituting a readily available isotopically labeled reagent for a non-isotopic reagent, using the methods disclosed in the examples.

[0120] When designing the synthesis of a specific enantiomer of a compound of the invention, it can be prepared by asymmetric synthesis or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can then be removed to obtain the pure enantiomers. Additionally, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, then diastereomeric salts can be formed with an appropriate optically active acid or base, which can then be separated by conventional means, such as separation by crystallization or chromatography, and the pure enantiomers can then be obtained.

[0121] As described herein, the compounds of the present invention may be combined with any number of substituents or functional groups to expand the scope of their inclusion. In general, the general formulas containing substituents in the formulas of the present invention refer to the substitution of hydrogen radicals with the designated structural substituents, regardless of whether the term "substituted" appears before or after the term "optionally". When multiple positions in a particular structure are substituted with multiple specific substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substitutions include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the heteroatom nitrogen can have a hydrogen substituent or any of the permissible organic compounds listed above to fill its valence. Furthermore, the present invention is not intended to limit the permissible substitutions of organic compounds in any manner. The present invention believes that the combination of substituents and variables is superior for treating diseases in the form of a stable compound. The term "stable" as used herein refers to a compound that has stability long enough to maintain the structural integrity of the compound, preferably long enough to be capable of being experimented with and be effective as used for the purposes described above herein.

[0122] Metabolites of the compounds involved in the present invention and their pharma- ceutically acceptable salts, as well as prodrugs that can be converted to the structures of the compounds involved in the present invention and their pharma- ceutically acceptable salts, are also included within the scope of the present invention.

[0123] Preparation method The following schemes and examples describe methods for preparing compounds of formula I'. Raw materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In certain cases, the order of carrying out the steps of the reaction schemes can be altered to facilitate the reaction or to avoid undesired side reaction products.

[0124] The preparation method of the compound of the formula I' of the present invention will be described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can be easily prepared by arbitrarily combining various synthetic methods described in this specification or well known to those skilled in the art, and such combination can be easily performed by those skilled in the art to which the present invention belongs.

[0125] In general, in the preparation flow, each reaction is usually carried out under inert gas protection in a suitable solvent at 0 to 90° C., and the reaction time is usually 2 to 24 hours.

[0126] Preferably, the preparation method is as follows. Method one: [ka] 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] By reacting with [ka] Obtained, 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] and [ka] By reacting with [ka] Obtained, Third step: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka] and [ka] to obtain the compound of formula I'.

[0127] Method 2 [ka] 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] and [ka] By reacting with [ka] Obtained, 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] and [ka] By reacting with [ka] Obtained, Third step: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka] and [ka] to obtain the compound of formula I'. 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 (e.g., [ka] ) and X3' is OH, -NHR8, -CHR9R 10 , [ka] is selected from X5' is -C(O)-OH, -S(O)-OH, -S(O)2-OH, [ka] is selected from R1, X3, W, Q1, X5, X6, R2, R3, R4, A, Q2, m and n are as defined above.

[0128] Preferably, the compounds are prepared using the following method. Method one: [ka] First step: In an inert solvent (e.g., DMF / H2O, ethylene glycol dimethyl ether, dioxane or toluene), in the presence of a base (e.g., potassium carbonate or sodium carbonate, etc.), a catalyst and a ligand (e.g., Pd(PPh3)4), [ka] and [ka] By reacting with [ka] Obtained, Step 2: In an inert solvent (e.g., methanol, ethanol, or ethyl acetate, etc.), under a hydrogen gas atmosphere, [ka] is reduced and then halogenated or reacted with trifluoromethanesulfonic anhydride to give an intermediate, which is reacted in the presence of a base (e.g., diisopropylethylamine, potassium carbonate, sodium carbonate, or triethylamine, etc.) by [ka] React with [ka] Obtained, Third step: reacting in an inert solvent (e.g., methanol, ethanol, tetrahydrofuran or water) under basic conditions (e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide, etc.), [ka] Obtained, Step 4: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka] and [ka] to obtain Formula I, Method two: [ka] Step 1: In an inert solvent (e.g., DMSO or DMF, etc.), under basic conditions (e.g., diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, etc.), [ka] React with [ka] Obtained, Second step: In an inert solvent (e.g., DMF / H2O, ethylene glycol dimethyl ether, dioxane or toluene, etc.), in a basic solution (e.g., potassium carbonate, sodium carbonate, etc.), in the presence of a base, a catalyst and a ligand (e.g., Pd(dppf)Cl2), [ka] and [ka] By reacting with [ka] Obtained, Step 3: In an inert solvent (e.g., methanol, ethanol, or ethyl acetate, etc.), under a hydrogen gas atmosphere, [ka] By reducing [ka] Obtained, Step 4: In an inert solvent (e.g., DMF), in the presence of a condensing agent (e.g., DMAP, HATU, PyBOP, etc.), [ka] and [ka] to obtain Formula I, In the formula, G and G' are each independently a halogen (e.g., Cl, Br), R'1 is as defined above.

[0129] Unless otherwise stated, all starting materials mentioned above can be purchased from commercial sources or synthesized according to reported literature.

[0130] Pharmaceutical Compositions and Methods of Administration The pharmaceutical compositions according to the present invention are used for preventing and / or treating diseases such as inflammation, cancer, cardiovascular disease, infection, immune disorders, metabolic disorders, etc.

[0131] The compounds described in the present invention can be used in combination with other drugs known to treat or improve similar conditions. In the case of combined administration, the compounds described in the present invention can be administered simultaneously or subsequently without changing the original drug administration method and dosage. When the compounds of the present invention are administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compounds of the present invention can be preferably used. The combination of drugs also includes taking the compounds of the present invention and one or more other known drugs at overlapping times. When the compounds of the present invention are combined with one or more other drugs, the dosage of the compounds of the present invention or the known drugs may be lower than the dosage of the compounds used alone.

[0132] Drugs or active ingredients that can be used in combination with the compounds described in the present invention include PD-1 inhibitors (e.g., nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX 10 , BAT1306, AK105, LZM009 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, GR 1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, tositumomab, imomumab, etc.), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., ceritinib, alectinib, , brigatinib, lorlatinib, ocatinib), PI3K inhibitors (e.g., adelaris, dactolisib, taselisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, etc.), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (e.g., sorafenib, pazopanib, rivatinib, cabozantinib, etc.) , sunitinib, donafenib, etc.), HDAC inhibitors (e.g., givinostat, droxinostat, entinostat, dasilast, tecdenine, 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.), Akt inhibitors (e.g., MK-2206, ipatasertib, capivasertib, afuresertib, uprosertib, etc.), mTOR inhibitors (e.g., bistusertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (e.g., ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.) or combinations thereof.

[0133] The dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, films, drops, topical applications, controlled or sustained release forms, or nanoformulations.

[0134] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or vector. Here, the "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / drug of the present invention, more preferably 10-1000 mg of the compound / drug of the present invention. Preferably, the "single dose" is one capsule or tablet.

[0135] "Pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatible" means that the components in the composition can be intermixed with and among the compounds of the present invention without significantly decreasing the efficacy of the compounds. Some examples of pharma- ceutically acceptable vectors include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., TweenR), moisturizing agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0136] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0137] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; (d) agar, calcium carbonate, potato starch, tapioca starch, alginic acid, or (e) a sorbent, such as glycerin; The pharmaceutical composition is mixed with ingredients such as disintegrating agents such as (a) glyceryl stearate, (b) glyceryl monostearate, (c) glyceryl monostearate, (d) glyceryl monostearate, (e) glyceryl monostearate, (f) glyceryl monostearate, (g) glyceryl monostearate, (h) glyceryl monostearate, (i) talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0138] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials such as enteric coating and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules using one or more of the above-mentioned excipients.

[0139] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or ignitable solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0140] Besides these inert diluents, compositions can also include wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In addition to the active compounds, the suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures of these substances.

[0141] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vectors, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0142] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants that may be required.

[0143] The therapeutic methods of the present invention can be administered alone or in combination with other therapeutic procedures or agents. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage at the time of administration is a pharma- ceutical acceptable effective dosage, and for a human weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must take into account factors within the skill range of a skilled physician, such as the route of administration and the health condition of the patient.

[0144] The present invention further provides a method for preparing a pharmaceutical composition, comprising mixing a pharma- ceutically acceptable vector 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. The present invention further includes a method of treatment comprising administering to a subject in need thereof a compound of formula I' as described in the present invention, or a crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described in the present invention, to inhibit RET.

[0145] The present invention has the following main advantages: (1) The compound of the present invention has excellent inhibitory potency against RET kinase, particularly against WT-RET, RET-V804L and RET-V804M. (2) The compounds of the present invention have lower toxicity and side effects. (3) The compounds of the present invention have superior pharmacodynamic and pharmacokinetic properties. (4) The compounds of the present invention can effectively inhibit tumor growth.

[0146] 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.

[0147] Example 1 Compounds synthesized in the present invention: [ka] The experimental process is as follows.

[0148] 1. Synthesis of intermediate C1-7 The synthetic route is as follows: [ka]

[0149] 1.Synthesis of C1-9 In a 100 mL single-mouth bottle, 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 added, and the mixture was reacted at 100° C. for 15 hours, cooled to room temperature, poured into water, filtered and dried to obtain 5.93 g of compound C1-9. NMR analysis data of compound C1-9: 1 H NMR(400MHz,CDCl3):δ 8.96-8.95(d,J=1.8Hz,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).

[0150] 2.Synthesis of C1-10 In a 100 mL three-necked bottle, add C1-9 (4.2 g, 0.02 mol), R-tert-butylsulfinamide (2.48 g, 0.02 mol), tetraethyl titanate (9.34 g, 0.041 mol) and THF (50 mL), react at 75 °C for 15 h, cool to room temperature, pour into water, filter, wash the filter cake with ethyl acetate, combine the organic phases, dry, concentrate and obtain 5.35 g of compound C1-10 by column chromatography. NMR analysis data of compound C1-10: 1 H NMR(400MHz,CDCl3):δ 8.96-8.95(d,J=1.8Hz,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).

[0151] 3.Synthesis of C1-11 In a 100mL three-necked bottle, add C1-10 (3.5g) and THF (50mL), cool to -70℃, add THF solution of lithium tri-sec-butyl borohydride (1M, 34.1mL) dropwise, stir at this temperature for 30 minutes, allow to warm to room temperature, TLC shows the reaction is complete, add methanol (5mL) to quench the reaction, add water, filter, and wash the filter cake with ethyl acetate. Combine the organic phases, dry, concentrate, and obtain 3.1g of compound C1-11 by column chromatography. NMR analysis data of compound C1-11: 1 H NMR(400MHz,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).

[0152] 4. Synthesis of C1-7 In a 100 mL three-necked bottle, add C1-11 (3.1 g), methanol (10 mL) and 1,4-dioxane (10 mL), stir to dissolve, then add HCl / 1,4-dioxane (4 M, 25 mL), stir at room temperature for 2 hours, concentrate the reaction solution to obtain a crude product, and slurried the crude product with ethyl ether to obtain 2.27 g of compound C1-7. NMR analysis data of compound C1-7: 1 H NMR(400MHz,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).

[0153] 2. Synthesis of intermediate C1-3 The synthetic route is as follows: [ka] 1. Synthesis of Compound C1-13 In a 250 mL three-necked bottle, add bromoform (125 mL) and C1-12 (128 mmol, 20 g), stir to dissolve, cool to 0 °C, and slowly add a solution of KOH (1 mol, 57.4 g) in methanol (300 mL). After addition is complete, warm to room temperature and stir for 16 h. TLC shows the reaction is complete, concentrate the mother liquor, dilute with water (50 mL), extract three times with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, and concentrate under reduced pressure to give 25 g of product C1-13, which is used directly in the next step.

[0154] 2. Synthesis of Compound C1-14 In a 500mL single-mouth bottle, add C1-13 (86mmol, 20g) and methanol (200mL), add concentrated hydrochloric acid (100mL) while stirring at room temperature, stir at room temperature for 16 hours, TLC shows the reaction is complete, concentrate the mother liquor, add saturated NaHCO3 aqueous solution to adjust pH=6~7, extract with ethyl acetate three times, wash the organic phase with saturated saline, dry the organic phase, concentrate under reduced pressure to obtain the crude product, and purify by column chromatography (eluent: ethyl acetate / petroleum ether=1:30~1:5) to obtain 10g of product C1-14.

[0155] 3. Synthesis of Compound C1-15 In a 250 mL three-necked bottle, add anhydrous toluene (50 mL) and anhydrous pyridine (4.5 mL, 53 mmol) and cool to -10 °C. Under nitrogen gas protection, slowly add a solution of trifluoromethanesulfonic anhydride (10.8 mL, 60 mmol) in anhydrous toluene (60 mL). After the addition is complete, slowly warm to room temperature and add a solution of C1-14 (9 g, 48 mmol) in anhydrous toluene (30 mL). Warm the reaction solution to 40 °C and stir for 16 hours. When the reaction is complete by TLC, add 10 mL of water to dilute, extract three times with ethyl acetate, wash the organic phase with saturated saline, dry the organic phase, and concentrate under reduced pressure to obtain the crude product, which is purified by column chromatography (developer: ethyl acetate / petroleum ether = 1:40 to 1:20) to obtain 9 g of product C1-15.

[0156] 4. Synthesis of Compound C1-3 Under nitrogen gas protection, C1-15 (9 g, 28 mmol), double pinacol borate (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 added in sequence to a 250 mL three-necked bottle, and the mixture was replaced with nitrogen gas three times. The reaction solution was then stirred at 95 ° C for 16 hours, and the reaction was shown to be complete by TLC. After filtration, the mixture was concentrated under reduced pressure, and then diluted with 20 mL of water, extracted with ethyl acetate three times, washed with saturated saline, dried the organic phase, and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1:20 to 1:10) to obtain product C1-3 (light yellow solid, 8 g).

[0157] 3. Synthesis of Compound C1 The synthetic route is as follows: [ka]

[0158] 1. Synthesis of Compound C1-2 Compound C1-1 (1.0 g, 4.93 mmol) is dissolved in anhydrous THF (20 mL), and then a solution of potassium tert-butoxide (1.1 g, 9.86 mmol) and p-methoxybenzyl alcohol (0.68 g, 4.93 mmol) in anhydrous THF (20 mL) is added dropwise under ice-salt bath cooling, and after the addition is completed, the mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by adding saturated saline, and then extracted with ethyl acetate, and the organic phase is separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain 0.7 g of compound C1-2. 1H NMR (400MHz, DMSO-d6): δ 8.26(s,1H),7.50-7.47(d,2H,J=9.03Hz),6.99-6.97(d,2H,J=9.03Hz),5.54(s,2H),3.97(s,3H),3.78(s,3H).

[0159] 2. Synthesis of Compound C1-4 Compound C1-2 (680 mg, 2.24 mmol) and compound C1-3 (795 mg, 2.68 mmol) are dissolved in a mixed solvent of 20 mL of 1,4-dioxane and 4 mL of water, and palladium acetate (50 mg, 0.224 mmol), dppf (248 mg, 0.447 mmol) and potassium carbonate (463 mg, 3.36 mmol) are added in sequence, and the reaction solution is stirred overnight at 102 °C under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 515 mg of compound C1-4. MS [M + H] 439.1.

[0160] 3. Synthesis of Compound C1-5 Compound C1-4 (515 mg, 1.17 mmol) is dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL), then Pd / C (103 mg) is added and stirred overnight at room temperature under a hydrogen gas atmosphere. After the reaction is complete, the reaction solution is filtered through Celite, washed with methanol, and the filtrate is concentrated under reduced pressure to obtain 255 mg of compound C1-5. 1 H NMR(400MHz,MeOD-d4):δ 7.89(s,1H),3.86-3.84(d,3H,J=6.46Hz),3.69-3.65(d,3H,J=13.25Hz),3.18-3.14(d,3H,J=13.62Hz),2.66 -2.57(m,1H),2.39-2.50(m,1H),2.07-2.04(m,1H),1.95-1.82(m,2H),1.76-1.69(m,3H),1.55-1.51(m,1H).

[0161] 4. Synthesis of Compound C1-6 Compound C1-5 (255 mg) is dissolved in phosphorus oxychloride (5 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 254 mg of crude product compound C1-6, which is used directly in the next step without purification. 1 H NMR(400MHz,MeOD-d4):δ 8.08(s,1H),3.99-3.98(d,3H,J=3.86Hz),3.67-3.66(d,3H,J=3.19Hz),3.19-3.16(d,3H ,J=13.74Hz),2.96-2.87(m,1H),2.29-2.24(m,1H),2.09-1.74(m,6H),1.59-1.52(m,1H).

[0162] 5. Synthesis of Compound C1-9 Compound C1-6 (300 mg, 0.89 mmol) and compound C1-8 (210 mg, 1.07 mmol) are dissolved in 10 mL of ultra-dry 1,4-dioxane, then Pd2(dba)3 (91 mg, 0.09 mmol), t-Buxphos (75 mg, 0.18 mmol) and KOAc (171 mg, 1.78 mmol) are added sequentially, and the reaction solution is stirred overnight at 60 °C under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, the solvent is removed by concentration under reduced pressure, diluted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 279 mg of compound C1-9. MS [M + H] 500.4. 1H NMR(400MHz,MeOD-d4):δ 8.15-8.12(d,1H,J=7.36Hz),7.02(s,1H),3.90-3.89(d,3H,J=3.40Hz),3.69-3.67(d,3H,J=8.58Hz),3.25( s,3H),2.80-2.77(m,1H),2.51(s,3H),2.34-2.24(m,1H),2.09-1.92(m,4H),1.81-1.77(m,3H),1.56(s,9H).

[0163] 6. Synthesis of Compound C1-10 Compound C1-9 (279 mg, 0.56 mmol) was dissolved in a mixed solvent of methanol (10 mL) and water (2 mL), lithium hydroxide monohydrate (70 mg, 1.68 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 300 mg of crude product C1-10.

[0164] 7. Synthesis of Compound C1 Compound C1-10 (285 mg, 0.73 mmol) and compound C1-7 (177 mg, 0.73 mmol) are dissolved in DMF (5 mL), DIPEA (752 mg, 5.83 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (416 mg, 1.09 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C1 (Ms[M+H]574) and compound C1A ([M+H]574). NMR of compound C1: 1H NMR(400MHz,DMSO+D2O):δ 8.70-8.69(d,1H,4.05Hz),8.57-8.55(d,1H,8.31Hz),8.45-8.44(d,1H,2.15Hz),8.33(br,1H),8.02-7.99(dd,1H,8.58Hz,2.41Hz),7.93-7.88( m,2H),6.77(br,1H),5.10-5.03(m,1H),3.90(s,3H),3.18(s,3H),2.78- 2.68 (m, 1H), 2.28 (s, 3H), 2.03-1.64 (m, 8H), 1.48-1.46 (d, 3H, 6.97Hz).

[0165] C1 and C1A were separated by Agilent high performance liquid chromatography, and the preparation and separation conditions were as follows: Equipment: Agilent 1290 infinity II Chromatography column: Agilent Prep-C18 (250 x 21.2 mm, 10 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: DMSO Sampling concentration: approx. 50mg / ml Sample size: 500μL C1 peak time: 24.5 min C1A peak time: 20.5 min Gradient Program: [Table 1]

[0166] Example 2 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0167] 1.Synthesis of C2-2 Compound C2-1 (1.0 g, 5.32 mmol) is dissolved in dichloromethane (30 mL), then DIPEA (2.06 g, 15.96 mmol) is added, cooled to 0 ° C in an ice-water bath, SEM-Cl (2.22 g, 13.30 mmol) is added dropwise, stirred for 1.5 hours while maintaining the temperature, diluted with water, and extracted with dichloromethane. The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.19 g of compound C2-2. 1 H NMR (400MHz, CDCl3): δ 8.23 ​​(s, 1H), 5.82 (s, 2H), 3.72-3.68 (t, 2H), 0.99-0.95 (t, 2H), 0.00 (s, 9H).

[0168] 2. Synthesis of C2-3 Compound C2-2 (1.09 g, 3.43 mmol) is dissolved in anhydrous THF (50 mL), and then a solution of potassium t-butoxide (0.38 g, 3.43 mmol) and p-methoxybenzyl alcohol (0.45 g, 3.26 mmol) in anhydrous THF (20 mL) is added dropwise under ice-salt bath cooling, and after the addition is completed, the mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by adding saturated saline, and then extracted with ethyl acetate, and the organic phase is separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain 0.7 g of compound C2-3. 1 H NMR(400MHz,CDCl3):δ 8.04(s,1H),7.46-7.44(d,2H,J=7.31Hz),6.95-6.93(d,2H,J=9.02Hz),5.72(s,2 H),5.55(s,2H),3.82(s,3H),3.65-3.62(t,2H),0.95-0.90(t,2H),-0.04(s,9H).

[0169] 3. Synthesis of C2-4 Compound C2-3 (633 mg, 1.51 mmol) and compound C1-3 (535 mg, 1.81 mmol) are dissolved in a mixed solvent of 30 mL of 1,4-dioxane and 6 mL of water, and palladium acetate (34 mg, 0.16 mmol), tricyclohexylphosphine (85 mg, 0.30 mmol) and potassium carbonate (312 mg, 2.26 mmol) are added in sequence, and the reaction solution is stirred overnight at 90 ° C under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 574 mg of compound C2-4. 1 H NMR(400MHz,CDCl3):δ 8.06(s,1H),7.51-7.49(d,2H,J=9.59Hz),7.42(s,1H),6.99-6.97(d,2H,J=8.39Hz),5.82(s,2H),5.62(s,2H),3.88(s, 3H),3.87(s,3H),3.73-3.68(t,2H),3.39(s,3H),2.93-2.67(m,4H),2.35-2.30(m,2H),2.21-2.17(m,1H),0.00(s,9H).

[0170] 4. Synthesis of C2-5 Compound C2-4 (762 mg, 1.38 mmol) was dissolved in a mixture of 30 mL ethyl acetate and 30 mL methanol, then Pd(OH)2 / C (76 mg) was added and the reaction was stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 600 mg of crude product compound C2-5, which was used directly in the next step without purification. MS [M+H] 437.1.

[0171] 5. Synthesis of C2-6 Compound C2-5 (120 mg, crude product) is dissolved in phosphorus oxychloride (5 mL), then DIPEA (177 mg, 1.376 mmol) is added, and the mixture is stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and 70 mg of compound C2-6 is obtained by column chromatography. 1 H NMR(400MHz,CDCl3):δ 8.18(s,1H),5.86-5.84(d,2H,J=8.23Hz),3.84-3.83(d,2H,J=2.10Hz),3.74-3.70(m,2H),3.34-3.33(d,3H,J=5.26Hz),3. 17-3.03(m,1H),2.46-2.40(m,1H),2.26-2.18(m,2H),2.08-1.86(m,5H),1.76-1.68(m,1H),1.10-0.96(m,2H),0.00(s,9H).

[0172] 6. Synthesis of C2-8 Compound C2-6 (98 mg, 0.22 mmol) and compound C2-7 (23 mg, 0.24 mmol) are dissolved in dimethyl sulfoxide (1 mL), then DIPEA (56 mg, 0.43 mmol) is added, and the reaction mixture is stirred overnight at 100° C. under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 90 mg of compound C2-8. MS [M+H] 516.4.

[0173] 7. Synthesis of C2-9 Compound C2-8 (90 mg, 0.18 mmol) was dissolved in a mixture of methanol (2 mL) and water (0.4 mL), lithium hydroxide monohydrate (23 mg, 0.53 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 68 mg of crude product compound C2-9, which was used directly in the next step without purification.

[0174] 8. Synthesis of C2 Compound C2-9 (68 mg, 0.14 mmol) and compound C1-7 (37 mg, 0.15 mmol) are dissolved in 2 mL of DMF, DIPEA (145 mg, 1.12 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (80 mg, 0.21 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C2 (Ms[M+H] 691) and compound C2A (MS[M+H] 691).

[0175] Example 3 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0176] 1.Synthesis of C3-1 Compound C2-1 (1.0 g, 5.29 mmol) and triphenylphosphine (2.22 g, 8.46 mmol) are dissolved in anhydrous tetrahydrofuran (30 mL), then deuterated methanol (500 mg, 14.28 mmol) is added, the reaction solution is cooled to 0°C, DIAD (2.14 g, 10.58 mmol) is added dropwise, and after the addition is complete, the mixture is allowed to warm to room temperature and stirred overnight. After the reaction is complete, the reaction solution is concentrated and purified by column chromatography to obtain 0.7 g of compound C3-1. MS [M+H] 206.0. 1 H NMR (400MHz, CDCl3): δ 8.13 (s, 1H).

[0177] 2. Synthesis of C3 The synthesis of compound C3 refers to the synthesis of compound C1. 1H NMR(400MHz,DMSO+D2O):δ 8.69-8.67(d,1H,4.21Hz),8.54-8.52(d,1H,8.42Hz),8.44-8.43(d,1H,1.92Hz),8.34(br,1H),8.01-7.98(dd,1H,8.56Hz,2.18Hz),7.92 -7.87(m,2H),6.67(br,1H),5.08-5.04(m,1H),3.17(s,3H),2.79-2.16(m,1H),2.28(s,3H),2.03-1.64(m,8H),1.48-1.46(d,3H,7.35Hz).

[0178] Example 4 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0179] 1.Synthesis of C4-1 p-Methoxybenzyl alcohol (16.0 g, 116.4 mmol) and t-BuOK (24.9 g, 222.2 mmol) were dissolved in anhydrous dioxane (400 mL), and compound C2-1 (20.0 g, 105.8 mmol) dissolved in dioxane (300 mL) was added dropwise to the reaction bottle under ice bath, and after magnetic stirring for 2 hours, the solution gradually became colloidal. After the reaction was completed, water was added to quench, the aqueous phase was extracted with ethyl acetate, the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain the crude product, which was slurried with petroleum ether for 2 hours, suction filtered, and dried under vacuum to obtain 28.8 g of compound C4-1, MS [M + H] 291. 1 H NMR (400MHz, Chloroform-d): δ 8.07(s,1H),7.47(d,J=8.7Hz,2H),6.95(d,J=8.7Hz,2H),5.56(s,2H),3.84(s,3H).

[0180] 2.Synthesis of C4-2 Compound C4-1 (2.0 g, 6.80 mmol) was dissolved in anhydrous THF (60 mL), EtOH (1.1 mL, 17.2 mmol) and PPh3 (2.9 g, 11.0 mmol) were added in sequence, the reaction solution was protected with nitrogen gas, DIAD (2.8 g, 13.6 mmol) was added under ice bath, the mixture was allowed to warm to room temperature and stirred for 3 hours, the reaction was quenched by adding saturated saline, and then extracted with ethyl acetate, the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 1.78 g of compound C4-2, MS [M+H] 319. 1 H NMR(400MHz,Chloroform-d):δ 7.99(s,1H),7.45(d,J=8.8Hz,2H),6.94(d,J=8.7Hz,2H),5.54(s,2H),4.45(q,J=7.2Hz,2H),3.83(s,3H),1.50(t,J=7.3Hz,3H).

[0181] 3. Synthesis of C4-3 Compound C4-2 (1.78 g, 5.60 mmol) and compound C1-3 (1.82 g, 6.16 mmol) were dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (12 mL), and palladium acetate (126 mg, 0.56 mmol), dppf (621 mg, 1.12 mmol) and potassium carbonate (1.16 g, 8.40 mmol) were added in sequence, and the reaction solution was stirred overnight at 90 °C under nitrogen gas protection. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.52 g of compound C4-3, MS [M + H] 453. 1H NMR(400MHz,Chloroform-d):δ 7.93(s,1H),7.42(s,2H),7.35-7.29(m,1H),6.91(d,J=8.7Hz,2H),5.55(s,2H),4.46(q,J=7.3Hz,2H),3.81( d,J=2.9Hz,6H),3.33(s,3H),2.97-2.49(m,4H),2.41-2.20(m,1H),2.20-2.08(m,1H),1.50(t,J=7.2Hz,3H).

[0182] 4. Synthesis of C4-4 Compound C4-3 (1.52 g, 3.36 mmol) was dissolved in a mixture of ethyl acetate (15 mL) and methanol (15 mL), then wet palladium on carbon (152 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 1.33 g of compound C4-4, MS [M+H] 335. 1 H NMR(400MHz,Chloroform-d):δ 10.64(s,1H),8.00(s,1H),4.33(q,J=7.1Hz,2H),3.73(s,3H),3.24(s,3H),2.7 1-2.60(m,1H),2.14(d,J=12.4Hz,2H),1.97-1.72(m,6H),1.44(t,J=7.2Hz,3H).

[0183] 5. Synthesis of C4-5 Compound C4-4 (1.33 g, crude product) is dissolved in phosphorus oxychloride (30 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 936 mg of compound C4-5, MS [M+H] 353. 1H NMR(400MHz,Chloroform-d):δ 8.00(s,1H),4.46(q,J=7.3Hz,2H),3.73(s,3H),3.24(s,3H),3.09-2.84 (m,1H),2.13(d,J=11.8Hz,2H),2.00-1.72(m,6H),1.47(t,J=7.3Hz,3H).

[0184] 6. Synthesis of C4-6 Compound C4-5 (936 mg, 2.66 mmol) and compound C2-7 (284 mg, 2.92 mmol) are dissolved in DMSO (15 mL), then DIPEA (686 mg, 5.32 mmol) is added, and the mixture is stirred overnight under nitrogen gas protection at 100° C. After the reaction is completed, the mixture is cooled to room temperature, diluted with ethyl acetate, the organic phase is washed with saturated saline, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 728 mg of compound C4-6, MS [M+H] 414. 1 H NMR(400MHz,Chloroform-d):δ 7.78(s,1H),6.54(s,1H),4.44(q,J=6.3,5.3Hz,2H),3.80(s,3H),3.33(s,3H),2 .93-2.82(m,1H),2.36(s,J=6.5Hz,3H),2.23-1.62(m,8H),1.49(t,J=7.2Hz,3H).

[0185] 7. Synthesis of C4-7 Compound C4-6 (728 mg, 1.76 mmol) was dissolved in a mixed solvent of methanol (16 mL) and water (2 mL), lithium hydroxide monohydrate (222 mg, 5.29 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, methanol was removed under reduced pressure, and the mixture was slurried with DCM, suction filtered, and used directly in the next step without purification to obtain a total of 797 mg of crude product C4-7, MS [M+H] 400.

[0186] 8. Synthesis of C4 Compound C4-7 (114 mg, crude product) and compound C1-7 (69 mg, 0.28 mmol) are dissolved in DMF (5 mL), DIPEA (290 mg, 2.25 mmol) is added, and the mixture is stirred at room temperature for 15 min, followed by HATU (160 mg, 0.42 mmol) and stirring at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compounds C4 (Ms[M+H] 588) and C4A (MS[M+H] 588). NMR of compound C4: 1 H NMR(400MHz,Chloroform-d):δ 8.41-8.22(m,2H),7.97-7.79(m,1H),7.71(dd,J=8.6,2.4Hz,1H),7.51(dd,J=4.3,0.9Hz,1H),6.81(d,J=7.9Hz,1H),6.15(s,1H),5.10(p,J=7 .1Hz,1H),4.35(q,J=7.3Hz,2H),3.21(s,3H),2.92-2.78(m,1H),2.24( s, 3H), 2.01-1.75 (m, 8H), 1.51 (d, J = 7.0Hz, 3H), 1.42 (t, J = 7.3Hz, 3H).

[0187] Example 5 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0188] 1.Synthesis of C5-2 In a 50 mL single-mouth bottle, add C5-1 (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), and allow the reaction to react at 100 °C for 8 h. LC-MS shows the reaction is complete, pour the reaction into water (200 mL) with stirring to precipitate a solid, filter, wash the filter cake with water, and dry the filter cake to obtain 1.08 g of solid. [M+1]: 207.03.

[0189] 2.Synthesis of C5-3 In a 100 mL single-mouth bottle, add C5-3 (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) in that order, and react overnight at 75° C. Cool, dilute with water (30 mL), suction filter, extract the filtrate three times with ethyl acetate (20 mL), dry the organic phase with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and obtain 500 mg of product by column chromatography.

[0190] 3.Synthesis of C5-4 In a 50 mL single-mouth bottle, C5-3 (100 mg, 0.32 mmol) and dry tetrahydrofuran (2 mL) are added in sequence, cooled to -78 °C, tri-s-butyllithium borohydride (0.7 mL, 0.7 mmol, 1.0 M) is added dropwise, and the reaction is allowed to proceed at -78 °C for 1 hour. The reaction is 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 is dried, and evaporated to dryness under reduced pressure. 93 mg of the product is obtained by column chromatography. 1H NMR(400MHz,CDCl3):δ 9.23(d,J=1.4Hz,1H),8.36(d,J=1.5Hz,1H),8.33(d,J=4.6Hz,1H),7.66(d,J=4.3Hz, 1H),4.77(p,J=6.6Hz,1H),3.74(d,J=5.9Hz,1H),1.67(d,J=6.8Hz,3H),1.22(s,9H).

[0191] 4. Synthesis of C5-5 Add C5-4 (100 mg, 0.32 mmol), dichloromethane (3 mL), methanol (0.5 mL) and HCl / dioxane (4 M, 1.5 mL) in a 50 mL single-mouth bottle and react at room temperature for 3 h. Check the reaction for completion by LC-MS, dilute with dichloromethane, filter, wash the filter cake with ethyl acetate, and dry the filter cake to give 67 mg of product. [M+1]: 208.06.

[0192] 5. Synthesis of C5 Compound C4-7 (270 mg, 0.68 mmol) and compound C5-5 (165 mg, 0.68 mmol) are dissolved in DMF (9 mL), DIPEA (699 mg, 5.41 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (386 mg, 1.02 mmol) and stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C5 (Ms[M+H] 589) and compound C5A (MS[M+H] 589). NMR of compound C5: 1H NMR(400MHz,Chloroform-d):δ 9.23(d,J=1.4Hz,1H),8.37(d,J=1.4Hz,1H),8.34(d,J=4.6Hz,1H),7.78(s,1H),7.66(d,J=4.3Hz,2H),5.32(p,J=6.8Hz,1H),4. 44(q,J=7.2Hz,2H),3.32(s,3H),2.93-2.77(m,1H),2.38(s,3H),2.13-1.90(m,8H),1.56(d,J=6.9Hz,3H),1.48(t,J=7.2Hz,3H).

[0193] Example 6 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0194] 1.Synthesis of C6-1 Compound C4-1 (2.0 g, 6.90 mmol) is dissolved in anhydrous DMF (20 mL), and cesium carbonate (2.25 g, 6.90 mmol) and 1,1-difluoro-2-iodoethane (2.65 g, 13.79 mmol) are added in sequence, stirred at room temperature overnight, DMF is removed under reduced pressure, saturated saline is added to quench the reaction, and then extracted with ethyl acetate, the organic phase is separated, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, and purified to obtain 440 mg of compound C6-1. 1 H NMR(400MHz,CDCl3):δ 7.98(s,1H),7.40-7.37(d,2H,8.34Hz),6.88-6.86(d,2H,8.65Hz),6.29-5.99(m,1H),5.48(s,2H),4.72-4.64(m,2H),3.76(s,3H).

[0195] 2.Synthesis of C6-2 Compound C6-2 (440 mg, 1.24 mmol) and compound C1-3 (441 mg, 1.49 mmol) are dissolved in a mixed solvent of 10 mL of 1,4-dioxane and 2 mL of water, and palladium acetate (28 mg, 0.13 mmol), dppf (138 mg, 0.25 mmol) and potassium carbonate (257 mg, 1.86 mmol) are added in sequence, and the reaction solution is stirred overnight at 90 ° C under nitrogen gas protection. After completion of the reaction, it is cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 297 mg of compound C6-2. 1 H NMR(400MHz,CDCl3):δ 8.00(s,1H),7.44-7.42(d,2H,8.34Hz),7.37(br,1H),6.94-6.89(d,2H,9.10Hz),6.38-6.10(m,1H),5.5 7(s,2H),4.80-4.72(m,2H),3.82(s,3H),3.81(s,3H),3.40(s,3H),2.88-2.61(m,5H),2.34-2.11(m,3H).

[0196] 3.Synthesis of C6-3 Compound C6-2 (297 mg, 0.84 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL), then wet palladium on carbon (30 mg) was added and stirred overnight at room temperature under a hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 196 mg of compound C6-3. 1 H NMR(400MHz,MeOD-d4):δ 10.27-10.19(d,1H,57.39Hz),8.05(s,1H),6.30-6.02(m,1H),3.74-3.73(d,3H,6.02Hz),3.24- 3.22(d,3H,9.02Hz),2.75-2.61(m,1H),2.56-2.35(m,1H),2.27-2.02(m,3H),1.87-1.78(m,5H).

[0197] 4. Synthesis of C6-4 Compound C6-3 (168 mg) is dissolved in phosphorus oxychloride (5 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 118 mg of compound C6-4. MS [M+H] 389.2.

[0198] 5. Synthesis of C6-5 Compound C6-4 (118 mg, 0.31 mmol) and compound C2-7 (33 mg, 0.34 mmol) are dissolved in 1 mL of DMSO, then DIPEA (78 mg, 0.61 mmol) is added and stirred overnight at 100° C. under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 134 mg of compound C6-5. MS [M+H] 450.3. 1 H NMR(400MHz,CDCl3):δ 9.57(br,0.4H),8.24(br,0.6H),7.79(s,1H),6.57(br,1H),6.39-6.08(m ,1H),4.78-4.70(m,2H),3.80-3.79(d,3H,2.83Hz),3.34-3.30(d,3H,14. 91Hz),2.89-2.82(m,1H),2.44-2.40(m,1H),2.38-2.37(d,3H,5.91Hz),2 .21-2.17(m,1H),2.10-1.95(m,5H),1.90-1.82(m,1H),1.71-1.63(m,2H).

[0199] 6. Synthesis of C6-6 Compound C6-5 (134 mg, 0.30 mmol) was dissolved in a mixture of methanol (5 mL) and water (1 mL), lithium hydroxide monohydrate (38 mg, 0.90 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 151 mg of crude product compound C6-6, which was used directly in the next step without purification.

[0200] 7. Synthesis of C6 Compound C6-6 (54 mg, 0.12 mmol) and compound C1-7 (34 mg, 0.12 mmol) are dissolved in 1 mL of DMF, DIPEA (126 mg, 0.98 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (70 mg, 0.18 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C6 (Ms[M+H]624) and compound C6A ([M+H]624). NMR of compound C6: 1 H NMR (400MHz, CDCl3): δ 8.32-8.30(m,2H),7.85-7.83(d,1H,8.38Hz),7.71-7.68(dd,1H,8.72Hz,2.3 5Hz),7.67(br,1H),7.52-7.51(d,1H,4.36Hz),6.83-6.81(d,1H,8.05Hz),6. 38(br,1H),6.33-6.01(m,1H),5.12-5.09(q,1H),4.70-4.62(m,2H),3.23(s, 3H), 2.75 (br, 1H), 2.28 (s, 3H), 1.95-1.86 (m, 8H), 1.52-1.50 (d, 3H, 7.38Hz).

[0201] Example 7 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] 1. Synthesis of C7 Compound C6-6 (96 mg, crude product) and compound C5-5 (61 mg, 0.218 mmol) are dissolved in DMF (2 mL), DIPEA (225 mg, 1.744 mmol) is added, and the mixture is stirred at room temperature for 15 min, followed by HATU (124 mg, 0.327 mmol), followed by stirring at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C7. Ms[M+H] 625.4. 1 H NMR(400MHz,CDCl3):δ 9.16-9.15(d,1H,1.24Hz),8.29-8.26(m,2H),7.94(br,1H),7.59-7.58(m,1H),7.45-7.43(m,1H),6.30-6.01(m,2H),5.2 4-5.19(m,1H),4.71-4.63(m,2H),3.22(s,3H),2.85(br,1H),2.26(s,3H),1.99-1.88(m,9H),1.50-1.48(d,3H,7.11Hz).

[0202] Example 8 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] 1. Synthesis of C8 Compound C1-10 (100 mg, crude product) and compound C5-5 (72 mg, 0.256 mmol) are dissolved in DMF (2 mL), DIPEA (264 mg, 2.048 mmol) is added, and the mixture is stirred at room temperature for 15 min, followed by HATU (146 mg, 0.384 mmol), followed by stirring at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C8. Ms[M+H] 575.5. 1H NMR(400MHz,DMSO+D2O):δ 9.13-9.12(d,1H,1.32Hz),8.74-8.72(dd,1H,4.48Hz,0.66Hz),8.53-8.52(d,1H,1.32Hz),8.33(br,1H),8.03-8.02(dd,1H,4.21Hz,0.73Hz ),6.77(br,1H),5.16-5.10(m,1H),3.91(s,3H),3.22(s,3H),2.82-2.76(m,1H),2.28(s,3H),2.03-1.73(m,9H),1.51-1.49(d,3H,7.77Hz).

[0203] Example 9 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] 1. Synthesis of C9 Compound C3-8 (100 mg, crude product) and compound C5-5 (71 mg, 0.254 mmol) are dissolved in DMF (2 mL), DIPEA (262 mg, 2.032 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (145 mg, 0.381 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C9 (Ms[M+H]578) and compound C9A (MS[M+H]578). NMR of compound C9: 1H NMR(400MHz,DMSO+D2O):δ 9.13-9.12(d,1H,1.35Hz),8.74-8.73(dd,1H,4.56Hz,0.67Hz),8.52-8.51(d,1H,1.30Hz),8.29(br,1H),8.03-8.02(dd,1H,4.15Hz, 0.60Hz),6.83(br,1H),5.17-5.11(m,1H),3.23(s,3H),2.76-2.68(m,1H),2.27(s,3H),2.03-1.71(m,9H),1.51-1.49(d,3H,6.77Hz).

[0204] Example 10 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0205] 1.Synthesis of C10-2 Compound C10-1 (273 mg) is dissolved in phosphorus oxychloride (5 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 187 mg of compound C10-2. MS [M+H] 383.2. 1 H NMR(400MHz,CDCl3):δ 8.08-8.07(d,1H,1.21Hz),4.67-4.61(m,2H),3.90-3.86(q,2H),3.77-3.76(d,3H,1.57Hz),3.33-3.26(d,3H,5 .10Hz), 3.28-3.27(d,3H,7.25Hz),3.08-2.95(m,1H),2.38-2.11(m,3H),2.03-1.79(m,5H),1.70-1.64(m,1H).

[0206] 2.Synthesis of C10-3 Compound C10-2 (187 mg, 0.488 mmol) and compound C2-7 (52 mg, 0.537 mmol) are dissolved in DMSO (2 mL), then DIPEA (126 mg, 0.976 mmol) is added and stirred overnight at 100° C. under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 181 mg of compound C10-3. MS [M+H] 444.3.

[0207] 3.Synthesis of C10-4 Compound C10-3 (181 mg, 0.409 mmol) was dissolved in a mixture of methanol (10 mL) and water (2 mL), lithium hydroxide monohydrate (51.48 mg, 1.226 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 193 mg of crude product compound C10-4, which was used directly in the next step without purification.

[0208] 4. Synthesis of C10 Compound C10-4 (72 mg, crude product) and compound C5-5 (46.5 mg, 0.165 mmol) are dissolved in DMF (2 mL), DIPEA (170 mg, 1.32 mmol) is added, and the mixture is stirred at room temperature for 15 min, followed by HATU (94 mg, 0.248 mmol), followed by stirring at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C10. Ms[M+H] 619.5. 1H NMR(400MHz,DMSO-d6):δ 12.10(br,1H),10.61(br,1H),9.14(s,1H),8.74(s,1H),8.53-8.32(m,3H),8.04(s,1H),6.80(br,1H),6.38(br,1H),5.15(br,1 H),4.43(s,2H),3.77(s,2H),3.23(s,3H),3.21(s,3H),2.72(br,1H),2.27(s,3H),2.04-1.73(m,9H),1.52-1.50(d,3H,5.51Hz).

[0209] Example 11 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0210] 1.Synthesis of C11-2 Compound C4-1 (1.0 g, 3.448 mmol) is dissolved in DMF (15 mL), then cesium carbonate (1.124 g, 3.448 mmol) is added, and a solution of compound C11-1 (0.617 g, 4.138 mmol) in DMF (1 mL) is added dropwise under ice-water bath cooling, and the mixture is stirred for 15 minutes while maintaining the temperature, and stirred at room temperature for 0.5 hours, and the reaction is detected by TLC. The reaction mixture is diluted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 333 mg of compound C11-2. 1 H NMR(400MHz,CDCl3):δ 7.98(s,1H),7.40-7.38(dd,2H,6.92Hz,2.01Hz),6.88-6.86(dd,2H,6.69Hz,2 .01Hz),5.59-5.54(m,1H),5.52(s,2H),3.81-3.75(m,5H),3.58-3.51(m,2H).

[0211] 2.Synthesis of C11-3 Compound C11-2 (723 mg, 2.02 mmol) is dissolved in dichloromethane (20 mL), and then a solution of DAST (845 mg, 5.25 mmol) in dichloromethane (10 mL) is added dropwise at -10°C, allowed to warm to room temperature, stirred overnight, and concentrated under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain 255 mg of compound C11-3. 1 H NMR(400MHz,CDCl3):δ 7.92(s,1H),7.39-7.37(d,2H,9.06Hz),6.88-6.86(dd,2H,6.69Hz,2.14Hz),5. 47(s,2H),5.28-5.23(m,1H),3.76(s,3H),3.30-3.20(m,2H),3.12-3.03(m,2H).

[0212] 3.Synthesis of C11-4 Compound C11-3 (255 mg, 0.671 mmol) and compound C1-3 (239 mg, 0.805 mmol) are dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL), palladium acetate (15 mg, 0.067 mmol), dppf (75 mg, 0.134 mmol) and potassium carbonate (139 mg, 1.007 mmol) are added in sequence, and the reaction solution is stirred at 95 °C under nitrogen gas protection for 4 hours. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 347 mg of compound C11-4. MS [M + H] 515.3. 1 H NMR(400MHz,CDCl3):δ 7.91(s,1H),7.37-7.35(m,2H),7.29-7.27(m,1H),6.87-6.84(m,2H),5.49(s,2H),5.31-5.26(m,1H),3.76(s,3H),3.75(s,3H),3.4 3-3.31(m,2H),3.27(s,3H),3.20-3.199(d,1H,2.53Hz),3.12-3.02(m,2H),2.82-2.54(m,5H),2.27-2.18(m,2H),2.10-2.03(m,1H).

[0213] 4.Synthesis of C11-5 Compound C11-4 (347 mg, 0.675 mmol) is dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL), then wet palladium on carbon (35 mg) is obtained and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution is filtered through Celite, washed with methanol, and the filtrate is concentrated under reduced pressure to give 237 mg of compound C11-5. MS [M+H] 397.3.

[0214] 5.Synthesis of C11-6 Compound C11-5 (207 mg, 0.523 mmol) is dissolved in phosphorus oxychloride (5 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 153 mg of compound C11-6. MS [M+H] 415.2.

[0215] 6.Synthesis of C11-7 Compound C11-6 (153 mg, 0.370 mmol) and compound C2-7 (39 mg, 0.407 mmol) are dissolved in 3 mL of DMSO, then DIPEA (96 mg, 0.740 mmol) is added and stirred overnight at 100° C. under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 151 mg of compound C11-7. MS [M+H] 476.3.

[0216] 7.Synthesis of C11-8 Compound C11-7 (151 mg, 0.318 mmol) was dissolved in a mixture of methanol (5 mL) and water (1 mL), lithium hydroxide monohydrate (40 mg, 0.953 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 186 mg of crude product compound C11-8, which was used directly in the next step without purification.

[0217] 8. Synthesis of C11 Compound C11-8 (176 mg, crude product) and compound C5-5 (106 mg, 0.377 mmol) are dissolved in DMF (3 mL), DIPEA (389 mg, 3.016 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (215 mg, 0.566 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified to give compound C11. Ms[M+H] 651.4. 1 H NMR(400MHz,CDCl3):δ 9.54(br,1H),9.17-9.16(d,1H,1.40Hz),8.30-8.26(m,2H),7.70(br,2H),7.59-7.58(m,1H),7.50-7.49(m,1H),6.47(br,1H),5.28-5. 22(m,2H),3.37-3.27(m,2H),3.24(s,3H),3.11-3.01(m,2H),2.77(br,1H),2.32(s,3H),2.01-1.88(m,8H),1.50-1.48(d,3H,6.77Hz).

[0218] Example 12 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0219] 1.Synthesis of C12-2 Compound C4-1 (200 mg, 0.688 mmol) and triphenylphosphine (356 mg, 1.36 mmol) are dissolved in 6 mL of anhydrous tetrahydrofuran, then compound C12-1 (148 mg, 2.06 mmol) is added, the reaction solution is cooled to 0 ° C, DIAD (274 mg, 1.36 mmol) is added dropwise, and after the addition is completed, the mixture is allowed to warm to room temperature and stirred overnight. After the reaction is completed, the reaction solution is concentrated and purified by column chromatography to obtain 164 mg of compound C12-2.

[0220] 2.Synthesis of C12-3 Compound 12-2 (164 mg, 0.476 mmol) and compound C1-3 (169 mg, 0.571 mmol) are dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL), and palladium acetate (11 mg, 0.0476 mmol), dppf (53 mg, 0.095 mmol) and potassium carbonate (99 mg, 0.714 mmol) are added in sequence, and the reaction solution is stirred overnight at 90 °C under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 200 mg of compound C12-3. MS [M + H] 479.4.

[0221] 3.Synthesis of C12-4 Compound C12-3 (200 mg, 0.418 mmol) was dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL), then wet palladium on carbon (20 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 131 mg of compound C12-4. MS [M+H] 361.3.

[0222] 4.Synthesis of C12-5 Compound C12-4 (131 mg, 0.364 mmol) is dissolved in phosphorus oxychloride (3 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 90 mg of compound C12-5. MS [M+H] 379.3.

[0223] 5.Synthesis of C12-6 Compound C12-5 (90 mg, 0.238 mmol) and compound C2-7 (25.4 mg, 0.261 mmol) are dissolved in DMSO (1 mL), then DIPEA (61.4 mg, 0.476 mmol) is added and stirred overnight at 100° C. under nitrogen gas protection. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 56 mg of compound C12-6. MS [M+H] 440.4.

[0224] 6.Synthesis of C12-7 Compound C12-6 (56 mg, 0.128 mmol) was dissolved in a mixture of methanol (3 mL) and water (0.6 mL), lithium hydroxide monohydrate (16 mg, 0.383 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 73 mg of crude product compound C12-7, which was used directly in the next step without purification.

[0225] 7. Synthesis of C12 Compound C12-7 (73 mg, crude product) and compound C5-5 (47 mg, 0.169 mmol) are dissolved in DMF (2 mL), DIPEA (175 mg, 1.352 mmol) is added, and the mixture is stirred at room temperature for 15 min, followed by HATU (96.3 mg, 0.254 mmol), followed by stirring at room temperature for 1 h. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to give compound C12. Ms[M+H] 615.5. 1 H NMR (400MHz, DMSO-d6+D2O): δ9.14-9.13(d,1H,1.30Hz),8.75-8.74(d,1H,4.43Hz),8.53-8.49(m,2H),8.33(br,1H),8.05-8.04(d,1H,4.32Hz),6.8 3(br,1H),5.16-5.12(t,1H),4.16-4.15(d,1H,7.18Hz),3.23(s,3H),2.7 4-2.68 (m, 1H), 2.27 (s, 3H), 2.04-1.73 (m, 9H), 1.52-1.50 (d, 3H, 6.70Hz).

[0226] Example 13 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0227] 1.Synthesis of C13-2 Compound C13-1 (1.33 g, 8.23 ​​mmol) was dissolved in DMF (20 mL), and then 4-fluoro-1H-pyrazole (0.78 g, 9.05 mmol) and cesium carbonate (2.68 g, 8.23 ​​mmol) were added in sequence. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.43 g of compound C13-2. 1H NMR (400MHz, CDCl3): δ 8.22-8.20 (d, 1H, 4.98Hz), 8.03 (s, 1H), 7.66-7.65 (d, 1H, 4.28Hz), 2.57 (s, 3H).

[0228] 2.Synthesis of C13-3 Compound C13-2 (1.43 g, 6.79 mmol) and Rt-butylsulfinamide (1.48 g, 12.23 mmol) are dissolved in ultra-dry tetrahydrofuran (30 mL), then tetraethyl titanate (4.65 g, 20.37 mmol) is added, and the reaction solution is stirred overnight under nitrogen gas protection at 70 ° C. After the reaction is completed, it is cooled to room temperature and quenched by adding water, a large amount of solid appears, filtered through Celite, washed with ethyl acetate, the filtrate is washed with saturated saline, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.88 g of compound C13-3. 1 H NMR (400MHz, CDCl3): δ 8.15-8.13(dd,1H,4.74Hz,0.62Hz),7.79(s,1H),7.59-7.58(dd,1H,4.23Hz,0.59Hz),2.67(s,3H),1.23(s,9H).

[0229] 3.Synthesis of C13-4 Compound C13-3 (1.78 g, 5.65 mmol) is dissolved in 30 mL of ultra-dry tetrahydrofuran, and under nitrogen gas protection, 1 M L-selectride tetrahydrofuran solution (17 mL, 16.96 mmol) is added dropwise at -70 ° C., and the mixture is stirred for 30 minutes while maintaining the temperature. The reaction is quenched by adding methanol dropwise, and the mixture is warmed to room temperature and stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and purified to obtain 2.43 g of crude product compound C13-4. 1H NMR(400MHz,CDCl3):δ 8.18-8.17(d,1H,4.98Hz),7.38(s,1H),7.59-7.58(d,1H,4.42Hz),4.85-4.7 9(m, 1H), 3.44-3.43(d, 1H, 5.03Hz), 1.69-1.67(d, 3H, 6.58Hz), 1.24(s, 9H).

[0230] 4.Synthesis of C13-5 The crude product, compound C13-4 (2.33 g, 7.37 mmol), is dissolved in dichloromethane (10 mL) and anhydrous methanol (3 mL), and 4 M hydrochloric acid in 1,4-dioxane (18.4 mL, 73.73 mmol) is added with stirring, and the mixture is stirred at room temperature under nitrogen gas protection for 2 hours, and dilute with dichloromethane, and the solid is filtered, washed with dichloromethane, and dried under vacuum to give 1.1 g of compound C13-5. 1 H NMR(400MHz,DMSO-d6):δ 8.74-8.73(d,1H,4.48Hz),8.62(br,3H),8.07-8.06(d,1H,3.95Hz),7.74(s,1H),4.83-4.77(m,1H),1.62-1.61(d,3H,6.22Hz).

[0231] 5. Synthesis of C13 Compound C4-7 (60 mg, 0.148 mmol) and compound C13-5 (37 mg, 0.148 mmol) are dissolved in DMF (2 mL), DIPEA (153 mg, 1.184 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. HATU (84 mg, 0.222 mmol) is then added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified and separated by HPLC to obtain compound C13. Ms[M+H] 594.3. 1H NMR(400MHz,DMSO-d6+D2O):δ 8.67-8.63(m,2H),8.32(br,1H),7.47-7.46(d,1H,1.06Hz),6.82(br,1H),5.26-5.20(q,1H),4.33-4.28(q,2H),3.17(s, 3H),2.72-2.67(m,1H),2.25(s,3H),2.00-1.93(m,4H),1.80-1.73(m,4H),1.56-1.54(d,3H,6.88Hz),1.38-1.34(t,3H).

[0232] Example 14 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0233] 1.Synthesis of C14-1 Compound C4-1 (2.00 g, 6.90 mmol) was dissolved in DCE (150 mL), and 2,2-bipyridine (1.10 g, 6.90 mmol), Na2CO3 (1.50, 13.79 mmol), Cu(OAc)2 (0.85 g, 6.90 mmol) and cyclopropylboronic acid (1.20 g, 13.79 mmol) were added in sequence, and the mixture was stirred overnight in an oil bath at 60 ° C under nitrogen gas protection. After the reaction was completed, the reaction solution was suction filtered, concentrated, diluted with EA, washed with 1% dilute hydrochloric acid, and the organic phase was separated and washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 1.05 g of compound C14-1, MS [M + H] 331. 1 H NMR(400MHz,Chloroform-d):δ 7.91(s,1H),7.52-7.40(m,2H),6.98-6.89(m,2H),5.53(s,2H),3.86-3.75(m,4H),1.34-1.23(m,2H),1.22-1.07(m,2H).

[0234] 2.Synthesis of C14-2 Compound C14-1 (1.50 g, 4.55 mmol) and compound C1-3 (1.60 g, 5.45 mmol) were dissolved in a mixed solvent of 50 mL of 1,4-dioxane and 10 mL of water, and palladium acetate (102 mg, 0.45 mmol), dppf (504 mg, 0.91 mmol) and potassium carbonate (941 mg, 6.82 mmol) were added in sequence, and the reaction solution was stirred overnight under nitrogen gas protection at 90 ° C. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.40 g of compound C14-2, MS [M + H] 465. 1 H NMR(400MHz,Chloroform-d):δ 7.88(s,1H),7.43(d,J=8.7Hz,2H),7.36-7.32(m,1H),6.92(d,J=8.7Hz,2H),5.55(s,2H),3.90-3.84(m,1H),3.82( s,6H),3.34(s,3H),2.91-2.72(m,3H),2.71-2.50(m,1H),2.42-2.09(m,3H),1.36-1.31(m,2H),1.17-1.07(m,2H).

[0235] 3.Synthesis of C14-3 Compound C14-2 (1.36 g, 2.93 mmol) was dissolved in a mixture of ethyl acetate (20 mL) and methanol (20 mL), then wet palladium on carbon (150 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 985 mg of compound C14-3, MS [M+H] 347. 1H NMR(400MHz,Chloroform-d):δ 11.67(s,1H),8.01(s,1H),3.93-3.83(m,1H),3.80(s,3H),3.32(s,3H),2.25-2.06 (m,2H),2.05-1.84(m,5H),1.80-1.66(m,1H),1.36-1.28(m,2H),1.15-1.06(m,2H).

[0236] 4.Synthesis of C14-4 Compound C14-3 (985 mg, 2.85 mmol) is dissolved in phosphorus oxychloride (20 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 931 mg of compound C14-4, MS [M+H] 365. 1 H NMR (400MHz, Chloroform-d): δ 8.00(s,1H),3.97-3.87(m,1H),3.79(s,3H),3.30(s,3H),2.51-1.77(m,8H),1.45-1.27(m,2H),1.22-1.09(m,2H).

[0237] 5. Synthesis of C14-5 Compound C14-4 (931 mg, 2.56 mmol) and compound C2-7 (273 mg, 2.81 mmol) are dissolved in 7 mL of DMSO, then DIPEA (660 mg, 5.12 mmol) is added, and the mixture is stirred overnight under nitrogen gas protection at 100° C. After the reaction is completed, the mixture is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 700 mg of compound C14-5, MS [M+H] 426. 1H NMR(400MHz,Chloroform-d):δ 7.70(s,1H),6.56(s,1H),3.94-3.83(m,1H),3.80(d,J=6.7Hz,3H),3.32(d,J=16.5Hz,3H),2.97-2.83(m ,1H),2.37(d,J=7.1Hz,3H),2.24-1.80(m,6H),1.77-1.60(m,2H),1.35-1.22(m,2H),1.17-1.08(m,2H).

[0238] 6. Synthesis of C14-6 Compound C14-5 (700 mg, 1.65 mmol) was dissolved in a mixed solvent of methanol (12 mL) and water (2 mL), lithium hydroxide monohydrate (208 mg, 4.94 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the solid crude product was slurried with DCM and suction filtered, and then used directly in the next step without purification, to obtain a total of 885 mg of crude product C14-6, MS [M+H] 412.

[0239] 7. Synthesis of C14 Compound C14-6 (70 mg, crude product) and compound C13-5 (42 mg, 0.168 mmol) are dissolved in DMF (2 mL), DIPEA (173 mg, 1.344 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. HATU (96 mg, 0.252 mmol) is then added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified to give compound C14. Ms[M+H] 606.4. 1H NMR(400MHz,DMSO-d6+D2O):δ 8.67-8.63(m,2H),8.26(br,1H),7.99-7.98(m,1H),7.47-7.46(d,1H,1.07Hz),6.82(br,1H),5.24-5.20(q,1H),3.86-3.82(m,1H) ,3.18(s,3H),2.25(s,3H),2.00-1.93(m,4H),1.81-1.74(m,4H),1.56-1.54(d,3H,7.30Hz),1.16-1.09(m,2H),1.08-1.02(m,2H).

[0240] Example 15 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0241] 1.Synthesis of C15-2 Compound C15-1 (5 g, 0.03 mol) was suspended in dichloromethane (50 mL), then oxalyl chloride (7.75 mL, 0.09 mol) was added in one portion, 3 drops of DMF were added dropwise, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness under reduced pressure, and the crude product was dissolved in dichloromethane (30 mL) and used directly in the next step. N,O-Dimethylhydroxylamine hydrochloric acid (4.45 g, 0.045 mol) was suspended in dichloromethane (100 mL), triethylamine (29.5 mL, 0.18 mol) was added, and the mixture was stirred at room temperature for 5 minutes, followed by the elution of the ethyl acetate obtained in the above step. Acyl chloride Dropwise add dichloromethane solution of and stir at room temperature for 2 hours. After completion of the reaction, add saturated saline, extract with dichloromethane, combine the organic phase, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product, which is purified to obtain 5.14g of compound C15-2.1 H NMR (400MHz, CDCl3): δ 7.94 (s, 1H), 3.80 (s, 3H), 3.42 (s, 3H).

[0242] 2.Synthesis of C15-3 Compound C15-2 (4.03 g, 0.019 mol) was dissolved in anhydrous tetrahydrofuran (100 mL), and then under nitrogen gas protection, 1M methylmagnesium bromide tetrahydrofuran solution (32 mL, 0.032 mol) was added dropwise at 0°C, and the mixture was stirred for 1 hour while cooling with an ice-water bath. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified to obtain 1.98 g of compound C15-3. 1 H NMR (400MHz, CDCl3): δ 7.97 (s, 1H), 2.58 (s, 3H).

[0243] 3.Synthesis of C15-4 Compound C15-3 (1.83 g, 0.011 mmol) is dissolved in DMF (20 mL), then 4-fluoro-1H-pyrazole (1.17 g, 0.014 mol) and potassium carbonate (3.13 g, 0.022 mol) are added in sequence, and the mixture is stirred at 110° C. for 16 hours. After the reaction is completed, the solvent is evaporated to dryness under reduced pressure, and ethyl acetate is added to dilute the mixture. The organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.86 g of compound C15-4. 1 H NMR (400MHz, CDCl3): δ 8.21-8.20 (t, 1H), 7.84 (s, 1H), 7.57-7.56 (d, 1H, 4.02Hz), 2.57 (s, 3H).

[0244] 4.Synthesis of C15-5 Compound C15-4 (856 mg, 4.057 mmol) is dissolved in anhydrous tetrahydrofuran (30 mL), then Rt-butylsulfinamide (884 mg, 7.302 mmol) and tetraethyl titanate (2.77 g, 12.171 mmol) are added in sequence, and the reaction solution is stirred for 16 hours under nitrogen gas protection at 70 ° C. After the reaction is completed, the reaction solution is cooled to room temperature and quenched by adding water, a large amount of solid appears, filtered through Celite, washed with ethyl acetate, the filtrate is washed with saturated saline, dried over anhydrous sodium sulfate, and purified to obtain 1.05 g of compound C15-5. 1 H NMR (400MHz, CDCl3): δ 8.24-8.23(dd,1H,4.74Hz,0.73Hz),7.80(s,1H),7.63-7.62(dd,1H,4.21Hz,0.68Hz),2.81(s,3H),1.32(s,9H).

[0245] 5.Synthesis of C15-6 Compound C15-5 (1.05 g, 3.34 mmol) is dissolved in ultra-dry tetrahydrofuran (30 mL), and under nitrogen gas protection, 1M L-selectride tetrahydrofuran solution (10 mL, 10.03 mmol) is added dropwise at -70°C, and the mixture is stirred for 30 minutes while maintaining the temperature. The reaction is quenched by adding methanol dropwise, and the mixture is warmed to room temperature and stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and purified to obtain 810 g of compound C15-6. 1 H NMR(400MHz,CDCl3):δ 8.11-8.10(dd,1H,4.68Hz,0.60Hz),7.52-7.51(d,1H,4.28Hz),6.83-6.82(d,1H,0.62Hz ),4.59-4.52(q,1H),3.39-3.37(d,1H,5.99Hz),1.58-1.57(d,3H,6.99Hz),1.16(s,9H).

[0246] 6.Synthesis of C15-7 The crude product, compound C15-6 (810 mg, 2.56 mmol), is dissolved in dichloromethane (10 mL), and 4 M hydrochloric acid in 1,4-dioxane (6.4 mL, 25.6 mmol) is added with stirring. The mixture is stirred under nitrogen gas protection at room temperature for 2 hours, and dilute with dichloromethane. The solid is filtered, washed with dichloromethane, and dried under vacuum to give 550 mg of compound C15-7. 1 H NMR (400MHz, DMSO-d6): δ 9.61-9.58 (t, 4H), 9.08-8.07 (d, 1H, 4.10Hz), 8.58 (s, 1H), 5.52-5.49 (m, 1H), 4.44 (br, 3H).

[0247] 7. Synthesis of C15 Compound C4-7 (60 mg, 0.148 mmol) and compound C15-7 (37 mg, 0.148 mmol) are dissolved in DMF (2 mL), DIPEA (153 mg, 1.184 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (84 mg, 0.222 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to obtain compound C15. Ms[M+H] 594.4. 1 H NMR(400MHz,DMSO-d6+D2O):δ 8.72-8.71(d,1H,4.86Hz),8.39(br,1H),8.08-8.07(d,1H,3.89Hz),7.25(br,1H),6.90(br,1H),5.17-5.12(q,1H),4.42-4.36(q,2) H),3.32(s,3H),2.84-2.76(m,1H),2.35(s,3H),2.10-2.01(m,4H),1.89-1.83(m,4H),1.55-1.53(d,3H,6.89Hz),1.47-1.43(t,3H).

[0248] Example 16 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] 1. Synthesis of C16 Compound C14-6 (70 mg, 0.168 mmol) and compound C15-7 (42 mg, 0.168 mmol) are dissolved in DMF (2 mL), DIPEA (173 mg, 1.344 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. HATU (96 mg, 0.252 mmol) is then added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified to give compound C16. Ms[M+H] 606.4. 1 H NMR(400MHz,DMSO-d6+D2O):δ 8.64-8.63(d,1H,4.43Hz),8.30-8.22(m,1H),8.00-7.99(d,1H,4.11Hz),7.17(br,1H),6.81(br,1H),5.09-5.04(q,1H),3.86-3.83(m ,1H),3.24(s,3H),2.75-2.68(m,2H),2.26(s,3H),2.01-1.75(m,9H),1.47-1.45(d,3H,6.82Hz),1.16-1.11(m,2H),1.09-1.02(m,2H).

[0249] Example 17 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0250] 1.Synthesis of C17-2 Compound C17-1 (4.36 g, 40 mmol) and hydrazine hydrate (40 g, 800 mmol) are dissolved in ethanol (100 mL) and refluxed overnight with stirring. After cooling to room temperature, a solid precipitates, and a small amount of ethanol is added, stirred for 30 minutes, filtered, and the filtrate is concentrated to obtain crude product C17-2.

[0251] 2.Synthesis of C17-4 Compound C17-2 (1.04g, 10mmol) is dissolved in ethanol (8mL), and the solution is added dropwise to an ethanol solution (125mL) of C17-3 (2.1g, 10mmol) at -78℃. After the addition is completed, triethylamine (4.17mL, 30mmol) is added, and the mixture is stirred at the same temperature for 30 minutes. The mixture is allowed to warm to room temperature and stirred for 30 minutes. 3M hydrochloric acid is added until pH=5-6, and the mixture is concentrated. Ethyl acetate and water are added, and the layers are separated, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain product C17-4.

[0252] 3.Synthesis of C17-5 C17-4 (700 mg, 2.69 mmol), C2-7 (395 mg, 3.5 mmol) and diisopropylethylamine (694 mg, 5.38 mmol) are dissolved in DMSO (14 mL) and stirred for 3 hours at 25° C. After the reaction is completed, water is added, and the mixture is extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain 845 mg of product C17-5. 1 H NMR (400MHz, DMSO): δ 12.26 (s, 1H), 11.14 (s, 1H), 8.43 (s, 1H), 6.58 (s, 1H), 4.71 (s, 1H), 4.18 (s, 2H), 2.27 (s, 3H), 1.11 (s, 6H).

[0253] 4.Synthesis of C17-6 C17-5 (353 mg, 1.09 mmol), C1-3 (446 mg, 1.5 mmol), Pd(dppf)Cl2 (124 mg, 0.169 mmol) and sodium carbonate (175 mg, 1.65 mmol) were added to a mixture of dioxane (10 mL) and water (2 mL), and the mixture was reacted under nitrogen gas protection at 90°C for 24 hours, concentrated, water (20 mL) was added, and the mixture was extracted with ethyl acetate, dried, concentrated, and subjected to column chromatography to obtain 333 mg of compound C17-6.

[0254] 5. Synthesis of C17-7 C17-6 (284 mg, 0.62 mmol), palladium hydroxide on carbon (70 mg, 50% water) were added to a mixture of methanol (20 mL) and ethyl acetate (20 mL) and reacted at 45° C. for 7 days. The reaction was shown to be complete by HPLC, filtered, and concentrated to give 243 mg of crude compound C17-7. Ms[M+H] 458.40.

[0255] 6.Synthesis of C17-8 Compound C17-7 (56 mg, 0.122 mmol) was dissolved in a mixture of methanol (3 mL) and water (0.6 mL), lithium hydroxide monohydrate (20.5 mg, 0.49 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and methanol was removed under reduced pressure to obtain 73 mg of crude product compound C17-8, which was used directly in the next step without purification.

[0256] 7.Synthesis of C17 Compound C17-8 (50 mg, crude product) and compound C1-7 (32 mg, 0.11 mmol) are dissolved in DMF (2 mL), DIPEA (117 mg, 0.91 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (64 mg, 0.168 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to give compound C17. Ms[M+H] 632.50.

[0257] Example 18 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0258] 1.Synthesis of C18-1 Compound C4-1 (3.0 g, 10.34 mmol) was dissolved in anhydrous DMF (60 mL), and cesium carbonate (5.1 g, 15.52 mmol) and compound 1-fluoro-2-iodoethane (3.60 g, 20.68 mmol) were added in sequence, and the mixture was stirred in an oil bath at 50 ° C for 3 hours, and DMF was removed under reduced pressure, and saturated saline was added to quench the reaction, and then the mixture was extracted with ethyl acetate, and the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 2.13 g of compound C18-1, MS [M + Na] 359. 1 H NMR(400MHz,CDCl3):δ 7.96(s,1H),7.38(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),5.47(s,2H),4.84(dd,J=5.3,4.6Hz,1 H),4.73(dd,J=5.4,4.5Hz,1H),4.66(t,J=5.0Hz,1H),4.60(dd,J=5.4,4.5Hz,1H),3.76(s,3H).

[0259] 2.Synthesis of C18-2 Compound C18-1 (1.50 g, 4.46 mmol) and compound C1-3 (1.45 g, 4.91 mmol) were dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (10 mL), and palladium acetate (100 mg, 0.45 mmol), DPPF (495 mg, 0.89 mmol) and potassium carbonate (924 mg, 6.70 mmol) were added in sequence, and the reaction solution was stirred overnight at 90 °C under nitrogen gas protection. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.91 g of compound C18-2, MS [M + H] 471. 1 H NMR(400MHz,Chloroform-d):δ 7.92(s,1H),7.37(d,J=8.6Hz,2H),7.30-7.25(m,1H),6.85(d,J=8.6Hz,2H),5.49(s,2H),4.87(t,J=5.2Hz,1H),4.75(t,J=5.1H) z,1H),4.71-4.66(m,1H),4.62(dd,J=6.1,4.8Hz,1H),3.75(d,J=4.4Hz,6H),3.27(s,3H),2.88-2.49(m,4H),2.30-2.01(m,3H).

[0260] 2.Synthesis of C18-3 Compound C18-2 (1.91 g, 4.06 mmol) was dissolved in a mixture of ethyl acetate (25 mL) and methanol (25 mL), then wet palladium on carbon (191 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 1.37 g of compound C18-3, MS [M+H] 353. 1 H NMR(400MHz,Chloroform-d):δ 11.99(s,1H),8.11(s,1H),4.95-4.90(m,1H),4.84-4.77(m,1H),4.71-4.65(m,1H),4.65-4. 58(m,1H),3.79(s,3H),3.29(s,3H),2.92-2.71(m,1H),2.36-2.05(m,3H),2.04-1.80(m,5H).

[0261] 3.Synthesis of C18-4 Compound C18-3 (1.37g, 3.89mmol) is dissolved in phosphorus oxychloride (30mL) and stirred under nitrogen gas protection at 100℃ for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.03g of compound C18-4, MS [M+H] 371. 1 H NMR(400MHz,Chloroform-d):δ 8.13(s,1H),4.99-4.95(m,1H),4.88-4.73(m,3H),3.79(s,3H),3.31(s,3H),3.14-2.97(m,1H),2.42-2.09(m,3H),2.04-1.61(m,5H).

[0262] 4.Synthesis of C18-5 Compound C18-4 (1.03g, 2.80mmol) and compound C2-7 (299mg, 3.08mmol) are dissolved in DMSO (10mL), then DIPEA (722mg, 5.59mmol) is added, and the mixture is stirred overnight under nitrogen gas protection at 100°C. After the reaction is completed, the mixture is cooled to room temperature, diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 866mg of compound C18-5, MS [M+H] 431. 1 H NMR(400MHz,Chloroform-d):δ 7.82(s,1H),6.58(s,1H),4.93(q,J=4.8Hz,1H),4.81(q,J=4.8Hz,1H),4.68(dq,J=24.4, 5.5Hz, 2H), 3.79 (s, 3H), 3.33 (s, 3H), 3.01-2.78 (m, 1H), 2.34 (s, 3H), 2.22-1.78 (m, 8H).

[0263] 5.Synthesis of C18-6 Compound C18-5 (866 mg, 2.01 mmol) was dissolved in a mixed solvent of methanol (15 mL) and water (2.5 mL), lithium hydroxide monohydrate (254 mg, 6.03 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the solid crude product was slurried with DCM and suction filtered, and then used directly in the next step without purification, to obtain a total of 797 mg of crude product C18-6, MS [M+H] 418.

[0264] 6. Synthesis of C18 Compound C18-6 (62 mg, crude product) and compound C1-7 (36 mg, 0.15 mmol) are dissolved in DMF (4 mL), DIPEA (151 mg, 1.17 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (84 mg, 0.22 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to give compound C18 (MS[M+H] 606) and compound C18A (MS[M+H] 606). NMR of compound C18: 1 H NMR (400MHz, Chloroform-d): δ 8.42-8.30(m,2H),7.92(d,J=8.5Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.59( dd,J=4.4,0.9Hz,1H),6.85(d,J=8.0Hz,1H),6.45(s,1H),5.18(p,J=7.1Hz,1 H),4.94(t,J=5.1Hz,1H),4.82(t,J=5.1Hz,1H),4.70(dt,J=24.1,5.1Hz,2H) ,3.29(s,3H),2.87(br,1H),2.36(s,3H),1.99(m,8H),1.58(d,J=7.0Hz,3H).

[0265] Example 19 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0266] 1. Synthesis of C19 Compound C18-6 (100 mg, crude product) and compound C5-5 (70 mg, 0.24 mmol) were dissolved in DMF (5 mL), DIPEA (250 mg, 1.92 mmol) was added, and the mixture was stirred at room temperature for 15 min, followed by HATU (140 mg, 0.36 mmol), followed by stirring 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 give compound C19, MS [M+H] 607. 1 H NMR(400MHz,Chloroform-d):δ 9.23(d,J=1.4Hz,1H),8.57-8.21(m,2H),7.97(br,2H),7.66(dd,J=4.3 ,0.9Hz,1H),6.51(s,1H),5.40-5.22(m,1H),4.92(t,J=5.1Hz,1H),4.80 (t,J=5.1Hz,1H),4.72(t,J=5.2Hz,1H),4.66(t,J=5.3Hz,1H),3.32(s, 3H),2.85(s,1H),2.38(s,3H),2.11-1.90(m,8H),1.56(d,J=6.9Hz,3H).

[0267] Example 20 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0268] 1. Synthesis of C20 Compound C14-6 (100 mg, 0.24 mmol) and compound C5-5 (70 mg, 0.24 mmol) are dissolved in DMF (5 mL), DIPEA (250 mg, 1.95 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. HATU (140 mg, 0.36 mmol) is then added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 40 mg of compound C20 (MS [M+H] 601) and compound C20A (MS [M+H] 601). NMR of compound C20: 1 H NMR (400MHz, Chloroform-d): δ 9.23(d,J=1.4Hz,1H),8.69(s,1H),8.38(s,1H),8.34(d,J=4.6Hz,1H),7.76 (s,1H),7.66(d,J=4.3Hz,1H),6.53(s,1H),5.41-5.28(m,1H),3.85-3.77(m, 1H),3.32(s,3H),2.89(d,J=11.0Hz,1H),2.37(s,3H),2.13-1.83(m,8H),1. 56(d,J=6.9Hz,3H),1.30-1.22(m,2H),1.15-1.00(m,2H),0.94-0.80(m,1H).

[0269] Example 21 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0270] 1.Synthesis of C21-1 Compound C4-1 (1.50 g, 5.17 mmol) was dissolved in 30 mL of anhydrous DMF, and cesium carbonate (2.53 g, 7.76 mmol) and trifluoromethanesulfonic acid-3-oxetane (1.28 g, 6.21 mmol) were added in sequence, and the mixture was stirred overnight in an oil bath at 25 ° C., and DMF was removed under reduced pressure, and saturated saline was added to quench the reaction, and then the mixture was extracted with ethyl acetate, and the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 844 mg of compound C21-1, MS [M + H] 347. 1 H NMR(400MHz,Chloroform-d):δ 8.11(d,J=0.6Hz,1H),7.45(d,J=8.7Hz,2H),7.06-6.86(m,2H),6.13-5.9 8(m,1H),5.55(s,2H),5.25-5.19(m,2H),5.10-5.05(m,2H),3.83(s,3H).

[0271] 2.Synthesis of C21-2 Compound C21-1 (300 mg, 0.86 mmol) and compound C1-3 (283 mg, 0.95 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL), and palladium acetate (20 mg, 0.09 mmol), DPPF (96 mg, 0.17 mmol) and potassium carbonate (178 mg, 1.29 mmol) were added in sequence, and the reaction solution was stirred overnight at 90 ° C under nitrogen gas protection. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 275 mg of compound C21-2, MS [M + H] 481. 1H NMR(400MHz,Chloroform-d):δ 8.05(s,1H),7.44(d,J=8.7Hz,2H),7.37-7.33(m,1H),6.93(d,J=8.7Hz,2H),6.08(tt,J=7.9,6.6Hz,1H),5.56(s,2H),5.30( dd,J=6.6,1.3Hz,2H),5.09(dd,J=7.8,6.6Hz,2H),3.82(d,J=4.1Hz,6H),3.34(s,3H),2.90-2.57(m,4H),2.33-2.07(m,2H).

[0272] 3.Synthesis of C21-3 Compound C21-2 (230 mg, 0.48 mmol) was dissolved in a mixture of ethyl acetate (7 mL) and methanol (7 mL), then wet palladium on carbon (23 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 169 mg of compound C21-3, MS [M+H] 363. 1 H NMR(400MHz,Chloroform-d):δ 11.77(d,J=39.4Hz,1H),8.28-7.91(m,1H),6.12-5.70(m,1H),5.28-5.13(m,2H),5.10-4.93 (m,2H),3.75(d,J=7.5Hz,3H),3.24(d,J=12.0Hz,3H),2.86-2.65(m,1H),2.47-1.53(m,8H).

[0273] 4.Synthesis of C21-4 Compound C21-3 (100 mg, 0.28 mmol) and TEA (0.12 mL, 0.88 mol) are dissolved in DCM (5 mL), and Tf2O (0.14 mL, 0.88 mol) is added dropwise under nitrogen gas protection at -78 °C and stirred for 30 min. After completion of the reaction, the reaction is quenched by adding saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and spin-dried to obtain 132 mg of crude compound C21-4, MS [M + H] 495.

[0274] 5.Synthesis of C21-5 Compound C21-4 (172 mg, 0.35 mmol) and compound C2-7 (38 mg, 0.38 mmol) were dissolved in DMSO (5 mL), then DIPEA (90 mg, 70 mmol) was added, and the mixture was stirred overnight under nitrogen gas protection at 100° C. After the reaction was completed, the mixture was cooled to room temperature, 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 73 mg of compound C21-5, MS [M+H] 442.

[0275] 6.Synthesis of C21-6 Compound C21-5 (51 mg, 0.07 mmol) was dissolved in a mixed solvent of methanol (3 mL) and water (1 mL), lithium hydroxide monohydrate (9 mg, 0.21 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the solid crude product was slurried with DCM and suction filtered, and then used directly in the next step without purification to obtain a total of 78 mg of crude product C21-6, MS [M+H] 428.

[0276] 7.Synthesis of C21 Compound C21-6 (168 mg, 0.39 mmol) and compound C5-5 (96 mg, 0.39 mmol) are dissolved in DMF (5 mL), DIPEA (406 mg, 3.15 mmol) is added, and the mixture is stirred at room temperature for 15 minutes. HATU (225 mg, 0.59 mmol) is then added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 19 mg of compound C21 (MS [M+H] 617) and compound C21A (MS [M+H] 617). NMR of compound C21: 1H NMR(400MHz,Chloroform-d):δ 9.23(d,J=1.4Hz,1H),8.36(d,J=1.5Hz,1H),8.34(dd,J=4.6,0.8Hz,1H),7.84(s,1H),7.66(dd,J=4.3,0.9Hz,1H),7.57-7.48(m,1H),6.09(p, J=7.2Hz,1H),5.37-5.28(m,1H),5.25(td,J=6.5,2.4Hz,2H),5.08(t,J =7.2Hz,2H),3.31(s,3H),2.83(s,1H),2.39(s,3H),2.09-1.89(m,8H).

[0277] Example 22 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0278] 1.Synthesis of C22-1 Compound C4-1 (1.60 g, 5.52 mmol) was dissolved in anhydrous THF (50 mL), PPh3 (2.31 g, 8.83 mmol) and n-propanol (829 mg, 13.80 mmol) were added in sequence, and the mixture was cooled to 0 ° C in an ice bath under nitrogen gas protection, and then DIAD (2.23 mg, 11.03 mmol) was added dropwise, and the mixture was allowed to warm to room temperature naturally and stirred for 3 hours. After the reaction was completed, the reaction was quenched by adding saturated saline, and then extracted with ethyl acetate, and the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 1.82 g of compound C22-1, MS [M + H] 333. 1H NMR(400MHz,Chloroform-d):δ 7.99(s,1H),7.46(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H),5.54(s,2H),4. 45-4.28(m,2H),3.83(s,3H),1.94(q,J=7.3Hz,2H),0.91(t,J=7.4Hz,3H).

[0279] 2.Synthesis of C22-2 Compound C22-1 (1.82 g, 5.48 mmol) and compound C1-3 (1.78 g, 6.03 mmol) were dissolved in a mixed solvent of 1,4-dioxane (60 mL) and water (12 mL), and palladium acetate (123 mg, 0.55 mmol), DPPF (607 mg, 1.10 mmol) and potassium carbonate (1.14 g, 8.22 mmol) were added in sequence, and the reaction solution was stirred overnight under nitrogen gas protection at 90 °C. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.75 g of compound C22-2, MS [M + H] 467. 1 H NMR(400MHz,Chloroform-d):δ 7.94(s,1H),7.44(d,J=8.7Hz,2H),7.35-7.32(m,1H),6.92(d,J=8.7Hz,2H),5.56(s,2H),4.38(dd,J=7.4,6.7Hz,2H), 3.82(d,J=2.5Hz,6H),3.34(s,3H),2.94-2.58(m,4H),2.35-2.07(m,2H),1.95(q,J=7.2Hz,2H),0.90(t,J=7.4Hz,3H).

[0280] 3.Synthesis of C22-3 Compound C22-2 (1.75 g, 3.76 mmol) was dissolved in a mixture of ethyl acetate (15 mL) and methanol (15 mL), then wet palladium on carbon (175 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 1.41 g of compound C22-3, MS [M+H] 349.1 H NMR(400MHz,Chloroform-d):δ 11.72(s,1H),8.08(s,1H),4.32(dt,J=7.1,6.2Hz,2H),3.79(d,J=6.9Hz,3H),3.31(d,J= 12.3Hz, 3H), 2.91-2.72 (m, 1H), 2.25-2.08 (m, 2H), 2.02-1.67 (m, 8H), 1.01-0.88 (m, 3H).

[0281] 3.Synthesis of C22-4 Compound C22-3 (1.41 g, 4.05 mmol) is dissolved in phosphorus oxychloride (30 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.13 mg of compound C22-4, MS [M+H] 367. 1 H NMR(400MHz,Chloroform-d):δ 8.08(s,1H),4.57-4.28(m,2H),3.79(d,J=2.3Hz,3H),3.30(d,J=8.7Hz,3H) ,3.14-2.92(m,1H),2.37-2.12(m,2H),2.06-1.70(m,8H),1.08-0.87(m,3H).

[0282] 4.Synthesis of C22-5 Compound C22-4 (1.13 g, 3.07 mmol) and C2-7 (328 mg, 3.38 mmol) are dissolved in DMSO (15 mL), then DIPEA (793 mg, 6.14 mmol) is added and stirred overnight under nitrogen gas protection at 100° C. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 992 mg of compound C22-5, MS [M+H] 428. 1H NMR(400MHz,Chloroform-d):δ 7.78(s,1H),6.57(s,1H),4.49-4.25(m,2H),3.80(d,J=4.4Hz,3H),3.32(d,J=16 .3Hz,3H),3.02-2.81(m,1H),2.36(s,3H),2.21-1.75(m,10H),0.94-0.89(m,3H).

[0283] 5.Synthesis of C22-6 Compound C22-5 (992 mg, 2.32 mmol) was dissolved in a mixed solvent of 20 mL of methanol and 3 mL of water, lithium hydroxide monohydrate (293 mg, 6.96 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the solid crude product was slurried with DCM and suction filtered, and then used directly in the next step without purification, to obtain a total of 1.21 g of crude product C22-6, MS [M+H] 414.

[0284] 6.Synthesis of C22 Compound C22-6 (280 mg, crude product) and compound C5-5 (165 mg, 0.68 mmol) are dissolved in 9 mL of DMF, DIPEA (700 mg, 5.42 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (387 mg, 1.02 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 112 mg compound C22 (MS[M+H] 603) and compound C22A (MS[M+H] 603). NMR of compound C22: 1H NMR(400MHz,Chloroform-d):δ 9.23(d,J=1.4Hz,1H),8.37(d,J=1.5Hz,1H),8.34(dd,J=4.6,0.9Hz,1H),7.78(s,1H),7.66(dd,J=4.2,0.9Hz,2H),5.37-5.26(m,1 H),4.34(t,J=7.2Hz,2H),3.32(s,3H),2.86(s,1H),2.38(s,3H),2.12-1.85(m,10H),1.56(d,J=6.9Hz,3H),0.91(t,J=7.4Hz,3H).

[0285] Example 23 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] The synthetic route and experimental process are as follows:

[0286] 1.Synthesis of C23-1 Compound C4-1 (1.50 g, 5.17 mmol) was dissolved in anhydrous DMF (30 mL), and cesium carbonate (2.53 g, 7.76 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.44 g, 6.21 mmol) were added in sequence, and the mixture was stirred overnight in an oil bath at 25 ° C., and DMF was removed under reduced pressure, and saturated saline was added to quench the reaction, and then the mixture was extracted with ethyl acetate, and the organic phase was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 917 mg of compound C23-1 and 831 mg of C23-2, MS [M + H] 373. C23-1: 1H NMR (400MHz, Chloroform-d): δ 8.09(s,1H),7.46(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H),5.56(s,2H),4.98(q,J=8.2Hz,2H),3.83(s,3H). C23-2: 1 H NMR (400MHz, Chloroform-d): δ 8.13(s,1H),7.45(d,J=8.7Hz,2H),6.94(d,J=8.6Hz,2H),5.55(s,2H),4.96(q,J=8.1Hz,2H),3.83(s,3H).

[0287] 2.Synthesis of C23-3 Compound C23-1 (500 mg, 1.30 mmol) and compound C1-3 (440 mg, 1.50 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (4 mL), and palladium acetate (30 mg, 0.13 mmol), DPPF (150 mg, 0.26 mmol) and potassium carbonate (280 mg, 2.02 mmol) were added in sequence, and the reaction solution was stirred overnight at 90 °C under nitrogen gas protection. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 495 mg of compound C23-3, MS [M + H] 507. 1 H NMR(400MHz,Chloroform-d):δ 8.04(s,1H),7.44(d,J=8.7Hz,2H),7.40-7.37(m,1H),6.93(d,J=8.7Hz,2H),5.57(s,2H),5.00(q,J=8 .3Hz,2H),3.82(d,J=3.2Hz,6H),3.34(s,3H),2.95-2.49(m,5H),2.39-2.23(m,2H),2.19-2.10(m,1H).

[0288] 3.Synthesis of C23-4 Compound C23-3 (445 mg, 0.88 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL), then wet palladium on carbon (45 mg) was added and stirred overnight at room temperature under hydrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give 296 mg of compound C23-4, MS [M+H] 389. 1 H NMR(400MHz,Chloroform-d):δ 12.03(d,J=41.6Hz,1H),8.17(s,1H),4.96(q,J=8.4Hz,2H),3.81(d,J=1.7Hz,3H) ,3.31(d,J=11.1Hz,3H),2.95-2.76(m,1H),2.51-2.43(m,1H),2.16-1.65(m,8H).

[0289] 4.Synthesis of C23-5 Compound C23-4 (285 mg, 0.73 mmol) is dissolved in phosphorus oxychloride (6 mL) and stirred under nitrogen gas protection at 100° C. for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, and then crushed ice is added to adjust the saturated sodium bicarbonate solution to neutral, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 208 mg of compound C23-5, MS [M+H] 407. 1 H NMR (400MHz, Chloroform-d): δ 8.18(s,1H),5.07(q,J=8.1Hz,2H),3.79(s,3H),3.30(d,J=7.6Hz,3H),3.15-2.97(m,1H),2.26-1.64(m,8H).

[0290] 5.Synthesis of C23-6 Compound C23-5 (208 mg, 0.51 mmol) and compound C2-7 (55 mg, 0.56 mmol) are dissolved in DMSO (5 mL), then DIPEA (133 mg, 1.02 mmol) is added and stirred overnight under nitrogen gas protection at 100° C. After the reaction is completed, it is cooled to room temperature, diluted with ethyl acetate, the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 226 mg of compound C23-6, MS [M+H] 468. 1 H NMR(400MHz,Chloroform-d):δ 7.87(s,1H),6.54(s,1H),4.97(q,J=8.0Hz,2H),3.79(s,3H),3.32(d,J= 14.1Hz, 3H), 3.01-2.79 (m, 1H), 2.37 (d, J=5.0Hz, 3H), 2.21-1.73 (m, 8H).

[0291] 6.Synthesis of C23-7 Compound C23-6 (226 mg, 0.48 mmol) was dissolved in a mixed solvent of methanol (6 mL) and water (1 mL), lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added, and the mixture was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and the solid crude product was slurried with DCM and suction filtered, and then used directly in the next step without purification to obtain a total of 197 mg of crude product C23-7, MS [M+H] 454.

[0292] 7.Synthesis of C23 Compound C23-7 (187 mg, crude product) and compound C5-5 (116 mg, 0.41 mmol) are dissolved in DMF (8 mL), DIPEA (426 mg, 3.30 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (236 mg, 0.62 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 84 mg of compound C23 (MS[M+H] 643) and compound C23A (MS[M+H] 643). NMR of compound C23: 1H NMR(400MHz,Chloroform-d):δ 9.23(d,J=1.5Hz,1H),8.37(d,J=1.4Hz,1H),8.34(dd,J=4.6,0.8Hz,1H),8.19(s,1H),7.83(s,1H),7.66(dd,J=4.3,0.9Hz,1H),6.5 1(s,1H),5.37-5.27(m,1H),4.98(q,J=8.3Hz,2H),3.32(s,3H),2.85(s,1H),2.39(s,3H),2.09-1.89(m,8H),1.56(d,J=6.9Hz,3H).

[0293] Example 24 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] 1.Synthesis of C27 Compound C17-8 (50 mg, crude product) and compound C5-5 (32 mg, 0.11 mmol) are dissolved in 2 mL of DMF, DIPEA (117 mg, 0.91 mmol) is added, and the mixture is stirred at room temperature for 15 minutes, followed by HATU (64 mg, 0.168 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to give compound C27. Ms[M+H] 633.

[0294] Control Example 1 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0295] 1.Synthesis of C24-2 Compound C24-1 (800 mg, 2.47 mmol) and Cs2CO3 (1208 mg, 3.71 mmol) are dissolved in DMF (10 mL), iodomethane (697 mg, 4.94 mmol) is added, the mixture is stirred at room temperature for 2 hours, water is added, the mixture is extracted with EA, washed with saturated saline, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 832 mg of compound C24-1. 1 H NMR(400MHz,CDCl3):δ 7.06-7.05(dd,1H,J=3.47Hz,0.89Hz),6.47-6.45(dd,1H,J=3.47Hz,1.62Hz),3.79-3.77(d,3H,J=7.90Hz),3.72-3.71(d ,3H,J=5.20Hz),3.24-3.21(d,3H,J=9.21Hz),3.00-2.87(m,1H),2.37-2.32(m,1H),2.13-1.75(m,6H),1.63-1.56(m,1H).

[0296] 2.Synthesis of C24-3 Compound C24-2 (832 mg, 2.47 mmol), compound C1-8 (584 mg, 2.96 mmol), Pd2(dba)3 (226 mg, 0.25 mmol), t-Buxphos (210 mg, 0.5 mmol) and KOAc (474 ​​mg, 4.94 mmol) were dissolved in dry dioxane (25 mL), heated to 60° C. under nitrogen gas protection and stirred overnight, added with water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate and purified by column chromatography to obtain 671 mg of compound C24-3. 1 H NMR(400MHz,CDCl3):δ 7.81(br,1H),7.24-7.17(d,1H,J=31.17Hz),6.94-6.93(d,1H,J=3.74Hz),6.38(s,1H),3.81-3.79(m,6H),3.35-3.30( d,3H,J=20.88Hz),2.91-2.88(m,1H),2.62-2.57(d,3H,J=20.57Hz),2.45-2.42(m,1H),2.20-1.82(m,7H),1.65(s,9H).

[0297] 3.Synthesis of C24-4 Compound C24-3 (200 mg, 0.4 mmol) was dissolved in MeOH (10 mL) and HO (2 mL), LiOH (67 mg, 1.6 mmol) was added, the mixture was stirred at 60° C. overnight, spun dry, then slurried in refluxing DCM, filtered, and spun dry to give 232 mg of compound C24-4. [M+H]: 385.3.

[0298] 4. Synthesis of Control Example 1 Compound C24-4 (350 mg, crude product) and compound C1-7 (254 mg, 0.9 mmol) are dissolved in 15 mL of DMF, DIPEA (1.27 mL, 7.3 mmol) is added, and the mixture is stirred at room temperature for 5 minutes, HATU (519 mg, 1.4 mmol) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain 104 mg of control example 1. 1 H NMR(400MHz,DMSO-d6):δ 11.95(br,1H),9.77(br,1H),8.70-8.69(dd,1H,J=4.66Hz,0.80Hz),8.54-8.52(d,1H,J=8.78Hz),8. 45-8.44(d,1H,J=1.86Hz),8.02-7.99(dd,1H,J=8.78Hz,2.39Hz),7.93-7.92(dd,1H,J=4.52Hz,0.80H z),7.89-7.87(d,1H,J=8.51Hz),7.10-7.09(d,1H,J=2.93Hz),6.78(br,2H),5.11-5.05(m,1H),3.69 (s,3H),3.19(s,3H),2.69-2.67(m,1H),2.25(s,3H),2.06-1.64(m,8H),1.50-1.47(d,3H,J=6.92Hz).

[0299] Control Example 2 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka] The experimental process refers to the synthesis of Control Example 1 to obtain Control Example 2. NMR analysis data for control example 2: 1 H NMR(400MHz,CDCl3)8.40-8.39(m,2H),7.92(d,1H),7.83(s,1H),7.78(dd,1H),7.58(d,1H),6.85(d,1H),6.77(br ,1H),5.22-5.15(m,1H),3.86(s,3H),3.33(s.3H),2.93-2.88(m,1H),2.40(s,3H),2.05-1.97(m,8H),1.58(d,3H). Here, Control Examples 1 and 2 are compounds reported in WO2020175968A1.

[0300] Control Example 3 Compounds synthesized in the present invention: [ka] The synthetic route and experimental process are as follows: [ka]

[0301] The experimental process refers to the synthesis of C23 to obtain Control Example 3. NMR analysis data for Control Example 3: 1 H NMR(400MHz,Chloroform-d):δ 12.60(s,1H),9.25-9.15(m,2H),8.34(t,J=3.0Hz,2H),8.16(s,1H),7.66(d,J=4.1Hz,1H),7.43(d,J=8.2Hz,1H),6.03(s,1H) ),5.40-5.24(m,2H),4.80(q,J=8.1Hz,2H),3.25(s,3H),2.59(s,1H),2.35(s,3H),2.11-1.84(m,8H),1.55(d,J=6.9Hz,3H).

[0302] Test Example 1. Cell proliferation inhibition experiment 1. Experimental materials RPMI-1640 is purchased from BI. Fetal bovine serum is purchased from BI. CellTiter-GloR is purchased from Promega. Dimethyl sulfoxide (DMSO) is purchased from TCI. BaF3 cells are purchased from RIKEN BRC CELL BANK. Ba / F3-KIF5B-RET, Ba / F3-KIF5B-RET-V804L and Ba / F3-KIF5B-RET-V804M cells are constructed by Hefei PRECEDO company. Ba / F3-KIF5B-RET, Ba / F3-KIF5B-RET-V804L and Ba / F3-KIF5B-RET-V804M medium: RPMI-1640 + 10% FBS + 1% P / S. Plate Reader:Molecular Devices

[0303] II. Experimental Method 1. Compound Dilution 1000x compound solutions are prepared in DMSO and diluted in growth medium to a final concentration of 20x, ie, 2 μl of 1000x cpd is added to 98 μl of growth medium.

[0304] 2. Cell Plating After centrifugation, resuspend the cells in growth medium and count the cells using a cell counter. Dilute the cell suspension to the desired concentration with growth medium. Take 95uL of the diluted cell suspension into a 96-well plate. Add 5uL of 20x compound solution to the 96-well plate, resulting in a final DMSO concentration of 0.1% per well. Incubate the 96-well plate at 37°C and 5% CO2 for 72 hours.

[0305] 3. Detection Prior to detection, the 96-well plate is equilibrated to room temperature, 50 μl of CellTiter-GloR reagent is added to each well, cells are completely lysed by shaking on a shaker for 2 minutes, incubated at room temperature for 10 minutes, and fluorescence measurements are recorded using Paradigm detection.

[0306] 3. Data Analysis Cell activity was analyzed by Graphpad 7.0 software based on the formula Cell viability (CV%) = (RLU compound-RLU blank) / (RLU control-RLU blank)*100% and the corresponding IC 50 The data was calculated and in Table 1 below, the following notations are used: <10.00 nM=A, 10.01-50.0 nM=B, >50 nM=C, etc. [Table 2]

[0307] As can be seen from Table 1, the compounds of the present invention, especially Ba / F3-KIF5B-RET-V804M and Ba / F3-KIF5B-RET-V804L, have excellent RET inhibitory activity, and the parent core structure and the position of the substituent have a significant effect on the activity of the compounds of the present invention, where the activity of the compound of the parent core structure of pyrimidopyrazole is superior to that of pyrimidopyrrole and pyrimidazole, and furthermore, due to the different positions of the substituents, for example, there is a large difference between Control Example 3 and Compound C23 of the present invention, and the inhibitory effect of Compound C23 is superior to that of Control Example 3.

[0308] Test Example 2. In vivo efficacy study Experimental design Cell culture: Ba / F3-KIF5B-RET cell line is cultured in 1640 medium (Biological Industries) + 10% fetal bovine serum (BI) + 1% double antibody (Penicillin Streptomycin solution, Corning, USA) at 37°C, 5% CO2, and passaged twice a week. When the cell saturation is 80%-90% and the required number is reached, the cells are harvested, counted, and inoculated.

[0309] Animals: BALB / c nude mice, female, 6-8 weeks old, weighing 18-22 g, 18 mice, provided by Beijing VITAL RIVER Laboratory Animal Technology Co., Ltd. Tumor inoculation: 0.2 mL (2 × 10 6 100 pieces) of Ba / F3-KIF5B-RET cells (added with Matrigel, volume ratio is 1:1) were subcutaneously inoculated into the right dorsal region of each mouse, and the average tumor volume was approximately 150-200 mm. 3 Once this is reached, the groups will be split and treatment will begin.

[0310] Animal study grouping and dosing regime The grouping and administration method for the animal experiments are shown in Table 2. [Table 3]

[0311] Animal Housing: After the animals arrive, they are isolated, quarantined, and housed in a laboratory environment for 7 days before experiments can begin. Experimental parameters: tumor volume and body weight are measured twice a week. Tumor volume is measured by caliper, and the formula is TV=0.5a×b2, where a is the long diameter of tumor and b is the short diameter of tumor. The antitumor effect of the compound is evaluated by TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1-(mean tumor volume at the end of treatment of a treatment group-mean tumor volume at the start of treatment of the treatment group)) / (mean tumor volume at the end of treatment of the vehicle control group-mean tumor volume at the start of treatment of the vehicle control group)] x 100%.

[0312] Relative tumor growth rate T / C (%): the calculation formula is as follows: T / C%=TRTV / CRTV×100% (TRTV: RTV of the treatment group, CRTV: RTV of the negative control group). According to the results of tumor measurement, the relative tumor volume (RTV) is calculated, and the calculation formula is RTV=Vt / V0, where V0 is the average tumor volume measured at the time of administration (i.e., D0) by dividing the group, Vt is the average tumor volume at a specific measurement, and TRTV and CRTV are obtained on the same day. After the experiment, the tumor weight was detected and T / C weight Calculate the percentage and T weight and C weight represent the tumor weights of the treatment and vehicle control groups, respectively.

[0313] The experimental results are shown in Table 3 below. [Table 4]

[0314] As can be seen from Table 3 above, compared with Control Example 1, the compound of the present invention has excellent antitumor activity, and has the prospect of clinical application and good formulation.

[0315] The above description is merely an embodiment of the present invention and does not limit the scope of the patent of the present invention. Any equivalent conversion using the contents of the specification of the present invention or equivalent conversion used directly or indirectly in other related technical fields is included in the scope of the claims of the present invention.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt, or solvate thereof, 【Chemistry 1】 Where: R' １ is selected from hydrogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C1-C6 heteroalkyl group, and a 3-6 membered heterocyclyl group, wherein the alkyl group, deuterated alkyl group, alkoxy group, cycloalkyl group, heteroalkyl group, and heterocyclyl group are each independently selected from 0 to 5 R ａ is replaced by A is, 【Chemistry 2-1】 and 【Chemistry 2-2】 is selected from the group consisting of R a is selected from a C1-C6 alkyl group, a halogen, an amino group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a 3-8 membered heterocycloalkyl group, or a cyano group. wherein heteroalkyl refers to a substituted alkyl group having one or more skeletal atoms selected from oxygen, nitrogen, sulfur, phosphorus, Si, or combinations thereof; Here, the compound 【Chemistry 3】 Does not contain Characterized in that A compound of formula I above, or a pharma- ceutically acceptable salt, or solvate thereof.

2. The A ring is pyridine.

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

3. having a structure as shown in formula II-1 or formula III-1, 【Chemistry 4】 Where: 【Chemistry 5】 represents a single or double bond, X' １ , X' ２ are each independently N or CR ５ is selected from X' ３ , X' ４ are each independently selected from N or S; R ５ is selected from hydrogen, R' １ is as defined in claim 1, 2. A compound of formula I according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

4. R' 1 is selected from hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3-6 membered heterocyclyl, wherein alkyl, deuterated alkyl, alkoxy, cycloalkyl, heteroalkyl and heterocyclyl are substituted with 0 to 5 R a ; R a is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and C3-C6 cycloalkyl; 3. A compound of formula I according to claim 1 or 2, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

5. The A ring is 【Chemistry 6-1】 and 【Chemistry 6-2】 is a group selected from the group consisting of 3. A compound of formula I according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

6. R' 1 is selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, C1-C6 heteroalkyl, and 3- to 6-membered heterocyclyl; A is, 【Chemistry 7-1】 and 【Chemistry 7-2】 Characterized in that it is selected from the group consisting of 2. A compound of formula I according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

7. The compound has the following structure: 【Chemistry 8】 Characterized in that it is selected from 2. A compound of formula I according to claim 1, or a pharma- ceutically acceptable salt, or solvate thereof.

8. The pharma- ceutically acceptable salts are inorganic acid salts or organic acid salts, and the inorganic acid salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate, and the like. The organic acid salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, etc. e), tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate, A compound of formula I according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt or solvate thereof.

9. A process for preparing a compound of formula I according to claim 1, comprising the steps of: 【Chemistry 9】 i) in an inert solvent, in the presence of a condensing agent, 【Chemistry 10】 and 【Chemistry 11】 to obtain a compound of formula I, In the formula, R' １ and A are as defined in claim 1.

10. 1. A pharmaceutical composition comprising:

10. The pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 10, comprising The above use, characterized in that it is used for the preparation of i) a drug which is a RET kinase inhibitor, or ii) a drug for regulating RET kinase activity or treating a RET-related disease.

12. The RET-related disease is characterized in that it is cancer.

12. The use according to claim 11.

Images