TW202346294A - Pyrazinone derivative and use thereof in medicine - Google Patents

Abstract

The present invention relates to a compound described in general formula (A) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof. and application in the preparation of drugs for treating diseases related to PARP7 activity or expression.

Description

Pyrazinone derivatives and their applications in medicine

The present invention relates to a compound described in general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof. and application in the preparation of drugs for treating diseases related to PARP7 activity or expression.

PARP stands for poly-ADP-ribose polymerase, which is poly-ADP ribose polymerase. It participates in a series of cellular processes including DNA repair, genome stability, etc. This protein family consists of 17 members, divided into polyPARPs and monoPARPs. The MonoPARP protein family plays a role in multiple stress responses associated with the development of cancer, inflammatory diseases, and neurodegenerative diseases. Its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival.

Studies have found that many cancer cells rely on PARP7 for intrinsic cell survival, and PARP7 allows cancer cells to "hide" from the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the "brakes" that cancer uses to evade the immune system and suppress innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have demonstrated durable tumor growth inhibition, potent antiproliferative activity, and restoration of interferon signaling. PARP7 inhibitors are expected to become targets for the development of new anticancer drugs.

The purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used as PARP7 inhibitors. The compounds of the present invention can effectively inhibit PARP7 and can be used to treat tumors and other diseases.

The present invention provides a compound described in general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein (A)

In some embodiments, W is selected from bond, C(=O);

In some embodiments, W is selected from bonds;

In some embodiments, W is selected from C(=O);

In some embodiments, compounds of Formula (A) are selected from compounds of Formula (I), (I);

In some embodiments, compounds of Formula (I) are selected from compounds of Formula (II), ;

In some embodiments, Selected from ;

In some embodiments, Selected from ;

In some embodiments, Selected from ;

In some embodiments, Ring B is selected from , Is a single bond or a double bond;

In some embodiments, Selected from , , , , , , , , , , , , ;

In some embodiments, Selected from ;

In some embodiments, Z is selected from N, C, or CH;

In some embodiments, Y is selected from the group consisting of bonds, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(R ^y )-, -N(R ^y )-, C _1-4 alkylene, -OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _1-2 alkylene OC _1-2 Alkyl, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, -C _1-3 alkylene S(=O) ₂ -, -N(R ^y )C _1-3 alkylene-, -C _1-3 alkylene N(R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the The alkylene group is optionally substituted by 1 to 4 C _{1-6 alkyl groups selected from halogen, =O, =S, OH, cyano, C 1-6 alkyl, halogen, C 1-6 alkoxy ,} Substituted with C _3-6 cycloalkyl substituent;

In some embodiments, Y is selected from bond, -O-, -N(R ^y )-, C _1-3 alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O - _, -C _1-2 alkyleneOC _1-2 alkylene, -C 1-2 alkylene S-, -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 alkylene-, -C _1-2 alkylene N(R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the The alkylene group is optionally substituted by 1 to 4 C _{1-4 alkyl groups selected from halogen, =O, =S, OH, cyano, C 1-4 alkyl, halogen, C 1-4 alkoxy ,} Substituted with C _3-6 cycloalkyl substituent;

In some embodiments, Y is selected from the group consisting of bonds, -O-, -N(R ^y )-, -N(R ^y )C(=O)-, -C(=O)N(R ^y )-, - CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ - , -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(=O)N(R ^y )-, the CH ₂ is optionally substituted by 0 to 2 selected from H, =O, =S, OH, cyano, C _1-4 alkyl, halogen Substituted with substituents of C _1-4 alkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

In some embodiments, Y is selected from the group consisting of bonds, -O-, -NHC(=O)-, -C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, -NHC(=O)CH ₂ -, -CH ₂ C(=O)NH-, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ ) -, -CH ₂ C(=O)NH-, -CH ₂ C(=O)N(CH ₃ )-, -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -ring Propyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N( CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)-, -C(=O)N(CH ₂ -cyclopropyl)-, -C(=O)N( CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N (CH ₂ -Azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl)-, -C(= O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(= O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -ring propyl)-, , , -CH ₂ S(=O) ₂ -;

In some embodiments, R ^y is each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkyl substituents, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, each R ^y is independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkyl substituents, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, each R ^y is independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclohexyl, Pentyl and cyclohexyl are optionally substituted by 1 to 4 members selected from deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocycle Substituted with a substituent of a base or a C _3-6 cycloalkyl group, the heterocyclyl group contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, each R ^b is independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _{3- 6} cycloalkyl, the -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen Substituted by substituted C _1-6 alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl substituents;

In some embodiments, each R ^b is independently selected from H, halogen, cyano, OH, =O, C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _{3- 6} cycloalkyl, the -CH ₂ -, alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen Substituted by substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

In some embodiments, R ^b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, and the methyl, Ethyl, propyl or isopropyl is optionally substituted by 1 to 4 C _1-4 alkyl, C _1-4 alkyl selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen Substituted with oxygen or C _3-6 cycloalkyl substituents;

In some embodiments, each R ^b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, or isopropyl;

In some embodiments, Ring A is selected from a C _6-10 aromatic ring, a 5-10 membered heteroaromatic ring, or a 5-10 membered heterocyclic ring, and the heteroaromatic ring or heterocyclic ring contains 1 to 5 atoms selected from O, Heteroatoms of S _and N; in _some embodiments, ring The aromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;

In some embodiments, Ring Or the heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;

In some embodiments, ring

In some embodiments, Ring of heteroatoms;

In some _embodiments , Ring Ring heteroaromatic ring or 8-10 membered heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;

_{In some} embodiments _{, Ring} 4 to 7 membered monocyclic heterocycloalkyl, 5 to 10 membered paracyclic heterocycloalkyl, 5 to 11 membered spirocyclic heterocycloalkyl, 5 to 11 membered bridged heterocycloalkyl, phenyl, 5-6 Member heteroaromatic ring, 8-10 membered paracyclic heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;

In some embodiments, Ring 5 heteroatoms selected from O, S, and N;

In some embodiments, Ring

In some embodiments, Ring Azole ring, pyrimidooxazole ring, pyrimidooxazole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, Pyrimidoimidazole ring, pyrimidotriazole ring, pyrimidinofuran ring, pyrimidopyrrole ring, , , quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring (), triazolothiazole ring (such as), triazoloxazole ring, triazole imidazole ring, triazolopyrazole ring, , , , , ;

In some embodiments, Ring Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetihexyl, cyclopentyl Azetidinylspiroazepinyl, cyclopentylspiroazepinyl, cyclohexylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidine Cyclopentylspiroazacyclohexyl, azepanylazaspirocyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, Cyclopentacyclohexyl, cyclohexylcyclohexyl, cyclobutylazetidinyl, cyclobutylazetidine, cyclobutylazepine, cyclopentylazetidine base, cyclopenta-azacyclohexyl, cyclohexyl-aza-cyclohexyl, azeti-a-a-zepine- Cyclohexyl, azetyl azacyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, triazine ring , benzothiazole ring, pyridinothiazole ring, pyrimidothiazole ring, pyridazinothiazole ring, pyrazinothiazole ring, benzoxazole ring, pyridinoxazole ring, pyrimidoxazole ring, pyridazinoxazole ring Azole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, pyrimidotriazole ring, pyrimidine Furan ring, pyrimidopyrrole ring, , , quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, triazolo Azolopyrazole ring,, , , , , Pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiophene ring, thiazole ring, furan ring, oxazole ring, pyrrole ring, pyrazole ring or imidazole ring;

In some embodiments, Selected from , , , ;

In some embodiments, R ^x and R ^a are each independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy group, C _1-6 alkylthio group, -SO ₂ -C _1-6 alkyl group, -C(=O)C _1-6 alkyl group, -(CH ₂ ) _q -C _3-10 Carbocyclic ring or -(CH ₂ ) _q -3 to 12-membered heterocyclic ring, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, =O, NH ₂ , NH (C _1-6 alkyl), N (C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen substituted Substituted with C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents, the heterocyclic ring contains 1 to 3 selected from O, S , N heteroatoms;

In some embodiments, R ^a is selected from R ^a1 , R ^a2 ;

In some embodiments, R ^a1 and R ^a2 are each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Alkoxy group, C _1-6 alkylthio group, -SO ₂ -C _1-6 alkyl group, -C(=O)C _1-6 alkyl group, -(CH ₂ ) _q -C _3-10 carbocyclic ring or -(CH ₂ ) _q -3 to 12-membered heterocyclic ring, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 Each is selected from halogen, OH, cyano, =O, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 members Substituted by a heterocyclic substituent, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^x , R ^a1 , and R ^a2 are each independently selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy group, C _1-4 alkylthio group, -SO ₂ -C _1-4 alkyl group, -C(=O)C _1-4 alkyl group, -(CH ₂ ) _q -C _3-6 Carbocyclic ring or -(CH ₂ ) _q -3 to 6-membered heterocyclic ring, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 3 Substituted with a substituent of a 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^x , R ^a1 , and R ^a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH _3. -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxanyl Azolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, Ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl base, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl Optionally substituted by 1 to 4 selected from halogen, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituted by base;

In some embodiments, ^R base, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, Isopropyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl base, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, optionally 1 to 4 selected from F, OH, cyano, methyl, ethanol Substituted with a substituent of base, methoxy or ethoxy;

In some embodiments, ^Rx is each independently selected from H, F, Cl, Br, cyano, isopropyl, _CD3 , _CF3 , _CHF2 , _CH2F , cyclopropyl, cyclobutyl;

In some embodiments, R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methyl Oxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

In some embodiments, R ^a1 is selected from F, Cl, Br, CF ₃ , CHF ₂ , CH ₂ F, methyl, cyano, cyclopropyl, isopropyl;

In some embodiments, R ^a2 is selected from H;

In some embodiments, L is selected from -Q1-Ak1-Q2-Ak2-, connected to ring B on the right side;

In some embodiments, L is selected from -N(R ^q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R ^q )-Ak2-, -N( R ^q )-Ak1-N(R ^q )-Ak2-, the left side is directly connected to the pyridazinone ring;

In some embodiments, L is selected from , , , , , , , , , , , , , ,, , , the left side is directly connected to the pyridazinone ring;

In some embodiments, L is selected from , , , , , , , , the left side is directly connected to the pyridazinone ring;

In some embodiments, L is selected from ;

In some embodiments, Ak1 and Ak2 are each independently selected from C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R ^k1 Substituted, the Ak2 is optionally substituted by 0 to 4 R ^k2 ;

In some embodiments, Ak1 and Ak2 are each independently selected from C _1-3 alkylene, C _2-3 alkenylene, C _2-3 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R ^k1 Substituted, the Ak2 is optionally substituted by 0 to 4 R ^k2 ;

In some embodiments, Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and the Ak1 is optionally replaced by 0 to 4 R ^k1 substituted, and the Ak2 is optionally substituted with 0 to 4 R ^k2 ;

In some embodiments, R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -OC _3-6 carbocyclic ring, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the above The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkene Base, C _2-6 alkynyl group, halogen-substituted C _1-6 alkyl group, C _1-6 alkoxy group, -OC _3-8 carbocyclic ring, C _3-8 carbocyclic ring, 4 to 10 membered heterocyclic ring substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _{1- 4} alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxyl group, carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 Halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, 4 to 6 membered heterocyclic ring substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^k1 and R ^k2 are each independently selected from F, Cl, Br, I, cyano, OH, =O, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl , ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepanyl, azepanyl, oxacyclo Butyl, oxanyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl, oxetanyl, pyridine and phenyl are optionally selected from 1 to 4 Halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, 4 to 6 membered heterocyclic ring substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is either Selected from 1 to 4 selected from halogen, =O, OH, cyano, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl Substituted with substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is either Selected from 1 to 4 selected from halogen, =O, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted with a substituent, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

In some embodiments, Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O ), C(=O)O, OC(=O), S(=O), S(=O) ₂ , S(=O) ₂ N(R ^q ), N(R ^q )S(=O) _2. N(R ^q )C(=O)N(R ^q ), N(R ^q )C(=O)N(R ^q );

In some embodiments, Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O ), S(=O) ₂ ;

In some embodiments, R ^q is each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy;

In some embodiments, R ^q is each independently selected from H, C _1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF ₃ , OH, cyano, NH ₂ , C Substituted with _1-4 alkyl or C _1-4 alkoxy substituents;

In some embodiments, each R ^q is independently selected from H, methyl, and ethyl;

In some embodiments, R ^q is directly connected to R ^k1 or R ^k2 to form a 4- to 7-membered heterocycle, which is optionally substituted by 1 to 4 members selected from the group consisting of halogen, =O, OH, cyano, C Substituted with _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;

In some embodiments, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4- to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, and cyanide. Substituted with substituents such as C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, and C _3-6 cycloalkyl, the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;

In some embodiments, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4- to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, and cyanide. Substituted with substituents such as C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, and C _3-6 cycloalkyl, the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;

In some embodiments, each q is independently selected from 0, 1, 2, 3, or 4;

In some embodiments, a is selected from 0, 1, 2, 3, or 4;

In some embodiments, b is selected from 0, 1, 2, 3, or 4;

In some embodiments, x is selected from 0, 1, 2, 3, or 4;

In some embodiments, b is selected from 0, 1, 2, 3;

In some embodiments, x is selected from 1, 2;

Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D.

As a first embodiment of the present invention, the compound represented by the following general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, (A)

W is selected from key, C(=O);

Ring B is selected from , Is a single bond or a double bond;

Z is selected from N, C or CH;

Y is selected from the group consisting of bonds, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(R ^y )-, -N(R ^y ) -, C _1-4 alkylene, -OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _1-2 alkylene OC _1-2 alkylene, -C _{1 -3} Alkylene S-, -C _1-3 Alkylene S(=O)-, -C _1-3 Alkylene S(=O) ₂ -, -N(R ^y )C _1-3 Alkyl-, -C _1-3 alkylene N(R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S, OH, cyano, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl Substituted by the substituent of the base;

R ^y are each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF ₃ , OH , cyano group, NH ₂ , C _1-6 alkyl group, C _1-6 alkoxy group, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

R ^b is each independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, so The -CH ₂ -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-6 selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, and _halogen. Substituted by alkyl, C _1-6 alkoxy or C _3-6 cycloalkyl substituents;

Ring A is selected from a C _6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring. The heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N. ;

_{Ring _} , S, N heteroatoms;

R ^x and R ^a are each independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , C _1-6 alkylthio group, -SO ₂ -C _1-6 alkyl group, -C(=O)C _1-6 alkyl group, -(CH ₂ ) _q -C _3-10 carbocyclic ring or -(CH ₂ ) _q -3 to 12-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 4 Halogen, OH, cyano, =O, NH ₂ , NH(C _1-6 alkyl), N(C _1-6 alkyl) ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl , C _1-6 alkoxy group, C _3-6 cycloalkyl group or a substituent of a 3 to 10-membered heterocyclic ring, the heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N;

L is selected from -Q1-Ak1-Q2-Ak2-, and is connected to ring B on the right side;

Ak1 and Ak2 are each independently selected from C _1-4 alkylene, C _2-4 alkenylene, C _2-4 alkynylene, the Ak1 is optionally substituted by 0 to 4 R ^k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R ^k2 ;

R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -OC _3-6 carbocyclic ring, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl and alkenyl groups , alkynyl, alkoxy, carbocyclic or heterocyclic is optionally 1 to 4 selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, -OC _3-8 carbocyclic ring, C _3-8 carbocyclic ring, 4 to 10 membered heterocyclic substituents, the above The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 To 4 substituents selected from halogen, =O, OH, cyano, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), C(=O )O、OC(=O)、S(=O)、S(=O) ₂ 、S(=O) ₂ N(R ^q )、N(R ^q )S(=O) ₂ 、N(R ^q )C(=O)N(R ^q ), N(R ^q )C(=O)N(R ^q );

R ^q is each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, CF ₃ , OH, cyanide Substituted with substituents of base, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy;

Alternatively, R ^q is directly connected to R ^k1 or R ^k2 to form a 4 to 7-membered heterocycle, which is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C _1-6 Substituted with alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O, S, N heteroatoms;

q is independently selected from 0, 1, 2, 3 or 4;

a is selected from 0, 1, 2, 3 or 4;

b is selected from 0, 1, 2, 3 or 4;

x is selected from 0, 1, 2, 3 or 4;

Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D.

As a second embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

The compound of general formula (A) is selected from the compounds represented by general formula (I) (I)

The definitions of each group are the same as in the first embodiment.

As the third embodiment of the present invention, the compound represented by the following general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, (II)

Ring

Alternatively, ring

R ^a1 and R ^a2 are each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -6} alkylthio group, -SO ₂ -C _1-6 alkyl group, -C(=O)C _1-6 alkyl group, -(CH ₂ ) _q -C _3-10 carbocyclic ring or -(CH ₂ ) _q -3 to 12-membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 members selected from halogen, OH , cyano, =O, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

The definitions of the remaining groups are the same as in the second embodiment of the invention.

As the fourth embodiment of the present invention, the compound represented by the above general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Y is selected from bond, -O-, -N(R ^y )-, C _1-3 alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _{1- 2} alkylene OC _1-2 alkylene, -C _1-2 alkylene S-, -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 y Alkyl-, -C _1-2 alkylene N(R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted by the substituent of the base;

R ^y are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF ₃ , OH , cyano group, NH ₂ , C _1-4 alkyl group, C _1-4 alkoxy group, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

R ^x , R ^a1 , and R ^a2 are each independently selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy , C _1-4 alkylthio group, -SO ₂ -C _1-4 alkyl group, -C(=O)C _1-4 alkyl group, -(CH ₂ ) _q -C _3-6 carbocyclic ring or -(CH ₂ ) _q -3 to 6 membered heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 4 Halogen, OH, cyano, =O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 3 to 6 membered heterocycle Substituted with substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

R ^b is each independently selected from H, halogen, cyano, OH, =O, C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, so The -CH ₂ -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C _1-4 selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, and halogen. Substituted by alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl substituents;

Ak1 and Ak2 are each independently selected from C _1-3 alkylene, C _2-3 alkenylene, and C _2-3 alkynylene. The Ak1 is optionally substituted by 0 to 4 R ^k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R ^k2 ;

R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _{1 -4} alkoxy group, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 selected from halogen, OH, cyano group , NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, 4 to 6 membered heterocyclic substituents, the above The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 To 4 substituents selected from halogen, =O, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O ) ₂ ;

R ^q is each independently selected from H, C _1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl or Substituted with C _1-4 alkoxy substituents;

Alternatively, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;

The definitions of the remaining groups are the same as in the second or third embodiment of the present invention.

As the fifth embodiment of the present invention, the compound represented by the above general formula (II) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Ring

Alternatively, Ring Oxazole ring, pyridazinooxazole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, Pyrimidotriazole ring, pyrimidofuran ring, pyrimidopyrrole ring, , , quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, triazolo Azolopyrazole ring, , , , , ;

R ^x , R ^a1 , and R ^a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethylene group, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(= O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, Pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH _3. -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl are optionally substituted by 1 to 4 Substituted with a substituent selected from halogen, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or Isopropyl is optionally substituted by 1 to 4 C _1-4 alkyl groups selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen, C _1-4 alkoxy or C _3- Substituted by ₆ cycloalkyl substituents;

Y is selected from bonds, -O-, -N(R ^y )-, -N(R ^y )C(=O)-, -C(=O)N(R ^y )-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y )CH ₂ -, -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(= O)N(R ^y )-, the CH ₂ is optionally substituted by 0 to 2 C _1-4 alkyl selected from H, =O, =S, OH, cyano, C _1-4 alkyl, and halogen Substituted with substituents of base, C _1-4 alkoxy group, and C _3-6 cycloalkyl group;

R ^y is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are any 1 to 4 are selected from deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 Substituted with a cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;

Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and the Ak1 is optionally substituted by 0 to 4 R ^k1 , the Ak2 is optionally replaced by 0 to 4 R ^k2 ;

R ^k1 and R ^k2 are each independently selected from F, Cl, Br, I, cyano, OH, =O, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl, ethyl, propyl , methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepentyl, azetanyl, oxetanyl, oxetanyl Pentyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetyl Butyl, azetanyl, azepanyl, oxetanyl, oxetanyl, oxetanyl, pyridine, phenyl are optionally selected from 1 to 4 halogen, OH, cyano , NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, 4 to 6 membered heterocyclic substituents, the above The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;

Alternatively, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 To 4 substituents selected from halogen, =O, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;

Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O ) ₂ ;

R ^q is each independently selected from H, methyl, and ethyl;

Alternatively, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;

The definitions of the remaining groups are the same as in any one of the third or fourth embodiments of the present invention.

As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L is selected from -N(R ^q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R ^q )-Ak2-, -N(R ^q )-Ak1- N(R ^q )-Ak2-, the left side is directly connected to the pyridazinone ring;

Y is selected from the group consisting of bonds, -O-, -NHC(=O)-, -C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, - NHC(=O)CH ₂ -, -CH ₂ C(=O)NH-, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ )-, -CH ₂ C (=O)NH-, -CH ₂ C(=O)N(CH ₃ )-, -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(= O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -cyclopropyl)C(= O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)-, -C(=O)N(CH ₂ -cyclopropyl)-, -C(=O)N(CD ₃ )-, - C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -aza cyclobutyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl)-, -C(=O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C( =O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(=O)N(n- base)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -cyclopropyl)-, , , -CH ₂ S(=O) ₂ -;

The remaining group definitions are the same as in any one of the third, fourth or fifth embodiments of the present invention.

As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L is selected from , , , , , , , , , , , , , , the left side is directly connected to the pyridazinone ring;

R ^x is independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methyl Oxygen, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, Thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, Furyl, pyrrolyl, pyrazolyl and imidazolyl are optionally substituted by 1 to 4 substituents selected from F, OH, cyano, methyl, ethyl, methoxy or ethoxy;

R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy , -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

Selected from , , , , , , , , , , , , ;

R ^b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl;

The remaining group definitions are the same as in any one of the third, fourth, fifth or sixth embodiments of the present invention.

As an eighth embodiment of the present invention, the compound represented by the above general formula (II) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L is selected from , , , , the left side is directly connected to the pyridazinone ring;

R ^a1 is selected from F, Cl, Br, CF ₃ , CHF ₂ , CH ₂ F, methyl, cyano, cyclopropyl, isopropyl;

R ^x is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD ₃ , CF ₃ , CHF ₂ , CH ₂ F, cyclopropyl, cyclobutyl;

b is selected from 0, 1, 2, 3;

x is selected from 1, 2;

The definitions of the remaining groups are the same as in any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention.

As the ninth embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

W is selected from C(=O);

_Ring -10-membered paracyclic heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;

_{Preferably , ring _} 7-membered monocyclic heterocycloalkyl, 5- to 10-membered paracyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, 5- to 11-membered bridged heterocycloalkyl, phenyl, 5-6-membered heterocycloalkyl Aromatic ring, 8-10 membered paracyclic heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;

Preferably, Ring Cyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetihexyl, cyclopentylspiro Azepanyl, cyclopentylspiroazepinyl, cyclohexylazepine Basespiroazepinehexyl, azepanylazespirocyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentyl Cyclohexyl, cyclohexylcyclohexyl, cyclobutylazetidinyl, cyclobutylazetidine, cyclobutylazepine, cyclopentylazetidine, Cyclopentazacyclohexyl, cyclohexylazacyclohexyl, azetidinylazacyclohexyl, azetacyclopentazacyclohexyl, azetidineazacyclohexyl , azetidine azacyclohexyl, azetidinyl, azetitanyl, azetidinyl, oxetanyl, oxetanyl, oxetanyl, or ring X on request As mentioned in item 5;

The definitions of the remaining groups are the same as in any one of the second, third, fourth, fifth, sixth, seventh or eighth embodiments of the present invention.

As a tenth embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Selected from , , , ;

The definitions of the remaining groups are the same as in any one of the ninth embodiment of the present invention.

The present invention relates to the compound shown below or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one. Table E-1 .

The present invention relates to a pharmaceutical composition, including any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier.

The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical Acceptable carrier.

In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").

"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (eg, PARP7-related diseases such as prostate cancer) one or more symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg , 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.

A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable Salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably inhibited or degraded by AR or AR splicing mutant-related diseases (such as prostate cancer).

A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to 1 -A daily dose of 1000 mg/day is administered to the subject, which may be a single dose or divided dose. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10- 800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg/ Days, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.

The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or co-crystals, the amount of the compound of the present invention or its stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as the amount in the above-mentioned pharmaceutical composition same.

The present invention relates to any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of drugs for the treatment of diseases related to PARP7 activity or expression levels. For application in, preferably, the disease is selected from tumors.

The present invention relates to the application of the above pharmaceutical composition in the preparation of drugs for treating diseases related to PARP7 activity or expression. Preferably, the diseases are selected from tumors.

The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.

resolve resolution

In order to achieve the purpose of the present invention, the compound of the present invention can be prepared by the following scheme:

Scheme 1: Synthetic method when the compound of general formula (II) is selected from the compounds of general formula (M-13)

PG, PG1 or PG2 are each independently selected from amino protecting groups, preferably Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl);

R is selected from C _1-4 alkyl, preferably methyl or ethyl;

X is selected from a leaving group, preferably halogen, OMs, OTs or OTf,

The definitions of the remaining groups are consistent with the aforementioned general formula compound (II);

The compound of general formula (M-1) reacts with an amino protecting reagent to obtain the compound of general formula (M-2);

The compound of general formula (M-2) and X ₂ obtain the compound of general formula (M-3) through nucleophilic substitution reaction;

Compounds of general formula (M-3) and Compounds of general formula (M-4) are obtained through nucleophilic substitution reaction in the presence of alkaline reagents (such as NaH);

The compound of general formula (M-4) can obtain the compound of general formula (M-5) through deamination protecting group reaction;

The compound of general formula (M-5) reacts under alkaline conditions (such as triethylamine, DIPEA) to obtain the compound of general formula (M-6);

The compound of general formula (M-6) can obtain the compound of general formula (M-7) through deamination protecting group reaction;

Compounds of general formula (M-7) and general formula (A-1) are reacted with nucleophilic substitution under alkaline conditions (such as potassium carbonate, cesium carbonate) to obtain compounds of general formula (M-8);

Or the compound of general formula (M-7) and the general formula (A-1) can obtain the compound of general formula (M-8) through a coupling reaction in the presence of a metal catalyst;

The compound of general formula (M-8) is reacted under reducing agent (such as NaBH ₄ , LiAlH ₄ ) to obtain the compound of general formula (M-9);

The compound of general formula (M-9) and the compound of general formula (A-2) obtain the compound of general formula (M-10) through nucleophilic substitution reaction;

The compound of general formula (M-10) undergoes a deamination protecting group reaction to obtain a compound of general formula (M-11);

Compounds of general formula (M-11) and compounds of general formula (A-3) are obtained through nucleophilic substitution reaction under alkaline conditions (such as triethylamine, DIPEA) to obtain compounds of general formula (M-12);

The compound of general formula (M-12) is reacted with the deamination protecting group to obtain the compound of general formula (M-13).

Scheme 2: Synthesis method of intermediate M-9

The compound of the general formula (N-1) is obtained through a reduction reaction of the intermediate (M-6) compound under the condition of a reducing agent (such as NaBH ₄ , LiAlH ₄ );

Compounds of general formula (N-1) are obtained through deamination protection reaction to obtain compounds of general formula (N-2);

Compounds of general formula (N-2) and compounds of general formula (A-1) are obtained through nucleophilic substitution reaction under alkaline conditions (such as potassium carbonate, cesium carbonate) to obtain compounds of general formula (M-9);

Or the compound of general formula (N-2) and the compound of general formula (A-1) can obtain the compound of general formula (M-9) through a coupling reaction in the presence of a metal catalyst;

The compound of general formula (M-9) can be used to obtain the compound of general formula (M-13) through Scheme 1.

Scheme 3: Synthesis of general formula IB and general formula IC

For specific synthesis conditions, refer to the synthesis of compound 11.

By reacting 1c'' with M-14B and referring to the synthesis of compound 11, the compound represented by the general formula IC can be obtained. .

The definition of each group is the same as in any previous scheme.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, and nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Halogen" refers to F, Cl, Br or I.

"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is simply referred to as "halogenated."

"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl group and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.

"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replacement. Non-limiting examples include -X( _CH2 )vX( _CH2 )vX( _CH2 )vH (v is an integer from 1 to 5, and , O or S, and at least 1 X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states). Heteroalkyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10). Examples of alkylene include but do not Limited to methylene, ethylene, propylene, butylene, etc.

"Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) substitution. Non-limiting examples include -X( _CH2 )vX( _CH2 )vX( _CH2 )v-, v is an integer from 1 to 5, 1 X is selected from N, O or S.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro- 2H -pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl , piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups can be monovalent, divalent, trivalent or tetravalent

"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl base, 1-nonenyl, 3-nonenyl, 1-decene, 4-decene, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1- Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent .

"Alkoxy" refers to substituted or unsubstituted ‒O‒alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclo Propoxy and cyclobutoxy.

"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, , , or . "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a monocyclic ring with 3 to 8 members, or a monocyclic ring with 4 to 12 members. Bicyclic or 10 to 15-membered tricyclic ring system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabis Cycl[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl, , , , , , , , , , , , , or . "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Can contain 0 to 5 heteroatoms selected from N, O or S(=O) _n . Non-limiting examples include: . "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.

"Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S(=O) _n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: , , , "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain 0 or more double bonds and any ring in the ring system. It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) _n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include , , , , , cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.

"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article have the same definition as spirocycle.

"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms. The definition of "carbocyclic ring", "carbocyclic ring group", "carbocyclic ring group" or "carbocyclic ring group" appearing in this article is consistent with that of carbocyclic ring.

"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged carbocyclic ring group", "bridged carbocyclic ring group" or "carbon bridged ring group" appearing in this article are consistent with those of the bridged ring.

"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to the "heterocyclyl" or "heterocycle" of a monocyclic system. The heterocyclyl, "monocyclic heterocycle" appearing in this article "Basic" or "heteromonocyclyl", its definition is consistent with heterocyclic.

"Heterocyclic ring", "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring radical" refers to a "heterocyclic ring" containing heteroatoms. The definitions of heterocyclic ring, "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring group" appearing in this article are consistent with those of the heterocyclic ring group.

"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing heteroatoms. Heterospirocycle, "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" appearing in this article have the same definition as spirocycle.

"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" refers to a "bridged ring" containing heteroatoms. The definition of hetero-bridged ring, "hetero-bridged cyclyl", "bridged-ring heterocyclyl" or "hetero-bridged cyclyl" appearing in this article is consistent with that of bridged ring.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.

"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 optional heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include and . Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.

"5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring. At least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the entire group is aromatic, non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, Pyrazolothiophene ring.

"5-6-membered heteroaromatic ring" refers to a 5-6-membered fused heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaromatic and 5-membered heteroaromatic.

"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m - C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -ene Base ‒R ^a , OR ^d or -(CH ₂ ) _m -alkynyl ‒R ^a (where m, n is 0, 1 or 2), arylthio group, thiocarbonyl group, silyl group or ‒NR ^b R ^c and other groups, wherein R ^b and R ^c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoro Methanesulfonyl group, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclyl group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, Cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclyl, spirocyclyl or paracyclyl.

"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.

"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, and X is selected from any integer between 1 and 10. For example, "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. For example, "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F. replace.

The ring of X-Y members (X is selected from an integer less than Y and greater than or equal to 3, Y is selected from any integer between 4 and 12) includes member's ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7-member heteromonocyclic ring" refers to a heteromonocyclic ring with 4, 5, 6, or 7 members, and "5-10-membered heterocyclic ring" refers to a heterocyclic ring with 5, 6, 7, or 8 members. , 9-membered or 10-membered heterocyclic rings.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" means that the compounds of the present invention retain the biological effectiveness and properties of free acids or free bases, and the free acids are combined with non-toxic inorganic bases or organic Base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and A mixture of other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.

"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure states of API and CCF are uniform at room temperature. It is a solid and has a fixed stoichiometric ratio between its components. A eutectic is a multi-component crystal that includes both a two-member eutectic formed between two neutral solids and a multi-member eutectic formed between a neutral solid and a salt or solvate.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.

“IC ₅₀ ” is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).

The technical solution of the present invention will be described in detail below with reference to the examples, but the protection scope of the present invention includes but is not limited thereto.

The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD ), deuterated acetic acid (CD ₃ COOD), the internal standard is tetramethylsilane (TMS);

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Thin layer chromatography (TLC) uses silica gel plates with specifications of 0.15 mm-0.20 mm. Thin layer chromatography separation and purification products use specifications of 0.4 mm. - 0.5 mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

For the purposes of the present invention, the compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Chemicals" were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXIA (Shanghai) ) Chemical Industrial Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

In the synthesis experiment, the temperature is room temperature unless otherwise specified.

THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1

5-Chloro-2-[(4-methoxybenzyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one is intermediate 1 :

Example 1: Preparation of Compound 1

Step 1: Preparation of 1b’

Under an ice-water bath, 1a' (5.00 g, 19.36 mmol) was added to tetrahydrofuran (40 mL). After nitrogen replacement, lithium aluminum hydride (0.74 g, 19.43 mmol) was added, and the mixture was stirred in an ice-water bath for 2 hours. Add sodium sulfate decahydrate until the system no longer produces gas, and stir at room temperature for 10 min. Filter through diatomaceous earth, rinse the filter cake with tetrahydrofuran (40 mL x 3), and concentrate the filtrate under reduced pressure to obtain 1b' (4.00 g, 90%).

LCMS m/z =231.1 [M+1] ⁺ .

Step 2: Preparation of 1b”

Triethylamine (53.93 g, 532.72 mmol) was added to (2S)-2-aminopropan-1-ol (1a”) (10.00 g, 133.18 mmol) and phthalic anhydride (19.73 g, 133.18 mmol). Toluene (500 mL) solution, reflux and water separation reaction at 145°C for 7 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (dichloromethane: methanol (v/v) = 100:3) Obtained 1b” (20.00 g, 73%).

LCMS m/z =206.1 [M +1] ⁺

Step 3: Preparation of 1c”

To a solution of 1b” (2 g, 11.41 mmol) in dichloromethane (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.48 g, 9.74 mmol). Trichloroacetonitrile (3.52 g, 24.35 mmol) was reacted at room temperature for 2 h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 5:1) to obtain 1c" (1.74 g) Crude product.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 7.89-7.79 (m, 4H), 4.74-4.62 (m, 2H), 4.53 - 4.42 (m, 1H), 1.45 (d , 3H).

Step 4: Preparation of 1b

Dissolve L-serine (10.50 g, 99.88 mmol) and potassium bromide (40.41 g, 339.59 mmol) in water (80 mL), replace with nitrogen, and slowly add hydrobromic acid (33.67 g, 199.76 mmol, 48%) , cool to -15°C, slowly add sodium nitrite (8.68 g, 125.82 mmol) in water (25 mL) dropwise, and react at room temperature for 6 h. Blow nitrogen for 0.5h , extract with ethyl acetate (100 mL g) Crude product.

LCMS m/z =166.9 [M-1] ^- .

Step 5: Preparation of 1c

Dissolve 1b (14.70 g, 87.03 mmol,) and imidazole (23.70 g, 348.12 mmol) in DMF (50 mL), slowly add tert-butyldiphenylsilyl chloride (29.90 g, 108.79 mmol) dropwise, at room temperature Reaction was allowed to take place overnight. Pour into water (500 mL), extract with ethyl acetate (200 mL x 2), combine the organic phases, wash the organic phase with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, filter with suction, and reduce the filtrate to Concentrate under pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1, 1‰ glacial acetic acid) to obtain 1c (20.90 g, 51%, 2-step yield).

LCMS m/z =405.0 [M-1] ^- .

Step 6: Preparation of 1d

Dissolve 1c (2.52 g, 6.19 mmol) in oxalate chloride (25 mL), add 0.1 mL DMF, and react at 50°C for 2 h. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL) and concentrate under reduced pressure. Under an ice-water bath, the solution of the residue in dichloromethane (10 mL) was slowly added dropwise to the solution of 1b' (1.43 g, 6.20 mmol) and DIPEA (2.40 g, 18.60 mmol) in dichloromethane (20 mL). Warm reaction for 1 h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 1d (3.39 g, 88%).

LCMS m/z =541.2 [M-77] ⁺ .

Step 7: Preparation of 1e

Dissolve 1d (2.39 g, 3.85 mmol) in tetrahydrofuran (10 mL). After nitrogen replacement, sodium hydride (231 mg, 5.78 mmol, 60%) was added in batches at 0°C, and the reaction was carried out at 0°C for 1 h. Add saturated ammonium chloride solution (30 mL) to quench the reaction, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, and filter with suction. Concentrate under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 1e (1.22 g, 59%).

LCMS m/z =461.3 [M-77] ⁺ .

Step 8: Preparation of trifluoroacetate salt of 1f

Dissolve 1e (1.62 g, 3.01 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (20 mL), and react at room temperature for 2 h. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL x 2), and concentrate under reduced pressure to obtain crude trifluoroacetate salt of 1f .

LCMS m/z =439.3 [M+1] ⁺ .

Step 9: Preparation of 1g

The crude trifluoroacetate of 1f , 2-chloro-5-(trifluoromethyl)pyrimidine (690 mg, 3.78 mmol), and potassium carbonate (1.56 g, 11.25 mmol) were added to N-methylpyrrolidone (2 mL ), react at 90°C for 2 h. Pour into water (30 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, wash with saturated brine (20 mL x 5), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain crude product , the crude product was separated and purified by column chromatography (100% tetrahydrofuran) to obtain 1g (546 mg, 52%, 2-step yield).

LCMS m/z =347.0 [M+1] ⁺ .

Step 10: Preparation of Compound 1h

Dissolve 1g (50 mg, 0.14 mmol) and 1c” (98 mg, 0.28 mmol) in toluene (10 mL). After nitrogen replacement, add boron tribromide etherate complex (0.5 mL) at 0°C and react at 23°C. 16 h. Slowly add saturated sodium bicarbonate solution (10 mL) at 0°C to quench the reaction. Extract with ethyl acetate (50 mL x 3), combine the organic phases, and wash the organic phase once with saturated brine (20 mL), anhydrous. Dry over sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue is separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 3:2) to obtain 1h (16 mg, 21 %).

LCMS m/z =534.3[M+1] ⁺ .

Step 11: Preparation of 1i

Dissolve 1h (80 mg, 0.15 mmol) in ethanol (2 mL), and add hydrazine hydrate (47 mg, 0.75 mmol, 80%). React at room temperature for 2 hours. Concentrate under reduced pressure, and the crude product was purified by preparation plate (dichloromethane: methanol (v/v) = 10:1) to obtain 1i (27 mg, 45%).

LCMS m/z =404.2[M+1] ⁺ .

Step 12: Preparation of 1j

Dissolve 1i (27 mg, 0.7 mmol) in acetonitrile (2 mL), add triethylamine (14 mg, 0.13 mmol), and react at room temperature for 16 h. Concentrate under reduced pressure, and the crude product was purified by Prep-TLC (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 1j (45 mg, 98%).

LCMS m/z =686.2[M+1] ⁺ .

Step 13: Preparation of Compound 1

Dissolve 1j (45 mg, 0.07 mmol) in trifluoroacetic acid (2 mL), add trifluoromethanesulfonic acid (0.2 mL), and react at room temperature for 1 h. Concentrate under reduced pressure, dissolve the crude product in methanol, add DIPEA dropwise to adjust the pH to 8-9, after concentration under reduced pressure, the residue is purified by Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase, and the preparation column model is XBridge@ Prep C ₁₈ , inner diameter x length = 19mm x 250mm). Preparation method: Dissolve the crude product in DMF and filter it with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: Gradient elution with acetonitrile from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain compound 1 (15 mg, 40%).

LCMS m/z =566.1[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.74 (s, 2H), 7.91 (s, 1H), 6.31-6.20 (m, 1H), 4.44-4.36 (m, 1H ), 4.35-4.26 (m, 2H), 4.20-4.09 (m, 1H), 4.08-4.01 (m, 2H), 3.89-3.80 (m, 1H), 3.77-3.67 (m, 4H), 3.63-3.56 (m, 1H), 3.55-3.46 (m, 3H), 1.83-1.70 (m, 1H), 1.68-1.60 (m, 1H), 1.16 (d, 3H).

Example 2: Preparation of Compound 2-1 and Compound 2-2

Compound 1 was purified by SFC on ID column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 3 was dissolved in methanol, And filter with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1% NH3·H2O). Gradient elution method: 30% B iso-gradient elution (flow rate: 100mL/min ; Elution time: 1.6 min), and compound 2-1 and compound 2-2 were obtained after freeze-drying.

Analytical method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05%DEA ), 3.0ml/min.

The retention time T=1.325 min is compound 2-A ( compound 2-A is one of the structures of compound 2-1 and compound 2-2).

LCMS m/z=566.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.59 (s, 2H), 7.96 (s, 1H), 4.53- 4.44(m, 1H), 4.35-4.27(m, 2H), 4.20-4.06 (m, 3H), 4.01-3.93 (m, 1H), 3.89-3.78 (m, 4H), 3.72-3.61 (m, 3H), 3.56-3.50 (m, 1H), 1.97-1.84 (m, 1H), 1.75- 1.66 (m, 1H), 1.27 (d, 3H).

The retention time T=1.666 min is compound 2-B ( compound 2-B is one of the structures of compound 2-1 and compound 2-2).

LCMS m/z=566.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 2H), 7.95 (s, 1H), 4.56- 4.47(m, 1H), 4.36-4.27(m, 2H), 4.21-4.07 (m, 3H), 3.99-3.93 (m, 1H), 3.90-3.76 (m, 4H), 3.72-3.58 (m, 3H), 3.54-3.49 (m, 1H), 1.95-1.83 (m, 1H), 1.74- 1.65 (m, 1H), 1.27 (d, 3H).

Example 3: Preparation of Compound 3

Step 1: Preparation of 3c

Under an ice-water bath, oxalate chloride (8.29g, 65.31mmol) was slowly added dropwise to the solution of 1c (3.80g, 9.33mmol) in DCM (30mL) and DMF (0.05mL), and the reaction was carried out at 50°C for 2h. Concentrate under reduced pressure to obtain crude chloride.

Under an ice-water bath, the dichloromethane solution (10 mL) of the prepared chloride was slowly added dropwise to 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.93g, 8.92mmol), DIPEA ( 4.61g, 35.68mmol) in DCM (20mL) solution, react at room temperature for 1h. Silica gel was added, concentrated under reduced pressure and separated and purified by column chromatography (petroleum ether: tetrahydrofuran (V:V) = 5:1, 210nm wavelength detection) to obtain 3c (3.60g, 64%).

LCMS m/z=527.0[M-77] ⁺

Step 2: Preparation of Compound 3d

Under ice-water bath, add sodium hydrogen (0.36g, 9.03mmol, content: 60%) in batches to the THF (30mL) solution of 3c (3.60g, 5.94mmol), react in ice-water bath for 1 hour, and react at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (2 ml). Dichloromethane extraction (30mLx3). The organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (V:V) = 5:1, 210nm wavelength detection) to obtain 3d (1.50g). , 48%).

LCMS m/z=447.2[M-77] ⁺

Step Three: Preparation of Trifluoroacetate Salt of 3e

Trifluoroacetic acid (4 mL) was added to a solution of 3d (1.25 g, 2.38 mmol) in DCM (4 mL), and the reaction was stirred at room temperature for 2 h. Concentrate under reduced pressure to obtain the crude product of 3e trifluoroacetate (1.2g).

LCMS m/z=425.3[M+1] ⁺

Step 4: Preparation of 3f

Potassium carbonate (1.23g, 8.92mmol) was added to a solution of 3e trifluoroacetate (1.2g), 2-chloro-5-(trifluoromethyl)pyrimidine (0.45g, 2.45mmol) in DMSO (4mL) , react at 95°C for 3 hours. Cool to room temperature, add 50mL of ethyl acetate to dilute the reaction solution, wash with saturated sodium chloride aqueous solution (20mLx3), dry the organic phase with anhydrous sodium sulfate, and filter with suction. The filtrate is concentrated under reduced pressure to obtain a crude product, which is separated and purified by column chromatography. (Petroleum ether: tetrahydrofuran (v:v)=5:2) gave 3f (600 mg, 76%, 2-step yield).

LCMS m/z=333.1[M+1] ⁺

Step 5: Preparation of 3g

Dissolve 3f (400mg, 1.20mmol) and 1c” (839mg, 2.4mmol) in toluene (80mL). After nitrogen replacement, add boron trifluoride ether (4mL) at 0°C and react for 16h at 23°C. Drop slowly at 0°C. Add saturated sodium bicarbonate solution (20 mL) to quench the reaction, extract with ethyl acetate (50 mLx3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v) :v)=3:2) to get 3g (110mg, 18%).

LCMS m/z=520.1[M+1] ⁺

Step 6: Preparation for 3h

Hydrazine hydrate (0.15 mL) was added to a solution of 3 g (164 mg, 0.32 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, it was separated and purified by Prep-TLC (dichloromethane: methanol (v:v) = 10:1) to obtain 3h (75 mg, 61%).

LCMS m/z=390.2[M+1] ⁺

Step 7: Preparation of 3j

Intermediate 1 (73 mg, 0.23 mmol) was added to a solution of 3 h (75 mg, 0.19 mmol) and triethylamine (58 mg, 0.57 mmol) in acetonitrile (2 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 1:2) to obtain 3j (40 mg, 31%).

LCMS m/z=672.1[M+1] ⁺

Step 8: Preparation of Compound 3

Trifluoromethanesulfonic acid (32 mg, 0.21 mmol) was added to a solution of 3j (40 mg, 0.06 mmol) in TFA (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust pH=8 with ammonia. The aqueous solution was separated and purified through C ₁₈ column (mobile phase system: acetonitrile/water (containing 0.1% ammonia); gradient elution method: acetonitrile gradient elution from 5% to 40%) to obtain compound 3 (12 mg, 37%).

LCMS m/z=552.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d 6) δ 12.41 (s, 1H), 8.73 (s, 2H), 7.91 (s, 1H), 6.32-6.20 (m, 1H), 4.72-4.63 (m, 2H ), 4.45-4.35 (m, 1H), 4.23 (d, 1H), 4.15 (s, 1H), 3.95-3.81 (m, 3H), 3.79-3.70 (m, 1H), 3.58-3.46 (m, 3H ), 3.04-2.88 (m, 2H), 2.85-2.74 (m, 1H), 1.14 (d, 3H).

Example 4:

Compound 3 was purified by SFC on ID column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was: Chiralcel Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 3 was dissolved in methanol and mixed with 0.45 Filter through a μm filter membrane and prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1% NH ₃ .H ₂ O). Gradient elution method: 20% B iso-gradient elution (flow rate: 110mL/ min; elution time: 2.5 min), compound 4-1 and compound 4-2 were obtained after freeze-drying.

Analytical method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: Chiralcel OD-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05%DEA ), 3.0ml/min.

The retention time T=1.435 min is compound 4-A ( compound 4-A is one of the structures of compound 4-1 and compound 4-2).

LCMS m/z=552.1[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.59 (s, 2H), 7.94 (s, 1H), 4.91-4.84(m,1H),4.80-4.76 (m, 1H), 4.58-4.51 (m, 1H), 4.30-4.25 (m, 1H), 4.20-4.10 (m, 1H), 4.05-3.95 (m, 3H), 3.88-3.82 (m, 1H), 3.68-3.62 (m, 1H), 3.60- 3.50 (m, 2H), 3.17-3.07 (m, 1H), 3.05-2.96 (m, 1H), 2.92-2.81 (m, 1H), 1.24 (d, 3H).

The retention time T=1.720 min is compound 4-B ( compound 4-B is one of the structures of compound 4-1 and compound 4-2).

LCMS m/z=552.1[M+1] ⁺

1H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 2H), 7.95 (s, 1H), 4.88-4.84 (m, 1H), 4.82-4.79 (m, 1H), 4.60-4.54 (m, 1H ), 4.31-4.27 (m, 1H), 4.21-4.15 (m, 1H), 4.07-3.95 (m, 3H), 3.87-3.81 (m, 1H), 3.65-3.54 (m, 3H), 3.12-2.99 (m, 2H), 2.92-2.84 (m, 1H), 1.27 (d, 3H).

Example 5: Preparation of Compound 5

Step 1: Preparation of 5b

Dissolve D-serine (10.00 g, 95.13 mmol) and potassium bromide (40.41 g, 339.59 mmol) in water (80 mL), replace with nitrogen, and slowly add hydrobromic acid (33.47 g, 190.26 mmol, 48%) dropwise. , a solution of sodium nitrite (7.88 g, 114.16 mmol) in water (25 mL) was slowly added dropwise at -15°C, and the reaction was carried out at room temperature for 6 h. Blow nitrogen for 0.5h, extract with ethyl acetate ( 100 mL g) Crude product.

LCMS m/z =166.9 [M-1] ^- .

Step 2: Preparation of 5c

Dissolve 5b (13.00 g) and imidazole (20.95 g, 307.76 mmol) in DMF (50 mL), slowly add tert-butyldiphenylsilyl chloride (25.38 g, 92.33 mmol) dropwise, and react at room temperature overnight. Pour the reaction solution into water (500 mL), extract with ethyl acetate (200 mL x 2), combine the organic phases, wash the organic phase with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, and filter with suction. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1, 1‰ glacial acetic acid) to obtain 5c (12.00 g, 31%, 2-step yield).

LCMS m/z =405.1 [M-1] ^- .

Step 3: Preparation of 5d

Add oxalate chloride (8.29 g, 65.31 mmol) to 5c (3.80 g, 9.33 mmol) and 0.1 mL DMF in dichloromethane solution (20 mL), and react at 50°C for 2 hours. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL), and concentrate under reduced pressure to obtain a residue. Under an ice-water bath, the solution of the residue in dichloromethane (10 mL) was slowly added dropwise to the solution of 1b' (2.15 g, 9.33 mmol) and DIPEA (2.40 g, 18.60 mmol) in dichloromethane (20 mL). Warm reaction for 1 hour. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 5d (1.80 g, 31%).

Step 4: Preparation of 5e

Dissolve 5d (1.80 g, 2.90 mmol) in tetrahydrofuran (15 mL). After nitrogen replacement, sodium hydride (231 mg, 5.78 mmol, 60%) was added in batches at 0°C, and the reaction was carried out at 0°C for 1 h. Add saturated ammonium chloride solution (30 mL) to quench the reaction, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, and filter with suction. Concentrate under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 5e (900 mg, 58%).

Step 5: Preparation of the trifluoroacetate salt of 5f

Dissolve 5e (900 mg, 3.01 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (4 mL), and react at room temperature for 2 h. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL x 2), and concentrate under reduced pressure to obtain the crude trifluoroacetate salt of compound 5f .

LCMS m/z =439.2 [M+1] ⁺ .

Step 6: Preparation of 5g

The crude trifluoroacetate of 5f , 2-chloro-5-(trifluoromethyl)pyrimidine (309 mg, 1.69 mmol), and potassium carbonate (851 g, 6.16 mmol) were added in sequence to dimethylsulfoxide (4 mL ), react at 95°C for 1 h. Pour into water (30 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases, wash with saturated brine (20 mL x 5), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain crude product , the crude product was separated and purified by column chromatography (100% tetrahydrofuran) to obtain 5g (400 mg, 69%, 2-step yield).

LCMS m/z =347.1 [M+1] ⁺ .

Step 7: Preparation for 5h

Dissolve 5g (400 mg, 1.16 mmol), 1c” (811 mg, 2.32 mmol) in toluene (80 mL), replace with nitrogen, cool to 0°C, add boron tribromide etherate complex (4mL), React at 23°C for 16 hours. Cool to 0°C and slowly add saturated sodium bicarbonate solution (80 mL) dropwise to quench the reaction. Extract with ethyl acetate (50 mL x 3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 3:2) to obtain 5h (150 mg, 24%).

LCMS m/z =534.3[M+1] ⁺ .

Step 8: Preparation of 5j

Dissolve 5h (150 mg, 0.28 mmol) in ethanol (2 mL), and add hydrazine hydrate (172 mg, 0.15 mL, 80%). React at room temperature for 16 hours. After concentration under reduced pressure, the product was purified by Prep-TLC (dichloromethane: methanol (v/v) = 10:1) to obtain 5j (70 mg, 62 %).

LCMS m/z =404.2[M+1] ⁺ .

Step 9: Preparation for 5k

5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyrazin-3-one (60 mg, 0.19 mmol), 5j (70 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL), triethylamine (34.4 mg, 0.34 mmol) was added, and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, it was purified by Prep-TLC (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 5k (40 mg, 34%).

LCMS m/z =686.2[M+1] ⁺ .

Step 10: Preparation of Compound 5

Dissolve 5k (40 mg, 0.06 mmol) in trifluoroacetic acid (2 mL) and add trifluoromethanesulfonic acid (0.2 mL). Reaction at room temperature for 1 h. After concentration under reduced pressure, methanol was dissolved, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by C ₁₈ (preparation method: the crude product was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution. Flow. Phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient elution from 10% to 55% (flow rate: 60 mL/min; elution time 20min) to obtain compound 5 (17 mg, 52 %).

LCMS m/z =566.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.74 (s, 2H), 7.91 (s, 1H), 6.31-6.19 (m, 1H), 4.45-4.37 (m, 1H ), 4.36-4.26 (m, 2H), 4.21-4.10 (m, 1H), 4.09-3.98 (m, 2H), 3.88-3.80 (m, 1H), 3.78-3.66 (m, 4H), 3.63-3.46 (m, 4H), 1.83-1.70 (m, 1H), 1.68-1.59 (m, 1H), 1.16 (d, 3H).

Example 6:

Compound 5 was purified by SFC on OJ column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was: Chiralcel OJ Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Dissolve compound 5 with methanol, and use Filter through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1%NH ₃ .H ₂ O). Gradient elution method: 25% B iso-gradient elution (flow rate: 100mL /min; elution time 2 min), compound 6-1 and compound 6-2 were obtained after freeze-drying.

Analytical method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase system: A for CO ₂ and B for MeOH (0.05% diethylamine), 3mL/min.

The retention time T=1.326 min is compound 6-A ( compound 6-A is one of the structures of compound 6-1 and compound 6-2).

LCMS m/z=566.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 2H), 7.96 (s, 1H), 4.51-4.45 (m, 1H), 4.36-4.28 (m, 2H), 4.21-4.07 (m, 3H), 4.01-3.94 (m, 1H), 3.90-3.78 (m, 4H), 3.73-3.62 (m, 3H), 3.57-3.51 (m, 1H), 1.96-1.84 (m, 1H), 1.75- 1.67(m, 1H), 1.27(d, 3H).

The retention time T=1.665 min is compound 6-B ( compound 6-B is one of the structures of compound 6-1 and compound 6-2).

LCMS m/z=566.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 2H), 7.95 (s, 1H), 4.54-4.46 (m, 1H), 4.35-4.28 (m, 2H), 4.18-4.08 (m, 3H), 3.99-3.92 (m, 1H), 3.89-3.76 (m, 4H), 3.72-3.59 (m, 3H), 3.55-3.49 (m, 1H), 1.96-1.84 (m, 1H), 1.74- 1.66 (m, 1H), 1.27 (d, 3H).

Example 7:

Step One: Preparation of 7a

Dissolve 1b' (4.00 g, 17.37 mmol) in tetrahydrofuran (50 mL) and water (25 mL), add sodium bicarbonate (13.02 g, 154.94 mmol), and add benzyl chloroformate (3.56 g, 20.84) at 0 ^° C. mmol), react at room temperature for 16 hours, add 20 mL of water, and extract with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 77: 23) to obtain 7a (5.00 g, 79%).

LCMS m/z = 309.1 [M-55] ⁺

Step 2: Preparation of 7b

Dissolve triphenylphosphine (7.20 g, 27.44 mmol) and imidazole (1.87 g, 27.44 mmol) in anhydrous dry dichloromethane (30 mL) solution, and slowly add elemental iodine (6.96 g, 27.44 mmol) at 0 ^o C. , react at room temperature for 10 minutes, slowly add 7a (5.00 g, 13.72 mmol) at 0 ^o C, and react at room temperature for 16 hours. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85: 15) to obtain 7b (5.00 g, 77%)

LCMS m/z = 375.0 [M-99] ⁺

Step 3: Preparation of 7c

Dissolve diethyl malonate (8.44 g, 52.70 mmol) in anhydrous tetrahydrofuran solution (60 mL). After replacing the system with nitrogen, add sodium hydride (2.11 g, 52.70 mmol, 60% w/t) in batches at 0 ^o C. , after stirring at 0 ^o C for 20 minutes, slowly add 7b (5.00 g, 10.54 mmol), and react at room temperature for 16 h. Add saturated aqueous ammonium chloride solution at 0 ^° C to quench the reaction, wash with saturated brine (40 mL), extract with ethyl acetate (40 mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate and filter, and reduce the filtrate After concentration, the product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85: 15) to obtain 7c (5.50 g, crude product).

LCMS m/z = 407.3 [M-99] ⁺

Step 4: Preparation of 7d

Dissolve 7c (2.50 g) in methanol solution (30 mL), add ammonia water (0.7 mL) and palladium carbon (600 mg), replace with hydrogen three times, and react at room temperature for 16 h. Filter through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 7d (1.84 g, crude product).

LCMS m/z = 373.2 [M+1] ⁺

Step 5: Preparation of compound 7e

Add 7d (1.84 g, crude product) and ethanol (30 mL) into a glass sealed tube, add triethylamine (2.50 g, 24.7 mmol), and seal for 16 hours at 90 ^° C. Concentrate under reduced pressure to obtain 7e ( 1.61 g, crude product).

LCMS m/z = 327.2 [M+1] ⁺

Step 6: Preparation of the hydrochloride salt of 7f

7e (1.61 g, crude product) was dissolved in hydrogen chloride-1,4-dioxane solution (4.0 M, 20 mL, 80 mmol), and reacted at room temperature for 2 h. Concentrate under reduced pressure to obtain the crude product of 7f hydrochloride (1.48 g).

LCMS m/z = 227.2 [M+1] ⁺

Step 7: Preparation of 7g

Dissolve the hydrochloride of 7f (1.48 g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (0.99 g, 5.42 mmol) in N-methylpyrrolidone (25 mL), and add potassium carbonate (2.04 g , 14.74 mmol), reacted at 90 ^o C for 16 hours. Saturated brine (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). Combine the organic phases, wash them with saturated brine (30 mL 11: 9) gives 7g (1.65 g).

LCMS m/z = 373.2 [M+1] ⁺

Step 8: 7h preparation

Dissolve 7g (1.20 g, 3.22 mmol) in a mixed solution of tetrahydrofuran (50 mL) and absolute ethanol (50 mL), add sodium borohydride (122 mg, 3.22 mmol), stir at room temperature for 1 h, and separate at 0 ^° C. Calcium chloride (208 mg, 1.61 mmol) was added in batches and reacted at 0 ^o C for 2 hours. Slowly add saturated ammonium chloride aqueous solution dropwise to quench the reaction, add saturated brine for washing (30 mL), extract with ethyl acetate (30 mL x 2), combine the organic phases, dry the organic phases over sodium sulfate, filter, and reduce the pressure of the filtrate After concentration, it was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 4: 1) to obtain 7h (800 mg, 75%)

LCMS m/z = 331.1 [M+1] ⁺

Step 9: Preparation of 7i

Dissolve 7h (900mg, 2.72mmol) and 1c” (1.90g, 5.44mmol) in toluene (180 mL). After nitrogen replacement, add boron trifluoride ether solution (9 mL) at 0°C. React at 23°C for 16h. Add saturated sodium bicarbonate to adjust the pH at 0°C until there are no bubbles and the solid is completely dissolved. Extract with ethyl acetate (50mL The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 7i (250 mg, 18%).

LCMS m/z =518.2 [M +1] ⁺

Step 10: Preparation of 7j

Hydrazine hydrate (1mL, content: 80%) was added to a solution of 7i (250mg, 0.48mmol) in ethanol (4mL) and reacted at room temperature for 16h. After concentration under reduced pressure, it was separated and purified by Prep-TLC (dichloromethane: methanol (v:v) = 10:1) to obtain 7j (150 mg, 80%).

LCMS m/z =388.2 [M +1] ⁺

Step 11: Preparation of 7k

Dissolve 7j (150 mg, 0.39 mmol) and intermediate 1 (137 mg, 0.43 mmol) in acetonitrile (5 mL), add triethylamine (79 mg, 0.78 mmol), and react at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 7k (150 mg, 58%).

LCMS m/z =670.3[M+1] ⁺ .

Step 12: Preparation of compound 7-1 and compound 7-2

Trifluoromethanesulfonic acid (116mg, 0.77mmol) was added to the trifluoroacetic acid (2mL) solution of 7k (150mg, 0.22mmol), and the reaction was carried out at room temperature for 1h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust the pH to 7-9 with ammonia. The aqueous solution was purified through a C ₁₈ column to obtain 45 mg of crude product, which was purified by Pre-HPLC (instrument and preparation column: WATERS 2767 was used to prepare the liquid phase, and the preparation column model was Xselect C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: Filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: acetonitrile gradient elution from 5% to 50% (elution time: 15 minutes). After lyophilization, compound 7-A (6mg, 5%) and compound 7-B (8mg, 7%) were obtained.

Analytical method (instrument: Shimadzu high performance liquid chromatography (instrument model: LC-20AT) – reversed-phase chromatography; brand and model of preparative column: Yuexu (Xtimate C18 4.6*50mm, 3μm); mobile phase system: mobile phase A It is 0.05% TFA solution, mobile phase B is acetonitrile; flow rate: 1.0mL/min.

The retention time T=4.224 is compound 7-A (compound 7-A is one of the structures of compound 7-1 and compound 7-2).

LCMS m/z =550.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.72 (s, 2H), 7.93 (d, 1H), 6.35-6.20 (m, 1H), 4.70-4.53 (m, 2H ), 4.52-4.42 (m, 1H), 4.26-4.12 (m, 1H), 3.77-3.55(m,2H), 3.54-3.40 (m, 3H), 2.99-2.88(m, 1H), 2.86-2.76 (m, 1H), 2.73-2.62 (m, 1H), 2.49-2.45 (m, 1H), 2.04-1.61 (m, 4H), 1.16 (d, 3H).

The retention time T=4.284 is compound 7-B (compound 7-B is one of the structures of compound 7-1 and compound 7-2).

LCMS m/z =550.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.34 (s, 1H), 8.73 (s, 2H), 7.89 (d, 1H), 6.32-6.15 (m, 1H), 4.72-4.58 (m, 2H ), 4.52-4.39 (m, 1H), 4.25-4.09 (m, 1H), 3.76-3.57 (m, 2H), 3.53-3.37 (m, 3H), 3.09-2.95 (m, 1H), 2.86-2.74 (m, 1H), 2.71-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.08-1.95 (m, 1H), 1.88- 1.77 (m, 1H), 1.63-1.42 (m, 2H) , 1.15 (d, 3H).

Example 8:

Compound 7-B (58mg) was purified by SFC on ID column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 7 -B is dissolved in methanol and filtered with a 0.45μm filter to prepare a sample solution. Mobile phase system: A for CO ₂ and B for MeOH (0.1%NH ₃ .H ₂ O). Gradient elution method: 30% B, etc. Gradient elution (flow rate: 100mL/min; elution time 4.5min), and compound 8-A (26mg) and compound 8-B (20mg) were obtained after lyophilization.

Analysis method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05%DEA), 3.0ml/min. The retention time T=1.387 min is compound 8-A (compound 8-A is one of the structures of compound 8-1, compound 8-2, compound 8-3, and compound 8-4). The retention time T=2.009 min is compound 8 -B (Compound 8-B is one of the structures of compound 8-1, compound 8-2, compound 8-3, and compound 8-4).

Compound 8-A:

LCMS m/z=550.6[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.73 (s, 2H), 7.90 (s, 1H), 6.33-6.15 (m, 1H), 4.72-4.56 (m, 2H ), 4.49-4.38 (m, 1H), 4.24-4.09 (m, 1H), 3.73-3.60 (m, 2H), 3.55-3.45 (m, 1H), 3.43-3.34 (m, 2H), 3.09-2.96 (m, 1H), 2.85-2.75 (m, 1H), 2.70-2.57 (m, 1H), 2.46-2.37 (m, 1H), 2.08 -1.95 (m, 1H), 1.88-1.78 (m, 1H) , 1.64-1.39 (m, 2H), 1.15 (d, 3H).

Compound 8-B:

LCMS m/z=550.6[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.73 (s, 2H), 7.88 (s, 1H), 6.31-6.17 (m, 1H), 4.71-4.57 (m, 2H ), 4.52-4.42 (m, 1H), 4.23-4.09 (m, 1H), 3.75-3.67 (m, 1H), 3.65-3.57 (m, 1H), 3.51 -3.40 (m, 2H), 3.40-3.32 (m,1H), 3.09-2.94 (m, 1H), 2.85-2.73 (m, 1H), 2.72-2.59 (m, 1H), 2.47-2.34 (m 1H), 2.06-1.93(m, 1H), 1.90-1.77 (m, 1H), 1.60-1.42 (m, 2H), 1.15 (d, 3H).

Example 9: Preparation of Compound 9

Step One: Preparation of 9b

Dissolve 9a (18.28g, 79.37 mmol) in a mixed solution of tetrahydrofuran (200 mL) and water (100 mL), add sodium bicarbonate (59.48g, 708 mmol), and slowly add benzyl chloroformate (16.25 g, 95.24 mmol) in tetrahydrofuran solution, react at room temperature for 16 hours. Add 100 mL of water and extract with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 81: 19) Get 9b (15.48g, 54%).

LCMS m/z = 309.2 [M-55] ⁺

Step 2: Preparation of 9c

Dissolve triphenylphosphine (22.28 g, 84.96 mmol) and imidazole (5.78 g, 84.96 mmol) in anhydrous dichloromethane (120 mL), slowly add iodine element (21.56 g, 84.96 mmol) at 0°C, and react at room temperature. 10 minutes. The dichloromethane solution of 9b (15.48 g, 42.48 mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 16 hours. Slowly add saturated aqueous sodium thiosulfate solution dropwise at 0°C, add 100 mL of saturated brine, and extract with ethyl acetate (80 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9: 1) to obtain 9c (18.00g, 89%).

LCMS m/z = 375.1 [M-99] ⁺

Step 3: Preparation of 9d

Dissolve diethyl malonate (30.39 g, 189.75 mmol) in anhydrous tetrahydrofuran (120 mL). After nitrogen replacement, add sodium hydride (7.59 g, 189.75 mmol, 60%) in batches at 0°C and stir for 20 minutes at 0°C. , slowly add the tetrahydrofuran solution of 9c (18.00 g, 37.95 mmol) dropwise, and react at room temperature for 16 hours. Add saturated ammonium chloride aqueous solution at 0°C to quench the reaction, wash with saturated brine (80 mL), extract with ethyl acetate (80 mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. Separation and purification by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85: 15) gave 9d (17.50 g, 91%).

LCMS m/z = 407.4[M-99] ⁺

Step 4: Preparation of 9e

Palladium on carbon (400mg, 10%) was added to the solution of 9d (2.00g, 3.95mmol) in methanol (20mL) and ammonia (0.05mL, content: 25%-28%), and the reaction was carried out at room temperature in a hydrogen atmosphere for 16h. Filter and concentrate the filtrate under reduced pressure to obtain 9e (1.40g, crude product).

LCMS m/z=373.4[M+1] ⁺

Step 5: Preparation of 9f

Triethylamine (1.52g, 15.04mmol) was added to a solution of 9b (1.40g, crude product) in ethanol (15mL), and the reaction was carried out at 90°C for 16h. After cooling to room temperature, it was concentrated under reduced pressure to obtain 9f (1.20 g, crude product).

LCMS m/z=327.1[M+1] ⁺

Step 6: Preparation of 9g hydrochloride

Dissolve 9f (1.20g, crude product) in 4N dioxane hydrochloride (10mL) and react at room temperature for 2h. Concentrate under reduced pressure to obtain 9g of hydrochloride (1.00g, crude product).

LCMS m/z=227.2[M+1] ⁺

Step 7: Preparation for 9h

Potassium carbonate (2.10g, 15.24mmol) was added to the solution of 9d hydrochloride (1.00g, crude product) and 2,5-dichloropyrimidine (0.68g, 4.57mmol) in dimethylstyrene (10mL), React at 90°C for 2 hours. Cool to room temperature, add water (20ml) to quench the reaction, extract with ethyl acetate (30mlx3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 9h (1.25g, four-step yield: 93%)

LCMS m/z=339.1[M+1] ⁺

Step 8: Preparation of 9j

Under an ice-salt bath, calcium chloride (1.44g, 13mmol) and sodium borohydride (0.98g, 26mmol) were sequentially added to the mixed solution of compound 9h (1.10g, 3.25mmol) in tetrahydrofuran (12mL) and methanol (3mL). , ice-salt bath reaction for 0.5h. Add ethyl acetate (30 mL) and saturated sodium carbonate solution (10 mL) to quench the reaction, stir for 1 hour and then filter. The filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (dichloromethane (containing 9% methanol) : Petroleum ether (containing 16% ethyl acetate) (v:v)=5:1) to obtain compound 9j-1 (180 mg, 19%) and compound 9j-2.

Compound 9j-1 is compound 9j

LCMS m/z =297.1[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 2H), 4.59-4.41 (m, 4H), 3.73- 3.52 (m, 2H), 3.45-3.34 (m, 1H), 2.97-2.85 (m, 1H), 2.76-2.57 (m, 2H), 2.35-2.23 (m, 1H), 2.10-2.00 (m, 1H), 1.93-1.84 (m, 1H), 1.65-1.42 (m, 2H) .

Compound 9j-2

LCMS m/z =297.1[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (s, 2H), 4.69-4.63 (m, 1H), 4.56-4.42 (m, 3H), 3.69- 3.53 (m, 2H), 3.47-3.38 (m, 1H), 2.93-2.83 (m, 1H), 2.82-2.73 (m, 1H), 2.69-2.59 (m, 1H), 2.40-2.30 (m, 1H), 1.93-1.81 (m, 2H) , 1.80-1.62 (m, 2H).

Step 9: Preparation of 9k

Dissolve 9j (120mg, 0.40mmol) and 1c” (280mg, 0.80mmol) in toluene (10mL) at 0°C. After nitrogen replacement, slowly add boron trifluoride ether (1mL) at 0°C and react at 23°C 16h. Adjust the pH to 7-8 with saturated sodium carbonate solution at 0°C. Extract with ethyl acetate (100mLx3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum ether: Tetrahydrofuran (v:v)=10:3) gave 9k (70mg, 36%).

LCMS m/z=484.2[M+1] ⁺

Step 10: Preparation of Compound 9m

Hydrazine hydrate (0.1 mL, content: 80%) was added to a solution of compound 9k (135 mg, 0.28 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the mixture was pulped with ethyl acetate, filtered, the filter cake was washed with ethyl acetate (10 mLx3), and the filtrate was concentrated under reduced pressure to obtain compound 9m (100 mg, crude product).

LCMS m/z=354.2[M+1] ⁺

Step 11: Preparation of Compound 9n

Intermediate 1 (116 mg, 0.36 mmol) was added to a solution of compound 9m (100 mg, crude product) and triethylamine (113 mg, 1.12 mmol) in acetonitrile (5 mL), and the reaction was carried out at room temperature for 6 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v:v) = 5:1) to obtain compound 9n (100 mg, two-step yield 56%).

LCMS m/z=636.3[M+1] ⁺

Step 12: Preparation of Compound 9

Trifluoromethanesulfonic acid (105 mg, 0.70 mmol) was added to a solution of compound 9n (100 mg, 0.16 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, and add ethyl acetate (20 mL) to dilute the crude product. The pH of the mixture was adjusted to 8-9 with saturated sodium carbonate solution. Extract with ethyl acetate (20mL Compound 9 (45 mg, 55%) was obtained.

Compound 9 is one of the structures of compound 9-1 and compound 9-2.

LCMS m/z=516.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.45 (s, 2H), 7.88 (s, 1H), 6.30-6.17 (m, 1H), 4.57-4.40 (m, 3H ), 4.22-4.11 (m, 1H), 3.74-3.68 (m, 1H), 3.64-3.58 (m, 1H), 3.49-3.40 (m, 2H), 3.37-3.31 (m, 1H), 2.95-2.86 (m, 1H), 2.73-2.57 (m, 2H), 2.46-2.37 (m, 1H),2.05-1.95 m, 1H), 1.86-1.77 (m, 1H), 1.58-1.41 (m, 2H), 1.15 (d, 3H).

Example 10: Preparation of compound 10p and its stereoisomers (compound 10-a, compound 10-b, compound 10-c, compound 10-d)

Step One: Preparation of 10b

At 0°C, a solution of benzyl chloroformate (17.35g, 101.73mmol) in dichloromethane (50ml) was slowly added dropwise to the mixture of 10a (20.00g, 92.48mmol) in dichloromethane (300mL) and saturated sodium bicarbonate solution ( 300 mL) in the mixed solution and reacted at room temperature for 16 hours. Extract with dichloromethane ( 300mL .

LCMS m/z=251.0[M-99] ⁺

Step Two: Preparation of 10c

Dissolve 10b (33.00g, 94.18mmol) in dichloromethane (600mL), add Dess-Martin oxidant (41.94g, 98.89mmol) at 0°C, and react at 0°C for 2 hours. Slowly add saturated sodium bicarbonate aqueous solution (200 mL) to quench the reaction, let stand and separate layers to obtain an organic phase. Concentrate under reduced pressure, and the crude product is slurried with a mixed solution of water (500 mL) and ethyl acetate (500 mL) and filtered. The filtrate was extracted with ethyl acetate (500 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 10c (24.00g, 73%).

LCMS m/z=293.2[M-55] ⁺

Step 3: Preparation of 10d

Diethyl malonate (5.75g, 35.88mmol) was added to 10c (10.00g, 28.70mmol), benzoic acid (1.05g, 8.61mmol), hexahydropyridine (0.73g, 8.61mmol) in toluene (100mL) In the solution, react with water at 135°C for 8 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 10:1) to obtain 10d (5.20g, 33%).

LCMS m/z=435.1[M-55] ⁺

Step 4: Preparation of 10e

Palladium on carbon (0.50g, 10%) was added to a solution of compound 10d (5.20g, 10.60mmol) in methanol (50mL) and ammonia (0.05mL, content: 25%-28%), and the reaction was carried out at room temperature in a hydrogen atmosphere for 16h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 10e (3.50 g, crude product).

LCMS m/z=359.3[M+1] ⁺

Step 5: Preparation of 10f

Triethylamine (3.20g, 29.28mmol) was added to a sealed tube containing a solution of 10e (3.50g, 9.76mmol) in ethanol (30mL), and the reaction was carried out at 90°C for 2 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 10f (1.50g, 49%).

LCMS m/z=257.3[M-55] ⁺

Step 6: Preparation of 10g

Trifluoroacetic acid (10 ml) was added to a solution of 10f (1.50 g, 4.80 mmol) in dichloromethane (20 mL), and the reaction was carried out at room temperature for 3 h. Concentrate under reduced pressure to obtain 10g of trifluoroacetate (1.50g, crude product).

LCMS m/z=213.1[M+1] ⁺

Step 7: Preparation of 10n

Potassium carbonate (2.54g, 18.4mmol) was added to 10g of trifluoroacetate (1.50g, crude product), 2-chloro-5-(trifluoromethyl)pyrimidine (0.92g, 5.06mmol) in dimethyl (10 mL) solution, react at 95°C for 3 hours. After cooling to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 4:1) to obtain 10n (1.20g, two-step yield) :69%).

LCMS m/z=359.1[M+1] ⁺

Step 8: Preparation of 10j

Under an ice-salt bath, add calcium chloride (1.36g, 12.25mmol) and sodium borohydride (0.93g, 24.59mmol) in sequence to a 10n (1.10g, 3.07mmol) mixed solution of tetrahydrofuran (12mL) and ethanol (3mL). Medium, react in ice-salt bath for 0.5h. Add saturated sodium carbonate solution (10 mL) and ethyl acetate (100 mL) to quench the reaction, and stir for 0.5 h. Filter, and the filtrate is concentrated under reduced pressure and separated and purified by column chromatography (dichloromethane: methanol (v:v) = 10:1) to obtain 10j (930 mg, 96%).

LCMS m/z=317.1[M+1] ⁺

Step 9: Preparation of 10k

Dissolve 10j (1.00g, 3.16mmol) and 1c” (2.21g, 6.32mmol) in toluene (50mL) at 0°C. After nitrogen replacement, slowly add boron trifluoride ether (3mL) dropwise and react at 23°C. 16h. Add saturated sodium carbonate solution at 0°C to adjust the pH to 8-9. Extract with ethyl acetate (100mL =10:3) gets 10k (0.80g, 50%).

LCMS m/z=504.2[M+1] ⁺

Step 10: Preparation of 10m

Hydrazine hydrate (0.5 ml, 80%) was added to a solution of 10k (800 mg, 1.59 mmol) in ethanol (10 mL), and the reaction was carried out at room temperature for 16 h. Filter, and the filtrate is concentrated under reduced pressure to obtain crude product. The crude product was slurried with ethyl acetate (50 mL) and filtered again. The filtrate was concentrated under reduced pressure to obtain 10 m (600 mg) of the crude product.

LCMS m/z=374.2[M+1] ⁺

Step 11: Preparation for 10h

Intermediate 1 (667 mg, 2.09 mmol) was added to a solution of 10 m (600 mg, crude product) and triethylamine (0.65 g, 6.44 mmol) in acetonitrile (20 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: ethyl acetate (v:v) = 2:1) to obtain 10h (740 mg, two-step yield: 71%).

LCMS m/z=656.8[M+1] ⁺

Step 12: Preparation of 10p

At 0°C, trifluoromethanesulfonic acid (594 mg, 3.95 mmol) was added to the 10 h (740 mg, 1.13 mmol) trifluoroacetic acid (10 mL) solution, and the reaction was carried out at 0° C. for 1 hour. Concentrate under reduced pressure, add ethyl acetate (20 mL) and water (10 mL) to dissolve the crude product, add saturated sodium carbonate solution to adjust the pH to 8-9, and extract with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: ethyl acetate (v:v) = 5:4) to obtain 10p (440 mg, 73%).

LCMS m/z=536.1[M+1] ⁺

Step 13: Preparation of compound 10-a, compound 10-b, compound 10-c, and compound 10-d

Compound 10p was purified by SFC on AD column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was: Chiralpak AD Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 10p was dissolved in methanol, and used Filter through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for etoh. Gradient elution method: 35% B equal gradient elution (flow rate: 100ml/min; elution time 4.5min; column temperature: 25°C; column pressure: 100bar, absorption wavelength: 220nm) to obtain compound 10-P1 , compound 10-P2 and compound 10-P3 , of which compound 10-P3 is a mixture of two configurations.

Analytical method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase system: A for CO ₂ and B for etoh (0.05%DEA). Retention time T= 1.635 min is compound 10-P1 ( compound 10-P1 is one of the structures of compound 10-a , compound 10-b , compound 10-c , compound 10-d ); the retention time T=1.886 min is compound 10-P2 ( compound 10-P2 ). 10-P2 is compound 10-a , compound 10-b , compound 10-c , one of the structures of compound 10-d ); the retention time T=2.288min is compound 10-P3 ( compound 10-P3 is compound 10-a , Compound 10-b, compound 10-c, a mixture of two structures in compound 10-d).

Compound 10-P1

LCMS m/z=536.1[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.37 (s, 1H), 8.73 (d, 2H), 7.87 (s, 1H), 6.27-6.13 (m, 1H), 4.84-4.69 (m, 2H ), 4.20-4.07 (m, 1H), 3.95-3.87 (m, 1H), 3.68-3.62 (m, 1H), 3.54-3.38 (m, 4H), 2.94-2.84 (m, 1H), 2.82-2.71 (m, 2H), 2.70-2.62 (m, 1H), 2.05-1.95 (m, 1H), 1.86-1.75 (m, 1H), 1.13 (d, 3H).

Compound 10-P2

LCMS m/z=536.1[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.73 (d, 2H), 7.93 (s, 1H), 6.34-6.16 (m, 1H), 4.94-4.82 (m, 1H ), 4.81-4.72 (m, 1H), 4.28-4.15 (m, 1H), 3.92-3.82 (m, 1H), 3.69-3.56 (m, 2H), 3.54- 3.42 (m, 3H), 2.91-2.71 (m, 2H), 2.69-2.56 (m, 2H), 2.28-2.16 (m, 1H), 1.55-1.44 (m, 1H), 1.16 (d, 3H).

Compound 10-P3 was purified by SFC on OJ column (instrument and preparative column: Waters 150 SFC was used, and the preparative column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size)). Preparation method: Compound 10-P3 was dissolved in methanol and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for EtOH (0.1%NH ₃ •H ₂ O). Gradient elution method: 30% B equal gradient elution (flow rate: 120ml/min; elution time 2.0min; column temperature: 25°C; column pressure: 100bar, absorption wavelength: 220nm) to obtain compound 10-P3-1 and compound 10-P3-2 .

Analytical method (instrument: Shimadzu LC-30AD SFC; preparative column model: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase system: A for CO ₂ , B for 0.05%DEA in EtOH. Retention time T=1.124 min is compound 10-P3-1 ( compound 10-P3-P1 is one of the structures of compound 10-a , compound 10-b , compound 10-c , and compound 10-d ); the retention time T=1.886 min is compound 10- P3-2 ( Compound 10-P3-P2 is one of the structures of compound 10-a , compound 10-b , compound 10-c , and compound 10-d ).

Compound 10-P3-1

LCMS m/z=536.1[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (s, 1H), 8.73 (s, 2H), 7.89 (s, 1H), 6.25-6.10 (m, 1H), 4.88-4.67 (m, 2H ), 4.25-4.10 (m, 1H), 3.95-3.84 (m, 1H), 3.64-3.53 (m, 2H), 3.52-3.37 (m, 3H), 2.94-2.83 (m, 1H), 2.82-2.70 (m, 2H), 2.69-2.61 (m, 1H), 2.08-1.98 (m, 1H), 1.86-1.75 (m, 1H), 1.12 (d, 3H).

Compound 10-P3-2

LCMS m/z=536.1[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 (s, 1H), 8.74 (s, 2H), 7.92 (s, 1H), 6.41-6.28 (m, 1H), 4.90-4.73 (m, 2H ), 4.29-4.11 (m, 1H), 3.95-3.82 (m, 1H), 3.73-3.62 (m, 1H), 3.57-3.41 (m, 4H), 2.88-2.72 (m, 2H), 2.69-2.52 (m, 2H), 2.28-2.17 (m, 1H), 1.53-1.41 (m, 1H), 1.15 (d, 3H).

Example 11: Preparation of Compound 11

Step One: Preparation of 11b

Potassium carbonate (2.19g, 15.84mmol) was added to 9g of hydrochloride (1.04g, crude product), 2-chloro, 5-cyclopropylpyrimidine (730 mg, 4.75mmol) in dimethylsulfoxide (10ml) Solution, react at 90°C for 16 hours. Cool to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (30 mLx3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain compound 11b (1.00g, 73%).

LCMS m/z=345.3[M+1] ⁺

Step 2: Preparation of Compound 11c

Calcium chloride (1.03g, 9.28mmol) was added to a mixed solution of compound 11b (800 mg, 2.32mmol) in tetrahydrofuran (10ml) and methanol (2ml), and sodium borohydride (352mg, 9.28) was added in batches at -60°C. mmol), react at -5°C for 0.5h, add ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL) at -5°C to quench the reaction. After stirring for 1 hour, filter and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (dichloromethane (containing 9% methanol):petroleum ether (containing 16% ethyl acetate) (v:v)=5:1) to obtain compound 11c-1 (200 mg, 29%) and compound 11c-2 .

Compound 11c-1 is compound 11c.

LCMS m/z =303.4 [M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (s, 2H), 4.70-4.52 (m, 3H), 3.87-3.72 (m, 2H), 3.53-3.40 (m, 1H), 3.01-2.89 ( m, 1H), 2.80-2.64 (m, 2H), 2.49-2.38 (m, 1H), 2.19-2.08 (m, 1H), 2.02-1.92 (m, 1H), 1.82-1.66 (m, 2H), 1.66-1.54 (m, 1H), 0.97-0.88 (m, 2H), 0.66-0.59 (m, 2H).

Compound 11c-2

LCMS m/z =303.4 [M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.16(s, 2H), 4.65-4.52 (m, 3H), 3.86-3.74 (m, 2H), 3.56-3.44 (m, 1H), 2.99-2.88 ( m, 1H), 2.85-2.70 (m, 2H), 2.56-2.46 (m, 1H), 2.06-1.94 (m, 2H), 1.91-1.72 (m, 3H), 0.97-0.89 (m, 2H), 0.66-0.59 (m, 2H).

Step 3: Preparation of Compound 11d

Compound 11c (235 mg, 0.78 mmol) and compound 1c” (545 mg, 1.56 mmol) were dissolved in toluene (10 mL) at 0°C. After nitrogen replacement, boron trifluoride ether (1 mL) was slowly added dropwise to the system. React for 16 hours at 23°C. Adjust the pH to 7-8 with saturated sodium carbonate solution at 0°C. Extract with ethyl acetate (100mLx3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum) Ether: tetrahydrofuran (v:v)=10:3) to obtain compound 11d (190mg, 50%).

LCMS m/z=490.2[M+1] ⁺

Step 4: Preparation of compound 11e

Hydrazine hydrate (0.1 mL, content: 80%) was added to a solution of compound 11d (217 mg, 0.44 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the crude product was slurried with acetonitrile and filtered. The filtrate was concentrated under reduced pressure to obtain compound 11e (150 mg, crude product).

LCMS m/z=360.6[M+1] ⁺

Step 5: Preparation of Compound 11f

Intermediate 1 (174 mg, 0.55 mmol) was added to a solution of compound 11e (150 mg, crude product) and triethylamine (170 mg, 1.68 mmol) in acetonitrile (5 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v:v) = 5:1) to obtain compound 11f (150 mg, two-step yield 53%).

LCMS m/z=642.4[M+1] ⁺

Step 6: Preparation of Compound 11

Trifluoromethanesulfonic acid (116 mg, 0.77 mmol) was added to a solution of compound 11f (140 mg, 0.22 mmol) in trifluoroacetic acid (4 mL) at 0° C. and the reaction was carried out at 0° C. for 1 h. Concentrate under reduced pressure. After the crude product was diluted with ethyl acetate (20 ml), the pH was adjusted to 8-9 with saturated sodium carbonate solution. Extract with ethyl acetate (20mLx3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v)=5:2) to obtain compound 11 (72 mg, 63%).

Compound 11 is one of the structures of compound 11-1 and compound 11-2.

LCMS m/z=522.5[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.19 (s, 2H), 7.88 (s, 1H), 6.30-6.17 (m, 1H), 4.60-4.49 (m, 2H ), 4.49-4.41 (m, 1H), 4.22- 4.10 (m, 1H), 3.74-3.66 (m, 1H), 3.65-3.58 (m, 1H), 3.50-3.40 (m, 2H), 3.34-3.25 (m, 1H), 2.87-2.74 (m, 1H), 2.65-2.53 (m, 2H), 2.46-2.36 (m, 1H), 2.04-1.95 (m, 1H), 1.87-1.72 (m, 2H) , 1.59-1.41 (m, 2H), 1.15 (d,3H), 0.92- 0.84 (m, 2H), 0.68-0.59 (m, 2H).

Example 12: Preparation of compound 12 and its stereoisomers

Step One: Preparation of 12b

Dissolve 2-(dimethoxyphosphonyl)methyl acetate (26.19g, 143.79 mmol) in tetrahydrofuran (50 mL), replace with nitrogen, cool to -78°C, and add bis(trimethylsilyl)amino group dropwise Potassium (143.79 mL, 143.79 mmol, 1M), react at -78°C for 1 hour, then add dropwise a solution of 12a (synthesized with reference to patent WO2015013835) (16.7 g, 47.93 mmol) in tetrahydrofuran (50 mL), and react at -78°C for 2 hours. Add saturated ammonium chloride solution dropwise to quench the reaction, extract with ethyl acetate (50 mL Concentrate under pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9: 1) to obtain 12b (14 g, 72%).

LCMS m/z=349.1 [M-55] ⁺

Step 2: Preparation of 12c

Dissolve 12b (12.5 g, 30.91 mmol) in tetrahydrofuran (150 mL), add lithium borohydride (6.73 g, 309.1 mmol) in batches at 0°C, and react at room temperature for 18 h. Slowly add dilute hydrochloric acid (1M) dropwise to adjust the pH to 8-9, add ethyl acetate (150 mL x 3) for extraction, combine the organic phases, wash the organic phase with saturated brine (150 mL x 3), and dry over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4: 1) to obtain 12c (7 g, 60%).

LCMS m/z=279.2 [M-99] ⁺

Step 3: Preparation of 12d

Dissolve triphenylphosphine (9.45 g, 36.96 mmol) and imidazole (2.52 g, 36.96 mmol) in anhydrous dichloromethane (210 mL), and slowly add iodine element (9.38 g, 36.96 mmol) under nitrogen protection at 0°C. After reacting at room temperature for 10 minutes, 12c (7.00 g, 18.48 mmol) was slowly added dropwise at 0°C and allowed to react at room temperature for 16 hours. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 12: 1) to obtain 12d (7.00 g, 77%)

LCMS m/z = 389.0 [M-99] ⁺

Step 4: Preparation of 12e

Diethyl malonate (9.19 g, 57.35 mmol) was dissolved in anhydrous tetrahydrofuran solution (100 mL). After nitrogen replacement, sodium hydride (2.29 g, 57.35 mmol, 60% Wt) was added in batches at 0 ^° C. React at 0°C for 20 minutes, slowly add 12d (5.60 g, 11.47 mmol) anhydrous tetrahydrofuran (50 mL) solution dropwise, and react at room temperature for 16 hours. At 0°C, slowly add saturated aqueous ammonium chloride solution dropwise to quench the reaction, wash with saturated brine (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 8: 1) to obtain 12e (4.50 g, 75%).

LCMS m/z = 421.3 [M-99] ⁺

Step 5: Preparation of 12f

Dissolve 12e (4.50 g, 8.64 mmol) in ethanol (50 mL), add water (8.64 mL) and sodium hydroxide (0.35 g, 8.64 mmol), and react at room temperature for 16 h. Concentrate under reduced pressure, add dilute hydrochloric acid (2 N ) to adjust pH to 5-6 at 0°C, extract with ethyl acetate (50 mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate and filter, and reduce the filtrate to After pressure concentration, the crude product was obtained. The crude product was separated and purified by column chromatography (methanol:dichloromethane (v/v)=5:95) to obtain 12f (4.20 g, 98%).

LCMS m/z = 393.2 [M-99] ⁺

Step 6: Preparation of 12g

Dissolve 12f (5.10 g, 10.35 mmol) in methanol solution (100 mL), add ammonia (0.3 mL, content: 25%-28%) and palladium on carbon (510 mg, 10%) to it, and replace with hydrogen three times Then, react at room temperature for 16 hours. Filter through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 12g (3.71 g, crude product).

LCMS m/z = 359.2 [M+1] ⁺

Step 7: 12h preparation

Dissolve 12g (3.71 g, crude product) in DMF (30 mL), add DIPEA (4.01 g, 31.05 mmol) and HATU (3.94 g, 10.35 mmol), and react at room temperature overnight. Add water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (tetrahydrofuran: petroleum ether (v/v) = 1: 10) to obtain 12h (3.52 g, crude product).

LCMS m/z = 341.2 [M+1] ⁺

Step 8: Preparation of 12i hydrochloride

Dissolve 12h (3.52 g, crude product) in hydrogen chloride-1,4-dioxane solution (4.0 M, 20 mL, 80 mmol) and react at room temperature for 2 hours. Concentrate under reduced pressure to obtain 12i hydrochloride (2.86 g, crude product).

LCMS m/z = 241.2 [M+1] ⁺

Step 9: Preparation of 12j

Dissolve the hydrochloride of 12i (2.86 g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (1.89 g, 10.33 mmol) in dimethylstyrene (50 mL), and add potassium carbonate (4.28 g , 30.99 mmol), reacted at 90℃ for 16h. Cool to room temperature, add saturated brine (50 mL), and extract with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 5: 1) to obtain 12j (2 g, 64%).

LCMS m/z = 387.7 [M+1] ⁺

Step 10: Preparation of 12k

Dissolve 12j (0.90 g, 2.33 mmol) in a mixed solution of tetrahydrofuran (39 mL) and absolute ethanol (39 mL), add sodium borohydride (88.14 mg, 2.33 mmol), and react at room temperature for 1 h. Calcium chloride (150.28 mg, 1.17 mmol) was added in batches at 0°C, and the reaction was carried out at 0 ^° C for 2 hours. Slowly add saturated ammonium chloride aqueous solution dropwise to quench the reaction, add saturated brine for washing (30 mL), extract with ethyl acetate (30 mL x 2), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate and purify by column chromatography (petroleum ether: ethyl acetate (v/v) = 5: 3) to obtain 12k (750 mg, 93%).

LCMS m/z = 345.4 [M+1] ⁺

Step 11: Preparation of 12l

Dissolve 12k (700mg, 2.03 mmol) and 1c” (1.38 g, 3.95 mmol) in toluene (70 mL). After nitrogen replacement, cool to 0 ^° C, add boron trifluoride ether solution (7 mL), 23 React at ℃ for 16 hours. Add saturated sodium bicarbonate to adjust the pH at 0℃ until there are no bubbles and the solid is completely dissolved. Extract with ethyl acetate (50mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure The crude product was obtained, and the crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 12l (380mg, 35%).

LCMS m/z =532.2 [M +1] ⁺

Step 12: Preparation of 12m

Hydrazine hydrate (0.22 mL, content: 80%) was added to a solution of 12l (380mg, 0.71mmol) in ethanol (15mL) and reacted at room temperature for 16h. Concentrate under reduced pressure to obtain a crude product, which was separated and purified by a preparation plate (dichloromethane: methanol (v:v) = 10: 1) to obtain 12m (190 mg, 66%).

LCMS m/z =402.2 [M +1] ⁺

Step 13: Preparation of 12n

Dissolve 12m (190 mg, 0.47 mmol) and intermediate 1 (150 mg, 0.47 mmol) in acetonitrile (6 mL), add triethylamine (190 mg, 1.88 mmol), and react at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 12n (220 mg, 68%).

LCMS m/z =684.2[M+1] ⁺ .

Step 14: Preparation of compound 12 and its stereoisomers

Trifluoromethanesulfonic acid (340 mg, 2.27 mmol) was added to a solution of compound 12n (220 mg, 0.32 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust the pH to 7-9 with ammonia. After concentration under reduced pressure, it was purified by Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP was used to prepare the liquid phase, and the preparation column model was Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: Dissolve the crude product in acetonitrile and water, filter with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10Mm ammonium carbonate). Gradient elution method: acetonitrile gradient elution from 32% to 62% (elution time: 15 minutes). Compound 12 was obtained after lyophilization.

Compound 12 was purified by SFC on AD column (instrument and preparation column: Waters 150 SFC was used, and the preparation column model was Chiralpak IG Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 12 was dissolved in acetonitrile, and 0.45 Filter through a μm filter membrane and prepare a sample solution. Mobile phase system: A for CO ₂ and B for EtOH+ACN (0.1%NH ₃ •H ₂ O). Gradient elution method: 50% phase B (flow rate: 100mL/min ; Elution time: 2.8 min) to obtain compound 12-Peak-1 and compound 12-Peak-2 .

Analytical method (instrument and preparation column: SHIMADZU LC-30AD sf, preparation column model: Chiralpak AD-3 50×4.6mm ID, 3μm) Mobile phase system: A for CO ₂ and B for MeOH (0.05%DEA). The retention time T=0.971 is compound 12-Peak-1 (81 mg) (compound 12-Peak-1 is one of the structures of compound 12-P1, compound 12-P2, compound 12-P3 and compound 12-P4); retention time T=1.845 is compound 12-Peak-2 (77 mg) (compound 12-Peak-1 is one of the structures of compound 12-P1, compound 12-P2, compound 12-P3 and compound 12-P4).

Compound 12-Peak-1

LCMS m/z =564.7[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.72 (s, 2H), 7.90 (s, 1H), 6.31-6.18 (m, 1H), 4.25-3.98 (m, 4H ), 3.95-3.86 (m, 1H), 3.72-3.56 (m, 4H), 3.56-3.49 (m, 1H), 3.45-3.37 (m, 1H), 3.28-3.23 (m, 1H), 2.85-2.75 (m, 1H), 1.77-1.65 (m, 2H), 1.65-1.47 (m, 2H), 1.45-1.32 (m, 1H), 1.18-1.03 (m, 4H).

Compound 12-Peak-2

LCMS m/z =564.6[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.71 (s, 2H), 7.91 (s, 1H), 6.28-6.18 (m, 1H), 4.23-4.05(m, 3H ), 4.04-3.97(m, 1H), 3.96-3.87 (m, 1H), 3.72-3.55 (m, 4H), 3.49-3.45 (m, 2H), 3.33-3.29 (m, 1H), 2.87-2.77 (m, 1H), 1.81-1.66 (m, 2H), 1.66-1.51 (m, 2H), 1.45-1.32 (m, 1H), 1.19-1.05 (m, 4H).

Example 13: Preparation of Compound 13

Compound 13 was obtained using 12c as the starting material and referring to the synthesis method of compound 1.

LCMS m/z =580.3[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.72 (s, 2H), 7.94-7.88 (m, 1H), 6.30-6.19 (m, 1H), 4.80-4.70 (m , 1H), 4.68-4.46 (m, 3H), 4.24-4.07 (m, 2H), 3.91-3.82 (m, 1H), 3.74-3.57 (m, 3H), 3.56-3.46 (m, 2H), 3.43 -3.35 (m, 1H), 3.15-3.02(m, 1H), 2.89-2.77 (m, 1H), 1.88-1.63 (m, 2H), 1.55-1.43 (m, 1H), 1.28-1.19 (m, 1H), 1.16 (d, 3H).

Example 14: Preparation of Compound 14

Compound 14 was obtained using 14a as the starting material by referring to the synthetic method of compound 9. Compound 14 is one of the structures of compound 14-1 and compound 14-2.

LCMS m/z=550.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s,1H), 9.24 (s, 1H), 7.88 (s, 1H), 7.73-7.63(m, 2H), 7.63-7.57 (m, 1H ), 6.30-6.18 (m, 1H), 4.81-4.68 (m, 2H), 4.56-4.46(m, 1H), 4.23 – 4.08 (m, 1H), 3.76-3.67 (m, 1H), 3.66-3.58 (m, 1H), 3.50-3.42 (m, 2H), 3.42-3.33 (m, 1H), 3.02-2.90 (m, 1H), 2.77-2.62 (m, 2H), 2.47-2.38 (m, 1H) , 2.12-1.99 (m, 1H), 1.91 -1.77 (m, 1H), 1.61-1.45 (m, 2H), 1.15 (d, 3H).

Example 15: Preparation of Compound 15

Step One: Preparation of 15b

15a (3.00 g, 15.48 mmol), 2-fluorophenylboronic acid (2.17 g, 15.48 mmol), cesium carbonate (10.09 g, 30.96 mmol), 1,4-dioxane (40 mL) and water (4 mL ) were added into the one-neck bottle in sequence. After nitrogen replacement, tetrakis(triphenylphosphine)palladium (1.79 g, 1.55 mmol) was added and the reaction was carried out at 90°C for 16 h. Concentrate under reduced pressure, add water (50 mL) to quench the reaction, extract with ethyl acetate (40 mL x 2), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter with suction, and obtain the filtrate. Concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: dichloromethane (v/v) = 7:3) to obtain 15b (2.60 g, 80%)

LCMS m/z = 209.0[M+1] ⁺

Compound 1 5 was obtained using 15b as the substrate by referring to the synthetic method of compound 9. Compound 15 is one of the structures of compound 15-1 and compound 15-2 .

LCMS m/z=576.3[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.61 (d, 2H), 7.89 (s, 1H), 7.60-7.55 (m, 1H), 7.45-7.38 (m, 1H ), 7.36-7.28 (m, 2H), 6.30-6.19 (m, 1H), 4.72-4.61 (m, 2H), 4.53-4.45 (m, 1H), 4.23-4.10 (m, 1H), 3.75-3.68 (m, 1H), 3.66-3.59 (m, 1H), 3.49-3.41 (m, 2H), 3.41-3.32(m, 1H), 2.99-2.89 (m, 1H), 2.76-2.60 m, 2H), 2.47-2.38 (m, 1H), 2.07-1.97 (m, 1H), 1.89-1.78 (m, 1H), 1.60-1.44 (m, 2H), 1.15 (d, 3H).

Example 16: Preparation of trifluoroacetate salt of compound 16 Step One: Preparation of 16a

At 0°C, sodium borohydride (58mg, 1.53mmol) and calcium chloride (85mg, 0.77mmol) were added to the mixed solution of 9f (500mg, 1.53mmol) in tetrahydrofuran (5mL) and ethanol (5mL) at 0°C. Reaction 1h. Ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL) were added to quench the reaction. The liquids were separated, and the organic phase was concentrated under reduced pressure to obtain 16a (438 mg, crude product).

LCMS m/z =285.4[M+1] ⁺ .

Step 2: Preparation of 16b hydrochloride

Dissolve 16a (438 mg, crude product) in 4N dioxane hydrochloride (10 mL) and react at room temperature for 2 h. Concentrate under reduced pressure to obtain 16b hydrochloride (339 mg, crude product).

LCMS m/z=185.2[M+1] ⁺

The trifluoroacetate of compound 16 was obtained by using the hydrochloride of 16b as the substrate and referring to the synthesis method of compound 9. Compound 16 is one of the structures of compound 16-1 and compound 16-2 .

LCMS m/z=538.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ8.81 (s, 1H), 7.91 (s, 1H), 7.26-7.18 (m, 2H), 4.80-4.70 (m,2H), 4.64-4.56 (m , 1H), 4.23-4.11 (m, 1H), 4.02-3.92 (m, 1H), 3.64-3.53 (m, 2H), 3.52-3.36 (m, 2H), 3.15-3.03 (m, 1H), 2.93 -2.83 (m, 1H), 2.82-2.74 (m, 1H), 2.55-2.45 (m, 1H), 2.17-2.07 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.52 (m, 2H), 1.25 (d, 3H).

Example 17: Preparation of Compound 17

Compound 17 was obtained using 17a as a substrate by referring to the synthetic method of compound 9. Compound 17 is one of the structures of compound 17-1 and compound 17-2 .

LCMS m/z=522.3[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 6.27-6.20 (m, 1H), 4.62-4.53 (m, 2H ), 4.50-4.42 (m, 1H), 4.21-4.10 (m, 1H), 3.74-3.66 (m,1H), 3.64-3.58 (m, 1H), 3.49-3.40 (m, 2H), 3.36-3.33 (m, 1H), 2.82-2.72 (m, 5H), 2.62-2.53 (m, 2H), 2.45-2.37 (m, 1H), 2.04-1.95 (m, 3H), 1.86-1.78 (m, 1H) , 1.58-1.40 (m, 2H), 1.15 (d, 3H).

Example 18: Preparation of Compound 18

Compound 18 was obtained using 18a as the substrate by referring to the synthetic method of compound 9. Compound 18 is one of the structures of compound 18-1 and compound 18-2.

LCMS m/z=536.7[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (s, 1H), 9.14 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 6.32-6.16 (m, 1H), 4.70-4.57 (m, 2H), 4.54-4.43 (m, 1H), 4.22-4.11 (m, 1H), 4.07 (s, 3H), 3.76-3.67 (m, 1H), 3.66-3.58 (m, 1H ), 3.53-3.41 (m, 3H), 2.91-2.80 (m, 1H), 2.70 -2.58 (m, 2H), 2.47-2.37 (m, 1H), 2.09-1.97 (m, 1H), 1.88-1.79 (m, 1H), 1.62-1.42 (m, 2H), 1.15 (d, 3H).

Example 19: Preparation of Compound 19

Compound 19 was obtained using 19a as a substrate by referring to the synthetic method of compound 9. Compound 19 is one of the structures of compound 19-1 and compound 19-2.

LCMS m/z=538.1 [M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 9.09 (s, 1H), 8.28 (d, 1H), 7.88 (s, 1H), 7.28 (d, 1H), 6.32- 6.16 (m, 1H), 4.75-4.58 (m, 2H), 4.55-4.43 (m, 1H), 4.25-4.08 (m, 1H), 3.76-3.68 (m, 1H), 3.66-3.58 (m, 1H ), 3.50-3.41 (m, 2H), 3.40-3.33 (m, 1H), 2.96-2.82 (m, 1H), 2.73-2.58 (m, 2H), 2.48-2.37 (m, 1H), 2.11-1.97 (m, 1H), 1.90- 1.76 (m, 1H), 1.60-1.43 (m, 2H), 1.15 (d, 3H).

Example 20: Preparation of Compound 20

Step One: Preparation of 20b

Dissolve 20a (3.00 g, 17.75 mmol) in acetonitrile (150 mL), add sodium nitrite (2.45 g, 35.50 mmol) and hydrobromic acid aqueous solution (6 mL, content: 48%) in sequence, and react at room temperature for 16 h. Concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 75:25) to obtain 20b (3.00 g, 73%)

LCMS m/z = 232.0[M+1] ⁺

Step 2: Preparation of 20c

Dissolve 20b (2.67 g, 11.49mmol) in 1,4-dioxane (30 mL), and add 9g (2.60 g, crude product), potassium carbonate (3.18 g, 22.98mmol), tris(dibenzylidene) in sequence Acetone) palladium (526.08 mg, 0.57mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (664.83 mg, 1.15mmol), nitrogen replacement 3 times, reaction at 100°C for 16 h . Cool to room temperature, add water (50 mL), and extract with ethyl acetate (50 mL x 2). Combine the organic phases, wash them with saturated brine (60 mL v)=25:75) gets 20c (850 mg, 20%)

LCMS m/z = 378.1 [M+1] ⁺

Compound 20 was obtained using 20c as a substrate by referring to the synthetic method of compound 9. Compound 20 is one of the structures of compound 20-1 and compound 20-2.

LCMS m/z=555.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.70 (d, 1H), 7.88 (s, 1H), 7.67 (d, 1H), 7.04 (dd, 1H), 6.33- 6.15 (m, 1H), 4.58-4.46 (m, 1H), 4.23-4.03 (m, 3H), 3.75-3.66 (m, 1H), 3.65-3.57 (m, 1H), 3.51-3.40 (m, 3H ), 2.92-2.80 (m, 1H), 2.75-2.60 (m, 2H), 2.45-2.36 (m, 1H), 2.08-1.95 (m, 1H), 1.89-1.76 (m, 1H), 1.59-1.39 (m, 2H), 1.15 (d, 3H).

Example 21: Preparation of Compound 21

Compound 21 was obtained using 21a as the substrate by referring to the synthetic method of compound 9. Compound 21 is one of the structures of compound 21-1 and compound 21-2.

LCMS m/z=507.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.79 (s, 2H), 7.87 (s, 1H), 6.32-6.17 (m, 1H), 4.70-4.57 (m, 2H ), 4.52-4.40 (m, 1H), 4.22-4.08 (m, 1H), 3.76-3.68 (m, 1H), 3.64-3.57 (m, 1H), 3.48-3.42(m, 3H), 3.09-2.98 (m, 1H), 2.87-2.76 (m, 1H), 2.70-2.60 (m, 1H), 2.45-2.38 (m, 1H), 2.05-1.95 (m, 1H), 1.87-1.77 (m, 1H) , 1.60-1.41 (m, 2H), 1.14 (d, 3H).

Example 22: Preparation of Compound 22

Step One: Preparation of 22-b

Add N-bromosuccinimide (2.81 g, 15.82 mmol) in batches to a solution of 22a (2.15 g, 13.18 mmol) in acetonitrile (20 mL), and react at room temperature for 16 h. Concentrate under reduced pressure to obtain 22b (3.10 g, crude product).

LCMS m/z = 241.9 [M+1] ⁺

Step 2: Preparation of 22c

Potassium thiocyanate (1.49 g, 15.37 mmol) was added to a solution of 22b (3.10 g, crude product) in acetic acid (30 mL), and the reaction was carried out at 140°C for 3 h. Concentrate under reduced pressure to obtain a crude product, which is beaten with water (20 mL), filtered, and the filter cake is dried to obtain 22c (1.90 g, two-step yield: 65%).

LCMS m/z = 221.1 [M+1] ⁺

Step 3: Preparation of 22d

Dissolve 22c (1.80 g, 8.18 mmol) in acetonitrile (20 mL) solution, add tert-butyl nitrite (1.69 g, 16.36 mmol) and copper bromide (3.65 g, 16.36 mmol) in sequence, and keep the nitrogen atmosphere at 60°C. Reaction for 3 hours. Cool to room temperature, add 100 mL saturated sodium chloride solution, and extract with ethyl acetate (100 mL x 3). Combine the organic phases, wash them with saturated brine (80 mL v) = 83: 17) gives 22d (1.00 g, 43%).

¹ H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H).

Compound 22 was obtained using 22d as the substrate by referring to the synthetic method of compound 16. Compound 22 is one of the structures of compound 22-1 and compound 22-2.

LCMS m/z=607.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.92 (s, 1H), 7.88 (s, 1H), 6.34-6.18 (m, 1H), 4.58-4.46 (m, 1H ), 4.30-4.00 (m, 3H), 3.79-3.68 (m, 1H), 3.64-3.55 (m, 1H), 3.54-3.41 (m, 3H), 3.37-3.26 (m, 1H), 3.20-3.07 (m, 1H), 2.86-2.73 (m, 1H), 2.48-2.39 (m, 1H), 2.12-2.02 (m, 1H), 1.89-1.77 (m, 1H), 1.59-1.42 (m, 2H) , 1.15 (d, 3H).

Example 23: Preparation of Compound 23

Step One: Preparation of 23b

Bistriphenylphosphine palladium dichloride (1.56 g, 2.23 mmol) was added to 23a (7.80 g, 44.57 mmol), 2-fluorophenylboronic acid (6.24 g, 44.57 mmol), and potassium carbonate (13.55 g, 98.05 mmol). A mixed solution of dioxane (150 mL) and water (10 mL) was reacted in a nitrogen atmosphere at 95°C for 16 hours. Cool to room temperature, add saturated sodium chloride solution (200 mL) to the reaction solution, and extract with ethyl acetate (200 mLx3). The organic phases were combined and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v/v) = 83:17) to obtain 23b (6.40 g, 76%).

LCMS m/z =191.1[M+1] ⁺ ,

Step 2: Preparation of 23c

Tert-butyl nitrite (3.69 g, 35.76 mmol) was added dropwise to a solution of 23b (3.40 g, 17.88 mmol) and copper chloride (2.68 g, 26.82 mmol) in acetonitrile (50 mL), and the reaction was carried out at 60°C for 1 hour. Cool to room temperature, add saturated sodium chloride solution (50 mL), and extract with ethyl acetate (80 mLx3). The organic phases were combined and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 83:17) to obtain 23c (1.40 g, 37%).

LCMS m/z =210.1[M+1] ⁺

Compound 23 was obtained using 23c as a substrate by referring to the synthetic method of compound 16. Compound 23 is one of the structures of compound 23-1 and compound 23-2 .

LCMS m/z =577.3[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (s, 1H), 8.71 (d, 1H), 7.95-7.85 (m,2H), 7.58-7.48 (m, 1H), 7.42-7.33 (m ,2H), 6.32-6.18 (m, 1H), 4.77-4.60 (m,2H), 4.57-4.46 (m, 1H), 4.24-4.10 (m, 1H), 3.78-3.69 (m, 1H), 3.65 -3.58 (m, 1H), 3.50-3.38 (m, 3H), 3.15-3.02 (m, 1H), 2.92-2.82 (m, 1H), 2.79-2.68 (m, 1H), 2.48-2.41 (m, 1H), 2.12-1.98 (m, 1H), 1.89-1.81 (m, 1H), 1.60-1.46 (m,2H), 1.15 (d, 3H).

Example 24: Preparation of Compound 24

Compound 24 was obtained by using 9 g of hydrochloride and 3-chloro-6-trifluoromethylpyridazine as substrates by referring to the synthetic method of compound 9. Compound 24 is one of the structures of compound 24-1 and compound 24-2 .

LCMS m/z =550.8[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.45 (d, 1H), 6.31-6.18 (m, 1H), 4.54-4.37 (m, 3H), 4.23-4.12 (m, 1H), 3.79-3.68 (m, 1H), 3.64-3.57 (m, 1H), 3.50-3.39 (m, 3H), 3.12-3.00 (m , 1H), 2.87-2.71 (m, 2H), 2.48-2.40 (m, 1H), 2.06-1.96 (m, 1H), 1.90-1.78 (m, 1H), 1.62-1.42 (m, 2H), 1.15 (d, 3H).

Example 25: Preparation of Compound 25

Compound 25 was obtained using 2-chloro-5-fluoropyrimidine as a substrate by referring to the synthetic method of compound 9. Compound 25 is one of the structures of compound 25-1 and compound 25-2 .

LCMS m/z =500.7[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.47 (s, 2H), 7.88 (s, 1H), 6.32-6.18 (m, 1H), 4.58-4.40 (m, 3H ), 4.23-4.09 (m, 1H), 3.76-3.67 (m, 1H), 3.64-3.57 (m, 1H), 3.51-3.37 (m, 3H), 2.92-2.83 (m, 1H), 2.70-2.57 (m, 2H), 2.46-2.38 (m, 1H), 2.05-1.95 (m, 1H), 1.87-1.76 (m, 1H), 1.59 -1.41 (m, 2H), 1.15 (d, 3H).

Example 26: Preparation of Compound 26

Compound 26 was obtained using 2,6-dichlorobenzothiazole as a substrate and referring to the synthetic method of compound 9. Compound 26 is one of the structures of compound 26-1 and compound 26-2 .

LCMS m/z =571.1[M+1] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 7.93 (d, 1H), 7.89 (s, 1H), 7.45 (d, 1H), 7.31 (dd, 1H), 6.34-6.18 (m, 1H), 4.57-4.46 (m, 1H), 4.23-4.11 (m, 1H), 4.07-3.93 (m, 2H), 3.75-3.68 (m, 1H), 3.65-3.58 (m, 1H) , 3.48-3.43 (m, 3H), 3.18-3.09 (m, 1H), 3.00-2.91 (m, 1H), 2.79-2.69 (m, 1H), 2.48-2.39 (m, 1H), 2.10-1.99 ( m, 1H), 1.88-1.79 (m, 1H), 1.60-1.41 (m, 2H), 1.15 (d, 3H).

Example 27: Preparation of Compound 27

Step One: Preparation of 27b

Potassium carbonate (5.08 g, 36.76 mmol) was added to a solution of 9 g of hydrochloride (2.08 g, crude product) and 27a (2.18 g, 11.04 mmol) in dimethylstyrene (15 mL), and the reaction was carried out at room temperature overnight. Cool to room temperature, add water (80 mL) to quench the reaction, and extract with ethyl acetate (20 mL x 2). Combine the organic phases, wash them with saturated brine (50 mL v)= 68:32) gets 27b (2.72 g, 64%)

LCMS m/z = 388.1 [M+1] ⁺

Step 2: Preparation of 27c

N,N-dimethylformamide dimethyl acetal (1086 mg, 9.11mmol) was added to a solution of 27b (2.72 g, 7.01mmol) in toluene (20 mL), and the reaction was carried out at 120°C overnight. Cool to room temperature and concentrate under reduced pressure to obtain 27c (3.20 g, crude product).

LCMS m/z = 443.1 [M+1] ⁺

Step 3: Preparation of 27d

Under an ice-water bath, add hydroxylamine sulfonic acid (1084 mg, 9.59mmol) and pyridine (1083 mg, 13.7mmol) to a solution of 27c (3.03g, crude product) in methanol (30 mL), and react at room temperature for 18 hours. Add saturated aqueous sodium carbonate solution to adjust the pH to 8-9, concentrate under reduced pressure, add water (100 mL), and extract with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 64:36) to get 27d (2.30 g, two-step yield 79%)

LCMS m/z = 413.5 [M+1] ⁺

Compound 27 was obtained using 27d as the substrate by referring to the synthetic method of compound 9. Compound 27 is one of the structures of compound 27-1 and compound 27-2 .

Compound 27:

LCMS m/z=590.3 [M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.37 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 6.30-6.18 (m, 1H), 5.13 (t, 2H), 4.57-4.40 (m, 1H), 4.25-4.06 (m, 1H), 3.77-3.66 (m, 1H), 3.65-3.59 (m, 1H), 3.58-3.50 (m, 1H ), 3.49-3.40 (m, 2H), 3.29-3.24(m,1H),3.15-3.04 (m, 1H), 2.92-2.80 (m, 1H), 2.47-2.38 (m, 1H), 2.04-1.91 (m, 1H), 1.90-1.75 (m, 1H), 1.60-1.44 (m, 2H), 1.15 (d, 3H).

Example 28: Preparation of Compound 28

Step One: Preparation of 28b

DIPEA (2.31 g, 17.85 mmol) was added to a solution of 9 g of hydrochloride (1.62 g, crude product) and 28a (1.00 g, 5.97 mmol) in n-butanol (20 mL), and the reaction was carried out under microwave at 120°C for 2 h. Concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (dichloromethane: ethyl acetate (v/v) = 62:38) to obtain 28b (1.58 g, 68%)

LCMS m/z = 386.2 [M+1] ⁺

Step 2: Preparation of 28c

N-chlorosuccinimide (1.31 g, 9.80 mmol) was added to a solution of 28b (3.15 g, 8.17 mmol) in DMF (30 mL), and the reaction was carried out at room temperature for 16 h. Saturated aqueous sodium bicarbonate solution (100 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 58:42) yielded 28c (1.76 g, 51%).

LCMS m/z = 420.2 [M+1] ⁺

Compound 28 was obtained using 28c as a substrate by referring to the synthetic method of compound 9. Compound 28 is one of the structures of compound 28-1 and compound 28-2 .

Compound 28:

LCMS m/z=569.2 [M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.43 (s, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 6.35-6.17 (m, 1H), 5.23-4.97 (m, 2H), 4.57-4.43 (m, 1H), 4.20 (s, 3H), 4.19-4.10 (m, 1H), 3.7-3.56 (m, 2H), 3.51-3.36 (m, 3H ), 3.08-2.91 (m, 1H), 2.81-2.63 (m, 2H), 2.47 -2.37 (m, 1H), 2.07-1.93 (m, 1H), 1.89-1.77 (m, 1H), 1.60-1.44 (m, 2H), 1.15 (d, 3H).

Example 29: Preparation of Compound 29

Step One: Preparation of 29b

Sodium nitrite (1.64 g, 23.72 mmol) was added to the solution of 29a (2 g, 11.86 mmol) in acetonitrile (100 mL), and aqueous hydrobromic acid solution (4 mL, content: 48%) was slowly added dropwise, and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 4:1) to obtain 29b (1.92 g, 70%).

LCMS m/z=232.0[M+1] ⁺

Step 2: Preparation of 29c

29b (0.82 g, 3.53 mmol) was added to the hydrochloride salt of 16b (0.65 g, crude), DIPEA (1.37 g, 10.56 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol) in ethanol (20 mL ) solution, microwave reaction at 120°C for 3 hours. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain 29c-1 (0.165 g, 14%) and 29c-2 .

29c -1 is 29c

LCMS m/z =336.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.05-8.98 (m, 1H), 7.62-7.56 (m, 1H), 7.53-7.49 (m, 1H), 4.59-4.46 (m, 2H), 4.17 -4.05 (m, 2H), 3.73-3.64 (m, 1H), 3.63-3.53 (m, 1H), 3.52-3.41 (m, 1H), 2.94-2.81 (m, 1H), 2.78-2.60 (m, 2H), 2.35-2.23 (m, 1H), 2.14-2.00 (m, 1H), 1.95-1.83(m, 1H), 1.66-1.42 (m, 2H).

29c-2

LCMS m/z =336.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.05-8.98 (m, 1H), 7.62-7.55 (m, 1H), 7.54-7.47 (m, 1H), 4.67 (t, 1H), 4.58-4.46 (m, 1H), 4.14-4.03 (m, 2H), 3.70-3.43 (m, 3H), 2.92-2.75 (m, 2H), 2.74-2.63 (m, 1H), 2.41-2.30 (m, 1H) , 1.94-1.81 (m, 2H), 1.80-1.63 (m, 2H).

Compound 29 was obtained using 29c as a substrate by referring to the synthetic method of compound 16. Compound 29 is one of the structures of compound 29-1 and compound 29-2.

Compound 29:

LCMS m/z=555.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 9.06-8.98 (m, 1H), 7.88 (s, 1H), 7.62-7.56 (m, 1H), 7.54-7.49 (m , 1H), 6.29-6.20 (m, 1H), 4.57-4.47 (m, 1H), 4.22-4.03 (m, 3H), 3.74-3.66 (m, 1H), 3.65-3.58 (m, 1H), 3.49 -3.36(m, 3H), 2.92-2.81 (m, 1H), 2.73-2.61 (m,2H), 2.45-2.38 (m, 1H), 2.07-1.95 (m, 1H), 1.88-1.77 (m, 1H), 1.60-1.41 (m, 2H), 1.15 (d, 3H).

Example 30: Preparation of Compound 30

Step 1: Preparation of 30b

Ethyl isothiocyanate (14.47 g, 110.36 mmol) was added to the solution of 30a (15.00 g, 91.97mmol) in 1,4-dioxane (150 mL), and the reaction was carried out at 35°C for 72 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 30b (7.00 g, 26%).

LCMS m/z=295.1[M+1] ⁺

Step 2: Preparation of 30c

Hydroxylamine hydrochloride (6.61 g, 95.16 mmol) and triethylamine (7.22g, 71.35mmol) were added in sequence to the mixed solution of 30b (7.00 g, 23.79mmol) in methanol (100 mL) and ethanol (100 mL), at room temperature. The reaction was carried out for 2 h and at 80°C for 4 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 67:33) to obtain 30c (3.88 g, 80%).

LCMS m/z=204.1[M+1] ⁺

Step 3: Preparation of 30d

Sodium nitrite (2.65 g, 38.40 mmol) was added to the solution of 30c (3.90 g, 19.20 mmol) in acetonitrile (100 mL), concentrated hydrochloric acid aqueous solution (10 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 30d (1.16 g, 27%).

LCMS m/z=223.1[M+1] ⁺

Step 4: Preparation of 30e

30d (0.79 g, 3.53 mmol) was added to the hydrochloride salt of 16b (0.65 g, crude), DIPEA (1.82 g, 14.12 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol) in ethanol (20 mL ) solution, microwave reaction at 120°C for 3 h. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain 30e-1 (0.36 g, 27%) and 30e-2 .

30e -1 is 30e

LCMS m/z =371.4[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.14 (s, 1H), 4.62-4.49 (m, 2H), 4.23-4.12 (m, 2H), 3.73-3.64 (m , 1H), 3.63-3.55 (m, 1H), 3.54-3.43 (m, 1H), 3.08-2.95 (m, 1H), 2.90-2.80 (m, 1H), 2.76-2.64 (m, 1H), 2.37 -2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.96-1.85 (m, 1H), 1.67-1.44 (m, 2H).

30e-2

LCMS m/z =371.4[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.14 (s, 1H), 4.78-4.46 (m, 2H), 4.25-4.06 (m, 2H), 3.74-3.48 (m , 3H), 3.04-2.86 (m, 2H), 2.76-2.65 (m, 1H), 2.40-2.32 (m, 1H), 1.96-1.82(m, 2H), 1.81-1.67 (m, 2H).

Compound 30 was obtained using 30e as the substrate by referring to the synthetic method of compound 16. Compound 30 is one of the structures of compound 30-1 and compound 30-2.

Compound 30:

LCMS m/z=590.8[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (s, 1H), 9.64 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 6.30-6.18 (m, 1H), 4.60-4.48 (m, 1H), 4.25-4.09 (m, 3H), 3.76-3.67 (m, 1H), 3.65-3.56 (m, 1H), 3.49-3.36 (m, 3H), 3.07-2.93 (m , 1H), 2.87-2.76 (m,1H), 2.73-2.62 (m,1H), 2.47-2.38 (m, 1H), 2.10-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.61 -1.42 (m, 2H), 1.15 (d, 3H).

Example 31: Preparation of Compound 31

Step 1: Preparation of 31b

Palladium on carbon (400 mg, 10%) and potassium carbonate (1.60 g, 11.56 mmol) were added to the solution of 31a (2.00 g, 8.89 mmol) in tetrahydrofuran (50 mL). After hydrogen replacement, keep the autoclave (2.5 MPa hydrogen pressure) at 30°C for 24 h. Filter through diatomaceous earth, add silica gel to the filtrate, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 31b (0.80 g, 47%).

LCMS m/z=191.1[M+1] ⁺

Step 2: Preparation of 31c

31a (0.67 g, 3.53 mmol) was added to the hydrochloride salt of 16b (0.65 g, crude), DIPEA (1.82 g, 14.12 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol) in ethanol (20 mL ) solution, microwave reaction at 120°C for 3 h. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography. The crude product is separated and purified by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80 ) to obtain 31c-1 (0.42 g, 35%) and 31c-2 .

31c -1 is 31c

LCMS m/z =339.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.58 (s, 1H), 4.64-4.45 (m, 4H), 3.72-3.64 (m, 1H), 3.63-3.54 (m, 1H), 3.47-3.36 (m, 1H), 2.99-2.80 (m, 3H), 2.77-2.51 (m, 4H), 2.35-2.24 (m, 1H), 2.14-2.02 (m, 1H), 1.95-1.84(m, 1H) , 1.67-1.43 (m, 2H).

31c-2

LCMS m/z =339.2[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.58 (s, 1H), 4.70-4.65 (m, 1H), 4.64-4.43 (m, 3H), 3.72-3.53 (m, 2H), 3.50-3.37 (m, 1H), 2.94-2.75 (m, 4H), 2.71-2.52 (m, 3H), 2.42-2.31 (m, 1H), 1.94-1.82(m, 2H), 1.81-1.65 (m, 2H) .

Compound 31 was obtained using 31c as the substrate by referring to the synthetic method of compound 16. Compound 31 is one of the structures of compound 31-1 and compound 31-2.

Compound 31:

LCMS m/z=558.6[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.59 (s, 1H), 7.88 (s, 1H), 6.35-6.10 (m, 1H), 4.66-4.52 (m, 2H ), 4.51-4.40 (m, 1H), 4.24-4.08 (m, 1H), 3.76-3.57 (m, 2H), 3.50-3.40 (m, 2H), 3.40-3.31 (m, 1H), 3.00-2.80 (m, 3H), 2.75-2.52 (m, 4H), 2.47- 2.36 (m, 1H), 2.10-1.94 (m, 1H), 1.88-1.78 (m, 1H), 1.63-1.41 (m, 2H) , 1.15 (d, 3H).

Example 32: Preparation of Compound 32

Step 1: Preparation of 32b

Ethyl isothiocyanate (2.67 g, 20.36 mmol) was added to a solution of 32a (3.00 g, 18.51 mmol) in dioxane (30 mL), and the reaction was carried out at 100°C for 16 h in a nitrogen atmosphere. Cool to room temperature and concentrate under reduced pressure to obtain crude product. The crude product is beaten with a mixed solvent (petroleum ether: tetrahydrofuran (v/v) = 5:1) and filtered. The filter cake is 32b (5.00g, 92%).

LCMS m/z=294.2[M+1] ⁺

Step 2: Preparation of 32c

32b (4.70 g, 16.03 mmol) was added to a solution of hydroxylamine hydrochloride (4.46 g, 64.12 mmol) and triethylamine (4.87 g, 48.09 mmol) in ethanol (40 mL), and the reaction was carried out at 100°C for 3 h in a nitrogen atmosphere. Concentrate under reduced pressure to obtain a residue. Ethyl acetate (50 mL) and petroleum ether (50 mL) were added to the residue, stirred for 1 h, filtered, and the filtrate was concentrated again to obtain crude product. The crude product is beaten with a mixed solvent (petroleum ether: ethyl acetate (v/v) = 5:1) and filtered. The filter cake is 32c (2.40 g, 74%).

LCMS m/z=203.2[M+1] ⁺

Step 3: Preparation of 32d

Concentrated hydrochloric acid (1 mL) was added to a solution of 32c (1.10 g, 5.44 mmol) and sodium nitrite (940 mg, 13.60 mmol) in acetonitrile (10 mL) under an ice-water bath, and the reaction was slowly raised to room temperature for 2 h. Add ethyl acetate (100 mL) to dilute the reaction solution, and add saturated sodium carbonate solution to adjust the pH to 8-9. Extract with ethyl acetate (100 mL x 2), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 83:17) to obtain 32d (1.00 g, 83%).

LCMS m/z=222.1[M+1] ⁺

Step 4: Preparation of 32e

Add 32d (510 mg, 2.30 mmol) to a solution of 16b trifluoroacetate (755 mg, 2.53 mmol) and potassium carbonate (1.59 g, 11.50 mmol) in dimethylstyrene (7 mL), and react at 100°C 16h. Cool to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (30 mL x 3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (methylene chloride (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) )=75:25) to obtain 32e-1 (450 mg, 53%) and its diastereomer 32e-2 .

Compound 32e-1 is compound 32e

LCMS m/z=370.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.72-8.66 (m, 1H), 7.80 -7.72 (m, 1H), 7.24-7.17 (m, 1H), 4.73- 4.60 (m, 1H), 4.33- 4.20 (m, 2H), 3.88-3.74 (m, 2H), 3.65-3.54 (m, 1H), 3.11-2.99 (m, 1H), 2.90-2.76 (m, 2H), 2.51-2.41 (m, 1H ), 2.23-2.14 (m, 1H), 2.04-1.94 (m, 1H), 1.81-1.55 (m, 2H).

Compound 32e-2

LCMS m/z=370.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (d, 1H), 7.76 (s, 1H), 7.21 (dd, 1H), 4.73- 4.64 (m, 1H), 4.31-4.16 (m, 2H) , 3.91-3.77 (m, 2H), 3.71-3.59 (m, 1H), 3.12-2.92 (m, 2H), 2.91-2.80 (m, 1H), 2.60-2.46 (m, 1H), 2.13-1.97 ( m, 2H), 1.94-1.80 (m, 2H).

Step 5: Preparation of 32f

Under an ice-water bath, add boron trifluoride ether (4.5 mL) to the toluene (45 mL) solution of 32e (450 mg, 1.22 mmol) and 1c” (853 mg, 2.44 mmol), and react at 35°C for 16 h in a nitrogen atmosphere. . Under an ice-water bath, adjust the pH value to 7-8 with saturated sodium carbonate solution, extract with ethyl acetate (30 mL x 3), and combine the organic phases. Wash the organic phase with saturated brine (60 mL), dry over anhydrous sodium sulfate, and After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 67:33) to obtain 32f (40 mg, 6%).

LCMS m/z=557.2[M+1] ⁺

Step 6: Preparation of 32g

Hydrazine hydrate (0.5 mL, content: 80%) was added to a solution of 32f (220 mg, 0.40 mmol) in ethanol (5 mL), and the reaction was carried out at room temperature for 16 h. Filter and wash the filter cake with acetonitrile (10 mL x 3). After the filtrate was concentrated under reduced pressure, it was slurried again with acetonitrile (10 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain 32g (160 mg, crude product).

LCMS m/z=427.3[M+1] ⁺

Step 7: Preparation for 32h

Triethylamine (154 mg, 1.52 mmol) was added to a solution of intermediate 1 (145 mg, 0.46 mmol) and 32g (160 mg, crude product) in acetonitrile (4 mL), and the reaction was carried out at room temperature for 16 h. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether (containing 16% ethyl acetate): dichloromethane (containing 9% methanol) (v/v) = 75:25) to obtain 32h (160 mg, Two-step yield: 57%).

LCMS m/z=709.3[M+1] ⁺

Step 8: Preparation of compound 32

Add trifluoromethanesulfonic acid (121 mg, 0.81 mmol) to the 32h (160 mg, 0.23 mmol) trifluoroacetic acid (2 mL) solution under an ice-water bath, and react in an ice-water bath for 2 h. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), the pH was adjusted to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (petroleum ether (containing 16% ethyl acetate): dichloromethane (containing 9% methanol) (v/v) = 75:25) to obtain compound 32 (100 mg, 75%).

Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , column temperature: 35°C, flow rate: 1.0mL/min.

The retention time T=27.431 min is compound 32, which is one of the structures of compound 32-1 and compound 32-2.

LCMS m/z=589.7[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.91 (d, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.26 (dd, 1H), 6.32- 6.16 (m, 1H), 4.61-4.46 (m, 1H), 4.25-4.06 (m, 3H), 3.77-3.67 (m, 1H), 3.66-3.58 (m, 1H), 3.51-3.35 (m, 3H ), 3.00-2.85 (m, 1H), 2.80-2.61 (m, 2H), 2.47-2.36 (m, 1H), 2.10-1.96 (m, 1H), 1.90-1.78 (m, 1H), 1.62-1.41 (m, 2H), 1.15 (d, 3H).

Example 33: Preparation of Compound 33

Compound 33 was obtained using 33a as a substrate by referring to the synthetic method of compound 32. Compound 33 is one of the structures of compound 33-1 and compound 33-2.

LCMS m/z= 590.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (s, 1H), 9.37 (d, 1H), 7.88 (s, 1H), 7.56 (d, 1H), 6.31-6.14 (m, 1H), 4.62-4.47 (m, 1H), 4.26-4.06 (m, 3H), 3.78-3.66(m, 1H), 3.65-3.56 (m, 1H), 3.51-3.34 (m, 3H), 3.06-2.92 (m , 1H), 2.88-2.75 (m, 1H), 2.73-2.60 (m, 1H), 2.47-2.38 (m, 1H), 2.10-1.99 (m, 1H), 1.89-1.77 (m, 1H), 1.60 -1.43 (m, 2H), 1.15 (d, 3H).

Example 34: Preparation of Compound 34

Step One: Preparation of 34b

Ethyl isothiocyanate (4.86 g, 37.02 mmol) was added to the solution of 34a (5.00 g, 30.85 mmol) in 1,4-dioxane (50 mL), and the reaction was carried out at 100°C for 16 h. Concentrate under reduced pressure to obtain a crude product, which is beaten with a mixed solvent (petroleum ether: ethyl acetate (v:v) = 5:1), filtered, and the filter cake is dried to obtain 34b (7 g, 77%).

LCMS m/z=294.1[M+1] ⁺

Step 2: Preparation of 34c

Hydroxylamine hydrochloride (4.74 g, 68.20 mmol) and triethylamine (5.18 g, 51.15 mmol) were added to the ethanol (50 mL) solution of 34b (5.00 g, 17.05 mmol) in sequence, stirred at room temperature for 1 h, and reacted at 80°C 16h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 67:33) to obtain 34c (3.20 g, 93%).

LCMS m/z=203.1[M+1] ⁺

Step 3: Preparation of 34d

Sodium nitrite (2.18 g, 31.66 mmol) was added to the solution of 34c (3.20 g, 15.83 mmol) in acetonitrile (50 mL), concentrated hydrochloric acid (5 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 34d (2.60 g, 74%).

LCMS m/z=222.0[M+1] ⁺

Step 4: Preparation of 34e

34d (0.45 g, 2.03 mmol) was added to the hydrochloride salt of 16b (0.45 g, crude), DIPEA (1.05 g, 8.12 mmol), 4-dimethylaminopyridine (25 mg, 0.20 mmol) in ethanol (8 mL ) solution, microwave reaction at 120°C for 3 h. Silica gel was added, concentrated under reduced pressure and purified by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain compound 34e-1 (80 mg, 11%) and compound 34e-2 .

Compound 34e-1 is compound 34e

LCMS m/z =370.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.40-9.27 (m, 1H), 7.83-7.75 (m, 1H), 7.70-7.60 (m, 1H), 4.63-4.46 (m, 2H), 4.22 -4.08 (m, 2H), 3.74-3.64 (m,1H), 3.63-3.54 (m,1H), 3.53-3.43 (m,1H), 3.02-2.86 (m, 1H), 2.85-2.61 (m, 2H), 2.37-2.23 (m, 1H), 2.14–2.03 (m, 1H), 1.96-1.83 (m, 1H), 1.68–1.43 (m, 2H).

Compound 34e-2

LCMS m/z =370.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.39-9.25 (m, 1H), 7.84-7.72 (m, 1H), 7.70-7.59 (m, 1H), 4.76-4.62 (m, 1H), 4.60 -4.46 (m, 1H), 4.18–4.04 (m, 2H), 3.71–3.47 (m, 3H), 3.01-2.79(m, 2H), 2.78-2.64 (m, 1H), 2.44-2.31 (m, 1H), 1.96-1.83 (m, 2H), 1.82–1.65(m, 2H).

Step 5: Preparation of 34f

Dissolve 34e (0.19 g, 0.51 mmol) and 1c” (0.36 g, 1.02 mmol) in toluene (9.5 mL). After nitrogen replacement, boron trifluoride ether (0.57 mL) is slowly added at 0°C. Reaction at 35°C 16 h. Adjust the pH value to 7-8 with saturated sodium carbonate solution at 0°C, extract with ethyl acetate (20 mL x 3), and combine the organic phases. Wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, and Filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 70: 30) to obtain 34f (100 mg, 35%)

LCMS m/z = 557.2 [M+1] ⁺

Step 6: Preparation of 34g

Hydrazine hydrate (0.5 mL, content: 80%) was added to a solution of 34f (100 mg, 0.18 mmol) in ethanol (5 mL), and the reaction was carried out at room temperature for 16 h. Filter, wash the filter cake with ethyl acetate (10 mL x 3), and concentrate the filtrate under reduced pressure to obtain a residue. The residue was slurried with ethyl acetate (10 mL) and filtered. The filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 34g (110 mg, crude product).

LCMS m/z=427.4[M+1] ⁺

Step 7: Preparation for 34h

Triethylamine (73 mg, 0.72 mmol) was added to a solution of intermediate 1 (86 mg, 0.27 mmol) and 34 g (110 mg, crude product) in acetonitrile (10 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 50: 50) to obtain 34h (85 mg, two-step yield 67%).

LCMS m/z = 709.3[M+1] ⁺

Step 8: Preparation of compound 34

In an ice-water bath, trifluoromethanesulfonic acid (0.2 mL) was added to the 34h (85 mg, 0.12 mmol) trifluoroacetic acid (2 mL) solution, and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, add ethyl acetate (20 mL) to dilute the crude product, adjust the pH to 8-9 with saturated sodium carbonate solution, extract with ethyl acetate (20 mL x 3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) )= 20 :80) to obtain compound 34 (10 mg, 14%).

Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , Column temperature: 35°C, flow rate: 1.0mL/min.

The retention time T=26.649 min is compound 34 , which is one of the structures of compound 34-1 and compound 34-2 .

LCMS m/z=589.2[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.39 (s, 1H), 9.32 (s, 1H), 7.88 (s, 1H), 7.81-7.76 (m, 1H), 7.65 (d,1H), 6.32-6.13 (m, 1H), 4.59–4.45 (m, 1H), 4.23-4.03 (m, 3H), 3.76-3.66 (m, 1H), 3.65-3.57 (m, 1H), 3.50–3.34 (m , 3H), 2.98–2.87 (m, 1H), 2.80–2.60 (m, 2H), 2.47-2.38(m, 1H), 2.08–1.97 (m, 1H), 1.89-1.76 (m, 1H), 1.61 -1.42 (m, 2H), 1.15 (d, 3H).

Example 35: Preparation of Compound 35

Step One: Preparation of 35B

At 0°C, add benzyl alcohol (9.31 g, 86.07 mmol) and potassium carbonate (16.98 g, 122.90 mmol) to a solution of 35A (15.00 g, 81.93 mmol) in N,N-dimethylformamide (150 mL). in, react at room temperature for 16 h. After the reaction is completed, add the reaction solution to water (400 mL), extract with n-hexane (100 mL x 2), and combine the organic phases. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 99: 1) Obtain 35B (14.30 g, yield: 64%)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47-8.42 (m, 1H), 8.23 (dd, 1H), 7.57-7.46 (m, 2H), 7.45-7.30 (m, 3H), 5.53 (s , 2H).

Step 2: Preparation of 35C

At -78°C, n-butyllithium (10.02 mL, 25.04 mmol, 2.5 M in hexane) was added dropwise to a solution of 35B (7.00 g, 25.81 mmol) in tetrahydrofuran (70 mL). After reacting at -78°C for 30 minutes, Add N,N-dimethylformamide (2.26 g, 30.97 mmol) and continue the reaction for 1 h. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 95:5) Obtain 35C (6.02 g, yield: 78%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (d, 1H), 8.56 (s, 1H), 7.55-7.46 (m, 2H), 7.45 -7.33 (m, 3H), 5.57 (s, 2H ).

Step 3: Preparation of 35D

At room temperature, add hydrazine hydrate (33 mL, content: 80%) to a mixed solution of ethanol (30 mL) and 1,4-dioxane (150 mL) at 35C (11.20 g, 37.43 mmol). React at 95°C for 16 hours. After the reaction was completed, concentrate under reduced pressure, and then add water (100 mL). Extract with ethyl acetate (100 mL : Ethyl acetate (v/v) = 91:9) to obtain 35D (7.38 g, yield: 67%).

LCMS m/z = 294.1[M+H] ⁺

Step 4: Preparation of 35E

Sodium hydride (764 mg, 19.1 mmol, content: 60%) was added in portions to a solution of 35D (4.00 g, 13.64 mmol) in tetrahydrofuran (40 mL) at 0°C. After reacting at 0°C for 30 minutes, add methyl iodide (2.42 g, 17.05 mmol) and react at room temperature for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and after concentration under reduced pressure, water (100 mL) was added. Extract with dichloromethane (100 mL : Ethyl acetate (v/v) = 88:12) to obtain 35E (2.59 g, yield: 62%).

LCMS m/z = 308.1[M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.60 (s, 1H), 8.08-8.02 (m, 1H), 7.57-7.47(m, 2H), 7.456-7.31 (m, 3H), 5.61 (s , 2H), 4.24 (s, 3H).

Step 5: Preparation of 35F

Palladium on carbon (519 mg, content: 10%) was added to a solution of compound 35E (2.59 g, 8.43 mmol) in methanol (40 mL), and the reaction was carried out at room temperature under a hydrogen atmosphere for 16 h. After the reaction is completed, filter through diatomaceous earth, rinse with dichloromethane: methanol (v/v) = 10:1 (100 mL), and concentrate the filtrate under reduced pressure to obtain 35F (1.88 g, crude product).

LCMS m/z = 218.1[M+H] ⁺

Step 6: Preparation of 35G

The hydrochloride salt of compound 16b (1.31 g, crude product), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (4.03 g, 7.74 mmol), 1,8-diazabicyclo [5.4.0] Undec-7-ene (3.93 g, 25.80 mmol) was added sequentially to compound 35 F (1.40 g, crude product) in N,N-dimethylformamide (15 mL) at room temperature. React for 16 hours. After the reaction is completed, add water (100 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The crude product was separated and purified by column chromatography (dichloromethane: dichloromethane (containing 9% methanol) (v:v) = 71/29) to obtain 35G-1 (643 mg, two-step yield: 15%) and 35G -2 .

35G-1 is 35G.

LCMS m/z = 384.2[M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (s, 1H), 7.93-7.88 (m, 1H), 5.53-5.15 (m, 2H), 4.64- 4.42 (m, 2H), 4.22 (s , 3H), 3.74-3.65 (m, 1H), 3.64-3.55 (m, 1H), 3.54-3.44 (m, 1H), 3.24-3.11 (m, 1H), 2.97-2.86 (m, 1H), 2.80 -2.69 (m, 1H), 2.38-2.26 (m, 1H), 2.11-2.02 (m, 1H), 1.97-1.87 (m, 1H), 1.67-1.47 (m, 2H).

35G-2

LCMS m/z = 384.5[M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (s, 1H), 7.98-7.85 (m, 1H), 5.51-5.16 (m, 2H), 5.06-4.41 (m, 2H), 4.22 (s , 3H), 3.73-3.64 (m, 1H), 3.63-3.57 (m, 1H), 3.56-3.45 (m, 1H), 3.22-3.07 (m, 1H), 3.03-2.89 (m, 1H), 2.82 -2.69 (m, 1H), 2.44 -2.32 (m, 1H), 1.96-1.83 (m, 2H), 1.82-1.66 (m, 2H).

Compound 35 was obtained using 35G as the substrate by referring to the synthetic method of compound 16. Compound 35 is one of the structures of compound 35-1 and compound 35-2.

LCMS m/z= 603.7[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.44 (s, 1H), 7.94-7.85 (m, 2H), 6.39 -6.12 (m, 1H), 5.50-5.14 (m , 2H), 4.56-4.45 (m, 1H), 4.26-4.09 (m, 4H), 3.75-3.58 (m, 2H), 3.52-3.37 (m, 3H), 3.24-3.09(m, 1H), 2.96 -2.82 (m, 1H), 2.79-2.69 (m, 1H), 2.48 -2.39(m, 1H), 2.05-1.94 (m, 1H), 1.90 -1.78 (m, 1H), 1.61-1.44 (m, 2H), 1.15 (d, 3H).

Example 36: Preparation of Compound 36

Compound 36 was obtained using 36A as a substrate by referring to the synthetic method of compound 32. Compound 36 is one of the structures of compound 36-1 and compound 36-2.

LCMS m/z= 590.6[M+1] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 9.55 (s, 1H), 9.09 (s, 1H), 7.88 (s, 1H), 6.39-6.14(m, 1H), 4.63-4.45 (m, 1H), 4.25-4.06 (m, 3H), 3.79-3.67 (m, 1H), 3.65 -3.55 (m, 1H), 3.50-3.37 (m, 3H), 3.06-2.94 (m , 1H), 2.88-2.76 (m, 1H), 2.74-2.60 (m, 1H), 2.47- 2.37 (m, 1H), 2.11-1.97 (m, 1H), 1.90-1.74 (m, 1H), 1.60 -1.42 (m, 2H), 1.15 (d, 3H).

Example 37: Preparation of Compound 37

Compound 37 was obtained by using compound 34e-2 as the starting material and referring to the synthesis method of compound 34.

Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , column temperature: 35°C, flow rate: 1.0mL/min.

The retention time T=39.932 min is compound 37 , which is one of the structures of compound 34-1 and compound 34-2 .

LCMS m/z=589.2[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 9.00 (s, 1H), 7.98 (s, 1H), 7.75 (dd, 1H), 7.58 (d,1H), 4.70–4.62 (m, 1H), 4.30 -4.12 (m, 3H), 3.93-3.81 (m, 1H), 3.76-3.69 (m, 1H), 3.68-3.58 (m, 2H), 3.54-3.44 (m, 1H), 3.04-2.80 (m, 3H), 2.67-2.56(m, 1H), 2.09-1.78 (m, 4H), 1.28 (d, 3H).

Example 38: Preparation of Compound 38

Compound 38 was obtained using compound 32e-2 as the substrate and referring to the synthesis method of compound 32.

Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , column temperature: 35°C, flow rate: 1.0mL/min.

The retention time T=42.395 min is compound 38 , which is one of the structures of compound 32-1 and compound 32-2 .

LCMS m/z=589.3[M+1] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (d, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.22(dd,1H), 4.72-4.62 (m, 1H), 4.30 -4.13 (m, 3H), 3.93-3.83 (m, 1H), 3.77-3.69 (m, 1H), 3.68-3.59 (m, 2H), 3.54–3.45 (m, 1H), 3.04-2.80 (m, 3H), 2.67–2.56 (m, 1H), 2.10-1.79(m, 4H), 1.28 (d, 3H).

Example 39: Synthesis method of compound 8-4:

Step 1: Synthesis of 3 9a

Dissolve 9g of hydrochloride (4.61 g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (3.66 g, 20.05 mmol) in dimethylsulfoxide (50 mL), and add potassium carbonate (6.39 g, 46.23 mmol), react at 90 ^o C for 16 hours. Cool to room temperature, add saturated brine (40 mL) to the reaction solution, and extract with ethyl acetate (60 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) = 7: 3) to obtain 3 9a (5.00 g).

LCMS m/z = 373.2 [M+1] ⁺

Step 2: Synthesis of 3 9b

Dissolve 39a (6.5 g, 17.46 mmol) in a mixed solution of tetrahydrofuran (250 mL) and absolute ethanol (250 mL), add sodium borohydride (660 mg, 17.46 mmol) and calcium chloride (970 mg, 8.74 mmol) , keep the reaction at 0°C for 1 hour. Slowly add saturated ammonium chloride aqueous solution (6 mL) and ethyl acetate (6 mL) dropwise to quench the reaction, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (0~25% (MeOH:DCM=1:10) in (EA:PE=1:5)) to obtain 39b (2.18 g, 38%).

39b (diastereomer 1) H on C2 on ring A (δ 2.71–2.53) and H ¹ on C4 (δ 1.72-1.60) have obvious ¹ H- ¹ H NOESY signals (the deuterated solvent is CD ₃ COOD, ¹ H- ¹ H COSY (see Figure 1, ¹ H- ¹ H NOESY (see Figure 2)), prove that the configuration of 39b is as follows:

LCMS m/z = 331.1 [M+1] ⁺

¹ H NMR (400 MHz, CD ₃ COOD) δ 8.66 (d, 2H), 4.88-4.73 (m, 2H), 4.70-4.60 (m, 1H), 4.08-3.94 (m, 1H), 3.89-3.79 ( m, 1H), 3.66-3.54 (m, 1H), 3.29-3.13 (m, 1H), 3.00-2.83 (m, 2H), 2.71–2.53 (m, 1H), 2.27-2.14(m, 1H), 2.03-1.92 (m, 1H) , 1.85-1.72 (m, 1H) , 1.72-1.60 (m, 1H).

Step 3: Synthesis of 3 9c

Dissolve 39b (2.0 g, 6.05 mmol) and 1c” (4.10 g, 11.74 mmol) in toluene (100 mL). After nitrogen replacement, boron trifluoride ether solution (6 mL) was added dropwise at 0°C, and the temperature was raised to React for 16 hours at 25°C. Cool to 0°C, and slowly drop the reaction solution into the saturated sodium bicarbonate solution at 0°C. Extract with ethyl acetate (50 mL x 3), and combine the organic phases. The organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 3:1) to obtain 39c (1.3 g, 41%).

LCMS m/z =518.1 [M +1] ⁺

Step 4: Synthesis of 3 9d

Hydrazine hydrate (3 mL, content: 80%) was added to the solution of 39c (2.0 g, 3.86 mmol) in ethanol (100 mL), and the reaction was maintained at room temperature for 16 hours. Filter and wash the filter cake with ethanol. After the filtrate was concentrated under reduced pressure, ethyl acetate (100 mL) was added, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to obtain 39d (1.5 g, crude product).

LCMS m/z =388.1 [M +1] ⁺

Step 5: Synthesis of 3 9e

Dissolve 39d (1.5 g, crude product) and intermediate 1 (1.6 g, 5.03 mmol) in acetonitrile (20 mL), add triethylamine (1.57 g, 15.48 mmol), and react at room temperature for 16 hours. , the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 1:1) to obtain 39e (2.138 g, 83%, 2-step yield).

LCMS m/z = 670.8 [M+1] ⁺ .

Step 6: Synthesis of compound 8-4

Dissolve 39e (2.138 g, 3.19 mmol) in trifluoroacetic acid (20 mL) solution, add trifluoromethanesulfonic acid (20 mL) at 0°C, and keep the reaction at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate (50 mL) was added. At 0°C, slowly add saturated sodium bicarbonate aqueous solution to adjust the pH value of the system to weak alkalinity. Separate the organic phase, extract the aqueous phase with ethyl acetate (50 mL x 2), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:9) to obtain compound 8-4 (1.1 g). , 63%).

LCMS m/z =550.6[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.40 (s, 1H), 8.73 (s, 2H), 7.88 (s, 1H), 6.31-6.17 (m, 1H), 4.71-4.57 (m, 2H ), 4.52-4.42 (m, 1H), 4.23-4.09 (m, 1H), 3.75-3.67 (m, 1H), 3.65-3.57 (m, 1H), 3.51 -3.40 (m, 2H), 3.40-3.32 (m,1H), 3.09-2.94 (m, 1H), 2.85-2.73 (m, 1H), 2.72-2.59 (m, 1H), 2.47-2.34 (m 1H), 2.06-1.93(m, 1H), 1.90-1.77 (m, 1H), 1.60-1.42 (m, 2H), 1.15 (d, 3H).

Chiral HPLC: Analytical method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05%DEA), 3.0 ml/min, residence time T=2.009 min.

It was confirmed by ¹ H NMR and chiral HPLC that compound 8-B obtained in Example 8 was compound 8-4.

Biological test examples

1. NCI-H1373 cell proliferation inhibition

NCI-H1373 cells were purchased from ATCC. The culture conditions were: RPMI-1640 + 10% FBS + 1% double antibody. They were cultured at 37°C in a 5% CO ₂ incubator. On the first day, NCI-H1373 cells in the exponential growth phase were collected and plated into a transparent-bottomed white 96-well culture plate at a density of 500 cells/well. They were cultured overnight in a 37°C, 5% _CO2 incubator, and T ₀ wells were plated at the same time. Before adding the medicine on the next day, absorb the culture medium, add 90 µL of fresh culture medium and 10 µL of compounds of different concentrations to each well, so that the final DMSO concentration in each well is 0.1%, and incubate in a 37°C, 5% _CO2 incubator for 72 hours. , replace the culture medium and prepare new compounds, and continue culturing for 72 hours. The next day, the drug was added and the CellTiter-Glo kit was used to detect the T ₀ plate, which was recorded as RLU ₀ . After the culture, add 50 μL of detection solution (Cell Viability Assay, Promega, G7573) to each well, mix for 2 minutes, incubate at room temperature for 10 minutes, and detect chemiluminescence readings with a microplate reader. The results were processed according to formula (1), the cell survival rate of each concentration of the compound was calculated, and the origin9.2 software was used to calculate the GI ₅₀ value of the concentration of the compound when the proliferation rate was 50%. RLU _compound is the reading of the drug treatment group, and RLU _control is the average value of the solvent control group. Growth % =(RLU _compound -RLU ₀ )/(RLU _control - RLU ₀ )×100% Formula (1) Table 1 Inhibition of cell proliferation of NCI-H1373 cells by compounds serial number Compound number GI ₅₀ (nM) serial number Compound number GI ₅₀ (nM) 1 Compound 1 9 13 Compound 19 <50 2 Compound 2-A <50 14 Compound 20 1.30 3 Compound 5 <50 15 Compound 21 2.97 4 Compound 6-A <50 16 Compound 22 <50 5 Compound 7-B 8 17 Compound 25 <50 6 Compound 8-A <50 18 Compound 28 1.12 7 Compound 8-B 4 19 Compound 29 0.86 8 Compound 9 3.27 20 Compound 31 <50 9 Compound 10-P1 <50 twenty one Compound 32 1.35 10 Compound 12- Peak-2 <50 twenty two Compound 34 <50 11 Compound 13 <50 twenty three 12 Compound 17 1.94

Conclusion: The compounds of the present invention, such as the example compounds, have good cell proliferation inhibitory activity on NCI-H1373 cells. The inhibitory activity of some compounds on NCI-H1373 cell proliferation is shown in Table 1.

2. Mouse pharmacokinetic test

2.1 Test animals: Male Balb/c mice, about 22 g, 6 to 8 weeks old, 6 mice/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

2.2 Experimental design: On the day of the experiment, Balb/c mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration. Table 2. Dosing information Group quantity Dosing Information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 test compound 2.5 0.5 5 plasma veins G2 3 10 1 10 plasma Oral administration

Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; gastric administration vehicle: 0.5% MC

Before and after administration, 0.03 ml of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4 ^° C for 10 min to collect plasma. Blood collection time points for the intravenous group and intragastric group were: 0, 2, 5, 15, 30min, 1, 2, 4, and 7 h; before analysis and detection, all samples were stored at -80 ^o C. Table 3. Pharmacokinetic parameters of test compounds in mouse plasma test compound Dosing method AUC _0-t (hr*ng/mL) F(%) Compound 8-B ig (10 mg/kg) 1348±414 53.7±16 Compound 9 ig (10 mg/kg) 1654±127 98.6±7.5 Compound 31 ig (10 mg/kg) 986±71 27.2±1.9 Compound 32 ig (10 mg/kg) 687±241 25.5±8.9 Compound 34 ig (10 mg/kg) 1069±300 33.5±9.4

-: Not applicable.

Conclusion: The compounds of the present invention, such as the example compounds , have good pharmacokinetic properties. Specifically, compound 8-B , compound 9 , compound 31 and compound 34 have high exposure in mice and good bioavailability. Spend.

3. Pharmacokinetic test in beagle dogs

Purpose of the experiment: To administer the test substance to beagle dogs through a single dose intravenously and intragastrically, to measure the concentration of the test substance in the plasma of beagle dogs, and to evaluate the pharmacokinetic characteristics of the test substance in the beagle dogs.

Experimental animals: male beagle dogs, about 8-11 kg, 6/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Test method: On the day of the test, the beagle dogs were randomly divided into groups according to their weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration. Table 4. Dosing Information Group quantity Dosing information male test substance Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 test compound 1 1 1 plasma veins G2 3 5 1 5 plasma Oral administration

Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; gastric administration vehicle: 0.5% MC

Sampling: Take 1 ml of blood from the veins of the limbs before and after administration, and place it in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.

Blood collection time points: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and detection, all samples were stored at -80°C. Samples were quantitatively analyzed using LC-MS/MS. Table 5. Pharmacokinetic parameters of test compounds in beagle dog plasma test compound Dosing method AUC _0-t (hr*ng/mL) F(%) Compound 34 ig (5 mg/kg) 7337±735 79.1±7.9

-: Not applicable.

Conclusion: The compounds of the present invention, such as the example compounds , have good pharmacokinetic properties. Specifically, compound 34 has good PK performance in beagle dogs.

4. CYP450 enzyme inhibition test

The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC50 value, and evaluate the effect of the test substance on each Inhibitory potential of CYP enzyme isoforms. .

Conclusion: The compounds of the present invention, such as the example compounds, have poor inhibitory activity on CYP enzymes. Specifically, the IC50 values of compound 8-B against CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are all greater than 50 μM.

5. hERG potassium ion channel function test

Experimental platform: electrophysiology manual patch clamp system

Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is made from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after filling the electrode internal liquid is about 2-5 MΩ. Just insert the glass microelectrode into the amplifier probe. Connect to patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer. The sampling frequency is 10 kHz and the filtering frequency is 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV, and the step voltage of induced hERG potassium current (I hERG) was given by a 2 s depolarization voltage from -80 mV to +20 mV, and then repolarization to - 50 mV, lasts for 1 s and then returns to -80 mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n≥2).

Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) at different compound concentrations was calculated using the following formula: Inhibition % = [1 – (I / Io)]×100%

Among them, Inhibition % represents the inhibition percentage of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.

Compound IC ₅₀ was calculated by fitting the following equation using GraphPad Prism 5 software: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Among them, X is the Log value of the detected concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively. Table 6 : IC ₅₀ value of compounds on hERG potassium channel current inhibition compound IC ₅₀ (μM) Compound 31 >20μM Compound 34 >20μM

Conclusion: The compounds of the present invention, such as the compounds in the examples, have poor inhibitory activity on hERG. Specifically, the IC ₅₀ of compounds 31 and 34 on the inhibitory effect of hERG potassium channel current is greater than 20 μM.

7. PARP7 enzyme activity test experiment

PARP7 chemofluorescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 μL of the histone dilution solution to the microwell plate, and incubate at 4 °C overnight. After the incubation, wash the plate three times with PBST (0.05% Tween-20), add 100 μL of blocking solution to the microplate, and incubate at 25 °C for 90 minutes; after the incubation, wash the plate three times with PBST. Take 2.5 μL of compounds of different concentrations diluted in test buffer and 12.5 μL of substrate mixed solution (1.25 μL of 10X PARP test buffer; 1.25 μL of 10X PARP test mix; 10 μL of double-distilled water) to the microplate. Dilute the PARP7 enzyme to 6 ng/μL, take 10 μL into the microwell plate, and incubate the reaction system at 25 °C for 60 minutes;

After the incubation, wash the plate three times with PBST. Dilute Streptavidin-HRP 50 times with blocking solution, then transfer 25 μL to the microplate and incubate at 25 °C for 30 minutes. After the incubation, wash the plate three times with PBST, mix ELISA ECL substrate A and substrate B at a ratio of 1:1 (v/v), take 50 μL into the microwell plate, and read the chemiluminescence value.

Calculate the inhibition rate according to Equation 2, where RLU _sample is the reading value of the compound well, RLU _max is the reading value of the solvent control well, and RLU _min is the reading value of the control well without PARP7 enzyme. Use GraphPad Prism software to pass four parameters (log(inhibitor) vs . response -- Variable slope) to perform curve fitting and calculate IC ₅₀ values. Inhibition% =(1-(RLU _sample -RLU _min )/(RLU _max -RLU _min ))×100% (Formula 2)

Conclusion: The compounds of the present invention, such as the example compounds, have inhibitory effects on PARP7 enzyme.

8. MARylation test experiment in NCI-H1373 cells

NCI-H1373 cells were purchased from ATCC. The culture conditions were: RPMI-1640 + 10% FBS + 1% double antibody. They were cultured at 37°C in a 5% CO ₂ incubator. On the first day, NCI-H1373 cells in the exponential growth phase were collected and plated on a transparent-bottomed white 6-well culture plate at a density of 2 × 10 ⁵ cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. Before adding the medicine on the next day, aspirate the culture medium, add 1 mL of fresh culture medium and 1 mL of compounds of different concentrations to each well so that the final DMSO concentration in each well is 0.1%, and incubate in a 37°C, 5% _CO2 incubator for 48 hours. . After the culture is completed, cells are collected. Add 35 μL of cell lysis solution to each tube and lyse on ice for 15 minutes while vortexing; centrifuge at 4°C and 13,000 rpm for 10 minutes, and store the supernatant at low temperature. BCA detection kit (Beyotime, P0009) was used for protein quantification and the sample protein concentration was calculated. Dilute the protein concentration of each tube of sample to 0.8 mg/mL with 0.1×sample buffer, take 4 μL of diluent and 1 μL of 5×mix, mix well, and place at 95°C for 5 minutes for protein denaturation. Add samples according to WES (ProteinSimple) instructions, in which the dilution ratio of Poly/Mono-ADP Ribose (E6F6A) Rabbit mAb is 1:100, and the dilution ratio of β-Actin (8H10D10) Mouse mAb is 1:400, and the detection is carried out on the machine. The results were processed according to formula (3), the MARylation% of each concentration of the compound was calculated, and the IC ₅₀ value was fitted using GraphPad Prism 8 software. Corr.Area _compound is the peak area of the drug treatment group, and Corr.Area _control is the peak area of the solvent control group. MARylation % =Average (Corr.Area _compound / Corr.Area _control ) × 100 Formula (3) Table 7. Inhibitory activity of compounds on MARylation in NCI-H1373 cells serial number compound PARP7 IC ₅₀ (nM) 1 Compound 8-B 2.8 2 RBN-2397 9.3

Conclusion: The compounds of the present invention, such as the example compounds, have inhibitory effects on MARylation in NCI-H1373 cells. Specifically, the inhibitory activity of compound 8-B on MARylation in NCI-H1373 cells is better than that of the control RBN-2397.

9. Liver Microsome Stability Test

This experiment uses human liver microsomes as an in vitro model to evaluate the metabolic stability of the test substance.

At 37°C, 1 µM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC was used. -MS/MS method detects the concentration of the test substance in the sample, calculates T _1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the hepatic intrinsic clearance rate of liver microsomes CL _int(Liver) .

Table 8. Human liver microsome stability results Compound number T _1/2 (min) CL _{int(Liver) )} ,(mL/min/kg) Compound 8-B 119 13.6 Compound 32 ＞186 <6.71 Compound 34 ＞186 <6.71 RBN-2397 39.7 40.8

Conclusion: The compounds of the present invention, such as the example compounds, have good metabolic stability in human liver microsomes.

without

Figure 1: 1H-1H COSY of 39b (400 MHz .CD ₃ COOD);

Figure 2: 1H-1H NOESY of 39b (400 MHz .CD ₃ COOD).

without

Claims (15)

A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds represented by the general formula (A), wherein (A) W is selected from bond, C(=O); ring B is selected from , Is a single bond or a double bond; Z is selected from N, C or CH; Y is selected from bond, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(= O) ₂ N(R ^y )-, -N(R ^y )-, C _1-4 alkylene, -OC _1-3 alkylene-, -C _1-3 alkylene O-, -C _{1 -2} alkylene OC _1-2 alkylene, -C _1-3 alkylene S-, -C _1-3 alkylene S(=O)-, -C _1-3 alkylene S(= O) ₂ -, -N(R ^y )C _1-3 alkylene-, -C _1-3 alkylene N(R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the alkylene is optionally substituted by 1 _to 4 C 1-6 alkyl selected from halogen, =O, =S, OH, cyano, C _1-6 alkyl, and halogen substituted by substituents of C _1-6 alkoxy group and C _3-6 cycloalkyl group; R ^y is each independently selected from H, C _1-6 alkyl group or C _3-6 cycloalkyl group, and the The alkyl or cycloalkyl group is optionally substituted by 1 to 4 members selected from deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered hetero Substituted with a ring group or a substituent of C _3-6 cycloalkyl, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N; R ^b is each independently selected from H, halogen, cyanide base, OH, =O, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, the -CH ₂ -, alkyl, alkoxy The base or cycloalkyl group is optionally substituted by 1 to 4 atoms selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy or C Substituted with _3-6 cycloalkyl substituents; Ring A is selected from C _6-10 aromatic ring, 5-10 membered heteroaromatic ring or 5-10 membered heterocyclic ring, the heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, _{S ,} and N; ring The aromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N; R ^x and R ^a are each independently selected from H, halogen, cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 alkoxy, C _1-6 alkylthio, _{-SO 2 -C 1-6} alkyl, -C(=O)C _{1- 6} alkyl, -(CH ₂ ) _q -C _3-10 carbocyclic ring or -(CH ₂ ) _q -3 to 12 membered heterocyclic ring, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkyl The oxygen group, alkylthio group, carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 halogen, OH, cyano, =O, NH ₂ , NH (C _1-6 alkyl), N (C _1-6 Alkyl) ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents, The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; L is selected from -Q1-Ak1-Q2-Ak2-, and the right side is connected to ring B; Ak1 and Ak2 are each independently selected from C _{1 -4} alkylene, C _2-4 alkenylene, C _2-4 alkynylene, the Ak1 is optionally substituted by 0 to 4 R ^k1 , the Ak2 is optionally substituted by 0 to 4 R ^k2 ; R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -OC _3-6 carbocyclic ring, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl and alkenyl groups , alkynyl, alkoxy, carbocyclic or heterocyclic is optionally 1 to 4 selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, -OC _3-8 carbocyclic ring, C _3-8 carbocyclic ring, 4 to 10 membered heterocyclic substituents, the above The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N; As an option, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or 4 To a 7-membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from halogen, =O, OH, cyano, C _1-6 alkyl, and halogen _. , C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; Q1 and Q2 are each independently selected Since O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), C(=O)O, OC(=O ), S(=O), S(=O) ₂ , S(=O) ₂ N(R ^q ), N(R ^q )S(=O) ₂ , N(R ^q )C(=O)N (R ^q ), N(R ^q )C(=O)N(R ^q ); R ^q is each independently selected from H, C _1-6 alkyl or C _3-6 cycloalkyl, the alkyl or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, CF ₃ , OH, cyano, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy; Alternatively, R ^q is directly connected to ^Rk1 or ^Rk2 to form a 4- to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C _1-6 alkyl, halogen Substituted with substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N ; q is independently selected from 0, 1, 2, 3 or 4; a is selected from 0, 1, 2, 3 or 4; b is selected from 0, 1, 2, 3 or 4; x is selected from 0, 1, 2, 3 or 4; Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D. According to claim 1, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound of general formula (A) is selected from the group consisting of general formula (I) The compound shown, where (I). According to the compound described in claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds represented by the general formula (II), (II) Ring Selected from 8-10 membered paracyclic heteroaromatic ring or 8-10 membered paracyclic heterocyclic ring, the heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N; R ^a1 , R ^a2 is each independently selected from H, halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio base, -SO ₂ -C _1-6 alkyl, -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C _3-10 carbocyclic ring or -(CH ₂ ) _q -3 to 12 Member heterocycle, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 selected from halogen, OH, cyano, =O, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or 3 to 10 membered heterocyclic substituents, the above The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; the definitions of the remaining groups are the same as in weight 2. According to claim 3, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Y is selected from the group consisting of bonds, -O-, -N(R ^y )-, C _1-3 alkylene, -OC _1-2 alkylene-, -C _1-2 alkylene O-, -C _1-2 alkyleneOC _1-2 alkylene, - C _1-2 alkylene S-, -C _1-2 alkylene S(=O) ₂ -, -N(R ^y )C _1-2 alkylene-, -C _1-2 alkylene N (R ^y )-, -C _1-2 alkylene N(R ^y )-C _1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S , OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents; R ^y are each independently selected From H, C _1-4 alkyl or C _3-6 cycloalkyl, the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclic group or C _3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 selected from Heteroatoms of O, S, and N; R ^x , R ^a1 , and R ^a2 are each independently selected from H, halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, and C _2-4 alkyne group, C _1-4 alkoxy group, C _1-4 alkylthio group, -SO ₂ -C _1-4 alkyl group, -C(=O)C _1-4 alkyl group, -(CH ₂ ) _q -C _3-6 carbocyclic ring or -(CH ₂ ) _q -3 to 6 membered heterocyclic ring, the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring C _1-4 alkyl optionally substituted by 1 to 4 selected from halogen, OH, cyano, =O, C _1-4 alkyl, halogen, C _1-4 alkoxy, C _3-6 cycloalkyl substituted by a 3- to 6-membered heterocyclic group, the heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N; R ^b is each independently selected from H, halogen, cyano group, OH , =O, C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 cycloalkyl, the -CH ₂ -, alkyl, alkoxy or cycloalkyl The alkyl group is optionally substituted by 1 to 4 atoms selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy or C _3-6 Substituted with cycloalkyl substituents; Ak1 and Ak2 are each independently selected from C _1-3 alkylene, C _2-3 alkenylene, C _2-3 alkynylene, and the Ak1 is optionally substituted by 0 to 4 R ^k1 is substituted, and the Ak2 is optionally substituted by 0 to 4 R ^k2 ; R ^k1 and R ^k2 are each independently selected from halogen, cyano, OH, =O, NH ₂ , NHC _1-4 alkyl, N (C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxy group, carbon The ring or heterocycle is optionally substituted by 1 to 4 atoms selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _{3 -6} carbocyclic ring, 4 to 6 membered heterocyclic substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N; As an option, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring. The said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 members selected from halogen, =O, OH, Substituted with cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; Q1 and Q2 are each independently selected from O, S, N(R ^q ), C(=O), C(=O)N(R ^q ), N(R ^q )C(=O), S(=O) ₂ ; R ^q are each independently selected from H, C _1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF ₃ , OH, cyano, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; As an option, R ^q and R ^k1 , R ^q and R ^k2 are directly connected to form a 4 to 7-membered Heterocycle, the heterocycle is optionally substituted by 1 to 4 C _1-4 alkyl groups selected from halogen, =O, OH, cyano, C _1-4 alkyl, halogen, C _1-4 alkoxy It is substituted by a substituent of a C _3-6 cycloalkyl group, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N. The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ring X is selected from the group consisting of pyridine ring, pyrimidine ring, pyridine ring, Azine ring, pyridazine ring, thiophene ring, thiazole ring, furan ring, oxazole ring, pyrrole ring, pyrazole ring or imidazole ring; or ring X is selected from triazine ring, benzothiazole ring, pyridothiazole ring, pyrimidine Thiazole ring, pyridazinothiazole ring, pyrazinothiazole ring, benzoxazole ring, pyridoxazole ring, pyrimidoxazole ring, pyridazinoxazole ring, pyrazinoxazole ring, pyrido Pyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, pyrimidotriazole ring, pyrimidofuran ring, pyrimidopyrrole ring, , , quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, triazolo Azolopyrazole ring, , , , , ; ^Rx , R ^a1 and R ^a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, Vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C( =O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl , pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, - SCH ₃ , -SCH ₂ CH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optionally by 1 to Substituted with 4 substituents selected from halogen, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; R ^{b is} each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or isopropyl Propyl is optionally substituted with 1 to 4 C _1-4 alkyl groups selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen, C _1-4 alkoxy or C _3-6 Substituted by the substituent of cycloalkyl; Y is selected from bond, -O-, -N(R ^y )-, -N(R ^y )C(=O)-, -C(=O)N(R ^y ) -, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, - CH ₂ OCH ₂ -, -CH ₂ S-, -CH ₂ CH ₂ S-, -CH ₂ S(=O) ₂ -, -CH ₂ CH ₂ S(=O) ₂ -, -N(R ^y ) CH ₂ -, -N(R ^y )CH ₂ CH ₂ -, -CH ₂ N(R ^y )-, -CH ₂ CH ₂ N(R ^y )-, -N(R ^y )C(=O)CH ₂ -, -CH ₂ C(=O)N(R ^y )-, the CH ₂ is optionally replaced by 0 to 2 selected from H, =O, =S, OH, cyano, C _1-4 alkyl , substituted by halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents; R ^y is each independently selected from H, methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally selected from 1 to 4 deuterium, halogen, CF ₃ , OH, cyanide Substituted with substituents of base, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, 3 to 8 membered heterocyclyl or C _3-6 cycloalkyl, the heterocyclyl contains 1 to 3 heteroatoms selected from O, S, and N; Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, The Ak1 is optionally substituted by 0 to 4 R ^k1 , and the Ak2 is optionally substituted by 0 to 4 R ^k2 ; R ^k1 and R ^k2 are each independently selected from F, Cl, Br, I, cyano, OH , =O, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl, oxetanyl, pyridine, phenyl, the methyl, ethyl, propyl base, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepentyl, azetidinyl, oxetanyl, oxa Cyclopentyl, oxanyl, pyridine, and phenyl are optionally substituted with 1 to 4 _C 1-4 alkyl groups selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen, C Substituted with _1-4 alkoxy groups, C _3-6 carbocyclic rings, and 4 to 6 membered heterocyclic substituents, the heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, and N; As an option, R ^k1 and R ^k1 , R ^k2 and R ^k2 , R ^k1 and R ^k2 are directly connected to form a C _3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 Substituted with a substituent selected from halogen, =O, OH, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N; Q1 and Q2 are each independently selected from O, S, N (R ^q ), C (=O), C (=O) N(R ^q ), N(R ^q )C(=O), S(=O) ₂ ; R ^q is each independently selected from H, methyl, and ethyl; As an option, R ^q and R ^k1 , R ^q Directly connected to ^Rk2 to form a 4- to 7-membered heterocycle, which is optionally substituted by 1 to 4 C 1 selected from halogen, =O, OH, cyano, C _1-4 alkyl, and _{halogen. -4} alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N. The compound according to claim 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein L is selected from -N(R ^q )-Ak1- O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R ^q )-Ak2-, -N(R ^q )-Ak1-N(R ^q )-Ak2-, left and d The azinone ring is directly connected; Y is selected from bond, -O-, -NHC(=O)-, -C(=O)NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ O-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -CH ₂ NH-, -CH ₂ CH ₂ NH-, -NHC(=O)CH ₂ -, -CH ₂ C(=O)NH-, -N(CH ₃ )C(=O)-, -C(=O)N(CH ₃ ) -, -CH ₂ C(=O)NH-, -CH ₂ C(=O)N(CH ₃ )-, -N(CH ₂ CH ₃ )C(=O)-, -N(CH(CH ₃ ) ₂ )C(=O)-, -N(CH ₂ CH(CH ₃ ) ₂ )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH ₂ -ring Propyl)C(=O)-, -C(=O)N(CH ₂ CH ₃ )-, -C(=O)N(CH(CH ₃ ) ₂ )-, -C(=O)N( CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(cyclopropyl)-, -C(=O)N(CH ₂ -cyclopropyl)-, -C(=O)N( CD ₃ )-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N(CH ₂ -oxetanyl)-, -C(=O)N (CH ₂ -Azetidinyl)-, -C(=O)N(CH ₂ -pyrrolidinyl)-, -C(=O)N(CH ₂ -cyclopentyl)-, -C(= O)N(CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH(CH ₂ CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -C(=O)N(CH ₂ CH ₂ CH(CH ₃ ) ₂ )-, -C(=O)N(CH ₂ CH(CH ₃ )CH ₂ CH ₃ )-, -C(= O)N(n-octyl)-, -C(=S)N(CH ₃ )-, -C(=S)N(CH ₂ CH ₃ )-, -C(=S)N(CH ₂ -ring propyl)-, , , -CH ₂ S(=O) ₂ -; R ^a2 is selected from H. According to the compound described in claim 6 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, L is selected from , , , , , , , , , , , , , , , , the left side is directly connected to the pyridazinone ring; R ^x is independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, third Butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl , phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, vinyl, acetylene base, methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, Thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl and imidazolyl are optionally substituted by 1 to 4 selected from F, OH, cyano, methyl, ethyl, methoxy or ethoxy Substituted by the substituent of the base; R ^a1 is selected from H, F, Cl, Br, I, cyano, CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, propyl, isopropyl, ethynyl, Methoxy, ethoxy, -SCH ₃ , -SCH ₂ CH ₃ , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Selected from , , , , , , , , , , , , ; R ^b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl. According to the compound described in claim 7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, L is selected from , , , , , , , , the left side is directly connected to the pyridazinone ring; R ^a1 is selected from F, Cl, Br, CF ₃ , CHF ₂ , CH ₂ F, methyl, cyano, cyclopropyl, isopropyl; R ^x is independently selected From H, F, Cl, Br, cyano, isopropyl, CD ₃ , CF ₃ , CHF ₂ , CH ₂ F, cyclopropyl, cyclobutyl; b is selected from 0, 1, 2, 3; x is selected from Since 1, 2. The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, W is selected from C (=O); Ring X is selected from C _3-10 cycloalkyl, 4 to 10-membered heterocycloalkyl, phenyl, 5-6-membered heteroaromatic ring, 5-6-membered heterocyclic ring, 8-10-membered heteroaromatic ring or 8-10-membered paracyclic heteroaromatic ring Cyclic heterocycle, the heterocycloalkyl, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N; Preferably, ring X is selected from C _3-6 monocyclic cycloalkanes Base, C _5-10 paracyclic cycloalkyl group, C _5-11 spirocyclic cycloalkyl group, C _5-11 bridged cyclocycloalkyl group, 4 to 7 membered monocyclic heterocycloalkyl group, 5 to 10 membered paracyclic heterocyclic group Cycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, 5- to 11-membered bridged heterocycloalkyl, phenyl, 5-6-membered heteroaromatic ring, 8-10-membered paracyclic heteroaromatic ring, the described Heterocycloalkyl, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N; Preferably, ring X is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazepine Cyclobutyl, cyclobutylspiroazepinyl, cyclobutylspiroazepinyl, cyclopentylspiroazepinyl, cyclopentylspiroazepinyl, cyclohexylspiroazepinyl, Azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, cyclobutylcyclobutyl base, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclobutyl-azetidinyl, cyclobutyl Cyclopentaazepine, cyclobutylazepine, cyclopentylazepine, cyclopentylazepine, cyclohexylazepine, cyclohexylazepine Azepanyl, azepanyl azepanyl, azepanyl azepanyl, azepanyl azacyclohexyl, azetidinyl, azepanyl, Azepanyl, oxetanyl, oxetanyl, oxetanyl, or ring X is as described in claim 5; the definitions of the remaining groups are the same as in any one of claims 2 to 8. According to claim 9, the compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Selected from , , , ; The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structures shown in Table E-1 one. A pharmaceutical composition, including the compound described in any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and the required learning materials acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound described in any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical acceptable salts or eutectics. The compound according to any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation of treatments with PARP7 activity or Application in drugs for expression-related diseases. The application according to claim 13, characterized in that the disease is selected from tumors. A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any one of claims 1-11 or its stereoisomer, deuterated product, solvate, or prodrug , metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably related to PARP7 activity or expression.