CN119977947A - PRMT5 inhibitor, pharmaceutical composition thereof and use thereof in medicine - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical chemistry and relates to a class of PRMT5 inhibitors, pharmaceutical compositions thereof and their use in medicine. Specifically, the present invention relates to a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (I). The compound and pharmaceutical composition thereof of the present invention can be used to prepare a drug for preventing or treating PRMT5-related diseases, and can be particularly used to prepare a drug for preventing or treating PRMT5-related cancers.

Description

PRMT5 inhibitor, pharmaceutical composition thereof and application of PRMT5 inhibitor in medicines

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a PRMT5 inhibitor, a pharmaceutical composition thereof and application thereof in medicines.

Background

PRMT5 (protein ARGININE METHYLTRANSFERASE) is protein arginine methyltransferase 5, exists in the cytoplasm and cytoplasm matrix, is expressed in different degrees in various tissues and organs of human body, and has no obvious tissue specific distribution. The ligand is methyl donor SAM (S-adenosyl methionine, S adenosylmethionine), and after the ligand is combined with SAM, the ligand catalyzes the single methylation and symmetrical dimethyl methylation of arginine residues on histone and non-histone, belonging to the type II arginine methyltransferase. PRMT5 plays an important role in maintaining tissue stability, as well as the ability of stem/progenitor cells to survive and self-renew in the nervous system, muscle, reproductive and hematopoietic systems. PRMT5 is found in many human solid tumors such as lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia or lymphoma, and glioblastoma, and high expression of PRMT5 is closely related to the occurrence and development of tumors and poor prognosis.

MTAP is frequently co-deleted with the cancer suppressor gene CDKN2A in tumors. It was found that MTA accumulated in large amounts in MTAP-deleted tumor cells with reduced SAM synthesis compared to MTAP-normal cells, whereas MTA, which is a SAM analog, competed with SAM to bind PRMT5 selectively to attenuate PRMT5 activity, and that MTAP-deleted tumor cells were significantly dependent on PRMT5 survival. The development of a synergistic PRMT5-MTA inhibitor can stabilize the PRMT5-MTA complex structure and inhibit SAM from combining with PRMT5, so that MTAP-deleted tumor cells can be selectively killed, and normal MTAP cells are not affected.

MRTX1719 is a PRMT5-MTA synergistic inhibitor developed by Mirati therapeutics Inc company, and has remarkable anti-tumor effect in a plurality of tumor cell lines (MTAP deletion) in vitro. There remains a need to develop new PRMT5-MTA synergistic inhibitors to prevent and treat cancers associated with MTAP deficiency.

Disclosure of Invention

The invention provides a PRMT5-MTA synergistic inhibitor which can inhibit SAM and PRMT5 from combining, thereby selectively killing MTAP-deleted tumor cells to treat cancers. The invention further provides a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition thereof in preparing medicines for preventing or treating cancers.

In one aspect, the present invention provides a compound which is a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

Wherein,

X is N or CH;

q ¹ is N or CR ^7a;

Q ² is N or CR ^7b;

Q ³ is N or CR ^7c;

Q ⁴ is N or CR ^7d;

Q ⁵ is a bond, NH, O, or CH ₂;

n is 0 or 1;

ring a is a 5-12 membered heteroaryl or C _6-10 aryl, wherein said ring a is optionally substituted with 1 or 2R ^a;

Each R ^a is independently D, F, cl, br, I, CN, OH, C (=o) OH, -NR ⁹R⁸、C_1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, or C _1-6 haloalkyl;

Ring B is a 3-7 membered cycloalkyl or 3-7 membered heterocyclyl, wherein said ring B is optionally substituted with 1,2 or 3 substituents independently selected from D, F, cl, br, I, NH ₂、CN、OH、C(＝O)OH、C_1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl and C _1-6 haloalkyl;

R ¹、R²、R³ and R ⁴ are each independently H, D, F, cl, br, I, CN, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl 、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、C_1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C _6-10 aryl;

r ⁵ and R ⁶ are each independently H, D, F, cl, br, I, CN, OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl or C _1-6 haloalkyl, or R ⁵、R⁶ together with the carbon atoms to which they are attached form c=o;

r ^7a、R^7b、R^7c and R ^7d are each independently H, D, F, cl, br, I, CN, OH, C (=O) OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or C _1-6 haloalkyl, and

R ⁸ and R ⁹ are each independently H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C _6-10 aryl.

In some embodiments, ring a is pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, or phenyl, wherein said ring a is optionally substituted with 1 or 2R ^a;

Each R ^a is independently D, F, cl, br, I, CN, OH, C (=o) OH, -NR ⁹R⁸、C_1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _1-4 heteroalkyl, C _3-6 cycloalkyl, or C _1-4 haloalkyl.

In other embodiments, ring a is

Wherein said ring a is optionally substituted with 1 or 2R ^a;

Each R ^a is independently D、F、Cl、Br、I、CN、OH、C(＝O)OH、-NH₂、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or morpholinyl, wherein ring B is optionally substituted with 1, 2, or 3 substituents independently selected from D, F, cl, br, I, NH ₂、CN、OH、C(＝O)OH、C_1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, and C _1-4 haloalkyl.

In some embodiments, R ¹、R²、R³ and R ⁴ are each independently H, D, F, cl, br, I, CN, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl 、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、C_1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, or C _6-10 aryl;

R ⁵ and R ⁶ are each independently H, D, F, cl, br, I, CN, OH, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or C _1-4 haloalkyl, or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form c=o;

r ^7a、R^7b、R^7c and R ^7d are each independently H, D, F, cl, br, I, CN, OH, C (=O) OH, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or C _1-4 haloalkyl, and

R ⁸ and R ⁹ are each independently H, D, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C _6-10 aryl.

In other embodiments, R ¹、R²、R³ and R ⁴ are each independently H、D、F、Cl、Br、I、CN、OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH＝CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-C≡C(CH₃)、-C≡CCH₂CH₃、-CH₂C≡CH、-CH₂C≡C(CH₃)、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、-CHCl₂、-CH₂Cl、-CH₂Br、-(CH₂)₂Cl、-CH₂OH、-(CH₂)₂OH、-(CH₂)₃OH、-(CH₂)₄OH、-CH(OH)CH₃、-C(OH)(CH₃)₂、(CH₂)₄OH、-CH₂CN、-(CH₂)₂CN、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-OCF₃、-OCH₂F、-OCHF₂、-OCHCl₂、-OCH₂CF₃、-OCH₂CHCl₂、-OCH₂CHF₂、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl, or naphthyl;

R ⁵ and R ⁶ are each independently H、D、F、Cl、Br、I、CN、OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-OCH₃、-OCH₂CH₃、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R ⁵、R⁶ together with the carbon atom to which they are attached form c=o;

R ^7a、R^7b、R^7c and R ^7d are each independently H、D、F、Cl、Br、I、CN、OH、C(＝O)OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-OCH₃、-OCH₂CH₃、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, and

R ⁸ and R ⁹ are each independently H、D、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl or naphthyl.

In some embodiments, the compounds of the present invention are stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of the compounds of formula (IA) or (IB) or of the compounds of formula (IA) or (IB),

Wherein rings B, n, Q ⁵、R¹、R²、R³、R⁴, and R ^a each have the definition as described herein.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, optionally further comprising a pharmaceutically acceptable adjuvant.

In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating or treating cancer in a patient.

In some embodiments the cancer is an MTAP deficiency-related cancer, optionally the MTAP deficiency-related cancer is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

In another aspect, the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention, treatment or treatment of cancer.

In another aspect, the invention provides a method of preventing, treating or treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (IA) or (IB).

Unless otherwise indicated, all stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.

Salts of the compounds of the present invention also include salts of the isolated enantiomers of the compounds of formula (I), (IA) or (IB) or intermediates used in the preparation or purification of the compounds of formula (I), (IA) or (IB), but are not necessarily pharmaceutically acceptable salts.

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

"Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. All stereoisomers or mixtures of stereoisomers of the formulae described herein are within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

The stereochemical definitions and rules used in the present invention generally follow S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention, as described herein, may independently be optionally substituted with one or more substituents, such as those of the general formula above, or as exemplified by the specific examples provided herein, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the terms "independently optionally substituted" or "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In addition, unless explicitly stated otherwise, the description as used in this disclosure is "each..and". Independently "and". Independently "can be interchanged, and is to be understood broadly as meaning that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "alkyl" denotes a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted C _1-6 alkyl, in yet another embodiment the alkyl group contains 1 to 4 carbon atoms, denoted C _1-4 alkyl, and in yet another embodiment the alkyl group contains 1 to 3 carbon atoms, denoted C _1-3 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃), ethyl (Et, -CH ₂CH₃), n-propyl (n-Pr, -CH ₂CH₂CH₃), isopropyl (i-Pr, -CH (CH ₃)₂), n-butyl (n-Bu), -CH ₂CH₂CH₂CH₃), isobutyl (i-Bu, -CH ₂CH(CH₃)₂), sec-butyl (s-Bu, -CH (CH ₃)CH₂CH₃), tert-butyl (t-Bu), -C (CH ₃)₃), n-pentyl (-CH ₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH (CH ₃)CH₂CH₂CH₃), 3-pentyl (-CH (CH ₂CH₃)₂), 2-methyl-2-butyl (-C (CH ₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH (CH ₃)CH(CH₃)₂), 3-methyl-1-butyl (-CH ₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (-CH ₂CH(CH₃)CH₂CH₃), n-hexyl (-CH ₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH (CH ₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH (CH ₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C (CH ₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH (CH ₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH (CH ₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C (CH ₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH (CH ₂CH₃)CH(CH₃)₂), 2, 3-dimethyl-2-butyl (-C (CH ₃)₂CH(CH₃)₂), 3-dimethyl-2-butyl (-CH (CH ₃)C(CH₃)₃)), n-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp ² double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 6 carbon atoms, denoted as C _2-6 alkenyl, and in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms, denoted as C _2-4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch ₂), allyl (-CH ₂CH＝CH₂), 1-propenyl (i.e., propenyl, -ch=ch-CH ₃), and the like.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, denoted as C _2-6 alkynyl, and in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms, denoted as C _2-4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃), and the like.

The term "cyanoalkyl" denotes an alkyl group substituted with one or more cyano groups, wherein the cyano and alkyl groups have the definitions as described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted with one cyano group. In some embodiments, "cyanoalkyl" is C _1-6 cyanoalkyl, i.e., C _1-6 alkyl substituted with one or more cyano groups. In some preferred embodiments, C _1-6 cyanoalkyl is C _1-6 alkyl substituted with one cyano group. In other embodiments, "cyanoalkyl" is C _1-4 cyanoalkyl, i.e., C _1-4 alkyl substituted with one or more cyano groups. Examples of cyanoalkyl groups include, but are not limited to ,-CH₂CN、-CH₂CH₂CH₂CH₂CN、-CH₂CH₂CN、-CH₂CH(CN)CH₂CH₂CN、-CH₂CH(CN)CH₂CH(CH₃)CN, and the like.

The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl represents alkyl substituted with 1,2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl represents C _1-6 hydroxyalkyl, i.e., C _1-6 alkyl is substituted with one or more hydroxyl groups, preferably C _1-6 hydroxyalkyl represents alkyl in which C _1-6 alkyl is substituted with one hydroxyl group. In some embodiments, hydroxyalkyl represents C _1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl represents C _1-3 hydroxyalkyl. Examples of hydroxyalkyl groups include, but are not limited to ,-CH₂OH、-CH₂CH₂CH₂CH₂OH、-CH₂CH₂OH、-CH₂CH(OH)CH₂CH₂OH、-CH₂CH(OH)CH₂CH(CH₃)OH, and the like.

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein. In some embodiments, haloalkyl is C _1-6 haloalkyl, meaning that the C _1-6 alkyl group is substituted with one or more halogen atoms, in other embodiments haloalkyl is C _1-4 haloalkyl, meaning that the C _1-4 alkyl group is substituted with one or more halogen atoms, and in other embodiments haloalkyl is C _1-3 haloalkyl, meaning that the C _1-3 alkyl group is substituted with one or more halogen atoms. Examples of such include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl dichloromethyl, trichloromethyl, 2-chloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl, 1-dibromoethyl, etc.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment the alkoxy group contains 1 to 6 carbon atoms, representing a C _1-6 alkoxy group, in another embodiment the alkoxy group contains 1 to 4 carbon atoms, representing a C _1-4 alkoxy group, and in yet another embodiment the alkoxy group contains 1 to 3 carbon atoms, representing a C _1-3 alkoxy group. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃), ethoxy (EtO, -OCH ₂CH₃), 1-propoxy (n-PrO, n-propoxy, -OCH ₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, -OCH (CH ₃)₂), 1-butoxy (n-BuO, n-butoxy, -OCH ₂CH₂CH₂CH₃), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂CH(CH₃)₂), 2-butoxy (s-BuO), s-butoxy, -OCH (CH ₃)CH₂CH₃), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH ₃)₃), 1-pentoxy (n-pentoxy), -OCH ₂CH₂CH₂CH₂CH₃), 2-pentyloxy (-OCH (CH ₃)CH₂CH₂CH₃), 3-pentyloxy (-OCH (CH ₂CH₃)₂), 2-methyl-2-butoxy (-OC (CH ₃)₂CH₂CH₃), 3-methyl-2-butoxy (-OCH (CH ₃)CH(CH₃)₂), 3-methyl-l-butoxy (-OCH ₂CH₂CH(CH₃)₂), 2-methyl-l-butoxy (-OCH ₂CH(CH₃)CH₂CH₃), and the like.

The term "haloalkoxy" denotes an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the definition as defined herein. In some embodiments haloalkoxy represents haloalkoxy having 1 to 6 carbon atoms, i.e., C _1-6 haloalkoxy, in other embodiments haloalkoxy having 1 to 4 carbon atoms, i.e., C _1-4 haloalkoxy, and in other embodiments haloalkoxy represents haloalkoxy having 1 to 3 carbon atoms, i.e., C _1-3 haloalkoxy. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (-OCF ₃), monofluoromethoxy (-OCH ₂ F), 2-fluoroethoxy (-OCH ₂CH₂ F), and the like.

The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic carbocyclic ring system of 3 to 12 carbon atoms in which the-CH ₂ -group can optionally be replaced by-C (=o) - (or- (CO) -). In one embodiment, cycloalkyl contains 3 to 10 ring carbon atoms, i.e., C _3-10 cycloalkyl, in another embodiment, cycloalkyl contains 3 to 6 ring carbon atoms, i.e., C _3-6 cycloalkyl, and in another embodiment, cycloalkyl contains 3 to 5 ring carbon atoms, i.e., C _3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydro-pentalenyl, and the like. Examples of carbon rings in which the-CH ₂ -group may be replaced by-C (=O) -include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

The term "heterocycle" or "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms, wherein said heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When a heterocycle is attached to the rest of the molecule through a linking site, the heterocycle is denoted as monovalent. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH ₂ -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclyl consists of 3-10 atoms, denoted 3-10 membered heterocycle or 3-10 membered heterocyclyl, in other embodiments the heterocycle or heterocyclyl consists of 3-9 atoms, denoted 3-9 membered heterocycle or 3-9 membered heterocyclyl, in other embodiments the heterocycle or heterocyclyl consists of 5-9 atoms, denoted 5-9 membered heterocycle or 5-9 membered heterocyclyl, in other embodiments the heterocycle or heterocyclyl consists of 3-6 atoms, denoted 3-6 membered heterocycle or 3-6 membered heterocyclyl, in other embodiments the heterocycle or heterocyclyl consists of 5-6 atoms, denoted 5-6 membered heterocycle or 5-6 membered heterocyclyl. Examples of such heterocycles include, but are not limited to, ethylene oxide, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3, 8-diazabicyclo [3.2.1] octane, 3, 6-diazabicyclo [3.1.1] heptane, 2, 5-diazabicyclo [2.2.2] octane. The heterocyclic group includes, but is not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

The term "aryl" means a monovalent, monocyclic, bicyclic, and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms of rings. In some embodiments, aryl contains 6 to 12 ring atoms and is represented as a C _6-12 aryl or a 6 to 12 membered aryl. In some embodiments, aryl contains 6 to 10 ring atoms and is represented as a C _6-10 aryl or a 6 to 10 membered aryl. Examples of aryl groups may include phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, and anthracene.

The term "heteroaryl" or "heteroaromatic ring" means a monovalent monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, sulfur. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. When a-CH ₂ -group is present in the heteroaryl group, said-CH ₂ -group may optionally be replaced by a-C (=o) -. Unless otherwise indicated, the heteroaryl group may be attached to the remainder of the molecule (e.g., the host structure in the formula) at any reasonable point (which may be C or N). The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl is a heteroaryl containing 5-12 ring atoms, denoted as 5-12 membered heteroaryl, in other embodiments the heteroaryl is a heteroaryl containing 5-10 ring atoms, denoted as 5-10 membered heteroaryl, in other embodiments the heteroaryl is a heteroaryl containing 5-6 ring atoms, denoted as 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolyl, and the like.

The term "j-k atoms" or "j-k members" means that the cyclic group is composed of j-k ring atoms including carbon atoms and/or O, N, S, P or the like, each of which is independently any natural number other than zero and k > j, and that the "j-k" includes j, k and any natural number therebetween. For example, "3-8 atom" or "3-8 membered", "3-6 atom" or "3-6 membered", "5-10 atom" or "5-10 membered", or "5-6 atom" or "5-6 membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5,6,7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5,6,7,8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms including heteroatoms such as carbon atoms and/or O, N, S, P.

Ring a, as described herein, is a ring system formed by a bond to a central ring, and represents that ring a may be substituted at any substitutable position or at any reasonable position on the ring. As will be described below,

Represented as

It will be further appreciated that the compounds resulting from the combination of the groups of the present invention in embodiments should be stable and reasonably present structures. In the compounds of formula (I) according to the invention, when ring A is attached to either Q ¹、Q²、Q³ or Q ⁴, then Q ¹、Q²、Q³ or Q ⁴ is not N, in particular when ring A is attached to Q ¹, Q ¹ is not N, Q ¹ is CH, ring A is attached to C as a substituent on Q ¹, the remainder of Q ²、Q³ or Q ⁴ having the meaning as defined herein.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I) or (IA). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C _1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"Metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C ₁-C₈ sulphonates and aromatic sulphonates.

"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that are water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, one of the present compound molecules may be associated with one water molecule, such as a monohydrate, in another embodiment, one of the present compound molecules may be associated with more than one water molecule, such as a dihydrate, and in yet another embodiment, one of the present compound molecules may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.

The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

The term "therapeutically effective amount" means that the amount of the compound, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and severity, and the condition, age, weight, sex, etc., of the subject to be treated.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the invention are intended to be encompassed within the scope of the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.

Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, and iodine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and ¹²⁵ I.

Description of the Compounds of the invention

The invention provides a PRMT5-MTA synergistic inhibitor which can selectively inhibit SAM from combining with PRMT5 to treat related cancers. The invention further provides a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition thereof in preparing medicines for preventing or treating cancers.

The excellent properties of the compounds of the present invention, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can promote reduction of side effects, expansion of therapeutic index, improvement of tolerance, etc.

In one aspect, the present invention provides a compound which is a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

Wherein, ring a, ring B、X、n、R¹、R²、R³、R⁴、R⁵、R⁶、Q¹、Q²、Q³、Q⁴ and Q ⁵ each have the definition as described in the present invention.

In some embodiments, X is N or CH.

In some embodiments, Q ¹ is N or CR ^7a, wherein R ^7a has the meaning described herein.

In some embodiments, Q ² is N or CR ^7b, wherein R ^7b has the meaning described herein.

In some embodiments, Q ³ is N or CR ^7c, wherein R ^7c has the meaning described herein.

In some embodiments, Q ⁴ is N or CR ^7d, wherein R ^7d has the meaning described herein.

In some preferred embodiments, Q ¹、Q²、Q³ and Q ⁴ are both CH.

In some embodiments, Q ⁵ is a bond, NH, O, or CH ₂.

In some embodiments, Q ⁵ is a bond.

In some embodiments, Q ⁵ is O.

In some embodiments, n is 0 or 1.

In some embodiments, ring a is a 5-12 membered heteroaryl or C _6-10 aryl, wherein said ring a is optionally substituted with 1 or 2R ^a, wherein R ^a has the meaning described herein.

In some embodiments, ring a is pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, or phenyl, wherein said ring a is optionally substituted with 1 or 2R ^a, wherein R ^a has the meaning described herein.

In some embodiments, ring a is

Wherein said ring a is optionally substituted with 1 or 2R ^a, wherein R ^a has the meaning described herein.

In some embodiments, each R ^a is independently D, F, cl, br, I, CN, OH, C (=o) OH, -NR ⁹R⁸、C_1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, or C _1-6 haloalkyl.

In some embodiments, each R ^a is independently D, F, cl, br, I, CN, OH, C (=o) OH, -NR ⁹R⁸、C_1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _1-4 heteroalkyl, C _3-6 cycloalkyl, or C _1-4 haloalkyl.

In some embodiments, each R ^a is independently D、F、Cl、Br、I、CN、OH、C(＝O)OH、-NH₂、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some preferred embodiments, ring A is

In some embodiments, ring B is a 3-7 membered cycloalkyl or 3-7 membered heterocyclyl, wherein said ring B is optionally substituted with 1,2, or 3 substituents independently selected from D, F, cl, br, I, NH ₂、CN、OH、C(＝O)OH、C_1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, and C _1-6 haloalkyl.

In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or morpholinyl, wherein ring B is optionally substituted with 1, 2, or 3 substituents independently selected from D, F, cl, br, I, NH ₂、CN、OH、C(＝O)OH、C_1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, and C _1-4 haloalkyl.

In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or morpholinyl, wherein ring B is optionally substituted with 1,2, or 3 substituents independently selected from D、F、Cl、Br、I、NH₂、CN、OH、C(＝O)OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-OCH₃、-OCH₂CH₃、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments, R ¹、R²、R³ and R ⁴ are each independently H, D, F, cl, br, I, CN, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl 、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、C_1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, or C _6-10 aryl, wherein each R ⁸ and R ⁹ have the meaning described herein.

In some embodiments, R ¹、R²、R³ and R ⁴ are each independently H, D, F, cl, br, I, CN, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl 、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、C_1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, or C _6-10 aryl, wherein each R ⁸ and R ⁹ have the meaning described herein.

In some embodiments, R ¹、R²、R³ and R ⁴ are each independently H、D、F、Cl、Br、I、CN、OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH＝CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-C≡C(CH₃)、-C≡CCH₂CH₃、-CH₂C≡CH、-CH₂C≡C(CH₃)、-NR⁹R⁸、-S(＝O)₂R⁸、-S(＝O)R⁸、-C(＝O)OR⁸、-NR⁹C(＝O)R⁸、-C(＝O)NR⁹R⁸、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、-CHCl₂、-CH₂Cl、-CH₂Br、-(CH₂)₂Cl、-CH₂OH、-(CH₂)₂OH、-(CH₂)₃OH、-(CH₂)₄OH、-CH(OH)CH₃、-C(OH)(CH₃)₂、(CH₂)₄OH、-CH₂CN、-(CH₂)₂CN、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-OCF₃、-OCH₂F、-OCHF₂、-OCHCl₂、-OCH₂CF₃、-OCH₂CHCl₂、-OCH₂CHF₂、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl, or naphthyl, wherein each R ⁸ and R ⁹ have the meaning described herein.

In some embodiments, R ⁵ and R ⁶ are each independently H, D, F, cl, br, I, CN, OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, or C _1-6 haloalkyl.

In some embodiments, R ⁵ and R ⁶ are each independently H, D, F, cl, br, I, CN, OH, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or C _1-4 haloalkyl.

In some embodiments, R ⁵ and R ⁶ are each independently H、D、F、Cl、Br、I、CN、OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-OCH₃、-OCH₂CH₃、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, R ⁵、R⁶ together with the carbon atoms to which they are attached form c=o.

In some embodiments, R ⁸ and R ⁹ are each independently H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, or C _6-10 aryl.

In some embodiments, R ^7a、R^7b、R^7c and R ^7d are each independently H, D, F, cl, br, I, CN, OH, C (=o) OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, or C _1-6 haloalkyl.

In some embodiments, R ^7a、R^7b、R^7c and R ^7d are each independently H, D, F, cl, br, I, CN, OH, C (=o) OH, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, or C _1-4 haloalkyl.

In some embodiments, R ^7a、R^7b、R^7c and R ^7d are each independently H、D、F、Cl、Br、I、CN、OH、C(＝O)OH、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-OCH₃、-OCH₂CH₃、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or morpholinyl.

In some embodiments, R ⁸ and R ⁹ are each independently H, D, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, or C _6-10 aryl.

In some embodiments, R ⁸ and R ⁹ are each independently H、D、-CH₃、-CH₂CH₃、-(CH₂)₂CH₃、-CH(CH₃)₂、-(CH₂)₃CH₃、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CN、-CH₂F、-CHF₂、-CF₃、-(CH₂)₂F、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl, or naphthyl.

In some embodiments, the compounds of the present invention are compounds of formula (IA), or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of the compounds of formula (IA),

Wherein each of rings B, n, R ¹、R²、R³、R⁴, and R ^a has the definition set forth in the present invention.

In some embodiments, the compounds of the present invention are compounds of formula (IB), or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of the compounds of formula (IB),

Wherein each of rings B, n, Q ⁵、R¹、R²、R³、R⁴, and R ^a has the definition set forth herein.

In some embodiments, the compounds of the invention are stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds shown below,

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, optionally further comprising a pharmaceutically acceptable adjuvant.

In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating or treating cancer in a patient.

In another aspect, the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention, treatment or treatment of cancer.

In another aspect, the invention provides a method of preventing, treating or treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

In some embodiments, the cancer of the invention is an MTAP-deleted related cancer.

In some embodiments, the MTAP-deleted related cancer of the invention is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (IA) or (IB).

Unless otherwise indicated, all stereoisomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

Preparation, administration and use of pharmaceutical compositions of the compounds of the invention

The characteristics of the pharmaceutical composition of the invention comprise the compound shown in the formula (I), (IA) or (IB), the compound listed in the invention or the compound of the embodiment and pharmaceutically acceptable auxiliary agents. The compounds of the invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly according to the needs of the patient, the compounds described in other aspects of the present invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which as used herein, include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. ：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,, as described in the following documents, taken together with the content of the documents herein, demonstrate that various adjuvants can be employed in the preparation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

The compounds or pharmaceutical compositions of the present invention may be administered in the form of oral agents such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms used being well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.

The compounds or pharmaceutical compositions of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by transdermal route using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the administration period.

The compounds or pharmaceutical compositions of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The dosage regimen of a compound or pharmaceutical composition of the invention will vary with known factors such as the pharmacokinetic profile of the particular agent and its mode and route of administration, the age, sex, health condition, medical condition and weight of the recipient, the nature and extent of the symptoms, the nature and extent of concurrent therapy, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician may make decisions and prescribe an effective amount of the drug to prevent, counter or arrest the progression of cancer.

The compounds and compositions described herein may be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the invention may be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the invention may be included with other therapeutic agents in a single formulation or in separate formulations.

When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage when administered alone, given the additional or synergistic effect of the therapeutic agents when administered in combination.

The compositions and methods provided herein are particularly believed to be useful for inhibiting PRMT5 activity in cells in vivo. In some embodiments, cells in need of inhibition of PRMT5 activity are contacted in vivo with a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to down-regulate PRMT5 activity.

The compounds and compositions of the present invention are useful for treating a variety of cancers, including, but not limited to, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, lymphoma, glioblastoma, melanoma astrocytoma, colon cancer, rectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, bladder cancer, pancreatic cancer, liver cancer, cholangiocarcinoma, glioblastoma. In particular, these compounds are useful for the treatment of cardiac sarcomas, myxoma, rhabdomyomas, fibromas, lipomas and teratomas, lung bronchogenic carcinoma, alveolar carcinoma, bronchial adenomas, sarcomas, lymphomas, chomatous hamartomas, mesothelioma, gastrointestinal tract, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphomas), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, venomous tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma), genitourinary tract (kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma), liver (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatoma, hemangioma, biliary tract (gallbladder carcinoma, ampulla carcinoma, bile duct carcinoma), bone (osteogenic sarcoma, fibrosarcoma), Malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondral exotose, benign chondrioma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor, nervous system, skull (osteoma, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meningioma (meningioma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, glioblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas), gynaecology, uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer, granulosa-membranous cell tumors, support-stromal cell tumors, asexual cell tumors, malignant teratomas), vulva (squamous cell carcinoma, intraepithelial cancers, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), fallopian tube (carcinoma), hematological, blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma), malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, moles of grape embryo dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis, and adrenal gland neuroblastoma.

In some embodiments, the cancer is an MTAP-deleted related cancer.

In some embodiments, the MTAP-deficiency related cancer is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

General synthetic procedure

For the purpose of illustrating the invention, the following examples are provided to further illustrate the technical aspects of the invention. The following examples are intended only to illustrate the practice of the invention so that those skilled in the art will understand the invention and are not intended to limit the scope of the invention. In the specific implementation method of the present invention, technical means, methods, and the like not specifically described are conventional technical means, methods, and the like in the art.

Wherein the substituents are as defined herein, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated that all temperatures are set to degrees celsius (°c), room temperature in the examples represents 15 ℃ to 30 ℃, and in some examples, room temperature is 20 ℃ to 30 ℃. General reagents are commercially available unless otherwise indicated. Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. ¹ H NMR spectra were taken with CDC1 ₃、DMSO-d₆、CD₃ OD or acetone-d ₆ as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiplets occur, the abbreviations s (singlet ), d (doublet, doublet), t (triplet ), q (quartet, quartet), m (multiplet ), br (broadened, broad), br s (broadened singlet, br.s, broad singlet), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constant J, expressed in hertz (Hz).

The conditions for low resolution Mass Spectrometry (MS) data were Agilent 6120 four-stage HPLC-MS (column model: zorbax SB-C18,2.1x 30mm,3.5 microns, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid), electrospray ionization (ESI) was used, UV detection at 210nm/254 nm.

The pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following abbreviations are used throughout the present invention:

NBS N-bromosuccinimide

AIBN azo-bis-isobutyronitrile

XPhos G3 methane sulphonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)

Boc

PE Petroleum ether

EA, etOAc ethyl acetate

DCM dichloromethane

CD ₃ OD deuterated methanol

MeOH methanol

CDCl ₃ deuterated chloroform

Degree C

H hours

Mg

G

Mmol millimoles

M, mol/L

ML of

Synthetic scheme

The following synthesis schemes set forth general experimental procedures for the preparation of the compounds disclosed in the present invention, including modifications of the appropriate methods or adjustments of the starting materials, as appropriate to the circumstances of the person skilled in the art.

Synthesis scheme one

The compounds (I) can be prepared by the synthetic procedure of scheme one, in which ring A, ring B、X、n、R¹、R²、R³、R⁴、R⁵、R⁶、Q¹、Q²、Q³、Q⁴ and Q ⁵ each have the meaning according to the invention, hal ² is Cl, br or I, preferably Br or I, and Pg is an amino protecting group, preferably Boc. The compound (I-1) and the compound (I-2) are subjected to coupling reaction in a proper solvent (such as a mixed solution of 1, 4-dioxane and water) under a proper catalyst (such as 1,1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium) and a basic condition (such as sodium carbonate and the like) to obtain the compound (I-3), and the compound (I-3) is subjected to deamination protecting groups under an acidic condition (such as trifluoroacetic acid or hydrochloric acid and the like) to obtain the compound (I) or an acid addition salt of the compound (I).

Synthesis scheme II

The compounds (IA) can be prepared by the synthetic procedure of scheme II, wherein the rings B, n, R ¹、R²、R³、R⁴ and R ^a each have the meanings as given in the present invention, pg is an amino protecting group, preferably Boc. The compound (IA-1) reacts with N-iodosuccinimide to obtain a compound (IA-2), the compound (IA-2) reacts with the compound (IA-3) under a proper catalyst (such as 1,1' -bis (di-tert-butylphosphino) ferrocene dichloro palladium and the like) and a basic condition (such as sodium carbonate and the like) in a proper solvent (such as a mixed solution of 1, 4-dioxane and water and the like) to obtain a compound (IA-4), and amino protecting groups of the compound (IA-4) are removed under an acidic condition (such as trifluoroacetic acid or hydrochloric acid and the like) to obtain the compound (IA) or an acid addition salt of the compound (IA).

Synthesis of a third embodiment

The compounds (IB) can be prepared by the synthetic procedure of synthesis scheme three, wherein rings B, n, Q ⁵、R¹、R²、R³、R⁴ and R ^a each have the definition as described in the present invention, and Pg is an amino protecting group, preferably Boc. The compound (IB-3) is obtained by coupling reaction of the compound (IB-1) and N-iodosuccinimide to obtain the compound (IB-2), the compound (IB-2) and the compound (IA-3) under a proper catalyst (such as 1,1' -bis (di-tert-butylphosphino) ferrocene dichloro palladium and the like) and a basic condition (such as sodium carbonate and the like) in a proper solvent (such as a mixed solution of 1, 4-dioxane and water and the like), and the amino protecting group of the compound (IB-3) is removed under an acidic condition (such as trifluoroacetic acid or hydrochloric acid and the like) to obtain the compound (IB) or an acid addition salt of the compound (IB).

Synthesis scheme IV

Compound (IC) can be prepared by the synthetic procedure of synthesis scheme four, wherein ring B, R ¹、R²、R³、R⁴ and R ^a each have the definition as described herein, pg is an amino protecting group, preferably Boc. The compound (IC-3) is obtained by coupling reaction of the compound (IC-1) and N-iodosuccinimide to obtain the compound (IC-2), the compound (IC-2) and the compound (IA-3) under a proper catalyst (such as 1,1' -bis (di-tert-butylphosphino) ferrocene dichloro palladium and the like) and alkaline conditions (such as sodium carbonate and the like) in a proper solvent (such as a mixed solution of 1, 4-dioxane and water and the like), and the amino protecting group of the compound (IC-3) is removed under an acidic condition (such as trifluoroacetic acid or hydrochloric acid and the like) to obtain the compound (IC) or an acid addition salt of the compound (IC).

Synthesis scheme A

The synthesis of intermediate (IA-1) can be prepared by the synthetic procedure of synthetic scheme A, wherein ring B, n, R ¹、R²、R³、R⁴ and R ^a each have the definition as described herein, hal ¹ is Cl, br or I, compound (IA-1-10) is a C _2-6 alkane chain or a C _2-6 heteroalkane chain, and both ends of the chain are substituted with Br, wherein C _2-6 heteroalkane is where a carbon atom in the C _2-6 alkane is replaced with a heteroatom. The compound (IA-1-1) and the compound (IA-1-10) react under proper conditions (such as potassium hydroxide and tetrabutylammonium bromide) to obtain the compound (IA-1-2), the compound (IA-1-2) and the compound (IA-1-3) react under proper conditions (such as 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene, palladium acetate and cesium carbonate) to obtain the compound (IA-1-4), the compound (IA-1-4) reacts under alkaline conditions (such as sodium hydroxide and the like) to obtain the compound (IA-1-5), and the compound (IA-1-5) reacts under the action of N, N-carbonyl diimidazole and N, N-diisopropylethylamine to obtain the compound (IA-1).

Synthesis scheme B

The synthesis of intermediate (IA-1) can also be prepared by the synthetic procedure of synthesis scheme B, wherein ring B, n, R ¹、R²、R³、R⁴ and R ^a each have the definition as described herein, and Hal ¹ is Cl, br or I, preferably Br or I. The compound (IA-1-6) and the compound (IA-1-3) are reacted under proper conditions (such as under the action of cuprous iodide, potassium carbonate and 4A molecular sieve in N, N-dimethylformamide solvent) to obtain the compound (IA-1).

Synthesis scheme C

The synthesis of intermediate (IA-1) can also be prepared by the synthetic procedure of synthesis scheme C, wherein ring B, n, R ¹、R²、R³、R⁴ and R ^a each have the definition as described in the present invention, hal ¹ is Cl, br or I, preferably Br or I, compound (IA-1-10) is a C _2-6 alkane chain or a C _2-6 heteroalkane chain, and both ends of the chain are substituted with Br, wherein C _2-6 heteroalkane is where a carbon atom in the C _2-6 alkane is replaced with a heteroatom. The compound (IA-1-7) and the compound (IA-1-3) react under proper conditions (such as under the action of cuprous iodide, potassium carbonate and a 4A molecular sieve in an N, N-dimethylformamide solvent) to obtain the compound (IA-1-8), the compound (IA-1-8) reacts under the action of N, N-carbonyldiimidazole in a proper solvent (such as dichloromethane) to obtain the compound (IA-1-9), and the compound (IA-1-9) and the compound (IA-1-10) react under proper conditions (such as under the action of potassium hydroxide and tetrabutylammonium bromide) to obtain the compound (IA-1).

Synthesis scheme D

The synthesis of intermediate (IC-1) can also be prepared by the synthetic procedure of synthesis scheme D, wherein ring B, R ¹、R²、R³、R⁴ and R ^a each have the definition as described in the present invention, hal ¹ is Cl, br or I, preferably Br or I, alk represents C _1-4 alkyl, preferably methyl or ethyl, compound (IA-1-10) is a C _2-6 alkane chain or a C _2-6 heteroalkane chain, and both ends of the chain are substituted with Br, wherein the C _2-6 heteroalkane is where a carbon atom in the C _2-6 alkane is replaced with a heteroatom. The compound (IA-1-1) and the compound (IA-1-3) are heated and reacted under proper conditions (such as under the action of 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene, palladium acetate and cesium carbonate in a 1, 4-dioxane solvent) to obtain the compound (IC-1-2), the compound (IA-1-10) firstly generates a Grignard reagent under the action of iodine and magnesium and then reacts with the compound (IC-1-2) at a low temperature to obtain the compound (IC-1-3), and the compound (IC-1-3) and triphosgene are reacted under proper conditions (such as under the action of triethylamine in a dichloromethane solvent) to obtain the compound (IC-1).

Examples

EXAMPLE 11 ' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one Synthesis

Step 1 Synthesis of 1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

A mixture of 1- (2-iodophenyl) cyclopropane-1-carboxylic acid (500 mg,1.74 mmol), 1-methyl-5-aminopyrazole (340 mg,3.48 mmol), copper iodide (66 mg,0.35 mmol), potassium carbonate (721 mg,5.22 mmol), 4A molecular sieves (500 mg) and N, N-dimethylformamide (10 mL) was stirred under nitrogen for 2h at 100 ℃. The reaction solution was diluted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 ml×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a brown solid (89mg,21.43％).¹H NMR(400MHz,CDCl₃)δ7.62(d,J＝1.7Hz,1H),7.22(t,J＝7.7Hz,1H),7.10(t,J＝7.4Hz,1H),6.92(d,J＝7.3Hz,1H),6.76(d,J＝7.8Hz,1H),6.33(d,J＝1.8Hz,1H),3.75(s,3H),1.92–1.83(m,2H),1.70–1.60(m,2H);LC-MS:240.30[M+H]⁺.

Step 2 Synthesis of 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

1' - (1-Methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (84 mg,0.35 mmol) and N-iodosuccinimide (79 mg,0.35 mmol) were dissolved in acetic acid (5 mL), and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding ethyl acetate (50 mL) for dilution, washing the organic phase with water (30 mL×3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow solid (105mg,81.90％).¹H NMR(400MHz,CDCl₃)δ7.66(s,1H),7.25–7.20(m,1H),7.13(t,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.63(d,J＝7.8Hz,1H),3.79(s,3H),1.94–1.88(m,2H),1.70–1.67(m,2H);LC-MS:366.10[M+H]⁺.

Step 3 Synthesis of tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclopropane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1'- (4-Iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indolin ] -2 '-one (300 mg,0.82 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (494 mg,1.23 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (53 mg,0.08 mmol) and sodium carbonate (174 mg,1.64 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred for 2H under nitrogen protection, microwave conditions at 80 ℃. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow solid (153mg,36.33％).¹H NMR(400MHz,CDCl₃)δ(ppm)10.37(s,1H),8.28(d,J＝8.3Hz,1H),8.09(s,1H),7.77(s,1H),7.69(d,J＝8.4Hz,1H),7.16–7.05(m,2H),7.05–6.95(m,1H),6.56–6.45(m,1H),5.31(s,1H),4.42(dd,J＝16.4,5.3Hz,1H),4.27(dd,J＝16.4,5.2Hz,1H),3.81(s,3H),2.00–1.94(m,2H),1.69–1.65(m,2H),1.48(s,9H);LC-MS:513.50[M+H]⁺.

Step 4 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

The compound ((7- (1-methyl-5- (2 ' -oxospiro [ cyclopropan-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (55 mg,0.11 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (251 mg,2.2 mmol) was added and stirred at room temperature for 3H. The reaction solution was diluted with dichloromethane (50 mL), water (30 mL) was added, ph=9 was adjusted with sodium hydroxide solution (2M), the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a green solid (38mg,85.86％).¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝6.7Hz,1H),8.01(s,1H),7.72(d,J＝7.7Hz,1H),7.55(s,1H),7.17–7.05(m,2H),6.99(d,J＝6.5Hz,1H),6.54(d,J＝6.9Hz,1H),3.79(s,3H),3.78–3.60(m,2H),1.97–1.88(m,2H),1.81–1.70(m,2H);LC-MS:413.20[M+H]⁺.

EXAMPLE 2 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -methyl spiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (2-iodo-3-methylphenyl) methanol

Compound 2-iodo-3-methylbenzoic acid (3.5 g,13.36 mmol) was dissolved in tetrahydrofuran (26 mL), borane tetrahydrofuran complex (27 mL,1mol/L in tetrahydrofuran) was added, and stirred at room temperature for 5h. The reaction was stopped, the reaction mixture was slowly dropped into methanol (50 mL), concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid (2.38g,100％).¹H NMR(400MHz,CDCl₃)δ7.31–7.24(m,2H),7.22–7.15(m,1H),4.76–4.62(m,2H),2.50(s,3H).

Step 2 Synthesis of 1- (bromomethyl) -2-iodo-3-methylbenzene

(2-Iodo-3-methylphenyl) methanol (3.30 g,13.30 mmol) was dissolved in methylene chloride (50 mL), triphenylphosphine (3.84 g,14.63 mmol) was added, stirred at room temperature for 45min, N-bromosuccinimide (2.60 g,14.63 mmol) was added in portions, and the reaction was stirred at room temperature for 4h. The reaction solution was washed with saturated carbonic acid solution (50 mL) and saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: PE/EA (v/v) =20/1) to give the product (2.55 g, 62%) as a colorless oil.

Step 3 Synthesis of 2- (2-iodo-3-methylphenyl) acetonitrile

1- (Bromomethyl) -2-iodo-3-methylbenzene (2.55 g,8.20 mmol), cyanotrimethylsilane (0.98 g,9.84 mmol) and potassium carbonate (1.36 g,9.84 mmol) were dissolved in acetonitrile (30 mL) and reacted at 60℃with stirring for 5.5h. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), the combined organic phases were washed with saturated brine (50 mL. Times.2), the organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a pale yellow solid product (2.05g,97％).¹H NMR(400MHz,CDCl₃)δ7.41–7.21(m,3H),3.90(s,2H),2.52(s,3H);LC-MS:258.20[M+H]⁺.

Step 4 Synthesis of 1- (2-iodo-3-methylphenyl) cyclopropane-1-carbonitrile

2- (2-Iodo-3-methylphenyl) acetonitrile (2.00 g,7.78 mmol), potassium hydroxide (4.37 g,77.80 mmol) and tetrabutylammonium bromide (130 mg,0.39 mmol) were dissolved in water (10 mL), 1,2 dibromoethane (2.92 g,15.52 mmol) was added under stirring at 70℃under nitrogen protection, and the reaction was continued under stirring at temperature for 22h. The reaction was stopped, cooled to room temperature, extracted with ethyl acetate (20 ml×2), the combined organic phases were washed with water (20 ml×2), the organic phases were dried over anhydrous sodium sulfate and then purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give the product as a pale yellow solid (332 mg, 15%). LC-MS 284.10[ M+H ] ⁺.

Step 5 Synthesis of 1- (3-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

The compound 1- (2-iodo-3-methylphenyl) cyclopropane-1-carbonitrile (332 mg,1.17 mmol), 1-methyl-5-aminopyrazole (120 mg,1.29 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (140 mg,0.23 mmol), palladium acetate (26 mg,0.12 mmol) and cesium carbonate (760 mg,2.34 mmol) were dissolved in 1, 4-dioxane (8 mL) and reacted under stirring under nitrogen at 140℃for 4h under microwave conditions. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered and purified by column chromatography over silica gel (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (208 mg, 70%). LC-MS 253.20[ M+H ] ⁺.

Step 6 Synthesis of 1- (3-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (3-Methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (208 mg,0.82 mmol) and sodium hydroxide (1.31 g,32.80 mmol) were dissolved in a mixed solvent of water (3 mL) and methanol (3 mL), and reacted under stirring at 100℃for 16.5H under nitrogen. Potassium hydroxide (1.84 g,32.80 mmol) was added, the reaction was continued to stir overnight, the reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10 mL), pH=2 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (10 mL. Times.3), the combined organic phases were washed with saturated brine (10 mL. Times.2), the organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oily product (160 mg, 72%). LC-MS 272.20[ M+H ] ⁺.

Step 7 Synthesis of 7 '-methyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (3-Methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (160 mg,0.59 mmol), N-carbonyldiimidazole (140 mg,0.89 mmol) and N, N-diisopropylethylamine (150 mg,1.18 mmol) were dissolved in dichloromethane (10 mL), and the reaction was stirred at room temperature overnight. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and then purified by column chromatography on silica gel (eluent: PE/EA (v/v) =1/1) to give the product as a yellow oil (34 mg, 46%). LC-MS 254.40[ M+H ] ⁺.

Step 8 Synthesis of 1'- (4-iodo-1-methyl-1H-pyrazol-5-yl) -7' -methyl spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

7 '-Methyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (35 mg,0.14 mmol) and N-iodosuccinimide (32 mg,0.14 mmol) were dissolved in acetic acid (15 mL), and the reaction was stirred at room temperature for 1H. The solvent was removed by concentration under reduced pressure, the residue was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the product (52 mg, 99%) as a colorless oil. LC-MS 380.30[ M+H ] ⁺.

Step 9 Synthesis of tert-butyl ((7- (1-methyl-5- (7 '-methyl-2' -oxospiro [ cyclopropane-1, 3 '-indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

Tert-butyl 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) -7' -methyl spiro [ cyclopropane-1, 3' -indoline ] -2' -one (52 mg,0.14 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (84 mg,0.21 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (14 mg,0.02 mmol) and sodium carbonate (30 mg,0.28 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (2 mL) and reacted under 80 ℃ microwave conditions under nitrogen protection for 3H. The reaction was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and purified by column chromatography over silica gel under reduced pressure (eluent: PE/EtOAc (v/v) =1/4) to give the product as a pale yellow solid (18 mg, 25%). LC-MS 527.25[ M+H ] ⁺.

Step 10 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -methyl spiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (1-methyl-5- (7 '-methyl-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (18 mg,0.03 mmol) was dissolved in methanol (3 mL), and a1, 4-dioxane solution (3 mL,4 m) of hydrogen chloride was added thereto, and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure afforded the product as a pale yellow solid (13 g, 82%). LC-MS 428.20[ M+H-HCl ] ⁺.

EXAMPLE 3 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -fluoro-spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

Step 1 Synthesis of 2-bromo-1-bromomethyl-3-fluorobenzene

The compound 2-bromo-3-fluorotoluene (5.00 g,26.45 mmol), NBS (4.71 g,26.45 mmol) and AIBN (87 mg,0.53 mmol) were mixed in carbon tetrachloride (60 mL) and reacted for 2h with stirring at 90 ℃. Stopping the reaction, cooling to room temperature, adding petroleum ether (50 mL) for dilution, washing the organic phase with water (50 mL×3), drying with anhydrous sodium sulfate, and concentrating the solvent under reduced pressure to obtain a red solid (5.06g,71.40％).¹H NMR(400MHz,CDCl₃)δ7.29–7.23(m,2H),7.10–7.05(m,1H),4.61(s,2H);GC-MS:267.9[M]⁺.

Step 2 Synthesis of 2- (2-bromo-3-fluorophenyl) acetonitrile

The compound 2-bromo-1-bromomethyl-3-fluorobenzene (5.20 g,19.41 mmol), cyanotrimethylsilane (2.31 g,23.29 mmol) and potassium carbonate (5.37 g,38.82 mmol) were mixed in acetonitrile (60 mL) and reacted under stirring at 80 ℃ for 6h. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 ml×3), the combined organic phases were washed with saturated brine (50 ml×2), the organic phases were dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give colorless transparent liquid (2.91 g, 70.05%). GC-MS 212.96[ M ] ⁺.

Step 3 Synthesis of 1- (2-bromo-3-fluorophenyl) cyclopropane-1-carbonitrile

Sodium hydride (2.34 g,58.4mmol,60% strength) was dissolved in N, N-dimethylformamide (50 mL), and 2- (2-bromo-3-fluorophenyl) acetonitrile (2.50 g,11.68 mmol) was slowly added under ice-bath, stirred for 30min with heat preservation, 1, 2-dibromoethane (3.29 g,17.52 mmol) was added and stirred at room temperature for 3h. The reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and washed with saturated brine (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =5/1) to give a white solid (1.62g,57.77％).¹H NMR(400MHz,CDCl₃)δ(ppm)7.33–7.27(m,1H),7.18–7.11(m,2H),1.83–1.77(m,2H),1.38–1.33(m,2H);GC-MS:239.0[M]⁺.

Step 4 Synthesis of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

The compound 1- (2-bromo-3-fluorophenyl) cyclopropane-1-carbonitrile (500 mg,2.08 mmol), 1-methyl-5-aminopyrazole (220 mg,2.29 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (120 mg,0.21 mmol), palladium acetate (23 mg,0.10 mmol) and cesium carbonate (1.36 g,4.16 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring at 140℃under nitrogen blanket under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute the mixture, the organic phase was washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow oily substance (113mg,21.17％).LC-MS:257.15[M+H]⁺;¹H NMR(599MHz,CDCl₃)δ7.62(d,J＝1.9Hz,1H),6.96–6.87(m,2H),6.66–6.62(m,1H),6.33(d,J＝1.9Hz,1H),3.73(s,3H),1.80–1.72(m,2H),1.65–1.58(m,2H).

Step 5 Synthesis of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

The compound 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (100 mg,0.39 mmol) and sodium hydroxide (88 mg,1.56 mmol) were dissolved in a mixed solvent of water (2 mL) and ethanol (2 mL), and stirred at 100 ℃ for 12H. Adjusting ph=4 with 1, 4-dioxane solution of hydrogen chloride (4M), concentrating the solvent by rotary evaporation under reduced pressure, adding ethanol (20 mL) to the residue, filtering off solids, concentrating the solvent by rotary evaporation under reduced pressure to give a yellow liquid (68mg,63.31％).LC-MS:276.40[M+H]⁺;¹H NMR(600MHz,CDCl₃)δ7.94(s,1H),7.82(s,1H),7.39–7.34(m,1H),7.29–7.25(m,1H),7.24–7.19(m,1H),3.96(s,3H),1.58(q,J＝4.1Hz,2H),1.25(q,J＝4.2Hz,2H).

Step 6 Synthesis of 7 '-fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (3-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (110 mg,0.40 mmol) and N, N-carbonyldiimidazole (97 mg,0.60 mmol) were dissolved in dichloromethane (5 mL), and stirred at room temperature for 2H. Diluted with dichloromethane (50 mL), washed with water (30 ml×3), dried over anhydrous sodium sulfate, concentrated solvent by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a red solid (80mg,77.82％).LC-MS:258.20[M+H]⁺;¹H NMR(599MHz,CDCl₃)δ(ppm)7.56(d,J＝1.6Hz,1H),7.05–7.01(m,1H),6.98–6.92(m,1H),6.69(d,J＝7.4Hz,1H),6.34–6.28(m,1H),3.75(s,3H),1.94–1.87(m,2H),1.70–1.64(m,2H).

Step 7 Synthesis of 7 '-fluoro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

7 '-Fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (80 mg,0.31 mmol) and N-iodosuccinimide (70 mg,0.31 mmol) were dissolved in acetic acid (10 mL) and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding ethyl acetate (50 mL) for dilution, washing the organic phase with water (30 mL×3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow solid (110mg,92.32％).¹H NMR(599MHz,CDCl₃)δ(ppm)7.61(s,1H),7.09–7.04(m,1H),7.00–6.95(m,1H),6.72(d,J＝7.5Hz,1H),3.83(s,3H),1.98–1.93(m,2H),1.74–1.67(m,2H);LC-MS:384.05[M+H]⁺.

Step 8 Synthesis of tert-butyl (7- (5- (7 '-fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

7' -Fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (119 mg,0.31 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (187 mg,0.46 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (20 mg,0.03 mmol) and sodium carbonate (65.71 mg,0.62 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL), and stirred under nitrogen protection at 80℃for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow solid (80mg,48.55％).¹H NMR(599MHz,CDCl₃)δ10.76(s,1H),8.30(d,J＝8.3Hz,1H),8.02(s,1H),7.77(s,1H),7.68(d,J＝8.3Hz,1H),7.08–7.02(m,1H),6.92–6.86(m,1H),6.79(d,J＝7.4Hz,1H),5.40(s,1H),4.46(dd,J＝16.3,5.3Hz,1H),4.30(dd,J＝16.3,5.0Hz,1H),3.84(s,3H),2.02–1.97(m,2H),1.78–1.73(m,2H),1.47(s,9H);LC-MS:31.20[M+H]⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -fluoro spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

(7- (5- (7 '-Fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (70 mg,0.13 mmol) was dissolved in dichloromethane (1 mL), and a 1, 4-dioxane solution (1 mL,4.0mmol, 4M) of hydrogen chloride was added and stirred at room temperature for 3H. The reaction solution was diluted with dichloromethane (50 mL), water (30 mL) was added, ph=9 was adjusted with sodium hydroxide solution (2M), the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a yellow solid (50mg,88.04％).¹H NMR(599MHz,CDCl₃)δ(ppm)8.25(d,J＝8.3Hz,1H),8.15(s,1H),7.84(d,J＝8.3Hz,1H),7.63(s,1H),7.17–7.14(m,1H),7.01–6.99(m,1H),6.82–6.76(m,1H),3.83(s,3H),3.82–3.78(m,1H),3.70–3.65(m,1H),1.97–1.92(m,2H),1.92–1.85(m,2H);LC-MS:431.40[M+H]⁺.

EXAMPLE 4 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -fluoro-spiro [ cyclopropan-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 1- (bromomethyl) -4-fluoro-2-iodobenzene

4-Fluoro-2-iodo-1-toluene (0.1 g, 0.42 mmol) was dissolved in carbon tetrachloride (5 mL), azobisisobutyronitrile (34.48 mg,0.21 mmol) and N-bromosuccinimide (0.12 g,0.67 mmol) were added, nitrogen was replaced, and the reaction was stirred at 80℃for 2 hours. After cooling to room temperature, concentrated under reduced pressure, water (20 mL) was added, the aqueous layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: PE) to give a colorless liquid (80 mg, 59.96%).

Step 2 Synthesis of 2- (4-fluoro-2-iodophenyl) acetonitrile

1- (Bromomethyl) -4-fluoro-2-iodobenzene (2.02 g,6.41 mmol) was dissolved in acetonitrile (20 mL), and trimethylcyanosilane (0.76 g,7.69 mmol) and potassium carbonate (1.77 g,12.82 mmol) were added, followed by stirring at 80℃for 5.5h. Concentrating the reaction system under reduced pressure, and purifying with silica gel column chromatography (EA/PE (v/v) =15/85) to obtain colorless liquid (1.08g,64.50％).¹H NMR(400MHz,CDCl₃)δ7.66–7.61(m,1H),7.54–7.49(m,1H),7.18–7.12(m,1H),3.81(s,2H);LC-MS:262.25[M+H]⁺.

Step 3 Synthesis of 1- (4-fluoro-2-iodophenyl) cyclopropane-1-carbonitrile

2- (4-Fluoro-2-iodophenyl) acetonitrile (1.08 g,4.14 mmol) was dissolved in water (8 mL), and 1, 2-dibromoethane (1.56 g,8.28 mmol), tetrabutylammonium bromide (67 mg,0.21 mmol) and potassium hydroxide (2.32 g,41.4 mmol) were added thereto, followed by stirring at 70℃for 24 hours. Cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), the organic phases were dried over anhydrous sodium sulfate, the filtrate after filtration was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) =10/90) to give a yellow solid (0.7g,58.94％).¹H NMR(400MHz,CDCl₃)δ7.68–7.59(m,1H),7.32–7.26(m,1H),7.10–7.02(m,1H),1.85–1.78(m,2H),1.33–1.29(m,2H).

Step 4 Synthesis of 1- (4-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (4-Fluoro-2-iodophenyl) cyclopropane-1-carbonitrile (0.3 g,1.05 mmol) was dissolved in 1, 4-dioxane (10 mL), followed by 1-methyl-5-aminopyrazole (110 mg,1.16 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.12 g,0.21 mmol), palladium acetate (24 mg,0.11 mmol) and cesium carbonate (0.68 g,2.1 mmol) were added and the reaction was stirred under microwave 140℃for 4h. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) =10/90) to give a yellow oil (0.27g,100％).¹H NMR(400MHz,Chloroform-d)δ7.69–7.65(m,1H),6.79–6.73(m,1H),6.73–6.64(m,1H),6.38–6.33(m,1H),6.29–6.23(m,1H),3.71(s,3H),1.73–1.65(m,2H),1.60–1.53(m,2H);LC-MS:257.35[M+H]⁺.

Step 5 Synthesis of 1- (4-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (4-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (270 mg,1.05 mmol) was dissolved in a mixed solution of methanol (5 mL) and water (2 mL), sodium hydroxide (1.68 mg,42.00 mmol) was further added, nitrogen was replaced, and the reaction was stirred at 100℃for 24 hours. Cooled to room temperature, ph=6 was adjusted with dilute hydrochloric acid (2.0M), extracted with ethyl acetate (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow dope (150 mg, 51.57%). LC-MS 276.30[ M+H ] ⁺.

Step 6 Synthesis of 6 '-fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (4-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (150 mg,0.54 mmol) was dissolved in dichloromethane (5 mL), and N, N '-carbonyldiimidazole (0.26 g,1.62 mmol) and N, N' -diisopropylethylamine (0.28 g,2.16 mmol) were added thereto, and the reaction was stirred at room temperature for 23 hours. The reaction was concentrated under reduced pressure, water (10 mL) was added, extracted with dichloromethane (10 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) =30/70) to give a pale yellow solid (45 mg, 32.10%). LC-MS 258.30[ M+H ] ⁺.

Step 7 Synthesis of 6 '-fluoro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

6 '-Fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (45 mg,0.17 mmol) was dissolved in acetic acid (5 mL), and N-iodosuccinimide (76.49 mg,0.34 mmol) was added thereto, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, dissolved with EA, and then washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow viscous material (67 mg, 100%). LC-MS 384.05[ M+1] ⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (6 '-fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

6' -Fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (67 mg,0.17 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (9 mL) and water (3 mL), and tert-butyl ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (0.100 g,0.26 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (17 mg,0.026 mmol) and sodium carbonate (36 mg,0.34 mmol) were added thereto and reacted under stirring at 80℃for 4H. The reaction was concentrated under reduced pressure, dissolved with ethyl acetate, filtered (cotton filtration), water (10 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL. Times.5), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) =50/50-90/10) to give a brown solid (45mg,48.51％).¹H NMR(400MHz,CDCl₃)δ10.27(s,1H),8.33(d,J＝8.3Hz,1H),8.11(s,1H),7.81(s,1H),7.69(d,J＝9.5Hz,1H),6.96(dd,J＝8.1,5.1Hz,1H),6.81(td,J＝9.3,2.2Hz,1H),6.28(dd,J＝8.3,2.1Hz,1H),5.36(s,1H),4.48(dd,J＝16.4,5.3Hz,1H),4.34(dd,J＝16.4,5.3Hz,1H),3.84(s,3H),1.50(s,9H),1.29(d,J＝14.7Hz,4H);MS(ESI,pos.ion)m/z:530.55[M+1]⁺:531.30.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -fluoro-spiro [ cyclopropyl-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (6 '-fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (30 mg,0.057 mmol) was dissolved in methanol (3 mL), and a1, 4 dioxane solution (3 mL,4 mol/L) of hydrogen chloride was added thereto, followed by stirring at room temperature for reaction for 2 hours. Concentrating the reaction system under reduced pressure to obtain a white solid (26mg,98.49％).¹H NMR(400MHz,DMSO-d₆)δ12.86(s,1H),8.55(s,2H),8.43(s,1H),8.17(d,J＝9.1Hz,1H),7.81–7.66(m,2H),7.28(s,1H),6.96(d,J＝7.9Hz,1H),6.51(d,J＝9.3Hz,1H),3.73(s,3H),3.17(s,2H),2.03–1.77(m,4H);LC-MS:431.20[M+H-HCl]⁺;HRMS:431.1619[M+H-HCl]⁺.

EXAMPLE 5 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chlorospiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (4-chloro-2-iodophenyl) methanol

4-Chloro-2-iodobenzoic acid (2.5 g,8.85 mmol) was dissolved in tetrahydrofuran (15 mL), a solution of borane in tetrahydrofuran (27 mL,1 mol/L) was added and the reaction stirred at 50℃for 2h. The reaction was stopped and cooled to room temperature, the reaction solution was slowly dropped into methanol (10 mL), concentrated under reduced pressure, the residue was dissolved in ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow solid product (2.38 g, 100%).

Step 2 Synthesis of 4-chloro-1- (chloromethyl) -2-iodobenzene

(4-Chloro-2-iodophenyl) methanol (2.4 g,8.94 mmol) was dissolved in dichloromethane (20 mL), thionyl chloride (3.2 mL) and N, N-dimethylformamide (1 mL) were added, the reaction was stirred at room temperature for 3h, the solvent was removed by concentration under reduced pressure, the residue was dissolved with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, and after filtration, concentrated under reduced pressure to give a brown liquid product (2.56 g, 100%).

Step 3 Synthesis of 2- (4-chloro-2-iodophenyl) acetonitrile

4-Chloro-1- (chloromethyl) -2-iodobenzene (2.6 g,9.06 mmol), cyanotrimethylsilane (1.08 g,10.87 mmol) and potassium carbonate (1.50 g,10.87 mmol) were dissolved in acetonitrile (20 mL) and reacted at 80℃with stirring for 10h. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure after filtration, and purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give a yellow solid product (1.10 g, 44%).

Step 4 Synthesis of 1- (4-chloro-2-iodophenyl) cyclopropane-1-carbonitrile

2- (4-Chloro-2-iodophenyl) acetonitrile (1.1 g,3.96 mmol), potassium hydroxide (2.2 g,39.6 mmol) and tetrabutylammonium bromide (64 mg,0.20 mmol) were dissolved in water (5 mL), 1,2 dibromoethane (1.5 g,7.92 mmol) was added under stirring at 70℃under nitrogen protection, and the reaction was continued with stirring at 70℃for 24h. The reaction was stopped, cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, and then purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give the product as a yellow solid (619mg,51％).¹H NMR(600MHz,DMSO-d₆)δ8.04(d,J＝2.1Hz,1H),7.53–7.49(m,1H),7.49–7.45(m,1H),1.80(q,J＝5.1Hz,2H),1.39(q,J＝5.1Hz,2H);LC-MS:304.20[M+H]⁺.

Step 5 Synthesis of 1- (4-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (4-Chloro-2-iodophenyl) cyclopropane-1-carbonitrile (450 mg,1.48 mmol), 1-methyl-5-aminopyrazole (160 mg,1.63 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (170 mg,0.30 mmol), palladium acetate (33 mg,0.15 mmol) and cesium carbonate (960 mg,2.96 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring at 140℃under nitrogen protection under microwave conditions for 4h. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography over silica gel (eluent: DCM: meoh=20:1) to give the product as a brown oil (380 mg, 94%). LC-MS 273.30[ M+H ] ⁺.

Step 6 Synthesis of 1- (4-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (4-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (380 mg,1.39 mmol) and sodium hydroxide (1100 mg,27.80 mmol) were dissolved in a mixed solvent of water (5 mL) and methanol (7.5 mL), and reacted under stirring at 100℃for 14H under nitrogen. Sodium hydroxide (560 mg,13.90 mmol) was added and the reaction was continued to stir overnight, stopped, concentrated under reduced pressure to remove the solvent, diluted with water (10 mL), ph=2 adjusted with hydrochloric acid (2M), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a brown oil (255 mg, 63%). LC-MS 292.30[ M+H ] ⁺.

Step 7 Synthesis of 6 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (4-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (255 mg,0.87 mmol), N-carbonyldiimidazole (210 mg,1.30 mmol) and N, N-diisopropylethylamine (220 mg,1.74 mmol) were dissolved in dichloromethane (8 mL), and the reaction was stirred at room temperature overnight. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: PE/EA (v/v) =3/1) to give the product as a colourless oil (134 mg, 56%). LC-MS 274.15[ M+H ] ⁺.

Step 86 '-chloro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

6 '-Chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (60 mg,0.24 mmol) and N-iodosuccinimide (72 mg,0.32 mmol) were dissolved in acetic acid (16 mL), and the reaction was stirred at room temperature for 1H. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the product as a colorless oil (128 mg, 100%). LC-MS 400.00[ M+H ] ⁺.

Step 9 Synthesis of tert-butyl ((7- (5- (6 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

6' -Chloro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (128 mg,0.32 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (190 mg,0.48 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (31 mg,0.05 mmol) and sodium carbonate (68 mg,0.64 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (2 mL) and reacted under stirring under nitrogen protection at 100 ℃. The reaction was stopped, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4) to give the product as a white solid (55 mg, 31%). LC-MS 547.15[ M+H ] ⁺.

Step 10 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chlorospiro [ cyclopropane-1, 3 '-indoline ] -2' -one hydrochloride

Tert-butyl ((7- (5- (6 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (55 mg,0.10 mmol) was dissolved in methanol (3 mL), and a 1, 4-dioxane solution (4 m,4 mL) of hydrogen chloride was added thereto to stir the reaction at room temperature for 1H. Concentrating under reduced pressure to obtain pale yellow solid product (40mg,82％).¹H NMR(600MHz,DMSO-d₆)δ12.88(s,1H),8.51(s,3H),8.44(s,1H),8.19(d,J＝8.3Hz,1H),7.75(d,J＝8.5Hz,1H),7.73(s,1H),7.29(d,J＝8.1Hz,1H),7.21–7.16(m,1H),6.66–6.60(m,1H),4.35–4.28(m,1H),4.08–4.02(m,1H),3.74(s,3H),2.06–2.01(m,1H),2.00–1.92(m,1H),1.86–1.79(m,2H);LC-MS:447.10[M+H-HCl]⁺.

EXAMPLE 6 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropan-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (2-iodo-4- (trifluoromethyl) phenyl) methanol

2-Iodo-4- (trifluoromethyl) benzoic acid (2 g,6.33 mmol) was dissolved in THF (10 mL), nitrogen was replaced, and borane in tetrahydrofuran (20 mL,1 mol/L) was slowly added. The reaction was then stirred at room temperature for 14h. The reaction mixture was slowly dropped into methanol to quench the reaction, followed by concentration under reduced pressure, addition of water (10 mL), extraction with ethyl acetate (20 mL. Times.2), drying of the organic phase over anhydrous sodium sulfate and concentration under reduced pressure gave a colorless liquid product (1.91 g, 99.92%). ¹H NMR(400MHz,CDCl₃ ) Delta 8.04 (s, 1H), 7.65-7.57 (m, 2H), 4.69 (s, 2H).

Step 2 Synthesis of 1- (bromomethyl) -2-iodo-4- (trifluoromethyl) benzene

(2-Iodo-4- (trifluoromethyl) phenyl) methanol (0.3 g,0.99 mmol) was dissolved in methylene chloride (5 mL), triphenylphosphine (0.39 g,1.49 mmol) was further added, and after stirring at room temperature for 45min, N-bromosuccinimide (0.26 g,1.49 mmol) was added in portions, followed by stirring at room temperature. The reaction solution was washed with saturated sodium bicarbonate solution (10 mL), saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =20/1) to give the product as a colorless oil (0.15 g, 41.38%). LC-MS 364.93[ M+H ] ⁺.

Step 3 Synthesis of 2- (2-iodo-4- (trifluoromethyl) phenyl) acetonitrile

1- (Bromomethyl) -2-iodo-4- (trifluoromethyl) benzene (1.15 g,3.15 mmol) was dissolved in acetonitrile (10 mL), trimethylcyanosilane (0.38 g,3.78 mmol) and potassium carbonate (0.87 g,6.3 mmol) were added, and then the temperature was raised to 80℃and the reaction was stirred for 7h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =15/85) to give a colorless liquid (0.52 g, 53.05%). GC-MS 311.0[ M ] ⁺.

Step 4 Synthesis of 1- (2-iodo-4- (trifluoromethyl) phenyl) cyclopropane-1-carbonitrile

2- (2-Iodo-4- (trifluoromethyl) phenyl) acetonitrile (0.52 g,1.67 mmol) was dissolved in water (8 mL), potassium hydroxide (0.94 g,16.7 mmol) and tetrabutylammonium bromide (27 mg,0.084 mmol) were added, nitrogen was replaced, and 1, 2-dibromoethane (0.63 g,3.34 mmol) was further added and reacted under stirring at 70℃for 24 hours. Cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a pale yellow solid (303 mg, 53.77%).

Step 5 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) -4- (trifluoromethyl) phenyl) cyclopropane-1-carbonitrile

1- (2-Iodo-4- (trifluoromethyl) phenyl) cyclopropane-1-carbonitrile (0.3 g,0.89 mmol) was dissolved in 1, 4-dioxane (10 mL), and 1-methyl-5-aminopyrazole (95 mg,0.98 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.10 g,0.18 mmol), palladium acetate (20 mg,0.089 mmol) and cesium carbonate (0.58 g,1.78 mmol) were added and reacted under stirring at 140℃for 4h under microwave conditions. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (eluent: methanol/dichloromethane=1/9 to give a brown solid (0.27 g, 99.05%). LC-MS:307.15[ M+H ] ⁺.

Step 6 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) -4- (trifluoromethyl) phenyl) cyclopropane-1-carboxylic acid

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) -4- (trifluoromethyl) phenyl) cyclopropane-1-carbonitrile (50 mg,0.16 mmol) was dissolved in a mixed solution of methanol (3 mL) and water (1 mL), sodium hydroxide (128 mg,3.2 mmol) was further added, nitrogen was replaced, and the reaction was stirred at 100℃for 24 hours. Cooled to room temperature, ph=6 was adjusted with dilute hydrochloric acid (2.0M), extracted with ethyl acetate (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow solid (53.1 mg, 100%). LC-MS 326.00[ M+H ] ⁺.

Step 7 Synthesis of 1'- (1-methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) -4- (trifluoromethyl) phenyl) cyclopropane-1-carboxylic acid (284 mg,0.88 mmol) was dissolved in dichloromethane (10 mL), and N, N '-carbonyldiimidazole (0.42 g,2.64 mmol) and N, N' -diisopropylethylamine (0.46 g,3.52 mmol) were added thereto, and the reaction was stirred at room temperature for 21.5H. The reaction was concentrated under reduced pressure, water (10 mL) was added, extracted with dichloromethane (10 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give a pale yellow solid (74 mg, 27.39%). LC-MS 308.10[ M+H ] ⁺.

Step 8 Synthesis of 1'- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropyl-1, 3 '-indoline ] -2' -one

1'- (1-Methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (74 mg,0.24 mmol) was dissolved in acetic acid (5 mL), and N-iodosuccinimide (54 mg,0.24 mmol) was added thereto, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, dissolved in ethyl acetate, and then washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid (104.32 mg, 100%). LC-MS 434.30[ M+H ] ⁺.

Step 9 Synthesis of tert-butyl ((7- (1-methyl-5- (2 '-oxo-6' - (trifluoromethyl) spiro [ cyclopropane-1, 3 '-indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1' - (4-Iodo-1-methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropyl-1, 3' -indolin ] -2' -one (104 mg,0.24 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (12 mL) and water (4 mL), tert-butyl ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (0.14 g,0.36 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (23 mg,0.036 mmol) and sodium carbonate (51 mg,0.48 mmol) were added and the reaction was stirred under microwave 80 ℃ for 4H. The reaction solution was concentrated under reduced pressure, dissolved with ethyl acetate, filtered (cotton filtration), water (10 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL. Times.5), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) =50/50-90/10) to give a brown solid (16mg,11.48％).¹H NMR(400MHz,CDCl₃)δ11.45(s,1H),8.30(d,J＝8.3Hz,1H),8.12(s,1H),7.81(s,1H),7.65(d,J＝8.3Hz,1H),7.37(d,J＝7.8Hz,1H),7.11(d,J＝7.7Hz,1H),6.69(s,1H),5.30(s,3H),3.83(s,2H),1.48(s,9H),1.29–1.24(m,4H);LC-MS(ESI,pos.ion):581.60[M+H]⁺.

Step 10 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' - (trifluoromethyl) spiro [ cyclopropan-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (1-methyl-5- (2 '-oxo-6' - (trifluoromethyl) spiro [ cyclopropan-1, 3 '-indolin ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (16 mg,0.028 mmol) was dissolved in methanol (2 mL), and a1, 4 dioxane solution (1.5 mL,4 mol/L) of hydrogen chloride was added, followed by stirring at room temperature for 2H. The reaction was concentrated under reduced pressure to give a brown solid (14.25 mg, 93.00%). LC-MS (ESI, pos.ion) m/z 481.20[ M+H-HCl ] ⁺;HRMS:481.1593[M+H-HCl]⁺.

EXAMPLE 7 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chloro-7 ' -fluoro-spiro [ cyclopropan-1, 3' -indolin ] -2' -one hydrochloride

Step 1 Synthesis of 4-chloro-3-fluoro-2-iodobenzoic acid

N-hexane solution of n-butyllithium (57 mL,143mmol, 2.5M) was slowly added dropwise to anhydrous tetrahydrofuran (150 mL) solution of 4-chloro-3-fluorobenzoic acid (10.00 g,57.29 mmol) under nitrogen protection at-78℃with stirring for 1.5h at constant temperature, anhydrous tetrahydrofuran (70 mL) solution of iodine (36.35 g,143.22 mmol) was added dropwise, the reaction solution was slowly warmed to room temperature, and stirring was continued for 2h. Quenching the reaction by adding saturated ammonium chloride solution, removing most of the solvent by rotary evaporation under reduced pressure, adding ethyl acetate (100 mL) and water (100 mL) for dilution, separating the organic phase, extracting the aqueous phase with ethyl acetate (50 mL. Times.3), combining the organic phases, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain brown solid (11.19g,65.01％).¹H NMR(400MHz,CDCl₃)δ7.80(dd,J＝8.4,1.3Hz,1H),7.51(dd,J＝8.4,7.0Hz,1H);LC-MS:299.00[M-H]^-.

Step 2 Synthesis of (4-chloro-3-fluoro-2-iodophenyl) methanol

Borane tetrahydrofuran complex (74 mL,73.88mmol,1M in tetrahydrofuran) was slowly added dropwise to a solution of 4-chloro-3-fluoro-2-iodobenzoic acid (11.10 g,36.94 mmol) in anhydrous tetrahydrofuran (100 mL) and stirred at room temperature for 1h. Adding methanol for quenching reaction, removing most of solvent by rotary evaporation under reduced pressure, adding ethyl acetate (100 mL) and water (100 mL) for dilution, separating organic phase, extracting aqueous phase with ethyl acetate (50 mL×3), mixing organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain white solid (8.47g,80.03％).¹H NMR(400MHz,CDCl₃)δ7.43–7.37(m,1H),7.24(d,J＝8.3Hz,1H),4.68(s,2H);GC-MS:285.9[M]⁺.

Step 3 Synthesis of 1- (bromomethyl) -4-chloro-3-fluoro-2-iodobenzene

Methanesulfonyl chloride (5.04 g,43.98 mmol) was slowly added dropwise to a solution of (4-chloro-3-fluoro-2-iodophenyl) methanol (8.40 g,29.32 mmol) and triethylamine (5.93 g,58.64 mmol) in dichloromethane (100 mL) at 0℃and stirred at room temperature for 0.5h. The solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100 mL) was added to the residue, stirred for 5min, the solid was filtered off through celite, lithium bromide (15.28 g,175.92 mmol) was added to the filtrate, and stirred at room temperature for 3h. The reaction solution was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give a yellow liquid (7.15g,69.79％).¹H NMR(400MHz,CDCl₃)δ7.37–7.33(m,1H),7.24–7.21(m,1H),4.59(s,2H);GC-MS:349.8[M]⁺.

Step 4 Synthesis of 2- (4-chloro-3-fluoro-2-iodophenyl) acetonitrile

A mixture of 1- (bromomethyl) -4-chloro-3-fluoro-2-iodobenzene (7.10 g,20.32 mmol), trimethylcyanosilane (2.42 g,24.38 mmol), potassium carbonate (5.62 g,40.64 mmol) and acetonitrile (70 mL) was stirred at 80℃for 3h. Stopping heating and stirring, cooling to room temperature, evaporating the concentrated solvent under reduced pressure, adding ethyl acetate (50 mL) into the residue, washing with saturated saline (30 mL×3), evaporating the concentrated solvent under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =20/1) to obtain colorless transparent liquid (3.92g,65.28％).¹H NMR(400MHz,CDCl₃)δ7.45(t,J＝8.3Hz,1H),7.30(d,J＝8.3Hz,1H),3.84(s,2H);GC-MS:294.9[M]⁺.

Step 5 Synthesis of 1- (4-chloro-3-fluoro-2-iodophenyl) cyclopropane-1-carbonitrile

A mixture of 2- (4-chloro-3-fluoro-2-iodophenyl) acetonitrile (500 mg,1.69 mmol), 1, 2-dibromoethane (0.63 g,3.38 mmol), potassium hydroxide (0.57 g,10.14 mmol), tetrabutylammonium bromide (0.54 g,1.69 mmol) and water (5 mL) was stirred for 1h at 50 ℃. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (202mg,37.13％).¹H NMR(400MHz,CDCl₃)δ7.38(dd,J＝8.3,7.3Hz,1H),7.07(dd,J＝8.3,1.3Hz,1H),1.88–1.82(m,2H),1.34–1.29(m,2H);GC-MS:320.9[M]⁺.

Step 6 Synthesis of 1- (4-chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (4-Chloro-3-fluoro-2-iodophenyl) cyclopropane-1-carbonitrile (200 mg,0.62 mmol), 1-methyl-5-aminopyrazole (66 mg,0.68 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (36 mg,0.06 mmol), palladium acetate (7 mg,0.03 mmol) and cesium carbonate (0.40 g,1.24 mmol) were dissolved in 1, 4-dioxane (2 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute the mixture, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a brown solid (96mg,53.09％).¹H NMR(400MHz,CDCl₃)δ7.63(d,J＝1.8Hz,1H),7.00(dd,J＝8.0,6.3Hz,1H),6.56(d,J＝8.0Hz,1H),6.34(d,J＝1.9Hz,1H),3.73(s,3H),1.81–1.73(m,2H),1.63–1.57(m,2H);LC-MS:291.15[M+H]⁺.

Step 7 Synthesis of 1- (4-chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

The compound 1- (4-chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (90 mg,0.31 mmol) and potassium hydroxide (350 mg,6.2 mmol) were dissolved in a mixed solvent of ethylene glycol (3 mL) and water (3 mL), and stirred at 140℃for 4H. The ph=4 was adjusted with dioxane solution of hydrogen chloride (4M), the solvent was concentrated by rotary evaporation under reduced pressure, ethanol (20 mL) was added to the residue, the solid was filtered off, and the solvent was concentrated under reduced pressure to give a yellow liquid (80 mg, 83%). LC-MS 310.10[ M+H ] ⁺.

Step 8 Synthesis of 6' -chloro-7 ' -fluoro-1 ' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

1- (4-Chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (210 mg,0.68 mmol) and N, N-carbonyldiimidazole (440 mg,2.72 mmol) were dissolved in dichloromethane (5 mL), and stirred at room temperature for 2H. Diluted with dichloromethane (50 mL), washed with water (30 ml×3), dried over anhydrous sodium sulfate, concentrated solvent by rotary evaporation under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =4/1) to give yellow solid (122mg,61.68％).¹H NMR(400MHz,CDCl₃)δ8.14(s,1H),7.58(d,J＝2.0Hz,1H),7.43(s,1H),7.11(dd,J＝8.0,6.3Hz,1H),7.06(s,1H),6.66–6.60(m,1H),6.32(d,J＝1.9Hz,1H),3.76(s,3H),1.99–1.88(m,2H),1.70–1.65(m,2H);LC-MS:292.10[M+H]⁺.

Step 9 Synthesis of 6' -chloro-7 ' -fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

The compound 6' -chloro-7 ' -fluoro-1 ' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indolin ] -2' -one (120 mg,0.41 mmol) and N-iodosuccinimide (92 mg,0.41 mmol) were dissolved in acetic acid (20 mL) and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding dichloromethane (100 mL) for dilution, washing the organic phase with water (50 mL×3), drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain gray viscous liquid (132mg,76.84％).¹H NMR(400MHz,CDCl₃)δ7.61(s,1H),7.14(dd,J＝8.0,6.4Hz,1H),6.65(d,J＝8.1Hz,1H),3.82(s,3H),1.98–1.94(m,2H),1.74–1.67(m,2H);LC-MS:418.00[M+H]⁺.

Step 10 Synthesis of tert-butyl ((7- (5- (6 ' -chloro-7 ' -fluoro-2 ' -oxospiro [ cyclopropane-1, 3' -indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

The compound 6 '-chloro-7' -fluoro-1 '- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropan-1, 3' -indolin ] -2 '-one (120 mg,0.29 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (175 mg,0.43 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (19 mg,0.03 mmol) and sodium carbonate (61 mg,0.58 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80℃for 4H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (32mg,19.71％).¹H NMR(400MHz,CDCl₃)δ10.96(s,1H),8.32(d,J＝8.3Hz,1H),8.03(s,1H),7.77(s,1H),7.66(d,J＝8.3Hz,1H),7.11(dd,J＝8.0,6.5Hz,1H),6.72(d,J＝8.1Hz,1H),5.45(t,J＝4.3Hz,1H),4.49(dd,J＝16.4,5.3Hz,1H),4.33(dd,J＝16.3,5.0Hz,1H),3.83(s,3H),2.02–1.93(m,2H),1.83–1.71(m,2H),1.47(s,9H);LC-MS:565.20[M+H]⁺.

Step 11 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chloro-7 ' -fluoro-spiro [ cyclopropan-1, 3' -indoline ] -2' -one hydrochloride

Tert-butyl ((7- (5- (6 ' -chloro-7 ' -fluoro-2 ' -oxospiro [ cyclopropan-1, 3' -indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (30 mg,0.05 mmol) was dissolved in ethanol (1 mL), and a dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto and stirred at room temperature for 3H. Concentrating under reduced pressure by rotary evaporation to obtain white solid (24mg,90.16％).¹H NMR(400MHz,CD₃OD)δ8.29(d,J＝8.7Hz,1H),8.23(s,1H),7.82–7.75(m,2H),7.30–7.22(m,1H),7.01(d,J＝8.1Hz,1H),4.44(d,J＝15.8Hz,1H),4.29(d,J＝16.1Hz,1H),3.83(s,3H),2.00–1.90(m,2H),1.37–1.25(m,2H);LC-MS:465.20[M+H]⁺.

EXAMPLE 8 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5' -fluoro-spiro [ cyclopropan-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 2- (bromomethyl) -4-fluoro-1-iodobenzene

4-Fluoro-1-iodo-2-toluene (5.00 g,21.18 mmol) was dissolved in carbon tetrachloride (40 mL), N-bromosuccinimide (4.52 g,25.42 mmol) was added and reacted with azobisisobutyronitrile (1.04 g,6.35 mmol) with stirring at 80℃for 21.5h. The solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane (30 mL), washed with water (30 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was purified by column chromatography over silica gel (eluent: PE) after concentration under reduced pressure to give a white solid product (2.00g,30％).¹H NMR(400MHz,CDCl₃)δ7.85–7.77(m,1H),7.27–7.22(m,1H),6.83–6.74(m,1H),4.58–4.53(m,2H).

Step 2 Synthesis of 2- (5-fluoro-2-iodophenyl) acetonitrile

2- (Bromomethyl) -4-fluoro-1-iodobenzene (3.12 g,9.91 mmol), trimethylcyanosilane (1.28 g,12.88 mmol) and potassium carbonate (1.78 g,12.88 mmol) were dissolved in acetonitrile (30 mL) and the reaction stirred at 60 ℃. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined and washed with saturated brine (50 ml×2), the organic phases were dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give a white solid product (1.70 g, 66%).

Step 3 Synthesis of 1- (5-fluoro-2-iodophenyl) cyclopropane-1-carbonitrile

2- (5-Fluoro-2-iodophenyl) acetonitrile (1.70 g,6.51 mmol), potassium hydroxide (3.65 g,65.10 mmol) and tetrabutylammonium bromide (100 mg,0.33 mmol) were dissolved in water (10 mL), 1,2 dibromoethane (2.45 g,13.02 mmol) was added under stirring at 70℃under nitrogen protection, and the reaction was continued with stirring at temperature for 20h. The reaction was stopped, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow solid product (1.59 g, 85%). LC-MS 288.00[ M+H ] ⁺.

Step 4 Synthesis of 1- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (5-Fluoro-2-iodophenyl) cyclopropane-1-carbonitrile (500 mg,1.74 mmol), 1-methyl-5-aminopyrazole (190 mg,1.91 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (200 mg,0.35 mmol), palladium acetate (39 mg,0.17 mmol) and cesium carbonate (1.13 g,3.48 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring at 140℃under nitrogen blanket under microwave conditions for 4h. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (420 mg, 94%). LC-MS 257.20[ M+H ] ⁺.

Step 5 Synthesis of 1- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (5-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (420 mg,1.64 mmol) and potassium hydroxide (1.84 g,32.80 mmol) were dissolved in a mixed solvent of water (8 mL) and ethylene glycol (8 mL), and reacted under stirring at 140℃for 4 hours under nitrogen. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10 mL), ph=6 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a yellow solid product (280 mg, 62%). LC-MS 276.20[ M+H ] ⁺.

Step 6 Synthesis of 5 '-fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (5-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (280 mg,1.02 mmol), N-carbonyldiimidazole (250 mg,1.53 mmol) and N, N-diisopropylethylamine (260 mg,2.04 mmol) were dissolved in dichloromethane (10 mL) and the reaction was stirred at room temperature. The reaction was stopped, the reaction mixture was diluted with dichloromethane (20 mL) and washed with dilute hydrochloric acid (1 m,10 mL) and saturated brine (10 mL) in this order, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (eluent: PE/EA (v/v) =1/1) to give the product as a colourless oil (162 mg, 62%). LC-MS 258.15[ M+H ] ⁺.

Step 7 Synthesis of 5 '-fluoro-1' - (4-iodo-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

5 '-Fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (162 mg,0.63 mmol) and N-iodosuccinimide (170 mg,0.76 mmol) were dissolved in acetic acid (20 mL), and the reaction was stirred at room temperature. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product as a yellow solid (200 mg, 83%). LC-MS 384.30[ M+H ] ⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (5 '-fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

5' -Fluoro-1 ' - (4-iodo-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indolin ] -2' -one (100 mg,0.26 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridazin-1-yl) methyl) carbamic acid tert-butyl ester (160 mg,0.39 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (25 mg,0.04 mmol) and sodium carbonate (55 mg,0.52 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (8 mL) and water (2 mL) and reacted overnight under stirring under nitrogen protection at 80 ℃. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4) to give a white solid product (45 mg, 33%). LC-MS 531.30[ M+H ] ⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5' -fluoro-spiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (5 '-fluoro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (45 mg,0.09 mmol) was dissolved in methanol (4 mL), and a1, 4-dioxane solution (4 m,5 mL) of hydrogen chloride was added thereto to stir the reaction at room temperature for 1H. Concentrating under reduced pressure to obtain pale yellow solid product (39mg,98％).¹H NMR(400MHz,DMSO-d₆)δ12.87(s,1H),8.57–8.46(m,2H),8.43(s,1H),8.17(d,J＝8.3Hz,1H),7.84–7.64(m,2H),7.30–7.17(m,1H),7.01–6.86(m,1H),6.60–6.47(m,1H),4.31(d,J＝16.7Hz,1H),4.03(d,J＝16.1Hz,1H),3.72(s,3H),1.82(s,2H),1.23(s,2H);LC-MS:431.50[M+H-HCl]⁺.

EXAMPLE 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5' -chlorospiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 2- (bromomethyl) -4-chloro-1-iodobenzene

4-Chloro-1-iodo-2-methylbenzene (5.00 g,19.80 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (4.23 g,23.76 mmol) was added and reacted with azobisisobutyronitrile (0.98 g,5.94 mmol) under stirring at 80℃for 40h. The solvent was removed by concentration under reduced pressure, and the residue was dissolved with dichloromethane (30 mL), washed with water (30 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, and the organic phase was purified by column chromatography (eluent: PE) after concentration under reduced pressure to give the product (1.60 g, 24%) as a violet oil.

Step 2 Synthesis of 2- (5-chloro-2-iodophenyl) acetonitrile

2- (Bromomethyl) -4-chloro-1-iodobenzene (1.60 g,4.83 mmol), trimethylcyanosilane (0.62 g,6.28 mmol) and potassium carbonate (0.87 g,6.28 mmol) were dissolved in acetonitrile (20 mL) and reacted at 65℃with stirring for 5.5h. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (PE/EA (v/v) =10/1) to give a white solid product (0.80g,60％).¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝8.4Hz,1H),7.56(q,J＝3.0Hz,1H),7.12–7.04(m,1H),3.81(s,2H).

Step 3 Synthesis of 1- (5-chloro-2-iodophenyl) cyclopropane-1-carbonitrile

2- (5-Chloro-2-iodophenyl) acetonitrile (0.75 g,2.70 mmol), potassium hydroxide (1.51 g,27.00 mmol) and tetrabutylammonium bromide (44 mg,0.14 mmol) were dissolved in water (10 mL), and 1,2 dibromoethane (1.01 g,5.40 mmol) was added to the reaction solution under stirring at 70℃under nitrogen protection, and the reaction was continued under stirring at temperature for 34 hours. The reaction was stopped, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), the organic phases were dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow solid product (643 mg, 78%). LC-MS 304.00[ M+H ] ⁺.

Step 4 Synthesis of 1- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (5-Chloro-2-iodophenyl) cyclopropane-1-carbonitrile (643 mg,2.12 mmol), 1-methyl-5-aminopyrazole (230 mg,2.33 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (250 mg,0.42 mmol), palladium acetate (48 mg,0.21 mmol) and cesium carbonate (1.38 g,4.24 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted overnight under stirring under nitrogen at 100 ℃. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phases were dried over anhydrous sodium sulfate, and the organic phases were purified by column chromatography over silica gel (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (372 mg, 64%). LC-MS 273.30[ M+H ] ⁺.

Step 5 Synthesis of 1- (5-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (5-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (372 mg,1.36 mmol) and potassium hydroxide (1.53 g,27.20 mmol) were dissolved in a mixed solvent of water (8 mL) and ethylene glycol (8 mL), and reacted under stirring at 140℃for 4 hours under nitrogen. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10 mL), ph=6 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid product (358 mg, 90%). LC-MS 292.30[ M+H ] ⁺.

Step 6 Synthesis of 5 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (5-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (356 mg,1.23 mmol), N-carbonyldiimidazole (300 mg,1.84 mmol) and N, N-diisopropylethylamine (320 mg,2.46 mmol) were dissolved in dichloromethane (10 mL), and the reaction was stirred at room temperature. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: PE/EA (v/v) =1/1) to give the product as a yellow oil (281mg, 84%). LC-MS 274.30[ M+H ] ⁺.

Step 7 Synthesis of 5 '-chloro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

The compound 5 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (279 mg,1.00 mmol) and N-iodosuccinimide (270 mg,1.20 mmol) were dissolved in acetic acid (24 mL) and the reaction was stirred at room temperature. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the product as a yellow solid (387 mg, 96%). LC-MS 400.20[ M+H ] ⁺.

Step 8 Synthesis of tert-butyl((7- (5 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

5' -Chloro-1 ' - (4-iodo-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indolin ] -2' -one (300 mg,0.75 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridazin-1-yl) methyl) carbamic acid tert-butyl ester (450 mg,1.13 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (73 mg,0.11 mmol) and sodium carbonate (159 mg,1.50 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (5 mL) and reacted overnight under stirring under nitrogen protection at 80 ℃. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4) to give a pale yellow solid product (221 mg, 54%). LC-MS 547.20[ M+H ] ⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5' -chlorospiro [ cyclopropane-1, 3 '-indoline ] -2' -one hydrochloride

The compound ((7- (5 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (221 mg,0.40 mmol) was dissolved in methanol (8 mL), and a 1, 4-dioxane solution of hydrogen chloride (4 m,14 mL) was added thereto, and the reaction was stirred at room temperature for 1.5H. The reaction solution is decompressed and concentrated to obtain a pale yellow solid product (180mg,100％).¹H NMR(400MHz,DMSO-d₆)δ12.88(s,1H),8.57–8.51(m,2H),8.44(s,1H),8.17(d,J＝8.4Hz,1H),7.77(s,1H),7.71(d,J＝8.3Hz,1H),7.43–7.40(m,1H),7.22–7.16(m,1H),6.56(d,J＝8.4Hz,1H),4.41–4.30(m,1H),4.14–4.05(m,1H),3.72(s,3H),2.12–1.96(m,2H),1.89–1.74(m,2H);LC-MS:447.40[M+H]⁺.

EXAMPLE 10 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -chlorospiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 2- (bromomethyl) -1-chloro-3-iodobenzene

1-Chloro-3-iodo-2-methylbenzene (2.50 g,9.90 mmol) was dissolved in carbon tetrachloride (20 mL), N-bromosuccinimide (1.94 g,10.89 mmol) was added and reacted with benzoyl peroxide (320 mg,0.99 mmol) under stirring at 90℃for 37 hours. The solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane (30 mL), washed with water (30 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (eluent: PE) to give the product as a white solid (2.17 g, 56%).

Step 2 Synthesis of 2- (2-chloro-6-iodophenyl) acetonitrile

2- (Bromomethyl) -1-chloro-3-iodobenzene (2.17 g,6.55 mmol), trimethylcyanosilane (0.78 g,7.86 mmol) and potassium carbonate (1.09 g,7.86 mmol) were dissolved in acetonitrile (20 mL) and the reaction stirred at 60 ℃. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined and washed with saturated brine (50 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown liquid product (1.70 g, 94%).

Step 3 Synthesis of 1- (2-chloro-6-iodophenyl) cyclopropane-1-carbonitrile

2- (2-Chloro-6-iodophenyl) acetonitrile (1.72 g,6.20 mmol), potassium hydroxide (3.48 g,62.00 mmol) and tetrabutylammonium bromide (100 mg,0.31 mmol) were dissolved in water (5 mL), 1,2 dibromoethane (2.33 g,12.40 mmol) was added under stirring at 70℃under nitrogen protection, and the reaction was continued with stirring at temperature for 19h. The reaction was stopped, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), the organic phases were dried over anhydrous sodium sulfate, and the organic phases were concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow solid product (1.24g,66％).LC-MS:304.25[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.88–7.84(m,1H),7.48–7.41(m,1H),6.99(t,J＝8.0Hz,1H),2.17–1.92(m,2H),1.55–1.38(m,2H).

Step 4 Synthesis of 1- (2-chloro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (2-Chloro-6-iodophenyl) cyclopropane-1-carbonitrile (500 mg,1.65 mmol), 1-methyl-5-aminopyrazole (180 mg,1.81 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (190 mg,0.33 mmol), palladium acetate (37 mg,0.17 mmol) and cesium carbonate (1.08 g,3.30 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring at 140℃under nitrogen blanket under microwave conditions for 4h. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined and washed with saturated brine (20 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (320mg,71％).¹H NMR(400MHz,CDCl₃)δ7.72–7.66(m,1H),7.07(t,J＝8.0Hz,1H),6.98–6.87(m,1H),6.42(d,J＝7.8Hz,1H),6.37–6.32(m,1H),3.71(s,3H),2.42–2.36(m,2H),1.62–1.50(m,2H);LC-MS:273.30[M+H]⁺.

Step 5 Synthesis of 1- (2-chloro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (2-Chloro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (300 mg,1.10 mmol) and sodium hydroxide (1.32 g,33.00 mmol) were dissolved in a mixed solvent of water (6 mL) and methanol (9 mL), and reacted under stirring at 100℃for 20.5 hours under nitrogen. The reaction was stopped, the solvent was removed by concentration under reduced pressure, the residue was diluted with water (10 mL), ph=2 was adjusted with 2M hydrochloric acid, extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give a yellow solid product (320 mg, 100%). LC-MS 292.10[ M+H ] ⁺.

Step 6 Synthesis of 4 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (2-Chloro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (320 mg,1.10 mmol), N-carbonyldiimidazole (270 mg,1.65 mmol) and N, N-diisopropylethylamine (280 mg,2.20 mmol) were dissolved in dichloromethane (5 mL) and the reaction was stirred at room temperature. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: PE/EA (v/v) =5/1) to give the product as a colourless oil (52 mg, 17%). LC-MS 274.30[ M+H ] ⁺.

Step 7 Synthesis of 4 '-chloro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

4 '-Chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (54 mg,0.20 mmol) and N-iodosuccinimide (45 mg,0.20 mmol) were dissolved in acetic acid (15 mL), and the reaction was stirred at room temperature. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product as a colourless oil (73 mg, 93%). LC-MS 400.30[ M+H ] ⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (4 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

4' -Chloro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (73 mg,0.18 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (110 mg,0.27 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (18 mg,0.03 mmol) and sodium carbonate (38 mg,0.36 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (2 mL) and reacted under 80 ℃ microwave conditions under nitrogen protection for 3H. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4) to give a white solid product (49 mg, 49%). LC-MS 547.18[ M+H ] ⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -chlorospiro [ cyclopropane-1, 3 '-indoline ] -2' -one hydrochloride

The compound ((7- (5- (4 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (49 mg,0.09 mmol) was dissolved in methanol (3 mL), and a1, 4-dioxane solution (4 m,5 mL) of hydrogen chloride was added thereto, and the reaction was stirred at room temperature for 1H. Concentrating under reduced pressure to obtain pale yellow solid product (40mg,92％).¹H NMR(400MHz,DMSO-d₆)δ12.88(s,1H),8.58–8.47(m,2H),8.42(s,1H),8.19(d,J＝8.3Hz,1H),7.83(s,1H),7.67(d,J＝8.2Hz,1H),7.22–7.07(m,2H),6.55(d,J＝6.4Hz,1H),4.44–4.34(m,1H),4.28–4.14(m,1H),3.73(s,3H),2.44–2.38(m,2H),1.78–1.70(m,2H);LC-MS:447.20[M-HCl+H]⁺.

EXAMPLE 11 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -fluoro-spiro [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (2-fluoro-6-iodophenyl) methanol

2-Fluoro-6-iodobenzoic acid (4.0 g,15.40 mmol) was dissolved in borane tetrahydrofuran complex (38 mL,1mol/L in THF) and stirred overnight at room temperature. The reaction was stopped, the reaction mixture was slowly dropped into methanol (50 mL), concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow solid (3.79 g, 100%). Step 2 Synthesis of 2-fluoro-6-iodobenzyl methanesulfonate

(2-Fluoro-6-iodophenyl) methanol (1.50 g,5.95 mmol) and N, N-diisopropylethylamine (2.31 g,17.80 mmol) were dissolved in dichloromethane (20 mL), methanesulfonyl chloride (0.89 g,7.74 mmol) was added under ice-bath, and the mixture was transferred to room temperature and stirred for 3h. The reaction solution was diluted with water (10 mL), ph=6 was adjusted with dilute hydrochloric acid (1M), the solution was separated, washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (PE/EA (v/v) =10/1) to give a white solid product (1.10 g, 56%).

Step 3 Synthesis of 2- (2-fluoro-6-iodophenyl) acetonitrile

2-Fluoro-6-iodobenzyl methanesulfonate (1.10 g,3.33 mmol), cyanotrimethylsilane (0.40 g,4.00 mmol) and potassium carbonate (0.55 g,4.00 mmol) were dissolved in acetonitrile (10 mL) and the reaction stirred at 50℃overnight. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the combined organic phases were washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and purified by column chromatography (PE/EA (v/v) =10/1) to give the product as a white solid (0.87 g, 100%).

Step 4 Synthesis of 1- (2-fluoro-6-iodophenyl) cyclopentane-1-carbonitrile

Sodium hydrogen (270 mg,6.69 mmol) was dissolved in N, N-dimethylformamide (12 mL), and 2- (2-fluoro-6-iodophenyl) acetonitrile (583 mg,2.23 mmol) was slowly added under ice-bath, followed by stirring for 30min, 1, 4-dibromobutane (580 mg,2.68 mmol) and stirring at room temperature for 2h. Quench the reaction with water (20 mL), extract with ethyl acetate (20 ml×2), wash the combined organic phases with saturated brine (20 mL), dry the organic phases over anhydrous sodium sulfate, filter and purify by column chromatography (eluent: PE/EA (v/v) =20/1) to give the product as a colourless oil (405 mg, 58%). LC-MS 316.05[ M+H ] ⁺.

Step 5 Synthesis of 1- (2-fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile

1- (2-Fluoro-6-iodophenyl) cyclopentane-1-carbonitrile (645 mg,2.05 mmol), 1-methyl-5-aminopyrazole (220 mg,2.25 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (240 mg,0.41 mmol), palladium acetate (46 mg,0.20 mmol) and cesium carbonate (1.34 g,4.10 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted overnight under stirring under nitrogen at 100 ℃. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (474 mg, 81%). LC-MS 285.20[ M+H ] ⁺.

Step 6 Synthesis of 4 '-fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

1- (2-Fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile (470 mg,1.67 mmol) and sodium hydroxide (1.87 g,33.40 mmol) were dissolved in a mixed solvent of water (8 mL) and methanol (8 mL), and reacted under stirring at 140℃for 4 hours under nitrogen. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10 mL), ph=6 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (10 ml×3), the organic phases were combined and washed with saturated brine (10 ml×2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a brown oil (330 mg, 70%). LC-MS 286.10[ M+H ] ⁺.

Step 7 Synthesis of 4 '-fluoro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

4 '-Fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (330 mg,1.16 mmol) and N-iodosuccinimide (290 mg,1.28 mmol) were dissolved in acetic acid (20 mL) and the reaction was stirred at room temperature for 1.5H. The solvent was removed by concentration under reduced pressure, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product (400 mg, 84%) as a colorless oil. LC-MS 412.05[ M+H ] ⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (4 '-fluoro-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

4' -Fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2' -one (200 mg,0.49 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridazin-1-yl) methyl) carbamic acid tert-butyl ester (290 mg,0.73 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (48 mg,0.07 mmol) and sodium carbonate (104 mg,0.98 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (5 mL) and reacted overnight under stirring at 80℃under nitrogen protection. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product (129 mg, 47%) as a pale yellow solid by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/3). LC-MS 559.25[ M+H ] ⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -fluoro-spiro [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (4 '-fluoro-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (100 mg,0.18 mmol) was dissolved in methanol (4 mL), and a1, 4-dioxane solution (4 m,10 mL) of hydrogen chloride was added thereto to stir the reaction at room temperature for 1.5H. Concentrating under reduced pressure to obtain pale yellow solid product (89mg,100％).¹H NMR(400MHz,DMSO-d₆)δ12.89(s,1H),8.57–8.52(m,2H),8.43(s,1H),8.19(d,J＝8.3Hz,1H),7.91(s,1H),7.59(d,J＝8.3Hz,1H),7.32–7.16(m,1H),7.00(t,J＝9.1Hz,1H),6.38(d,J＝7.8Hz,1H),4.44–4.20(m,2H),3.72(s,3H),2.31–2.09(m,4H),2.00(s,4H);LC-MS:459.20[M+H-HCl]⁺.

EXAMPLE 12 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indoline ] -2' -one hydrochloride

Step 1 Synthesis of 2- (2-iodophenyl) acetonitrile

1- (Bromomethyl) -2-iodobenzene (4.0 g,13.47 mmol), cyanotrimethylsilane (1.6 g,16.16 mmol) and potassium carbonate (2.23 g,16.16 mmol) were dissolved in acetonitrile (30 mL) and reacted at 60℃with stirring for 6h. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined and washed with saturated brine (50 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown liquid product (3.17 g, 97%).

Step 2 Synthesis of 1- (2-iodophenyl) cyclobutane-1-carbonitrile

Sodium hydrogen (1.3 g,32.60 mmol) was dissolved in N, N-dimethylformamide (30 mL), 2- (2-iodophenyl) acetonitrile (3.2 g,13.04 mmol) was slowly added under ice bath, and after stirring for 30 minutes, 1, 3-dibromopropane (2.63 g,13.04 mmol) was added and the reaction stirred at room temperature. The reaction was stopped, quenched with water (100 mL), the reaction was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined and washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography (eluent: PE/EA (v/v) =10/1) to give the product as a white solid (0.6 g, 16%). LC-MS 284.00[ M+H ] ⁺.

Step 3 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclobutane-1-carbonitrile

1- (2-Iodophenyl) cyclobutane-1-carbonitrile (220 mg,0.78 mmol), 1-methyl-5-aminopyrazole (83 mg,0.86 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (90 mg,0.16 mmol), palladium acetate (18 mg,0.08 mmol) and cesium carbonate (510 mg,1.56 mmol) were dissolved in 1, 4-dioxane (6 mL) and the reaction stirred under nitrogen under microwave conditions at 140 ℃. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (188mg,96％).¹H NMR(599MHz,DMSO-d₆)δ7.72–7.64(m,1H),7.63–7.53(m,1H),7.20–7.15(m,1H),7.08–7.01(m,1H),6.51–6.25(m,2H),3.57(s,3H),2.68–2.55(m,2H),2.44–2.08(m,4H);LC-MS,:253.40[M+H]⁺.

Step4 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclobutane-1-carboxylic acid

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) phenyl) cyclobutane-1-carbonitrile (188 mg,0.75 mmol) and sodium hydroxide (600 mg,15.00 mmol) were dissolved in a mixed solvent of water (4 mL) and methanol (6 mL), and reacted under stirring at 100℃under nitrogen. The reaction was stopped, the solvent was removed by concentration under reduced pressure, the mixture was diluted with water (10 mL), ph=2 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated brine (20 ml×2), the organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a brown oil (166 mg, 82%). LC-MS272.15[ M+H ] ⁺.

Step 5 Synthesis of 1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indoline ] -2' -one

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) phenyl) cyclobutane-1-carboxylic acid (166 mg,0.61 mmol), N-carbonyldiimidazole (150 mg,0.92 mmol) and N, N-diisopropylethylamine (160 mg,1.22 mmol) were dissolved in dichloromethane (5 mL) and the reaction was stirred at room temperature. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluent: PE/EA (v/v) =3/1) to give the product as a colourless oil (166 mg, 82%). LC-MS 254.35[ M+H ] ⁺.

Step 6 Synthesis of 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indoline ] -2' -one

1' - (1-Methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indolin ] -2' -one (60 mg,0.24 mmol) and N-iodosuccinimide (54 mg,0.24 mmol) were dissolved in acetic acid (12 mL), and the reaction was stirred at room temperature. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product as a colourless oil (90 mg, 100%). LC-MS 380.30[ M+H ] ⁺.

Step 7 Synthesis of tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclobutane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) carbamate

1'- (4-Iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indolin ] -2 '-one (88 mg,0.23 mmol), ((4-oxo-7- (4, 5-dioxaborolan-2-yl) -3, 4-dihydropyridazin-1-yl) methyl) carbamic acid tert-butyl ester (140 mg,0.35 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (22 mg,0.04 mmol) and sodium carbonate (49 mg,0.46 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL) and reacted under stirring under nitrogen protection, microwave conditions at 80 ℃. The reaction was stopped, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a colorless oil (45 mg, 37%) which was purified by column chromatography (eluent: PE/EA (v/v) =1/4). LC-MS 527.50[ M+H ] ⁺.

Step 8 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclobutane-1, 3' -indoline ] -2' -one hydrochloride

Tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclobutane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (45 mg,0.09 mmol) was dissolved in methanol, and a1, 4-dioxane solution (4 m,4 ml) of hydrogen chloride was added thereto to stir the reaction at room temperature for 2 hours. Concentrating under reduced pressure to obtain pale yellow solid product (30mg,82％).¹H NMR(600MHz,DMSO-d₆)δ12.86(s,1H),8.55(s,3H),8.44(s,1H),8.13(d,J＝8.4Hz,1H),7.87–7.77(m,2H),7.62(dd,J＝8.4,1.3Hz,1H),7.25–7.14(m,2H),6.45(d,J＝7.3Hz,1H),4.34–4.24(m,1H),4.13–4.04(m,1H),3.73–3.69(m,3H),2.63–2.56(m,3H),2.36–2.18(m,2H);LC-MS:427.20[M+H-HCl]⁺.

EXAMPLE 13 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

Step 1 Synthesis of 2- (2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) acetic acid

O-iodophenylacetic acid (2.97 g,11.33 mmol), 1-methyl-5-aminopyrazole (1.00 g,10.30 mmol), cuprous iodide (0.39 g,2.06 mmol) and potassium carbonate (2.85 g,20.6 mmol) were dissolved in DMF (10 mL) and stirred under nitrogen at 100℃for 1h. Ethanol (50 mL) was added to dilute, the solid was filtered off through celite, the filtrate was adjusted to ph=4 with 1, 4-dioxane solution of hydrogen chloride (4M), the solid was removed by filtration, and the solvent was concentrated under reduced pressure to give a yellow oil (1.94 g, 81.48%). LC-MS 232.20[ M+H ] ⁺.

Step 2 Synthesis of 1- (1-methyl-1H-pyrazol-5-yl) indol-2-one

2- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) phenyl) acetic acid (500 mg,2.16 mmol) and N, N-carbonyldiimidazole (0.39 g,2.38 mmol) were dissolved in dichloromethane (10 mL), and stirred at room temperature for 12H. The reaction solution was diluted with dichloromethane (50 mL), washed with water (30 ml×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =4/1) to give a yellow solid (0.32g,69.62％).¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝1.9Hz,1H),7.32(d,J＝7.4Hz,1H),7.23(d,J＝7.7Hz,1H),7.11(t,J＝7.5Hz,1H),6.66(d,J＝7.9Hz,1H),6.30(d,J＝1.9Hz,1H),3.75(s,3H),3.74(s,2H);LC-MS:214.20[M+H]⁺.

Step 3 Synthesis of 1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

1- (1-Methyl-1H-pyrazol-5-yl) indol-2-one (250 mg,1.17 mmol), 1, 4-dibromobutane (0.38 g,1.75 mmol), potassium hydroxide (0.39 g,7.02 mmol) and tetrabutylammonium bromide (0.38 g,1.17 mmol) were dissolved in water (5 mL), and stirred at 50℃for 1H. Dilute with ethyl acetate (50 mL), wash with saturated brine (30 ml×3), dry over anhydrous sodium sulfate, spin-evaporate the concentrated solvent under reduced pressure, and purify the residue by silica gel column chromatography (eluent: PE/EtOAc (v/v) =5/1) to give a yellow solid (0.15g,47.86％).¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝1.8Hz,1H),7.27(d,J＝7.8Hz,1H),7.23–7.17(m,1H),7.12(t,J＝7.4Hz,1H),6.67(d,J＝7.7Hz,1H),6.31(d,J＝1.8Hz,1H),3.71(s,3H),2.32–2.23(m,2H),2.16–2.06(m,2H),2.06–1.94(m,4H);LC-MS:268.13[M+H]⁺.

Step 4 Synthesis of 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

1' - (1-Methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one (150 mg,0.56 mmol) and N-iodosuccinimide (140 mg,0.56 mmol) were dissolved in acetic acid (20 mL), and stirred at room temperature for 1H. The reaction was quenched with saturated sodium bisulphite solution, concentrated under reduced pressure to remove acetic acid, the concentrate was diluted with ethyl acetate (50 mL), the organic phase was washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure to give a yellow solid (170mg,77.05％).¹H NMR(400MHz,CDCl₃)δ7.65(s,1H),7.30(d,J＝7.4Hz,1H),7.24–7.18(m,1H),7.17–7.11(m,1H),6.53(d,J＝7.6Hz,1H),3.77(s,3H),2.37–2.25(m,2H),2.18–2.09(m,2H),2.09–1.95(m,4H);LC-MS:394.10[M+H]⁺.

Step 5 Synthesis of tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclopentane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1'- (4-Iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2 '-one (100 mg,0.25 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (150 mg,0.38 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (16 mg,0.03 mmol) and sodium carbonate (53 mg,0.50 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection, microwave conditions at 80 ℃ for 4H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =30/1) to give a yellow solid (61mg,44.37％).¹H NMR(400MHz,CDCl₃)δ10.28(s,1H),8.25(d,J＝8.4Hz,1H),8.07(s,1H),7.93(s,1H),7.57(d,J＝8.2Hz,1H),7.37–7.28(m,1H),7.17–7.08(m,2H),6.48–6.39(m,1H),5.27(s,1H),4.48(s,2H),3.77(s,3H),2.37–2.19(m,2H),2.19–2.03(m,6H),1.48(s,9H);LC-MS:541.50[M+H]⁺.

Step 6 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

Tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclopentane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (60 mg,0.11 mmol) was dissolved in dichloromethane (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto and stirred at room temperature for 3H. The reaction solution was diluted with dichloromethane (50 mL) and water (30 mL), ph=9 was adjusted with sodium hydroxide (1M) solution, the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a yellow solid (31mg,63.41％).¹H NMR(400MHz,CDCl₃)δ8.28(d,J＝8.2Hz,1H),8.00(s,1H),7.69(d,J＝8.1Hz,1H),7.61(s,1H),7.38–7.31(m,1H),7.18–7.10(m,2H),6.51–6.42(m,1H),3.76(s,3H),3.79–3.70(m,2H),2.35–2.18(m,2H),2.16–2.02(m,6H);LC-MS:441.50[M+H]⁺.

EXAMPLE 14 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chloro-7 ' -fluoro-spiro [ cyclopentane-1, 3' -indolin ] -2' -one hydrochloride

Step 1 Synthesis of 1- (4-chloro-3-fluoro-2-iodophenyl) cyclopentane-1-carbonitrile

A mixture of 2- (4-chloro-3-fluoro-2-iodophenyl) acetonitrile (1.00 g,3.38 mmol), 1, 2-dibromobutane (1.46 g,6.76 mmol), potassium hydroxide (1.14 g,20.28 mmol), tetrabutylammonium bromide (1.09 g,3.38 mmol) and water (10 mL) was stirred at 50℃for 1h. Ethyl acetate (100 mL) was added to the reaction mixture to dilute it, the mixture was washed with saturated brine (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow solid (567mg,47.93％).¹H NMR(400MHz,CDCl₃)δ7.42–7.36(m,1H),7.14–7.08(m,1H),2.20–2.10(m,2H),2.10–1.99(m,3H),1.98–1.84(m,3H);GC-MS:349.0[M]⁺.

Step 2 Synthesis of 1- (4-chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile

1- (4-Chloro-3-fluoro-2-iodophenyl) cyclopentane-1-carbonitrile (550 mg,1.57 mmol), 1-methyl-5-aminopyrazole (170 mg,1.73 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (91 mg,0.16 mmol), palladium acetate (18 mg,0.08 mmol) and cesium carbonate (1.02 g,3.14 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute it, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow viscous liquid (203mg,40.47％).¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝1.8Hz,1H),7.00(dd,J＝8.0,6.2Hz,1H),6.94(d,J＝8.1Hz,1H),6.29(d,J＝1.9Hz,1H),3.67(s,3H),2.14–1.87(m,8H);LC-MS:319.20[M+H]⁺.

Step 3 Synthesis of 1- (4-chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carboxylic acid

1- (4-Chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile (180 mg,0.56 mmol) and potassium hydroxide (190 mg,3.36 mmol) were dissolved in a mixed solvent of ethanol (2 mL) and water (2 mL), and stirred at 140℃for 4H. The ph=4 was adjusted with 1, 4-dioxane solution of hydrogen chloride (4M), the solvent was concentrated by rotary evaporation under reduced pressure, ethanol (20 mL) was added to the residue, the solid was filtered off, and the solvent was concentrated by rotary evaporation under reduced pressure from the filtrate to give a yellow liquid (202 mg, 100%). LC-MS 338.20[ M+H ] ⁺.

Step 4 Synthesis of 6' -chloro-7 ' -fluoro-1 ' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

1- (4-Chloro-3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carboxylic acid (170 mg,0.50 mmol) and N, N-carbonyldiimidazole (0.32 g,2.00 mmol) were dissolved in dichloromethane (5 mL), and stirred at room temperature for 2H. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (30 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =4/1) to give a yellow solid (127mg,78.92％).¹H NMR(400MHz,CDCl₃)δ7.57(d,J＝2.0Hz,1H),7.14(dd,J＝8.0,6.3Hz,1H),6.99(d,J＝8.1Hz,1H),6.30(d,J＝1.9Hz,1H),3.72(s,3H),2.27(d,J＝12.8,7.2Hz,2H),2.16–2.08(m,2H),2.03–1.92(m,4H);LC-MS:320.15[M+H]⁺.

Step 5 Synthesis of 6' -chloro-7 ' -fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indoline ] -2' -one

6' -Chloro-7 ' -fluoro-1 ' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2' -one (125 mg,0.39 mmol) and N-iodosuccinimide (176 mg,0.78 mmol) were dissolved in acetic acid (20 mL), and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding dichloromethane (100 mL) for dilution, washing the organic phase with water (50 mL×3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow solid (156mg,89.54％).¹H NMR(400MHz,CDCl₃)δ7.60(s,1H),7.16(dd,J＝8.0,6.4Hz,1H),7.01(d,J＝8.1Hz,1H),3.81(s,3H),2.40–2.24(m,2H),2.16–1.94(m,6H);LC-MS:446.30[M+H]⁺.

Step 6 Synthesis of tert-butyl 7- (5- (6 ' -chloro-7 ' -fluoro-2 ' -oxospiro [ cyclopentane-1, 3' -indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

Tert-butyl 6 '-chloro-7' -fluoro-1 '- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2 '-one (160 mg,0.36 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (21 mg,0.54 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (24 mg,0.04 mmol) and sodium carbonate (76 mg,0.72 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80 ℃ for 4H under microwave conditions. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (28mg,13.11％).¹H NMR(400MHz,CDCl₃)δ11.19(s,1H),8.28(d,J＝8.3Hz,1H),8.01(s,1H),7.97(s,1H),7.52(d,J＝8.2Hz,1H),7.14(dd,J＝8.0,6.4Hz,1H),7.03(d,J＝8.1Hz,1H),5.43(s,1H),4.68–4.46(m,2H),3.78(s,3H),2.36–2.18(m,2H),2.17–1.98(m,6H),1.46(s,9H);LC-MS:593.20[M+H]⁺.

Step 7 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6' -chloro-7 ' -fluoro-spiro [ cyclopentane-1, 3' -indolin ] -2' -one hydrochloride

Tert-butyl (7- (5- (6 ' -chloro-7 ' -fluoro-2 ' -oxospiro [ cyclopentane-1, 3' -indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (26 mg,0.04 mmol) was dissolved in ethanol (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto and stirred at room temperature for 3H. Concentrating under reduced pressure by rotary evaporation to obtain white solid (24mg,90.48％).¹H NMR(400MHz,CD₃OH)δ8.27(d,J＝8.4Hz,1H),8.19(s,1H),7.87(s,1H),7.67(d,J＝9.4Hz,1H),7.29(d,J＝2.3Hz,2H),3.80(s,3H),3.76–3.71(m,1H),3.69–3.65(m,1H),2.37–2.26(m,1H),2.21–2.05(m,7H);LC-MS:493.40[M+H]⁺.

EXAMPLE 15 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indoline ] -2' -one hydrochloride

Step 1 Synthesis of 1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indoline ] -2' -one

1- (1-Methyl-1H-pyrazol-5-yl) indol-2-one (200 mg,0.94 mmol), 1, 5-dibromopentane (0.32 g,1.41 mmol), potassium hydroxide (0.32 g,5.64 mmol) and tetrabutylammonium bromide (0.30 g,0.94 mmol) were dissolved in water (5 mL), and stirred at 50℃for 1H. Dilute with ethyl acetate (50 mL) and wash with saturated brine (30 ml×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (185mg,70.11％).¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝2.0Hz,1H),7.50(d,J＝7.4Hz,1H),7.25–7.19(m,1H),7.15–7.09(m,1H),6.69(d,J＝7.7Hz,1H),6.31(d,J＝1.9Hz,1H),3.69(s,3H),2.06–1.87(m,4H),1.83–1.64(m,6H);LC-MS:282.20[M+H]⁺.

Step 2 Synthesis of 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indoline ] -2' -one

1' - (1-Methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indoline ] -2' -one (185 mg,0.66 mmol) and N-iodosuccinimide (156 mg,0.69 mmol) were dissolved in acetic acid (10 mL), and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding dichloromethane (50 mL) for dilution, washing the organic phase with water (30 mL×3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow solid (218mg,81.41％).¹H NMR(400MHz,CDCl₃)δ7.65(s,1H),7.52(d,J＝7.3Hz,1H),7.23(dd,J＝7.7,1.0Hz,1H),7.14(td,J＝7.6,0.9Hz,1H),6.54(d,J＝7.6Hz,1H),3.76(s,3H),2.03–1.94(m,4H),1.83–1.67(m,6H);LC-MS:408.10[M+H]⁺.

Step 3 Synthesis of tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclohexane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

Tert-butyl 1'- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2 '-one (200 mg,0.49 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (295 mg,0.73 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (32 mg,0.05 mmol) and sodium carbonate (104 mg,0.98 mmol) were added to a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80℃for 4H. The reaction solution was diluted with ethyl acetate (100 mL), the solid was filtered off, the organic phase was washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (93mg,34.14％).¹H NMR(400MHz,CDCl₃)δ10.50(s,1H),8.24(d,J＝8.3Hz,1H),8.07(s,1H),7.95(s,1H),7.61–7.52(m,2H),7.18–7.09(m,2H),6.47–6.40(m,1H),4.51(d,J＝4.6Hz,2H),3.75(s,3H),2.05–1.91(m,4H),1.86–1.66(m,6H),1.48(s,9H);LC-MS:555.30[M+H]⁺.

Step 4 Synthesis of 1' - (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indoline ] -2' -one hydrochloride

Tert-butyl ((7- (1-methyl-5- (2 ' -oxospiro [ cyclohexane-1, 3' -indoline ] -1' -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (60 mg,0.11 mmol) was dissolved in dichloromethane (1 mL), and a1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto and stirred at room temperature for 3H. Concentrating the reaction solution under reduced pressure to obtain brown solid (48mg,90.37％).¹H NMR(400MHz,Methanol-d₄)δ8.26–8.19(m,2H),7.80(s,1H),7.76–7.70(m,1H),7.68–7.61(m,1H),7.27–7.18(m,2H),6.60–6.54(m,1H),3.75(s,2H),3.65(s,3H),2.08–1.93(m,3H),1.90–1.67(m,7H);LC-MS:455.30[M-HCl+H]⁺.

EXAMPLE 16 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -1',4 '-dihydro-2' H-spiro [ cyclopropan-1, 3 '-quinolin ] -2' -one hydrochloride

Step1 Synthesis of 1- (2-iodobenzyl) cyclopropane-1-carbonitrile

Lithium diisopropylamide in tetrahydrofuran (1.5 mL, 2M) was dissolved in tetrahydrofuran (10 mL), cyclopropanecarbonitrile (170 mg,2.53 mmol) in tetrahydrofuran (5 mL) was added at-78℃and the reaction was stirred for 1h, then 2-iodobenzyl bromide (900 mg,3.04 mmol) was added and the mixture was transferred to room temperature and stirred for 2h. The reaction was stopped, diluted with water (40 mL), washed with ethyl acetate (40 mL. Times.3), the organic phases were combined and washed with saturated brine (40 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: PE) to give the product (400 mg, 56%) as a colorless oil. LC-MS 284.20[ M+H ] ⁺.

Step 2 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) benzyl) cyclopropane-1-carbonitrile

1- (2-Iodobenzyl) cyclopropane-1-carbonitrile (372 mg,1.31 mmol), 1-methyl-5-aminopyrazole (140 mg,1.44 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (150 mg,0.26 mmol), palladium acetate (29 mg,0.13 mmol) and cesium carbonate (850 mg,2.62 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring under nitrogen at 140℃under microwave conditions for 4h. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (89mg,27％).¹H NMR(400MHz,CDCl₃)δ7.67(d,J＝1.9Hz,1H),7.10(dd,J＝10.3,7.6Hz,2H),6.97(t,J＝7.0Hz,1H),6.29(d,J＝1.9Hz,1H),6.23(d,J＝8.0Hz,1H),3.57(s,3H),2.84(s,2H),1.29(s,2H),0.84–0.80(m,2H);LC-MS:253.40[M+H]⁺.

Step 3 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) benzyl) cyclopropane-1-carboxylic acid

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) benzyl) cyclopropane-1-carbonitrile (92 mg,0.36 mmol) and sodium hydroxide (430 mg,10.80 mmol) were dissolved in a mixed solvent of water (4 mL) and methanol (6 mL), and reacted under stirring at 100℃for 17.5H under nitrogen. The reaction was stopped, the reaction mixture was concentrated under reduced pressure to remove the solvent, diluted with water (10 mL), and ph=2 was adjusted with hydrochloric acid (2M), extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the product as a brown oil (90 mg, 91%). LC-MS 272.40[ M+H ] ⁺.

Step4 Synthesis of 1'- (1-methyl-1H-pyrazol-5-yl) -1',4 '-dihydro-2' H-spiro [ cyclopropane-1, 3 '-quinolin ] -2' -one

1- (2- ((1-Methyl-1H-pyrazol-5-yl) amino) benzyl) cyclopropane-1-carboxylic acid (90 mg,0.33 mmol), N-carbonyldiimidazole (80 mg,0.49 mmol) and N, N-diisopropylethylamine (85 mg,0.66 mmol) were dissolved in dichloromethane (5 mL) and the reaction was stirred at room temperature overnight. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1 m,10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (eluent: PE/EA (v/v) =5/1) to give the product as a colourless oil (34 mg, 46%). LC-MS 254.20[ M+H ] ⁺.

Step 5 Synthesis of 1'- (4-iodo-1-methyl-1H-pyrazol-5-yl) -1',4 '-dihydro-2' H-spiro [ cyclopropane-1, 3 '-quinolin ] -2' -one

1'- (1-Methyl-1H-pyrazol-5-yl) -1',4 '-dihydro-2' H-spiro [ cyclopropane-1, 3 '-quinolin ] -2' -one (38 mg,0.15 mmol) and N-iodosuccinimide (34 mg,0.15 mmol) were dissolved in acetic acid (12 mL), and the reaction was stirred at room temperature for 1H. The solvent was removed by concentration under reduced pressure, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product (50 mg, 88%) as a colorless oil. LC-MS 380.10[ M+H ] ⁺.

Step 6 Synthesis of tert-butyl ((7- (1-methyl-5- (2 ' -oxo-2 ' H-spiro [ cyclopropane-1, 3' -quinoline ] -1' (4'H) -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1' - (4-Iodo-1-methyl-1H-pyrazol-5-yl) -1',4' -dihydro-2 ' H-spiro [ cyclopropa-1, 3' -quinolin ] -2' -one (50 mg,0.13 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (78 mg,0.20 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (13 mg,0.02 mmol) and sodium carbonate (28 mg,0.26 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (6 mL) and water (2 mL) and reacted under 80 ℃ microwave conditions under nitrogen protection for 3H. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4) to give the product as a white solid (17 mg, 24%). LC-MS 527.65[ M+H ] ⁺.

Step 7 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -1',4 '-dihydro-2' H-spiro [ cyclopropan-1, 3 '-quinolin ] -2' -one hydrochloride

Tert-butyl ((7- (1-methyl-5- (2 ' -oxo-2 ' H-spiro [ cyclopropane-1, 3' -quinoline ] -1' (4'H) -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (17 mg,0.03 mmol) was dissolved in methanol (3 mL), and a1, 4-dioxane solution (4 m,3 mL) of hydrogen chloride was added thereto, and the reaction was stirred at room temperature for 1H. The reaction solution was concentrated under reduced pressure to give a pale yellow solid product (10 mg, 67%). LC-MS 427.50[ M+H-HCl ] ⁺;HRMS:427.1825[M+H-HCl]⁺.

EXAMPLE 17 Synthesis of 1' - (5- (1- (aminomethyl) -4-oxo-3, 4-dihydro-phthalazin-6-yl) pyridin-3-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

Step1 Synthesis of 1- (2-iodophenyl) cyclopropane-1-carboxylic acid

The title compound was synthesized as a yellow solid on page 62I-10 of the specification referred to CN 104736533B (2.27g,31.95％).¹H NMR(400MHz,CDCl₃)δ7.88–7.82(m,1H),7.34–7.26(m,2H),7.01–6.93(m,1H),2.02–1.72(m,2H),1.43–1.04(m,2H);LC-MS:289.05[M+H]⁺.

Step 2 Synthesis of 1' - (5-bromopyridin-3-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

A mixture of 1- (2-iodophenyl) cyclopropane-1-carboxylic acid (500 mg,1.74 mmol), 5-bromo-3-aminopyridine (450 mg,2.61 mmol), copper iodide (33 mg,0.17 mmol), potassium carbonate (480 mg,3.48 mmol) and N, N-dimethylformamide (10 mL) was stirred under nitrogen at microwave 100℃for 1h. N, N' -carbonyldiimidazole (1.13 g,6.96 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (100 mL), the organic phase was washed with water (50 ml×3), then dried over anhydrous sodium sulfate, the organic phase was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =5/1) to give a yellow solid (90mg,16.45％).¹H NMR(400MHz,CDCl₃)δ8.77–8.66(m,2H),8.04(t,J＝2.1Hz,1H),7.23(dd,J＝7.8,1.1Hz,1H),7.15–7.08(m,1H),6.99–6.91(m,2H),1.88(q,J＝4.1Hz,2H),1.66(q,J＝4.2Hz,2H);LC-MS:315.00[M+H]⁺.

Step 3 Synthesis of tert-butyl((4-oxo-6- (5- (2 ' -oxospiro [ cyclopropane-1, 3' -indoline ] -1' -yl) pyridin-3-yl) -3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1'- (5-Bromopyridin-3-yl) spiro [ cyclopropan-1, 3' -indolin ] -2 '-one (80 mg,0.25 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (151 mg,0.38 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (16 mg,0.03 mmol) and sodium carbonate (53 mg,0.50 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (1 mL) and water (0.2 mL) and stirred under nitrogen protection at 80℃for 2h. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a white solid (43mg,33.24％).¹H NMR(400MHz,CDCl₃)δ9.07–8.68(m,2H),8.53(d,J＝8.3Hz,1H),8.30(s,1H),8.19(s,1H),8.04(d,J＝8.7Hz,1H),7.23(d,J＝7.9Hz,1H),7.11(t,J＝7.5Hz,1H),7.01(d,J＝8.0Hz,1H),6.93(d,J＝7.2Hz,1H),4.68(s,2H),1.89(q,J＝4.1Hz,2H),1.67(q,J＝4.2Hz,2H),1.38(s,9H);LC-MS:510.20[M+H]⁺.

Step 4 Synthesis of 1' - (5- (1- (aminomethyl) -4-oxo-3, 4-dihydro-phthalazin-6-yl) pyridin-3-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one

Tert-butyl ((4-oxo-6- (5- (2 ' -oxospiro [ cyclopropan-1, 3' -indoline ] -1' -yl) pyridin-3-yl) -3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (45 mg,0.09 mmol) was dissolved in dichloromethane (1 mL), and a solution of 1, 4-dioxane (1 mL, 4M) of hydrogen chloride was added and stirred at room temperature for 3h. The reaction solution was diluted with dichloromethane (50 mL) and water (30 mL), ph=9 was adjusted with sodium hydroxide solution (1M), the organic phase was separated, washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a yellow solid (31mg,85.73％).¹H NMR(400MHz,DMSO-d₆)δ9.18(d,J＝1.7Hz,1H),8.81(d,J＝2.1Hz,1H),8.55–8.49(m,1H),8.41(s,1H),8.37(d,J＝8.3Hz,1H),8.32–8.25(m,1H),7.24(t,J＝7.6Hz,1H),7.17(d,J＝6.5Hz,1H),7.11(t,J＝7.3Hz,1H),6.98(d,J＝7.8Hz,1H),4.21(s,2H),1.82–1.74(m,2H),1.74–1.67(m,2H);LC-MS:410.20[M+H]⁺.

EXAMPLE 18 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -cyclopropylspiro [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 4 '-cyclopropyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

4 '-Bromo-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (100 mg,0.29mmol, see example 20, step 6), cyclopropylboronic acid (32 mg,0.36 mmol), potassium phosphate (216 mg,0.98 mmol), tricyclohexylphosphine (16 mg,0.06 mmol) and palladium acetate (6.5 mg,0.029 mmol) were dissolved in a mixed solvent of toluene (2 mL) and water (0.1 mL), and stirred under nitrogen at 110℃for 1H under microwave conditions. Ethyl acetate (100 mL) was added to the reaction mixture to dilute it, the mixture was washed with saturated brine (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =5/1) to give a yellow solid (56mg,63.07％).¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝1.9Hz,1H),7.10(t,J＝7.9Hz,1H),6.56(d,J＝8.0Hz,1H),6.46(d,J＝7.7Hz,1H),6.29(d,J＝1.9Hz,1H),3.71(s,3H),2.46–2.36(m,2H),2.24–2.15(m,4H),1.99(d,J＝10.8Hz,2H),1.31–1.21(m,1H),1.09–1.01(m,2H),0.88–0.80(m,2H);LC-MS:308.25[M+H]⁺.

Step 2 Synthesis of 4 '-cyclopropyl-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

4 '-Cyclopropyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (55 mg,0.18 mmol) and N-iodosuccinimide (45 mg,0.20 mmol) were dissolved in acetic acid (10 mL) and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution (10 mL), acetic acid was removed by concentrating under reduced pressure, dichloromethane (100 mL) was added to the concentrate, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulphate, concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (eluent: PE/EtOAc (v/v) =4/1) to give a yellow solid (78 mg, 100%). LC-MS 434.10[ M+H ] ⁺.

Step 3 Synthesis of tert-butyl ((7- (5- (4 '-cyclopropyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

4' -Cyclopropyl-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2' -one (75 mg,0.17 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (102 mg,0.26 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (11 mg,0.02 mmol) and sodium carbonate (36 mg,0.34 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80℃for 2H. The reaction solution was diluted with ethyl acetate (100 mL) and washed with water (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (30mg,29.85％).¹H NMR(400MHz,Chloroform-d)δ11.38(s,1H),8.26(d,J＝7.9Hz,1H),8.06(s,1H),7.90(s,1H),7.57(d,J＝7.9Hz,1H),7.01(t,J＝7.7Hz,1H),6.56(d,J＝7.9Hz,1H),6.22(d,J＝7.6Hz,1H),5.48–5.40(m,1H),4.51–4.38(m,2H),3.75(s,3H),2.51–2.37(m,2H),2.22–2.10(m,4H),2.00–1.94(m,2H),1.45(s,9H),1.37–1.35(m,1H),1.06(s,2H),0.88–0.79(m,2H);LC-MS:581.30[M+H]⁺.

Step 4 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -cyclopropylpara [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (4 '-cyclopropyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (20 mg, 34. Mu. Mol) was dissolved in ethanol (1 mL), and a1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto and stirred at room temperature for 3 hours. Concentrating under reduced pressure by rotary evaporation to obtain white solid (16mg,96.67％).¹H NMR(400MHz,Methanol-d₄)δ8.27–8.20(m,2H),7.82(s,1H),7.72(d,J＝8.2Hz,1H),7.09(t,J＝7.9Hz,1H),6.67(d,J＝8.0Hz,1H),6.32(d,J＝7.6Hz,1H),4.36(q,J＝16.2Hz,2H),3.75(s,3H),2.59–2.43(m,2H),2.15–2.01(m,6H),1.33–1.25(m,1H),1.13–1.06(m,2H),0.92–0.78(m,2H);LC-MS:481.20[M+H]⁺.

EXAMPLE 19 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -4' -carbonitrile hydrochloride

Step 1 Synthesis of 1'- (1-methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -4' -carbonitrile

4' -Bromo-1 ' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2' -one (100 mg,0.29 mmol), potassium ferricyanide (267 mg,0.72 mmol), XPhos G3 (25 mg,0.03 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (14 mg,0.03 mmol) and potassium acetate (71 mg,0.72 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (2 mL) and water (0.1 mL), and stirred under nitrogen for 6H at 110 ℃. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =4/1) to give a yellow solid (60mg,71.06％).¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝1.9Hz,1H),7.40–7.36(m,1H),7.30(t,J＝7.9Hz,1H),6.90–6.86(m,1H),6.31(d,J＝2.0Hz,1H),3.71(s,3H),2.38–2.22(m,4H),2.21–2.10(m,4H);LC-MS:293.40[M+H]⁺.

Step 2 Synthesis of 1'- (4-iodo-1-methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -4' -carbonitrile

1'- (1-Methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -4' -carbonitrile (60 mg,0.21 mmol) and N-iodosuccinimide (52 mg,0.23 mmol) were dissolved in acetic acid (10 mL) and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution, acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added for dilution, the organic phase was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =5/1) to give a yellow solid (85mg,99.02％).¹H NMR(400MHz,CDCl₃)δ7.67(s,1H),7.43–7.40(m,1H),7.32(t,J＝7.9Hz,1H),6.75–6.71(m,1H),3.78(s,3H),2.41–2.33(m,4H),2.25–2.15(m,4H);LC-MS:419.10[M+H]⁺.

Step 3 Synthesis of tert-butyl ((7- (5- (4 '-cyano-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

Tert-butyl 1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3' -indoline ] -4' -carbonitrile (80 mg,0.19 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (114 mg,0.29 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (12 mg,0.02 mmol) and sodium carbonate (40 mg,0.38 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80℃for 4H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (23mg,21.26％).¹H NMR(400MHz,CDCl₃)δ11.12(s,1H),8.28(d,J＝8.3Hz,1H),8.07(s,1H),7.93(s,1H),7.51(d,J＝8.3Hz,1H),7.39(d,J＝7.8Hz,1H),7.22(t,J＝7.9Hz,1H),6.61(d,J＝7.8Hz,1H),5.46–5.39(m,1H),4.53–4.44(m,2H),3.76(s,3H),2.45–2.14(m,8H),1.48(s,9H);LC-MS:566.30[M+H]⁺.

Step 4 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -4' -carbonitrile hydrochloride

Tert-butyl ((7- (5- (4 '-cyano-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (20 mg,35 μmol) was dissolved in ethanol (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto, followed by stirring at room temperature for 3 hours. Concentrating under reduced pressure by rotary evaporation to obtain yellow solid (17mg,95.77％).¹H NMR(400MHz,CD₃OD)δ8.27(d,J＝8.3Hz,1H),8.22(s,1H),7.83(s,1H),7.68(d,J＝8.3Hz,1H),7.51(d,J＝7.8Hz,1H),7.35(t,J＝7.9Hz,1H),6.84(d,J＝7.8Hz,1H),4.50–4.32(m,2H),3.78(s,3H),2.46–2.32(m,3H),2.27–2.13(m,5H);LC-MS:466.20[M+H]⁺.

EXAMPLE 20 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -bromospiro [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (2-bromo-6-iodophenyl) methanol

A solution of borane in tetrahydrofuran (31 mL,31mmol, 1M) was slowly added dropwise to a solution of 2-bromo-6-iodobenzoic acid (5.00 g,15.29 mmol) in anhydrous tetrahydrofuran (50 mL), and stirred at 70℃for 12h. The reaction was quenched with methanol, most of the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added to the residue to dilute, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: PE/EtOAc (v/v) =10/1) to give a white solid (4.11g,85.87％).¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝8.7Hz,1H),7.57(d,J＝8.8Hz,1H),6.83(t,J＝7.9Hz,1H),5.01(s,2H).

Step 2 Synthesis of 2-bromo-6-iodobenzyl methanesulfonate

Methanesulfonyl chloride (3.14 g,27.38 mmol) was slowly added dropwise to a solution of (2-bromo-6-iodophenyl) methanol (4.10 g,13.10 mmol) and triethylamine (2.65 g,26.20 mmol) in dichloromethane (30 mL) at 0℃and stirred at room temperature for 1h. DCM (50 mL) was added to dilute the reaction, followed by washing with water (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to give a yellow liquid (5.12g,100％).¹H NMR(400MHz,CDCl₃)δ7.82–7.77(m,1H),7.57–7.52(m,1H),6.81(t,J＝8.0Hz,1H),4.92(s,2H),2.75(s,3H).

Step 3 Synthesis of 2- (2-bromo-6-iodophenyl) acetonitrile

A mixture of 2-bromo-6-iodobenzyl methanesulfonate (5.10 g,13.04 mmol), trimethylcyanosilane (1.55 g,15.65 mmol), potassium carbonate (3.60 g,26.08 mmol) and acetonitrile (60 mL) was stirred at 80℃for 5h. The stirring under heating was stopped, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and ethyl acetate (50 mL) was added to the residue, followed by washing with saturated brine (30 mL. Times.3). The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: PE/EtOAc (v/v) =10/1) to give a colorless clear liquid (3.32g,79.07％).¹H NMR(400MHz,CDCl₃)δ7.85(dd,J＝8.0,1.0Hz,1H),7.62(dd,J＝8.0,1.0Hz,1H),6.89(t,J＝8.0Hz,1H),4.16(s,2H).

Step 4 Synthesis of 1- (2-bromo-6-iodophenyl) cyclopentane-1-carbonitrile

A mixture of 2- (2-bromo-6-iodophenyl) acetonitrile (3.00 g,9.32 mmol), 1, 2-dibromobutane (4.02 g,18.64 mmol), potassium hydroxide (3.14 g,55.92 mmol), tetrabutylammonium bromide (3.00 g,9.32 mmol) and water (30 mL) was stirred for 1h at 50 ℃. Ethyl acetate (100 mL) was added to the reaction mixture to dilute it, which was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) =10/1) to give a yellow solid (1.34g,38.24％).¹H NMR(400MHz,CDCl₃)δ8.06(dd,J＝7.8,1.3Hz,1H),7.67(dd,J＝7.9,1.3Hz,1H),6.72(t,J＝7.9Hz,1H),3.36–3.27(m,2H),2.38–2.25(m,2H),1.99–1.87(m,4H);GC-MS:374.9[M]⁺.

Step 5 Synthesis of 1- (2-bromo-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile

1- (2-Bromo-6-iodophenyl) cyclopentane-1-carbonitrile (1.00 g,2.66 mmol), 1-methyl-5-aminopyrazole (0.39 g,3.99 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (308 mg,0.53 mmol), palladium acetate (60 mg,0.27 mmol) and cesium carbonate (1.73 g,5.32 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h. To the reaction mixture was added ethyl acetate (100 mL) and the mixture was diluted, and the organic phase was washed with saturated brine (50 mL. Times.3) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: dichloromethane/methanol (v/v) =20/1) to give a reddish-white viscous liquid (0.67g,72.98％).¹H NMR(400MHz,CDCl₃)δ7.65(s,1H),7.15(d,J＝8.1Hz,1H),7.00(t,J＝7.9Hz,1H),6.39(d,J＝7.8Hz,1H),6.32(s,1H),3.67(s,3H),2.62–2.45(m,2H),2.23–2.06(m,6H);LC-MS:345.40[M+H]⁺.

Step 6 Synthesis of 4 '-bromo-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

1- (2-Bromo-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-carbonitrile (0.60 g,1.74 mmol) was dissolved in concentrated hydrochloric acid (5 mL, 36%) and acetic acid (5 mL), and stirred at 100℃for 6H. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, which was washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (453mg,72.35％).¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝1.9Hz,1H),7.25(d,J＝5.7Hz,1H),7.06(t,J＝8.0Hz,1H),6.61(d,J＝7.5Hz,1H),6.30(d,J＝2.0Hz,1H),3.71(s,3H),2.52–2.41(m,2H),2.18–2.06(m,6H);LC-MS:346.10[M+H]⁺.

Step 7 Synthesis of 4 '-bromo-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

4 '-Bromo-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (100 mg,0.29 mmol) and N-iodosuccinimide (65 mg,0.29 mmol) were dissolved in acetic acid (20 mL) and stirred at room temperature for 3H. Quenching the reaction with saturated sodium bisulphite solution, removing acetic acid by rotary evaporation under reduced pressure, adding dichloromethane (100 mL) for dilution, washing the organic phase with water (50 mL×3), drying over anhydrous sodium sulfate, concentrating the solvent by rotary evaporation under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to obtain yellow solid (125mg,91.67％).¹H NMR(400MHz,CDCl₃)δ7.65(s,1H),7.27(d,J＝8.3Hz,1H),7.08(t,J＝8.0Hz,1H),6.45(d,J＝7.8Hz,1H),3.76(s,3H),2.56–2.42(m,2H),2.22–2.10(m,6H);LC-MS:472.00[M+H]⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (4 '-bromo-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

4' -Bromo-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopentane-1, 3' -indolin ] -2' -one (100 mg,0.21 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (151 mg,0.38 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (16 mg,0.03 mmol) and sodium carbonate (53 mg,0.50 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80 ℃ for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (33mg,20.96％);¹H NMR(400MHz,CDCl₃)δ10.61(s,1H),8.27(d,J＝8.3Hz,1H),8.07(s,1H),7.97(s,1H),7.53(d,J＝8.3Hz,1H),7.29–7.26(m,1H),6.99(t,J＝8.0Hz,1H),6.37(d,J＝7.6Hz,1H),5.32(t,J＝5.8Hz,1H),4.54(d,J＝5.0Hz,2H),3.76(s,3H),2.59–2.32(m,4H),2.15–2.00(m,4H),1.48(s,9H);LC-MS:619.15[M+H]⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' -bromospiro [ cyclopentane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (4 '-bromo-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (10 mg,17 umol) was dissolved in ethanol (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution is decompressed, distilled and concentrated to obtain yellow solid (8mg,89.16％).¹H NMR(400MHz,CD₃OD)δ8.26(d,J＝8.3Hz,1H),8.22(s,1H),7.82(s,1H),7.70(d,J＝8.3Hz,1H),7.34(d,J＝8.1Hz,1H),7.10(t,J＝7.9Hz,1H),6.54(d,J＝7.6Hz,1H),4.48–4.30(m,2H),3.77(s,3H),3.66(s,2H),2.64–2.50(m,2H),2.23–1.95(m,6H);LC-MS:519.10[M+H-HCl]⁺.

EXAMPLE 21 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' - (difluoromethyl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 1- (2- (difluoromethyl) -6-iodophenyl) cyclohexane-1-carbonitrile

NaH (0.50 g,12.30mmol,60% strength) was added to a solution of 2- (2- (difluoromethyl) -6-iodophenyl) acetonitrile (0.60 g,2.05 mmol) in N, N-dimethylformamide (20 mL) at 0℃and stirred for 0.5h with heat preservation, and 1, 5-dibromopentane (0.71 g,3.07 mmol) was added and stirred for 4h at room temperature. The stirring was stopped, the reaction was quenched with water, concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow liquid (0.60g,80.87％).¹H NMR(400MHz,CDCl₃)δ8.23(d,J＝7.8Hz,1H),7.78(d,J＝7.1Hz,1H),7.54(t,J＝54.9Hz,1H),7.03(t,J＝7.9Hz,1H),2.59–2.50(m,2H),2.03–1.78(m,8H);GC-MS:361.0[M]⁺.

Step 2 Synthesis of 1- (2- (difluoromethyl) -6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile

1- (2- (Difluoromethyl) -6-iodophenyl) cyclohexane-1-carbonitrile (500 mg,1.38 mmol), 1-methyl-5-aminopyrazole (0.20 g,2.07 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (160 mg,0.28 mmol), palladium acetate (31 mg,0.14 mmol) and cesium carbonate (0.890 g,2.76 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h. Ethyl acetate (100 mL) was added to the reaction solution to dilute the mixture, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow solid (320mg,69.96％).¹H NMR(400MHz,CDCl₃)δ7.67(d,J＝1.8Hz,1H),7.29–7.23(m,2H),7.17(t,J＝54.8Hz,1H),6.48(d,J＝7.4Hz,1H),6.32(d,J＝1.8Hz,1H),5.53(d,J＝1.7Hz,1H),3.70(s,3H),2.37–2.21(m,2H),2.05–1.89(m,6H),1.74–1.64(m,2H).;LC-MS:331.20[M+H]⁺.

Step 3 Synthesis of 4'- (difluoromethyl) -1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

1- (2- (Difluoromethyl) -6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile (300 mg,0.91 mmol) was dissolved in a mixture of concentrated hydrochloric acid (2 mL, 36%) and acetic acid (2 mL), and stirred at 100℃for 6H. The solvent was concentrated by rotary evaporation under reduced pressure, and ethyl acetate (50 mL) was added to the residue, which was washed with saturated brine (30 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (142mg,47.19％).¹H NMR(400MHz,CDCl₃)δ7.70(s,1H),7.40(d,J＝7.9Hz,1H),7.34(t,J＝7.7Hz,1H),7.09(t,J＝54.8Hz,1H),6.76(d,J＝7.6Hz,1H),6.37(s,1H),3.75(s,3H),2.29–2.17(m,2H),2.06–1.87(m,6H),1.73–1.64(m,2H);LC-MS:332.20[M+H]⁺.

Step 4 Synthesis of 4'- (difluoromethyl) -1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

4'- (Difluoromethyl) -1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one (140 mg,0.42 mmol) and N-iodosuccinimide (95 mg,0.42 mmol) were dissolved in acetic acid (20 mL) and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution (10 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulphate, concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (181 mg, 93.69%). LC-MS 458.10[ M+H ] ⁺.

Step 5 Synthesis of tert-butyl ((7- (5- (4 '- (difluoromethyl) -2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

4' - (Difluoromethyl) -1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indolin ] -2' -one (100 mg,0.22 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (132 mg,0.33 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (14 mg,0.02 mmol) and sodium carbonate (47 mg,0.44 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80 ℃ for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (20mg,15.12％).¹H NMR(400MHz,CDCl₃)δ11.03(s,1H),8.28(d,J＝8.4Hz,1H),8.11(s,1H),7.96(s,1H),7.62(d,J＝8.3Hz,1H),7.41(d,J＝8.0Hz,1H),7.31–7.26(m,1H),7.13(t,J＝54.8Hz,1H),6.53(d,J＝7.8Hz,1H),5.40–5.32(m,1H),4.56–4.41(m,2H),3.77(s,3H),2.30–2.07(m,4H),2.04–1.87(m,4H),1.75–1.65(m,2H),1.48(s,9H);LC-MS:605.30[M+H]⁺.

Step 6 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4' - (difluoromethyl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (4 '- (difluoromethyl) -2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (10 mg,17 mol) was dissolved in ethanol (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto, followed by stirring at room temperature for 3 hours. Concentrating the reaction solution under reduced pressure to obtain yellow solid (8mg,89.41％).¹H NMR(400MHz,DMSO-d₆)δ8.54(s,1H),8.44(s,1H),8.16(d,J＝8.3Hz,1H),7.98(s,1H),7.56(t,J＝54.8Hz,1H),7.53(d,J＝8.3Hz,1H),7.38–7.31(m,1H),6.64(d,J＝7.4Hz,1H),4.45–4.28(m,2H),3.69(s,3H),2.19–1.97(m,4H),1.94–1.47(m,6H);LC-MS:505.20[M+H]⁺.

EXAMPLE 22:1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -fluoro-spiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of (3-fluoro-2-iodophenyl) methanol

A tetrahydrofuran solution (38 mL,38 mmol) of the borane tetrahydrofuran complex was slowly added dropwise to a solution of 3-fluoro-2-iodobenzoic acid (5.00 g,18.80 mmol) in anhydrous tetrahydrofuran (50 mL) and stirred at room temperature for 1h. The reaction was quenched with methanol, most of the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added for dilution, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain white solid (4.61g,97.32％).¹H NMR(400MHz,CDCl₃)δ7.37–7.30(m,1H),7.29–7.26(m,1H),7.03–6.97(m,1H),4.72(s,2H);GC-MS(ESI):251.9[M]⁺

Step 2 Synthesis of 3-fluoro-2-iodobenzyl methanesulfonate

Methanesulfonyl chloride (3.14 g,27.38 mmol) was slowly added dropwise to a solution of (3-fluoro-2-iodophenyl) methanol (4.60 g,18.25 mmol) and triethylamine (3.69 g,36.50 mmol) in dichloromethane (30 mL) at 0deg.C, stirred at room temperature for 0.5h, diluted with DCM (50 mL) was added, the reaction was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was concentrated by spin-evaporation under reduced pressure to give a yellow liquid (6.26g,100％).¹H NMR(400MHz,CDCl₃)δ7.31–7.24(m,2H),7.02–6.96(m,1H),4.69(s,2H),2.76(s,3H).

Step 3 Synthesis of 2- (3-fluoro-2-iodophenyl) acetonitrile

A mixture of 3-fluoro-2-iodobenzyl methanesulfonate (6.00 g,18.18 mmol), trimethylcyanosilane (2.16 g,21.82 mmol), potassium carbonate (5.03 g,36.36 mmol) and acetonitrile (60 mL) was stirred at 80℃for 3h. The heating and stirring were stopped, cooled to room temperature, and the solvent was concentrated by rotary evaporation under reduced pressure, and ethyl acetate (50 mL) was added to the residue, followed by washing with saturated brine (30 mL. Times.3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a colorless transparent liquid (2.86g,65.28％).¹H NMR(400MHz,CDCl₃)δ7.40–7.32(m,2H),7.07–7.02(m,1H),3.87(s,2H);GC-MS:260.9[M]⁺.

Step 4 Synthesis of 7-bromo-2- (3-fluoro-2-iodophenyl) heptanenitrile

A mixture of 2- (3-fluoro-2-iodophenyl) acetonitrile (1.00 g,3.83 mmol), 1, 2-dibromopentane (1.76 g,7.66 mmol), potassium hydroxide (1.29 g,22.98 mmol), tetrabutylammonium bromide (1.23 g,3.83 mmol) and water (10 mL) was stirred at 50℃for 1h. Ethyl acetate (100 mL) was added to the reaction mixture, which was diluted with saturated brine (50 mL. Times.3), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: PE/EtOAc (v/v) =10/1) to give a yellow solid (0.89g,56.65％).¹H NMR(400MHz,CDCl₃)δ7.40–7.34(m,2H),7.07–7.00(m,1H),4.24(dd,J＝9.4,5.2Hz,1H),3.41(t,J＝6.7Hz,2H),1.94–1.77(m,4H),1.66–1.51(m,4H);LC-MS:409.0[M+H]⁺.

Step 5 Synthesis of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile

7-Bromo-2- (3-fluoro-2-iodophenyl) heptanenitrile (500 mg,1.22 mmol), 1-methyl-5-aminopyrazole (0.13 g,1.34 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (71 mg,0.12 mmol), palladium acetate (14 mg,0.06 mmol) and cesium carbonate (0.80 g,2.44 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute the mixture, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a brown solid (184mg,50.58％).¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝1.9Hz,1H),7.23(d,J＝1.5Hz,1H),6.97–6.92(m,2H),6.29(d,J＝2.0Hz,1H),3.66(s,3H),1.98–1.86(m,5H),1.84–1.75(m,5H);LC-MS:299.20[M+H]⁺.

Step 6 Synthesis of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carboxylic acid

1- (3-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile (180 mg,0.61 mmol) and potassium hydroxide (0.20 g,3.60 mmol) were dissolved in a mixed solvent of ethanol (5 mL) and water (5 mL), and stirred at 140℃for 4H. The ph=4 was adjusted with a1, 4-dioxane solution of hydrogen chloride (4M), the solvent was concentrated by rotary evaporation under reduced pressure, ethanol (20 mL) was added to the residue, and the solid was filtered off. The filtrate was concentrated under reduced pressure to give a yellow liquid (201 mg, 100%). LC-MS 318.20[ M+H ] ⁺.

Step 7 Synthesis of 7 '-fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

1- (3-Fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carboxylic acid (191 mg,0.60 mmol) and N, N-carbonyldiimidazole (0.39 g,2.40 mmol) were dissolved in dichloromethane (10 mL), and stirred at room temperature for 2H. Dilute with dichloromethane (50 mL), wash with water (30 mL. Times.3), dry over anhydrous sodium sulfate, spin-evaporate the solvent under reduced pressure, and purify the residue by column chromatography on silica gel (eluent: PE/EtOAc (v/v) =4/1) to give a yellow solid (77mg,42.74％).¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝2.0Hz,1H),7.29–7.26(m,1H),7.08–7.05(m,1H),7.02–6.94(m,1H),6.29(d,J＝1.9Hz,1H),3.70(s,3H),2.05–1.89(m,4H),1.80–1.65(m,6H);LC-MS:300.20[M+H]⁺.

Step 8 Synthesis of 7 '-fluoro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

7 '-Fluoro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one (85 mg,0.28 mmol) and N-iodosuccinimide (63 mg,0.28 mmol) were dissolved in acetic acid (10 mL) and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulfite solution (10 mL), then the mixture was concentrated under reduced pressure to remove acetic acid, and methylene chloride (100 mL) was added to the concentrate for dilution. The organic phase was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a gray viscous liquid (110mg,91.10％).¹H NMR(400MHz,CDCl₃)δ7.60(s,1H),7.28(d,J＝7.5Hz,1H),7.12–7.06(m,1H),7.03–6.96(m,1H),3.79(s,3H),2.06–1.93(m,4H),1.83–1.66(m,6H);LC-MS:426.10[M+H]⁺.

Step 9 Synthesis of tert-butyl ((7- (5- (7 '-fluoro-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

7' -Fluoro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indolin ] -2' -one (110 mg,0.26 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (156 mg,0.39 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (17 mg,0.03 mmol) and sodium carbonate (55 mg,0.52 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 80 ℃ for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow solid (13mg,8.78％).¹H NMR(400MHz,CDCl₃)δ10.78(s,1H),8.26(d,J＝8.3Hz,1H),8.00(s,1H),7.95(s,1H),7.57(d,J＝8.0Hz,1H),7.32(d,J＝7.5Hz,1H),7.12–7.04(m,1H),6.98–6.89(m,1H),5.40–5.34(m,1H),4.57–4.48(m,2H),3.77(s,3H),2.05–1.88(m,4H),1.79–1.65(m,6H),1.47(s,9H);LC-MS:573.30[M+H]⁺.

Step 10 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -fluoro-spiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (7 '-fluoro-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (13 mg, 23. Mu. Mol) was dissolved in ethanol (1 mL), and a1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto, followed by stirring at room temperature for 3 hours. Concentrating the reaction solution by rotary evaporation under reduced pressure to obtain brown solid (11mg,95.20％).¹H NMR(400MHz,CD₃OD)δ8.25(d,J＝8.4Hz,1H),8.16(s,1H),7.85(s,1H),7.72–7.70(m,1H),7.46(d,J＝7.5Hz,1H),7.25–7.18(m,1H),7.10–7.03(m,1H),4.40–4.38(m,1H),4.28–4.26(m,1H),3.77(s,3H),2.06–1.88(m,4H),1.85–1.73(m,6H);LC-MS:473.50[M+H]⁺.

EXAMPLE 23 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -cyclopropylspiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 1- (3-bromo-2-iodophenyl) cyclohexane-1-carbonitrile

NaH (0.45 g,18.66mmol,60% strength) was added to a solution of 2- (3-bromo-2-iodophenyl) acetonitrile (1.00 g,3.11 mmol) in N, N-dimethylformamide (10 mL) at 0deg.C, the mixture was stirred for 0.5h with heat preservation, and then 1, 5-dibromopentane (1.07 g,4.67 mmol) was added and stirred at room temperature for 4h. The stirring was stopped, the reaction was quenched by addition of water, the solvent was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue to dilute it, and the residue was washed with water (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give a yellow solid (843mg,69.58％).¹H NMR(400MHz,CDCl₃)δ7.69(dd,J＝7.5,1.7Hz,1H),7.32–7.21(m,2H),2.76–2.63(m,2H),1.98–1.80(m,5H),1.75–1.63(m,2H),1.35–1.20(m,1H);GC-MS:388.9[M]⁺.

Step2 Synthesis of 1- (3-bromo-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile

1- (3-Bromo-2-iodophenyl) cyclohexane-1-carbonitrile (500 mg,1.28 mmol), 1-methyl-5-aminopyrazole (0.14 g,1.41 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (148 mg,0.26 mmol), palladium acetate (29 mg,0.13 mmol) and cesium carbonate (0.83 g,2.56 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h. Ethyl acetate (100 mL) was added to the reaction solution to dilute it, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow viscous liquid (283mg,61.45％).¹HNMR(400MHz,CDCl₃)δ7.61(d,J＝1.8Hz,1H),7.47(d,J＝7.8Hz,1H),7.32(d,J＝8.1Hz,1H),7.22(t,J＝7.8Hz,1H),6.31(d,J＝1.9Hz,1H),3.63(s,3H),2.01–1.87(m,4H),1.85–1.67(m,6H);LC-MS:359.05[M+H]⁺.

Step 3 Synthesis of 7 '-bromo-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

1- (3-Bromo-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclohexane-1-carbonitrile (0.50 g,1.39 mmol) was dissolved in concentrated hydrochloric acid (5 mL, 36%) and acetic acid (5 mL), and stirred at 100℃for 6H. Concentrating the solvent under reduced pressure, adding ethyl acetate (50 mL) to the residue for dilution, washing with saturated saline (30 mL. Times.3), drying with anhydrous sodium sulfate, concentrating the solvent under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to obtain yellow solid (386mg,76.99％).¹H NMR(400MHz,CDCl₃)δ7.58(d,J＝2.0Hz,1H),7.40–7.34(m,2H),6.99(t,J＝7.8Hz,1H),6.30(d,J＝2.0Hz,1H),3.67(s,3H),2.05–1.87(m,4H),1.79–1.60(m,6H);LC-MS:360.15[M+H]⁺.

Step 4 Synthesis of 7 '-cyclopropyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

7 '-Bromo-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one (100 mg,0.28 mmol), cyclopropylboronic acid (31.27 mg,0.36 mmol), potassium phosphate (208.02 mg,0.98 mmol), tricyclohexylphosphine (15.70 mg,0.056 mmol) and palladium acetate (6.29 mg,0.028 mmol) were dissolved in a mixed solvent of toluene (2 mL) and water (0.1 mL), and stirred under nitrogen at 110℃for 1H. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (63mg,70.61％).¹HNMR(400MHz,CDCl₃)δ7.55(d,J＝1.9Hz,1H),7.29(d,J＝7.2Hz,1H),7.03(t,J＝7.7Hz,1H),6.92(d,J＝7.8Hz,1H),6.30(d,J＝1.9Hz,1H),3.71(s,3H),2.08–1.88(m,4H),1.81–1.65(m,6H),1.29–1.22(m,1H),0.62–0.52(m,2H),0.44–0.32(m,2H);LC-MS:322.50[M+H]⁺.

Step 5 Synthesis of 7 '-cyclopropyl-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

7 '-Cyclopropyl-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3 '-indolin ] -2' -one (60 mg,0.19 mmol) and N-iodosuccinimide (47 mg,0.21 mmol) were dissolved in acetic acid (10 mL) and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution (10 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added for dilution, the organic phase was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =4/1) to give a yellow solid (83mg,99.40％).¹H NMR(400MHz,CDCl₃)δ7.58(s,1H),7.31(d,J＝7.3Hz,1H),7.06(t,J＝7.6Hz,1H),6.97(d,J＝7.8Hz,1H),3.81(s,3H),2.06–1.89(m,4H),1.82–1.69(m,6H),1.28–1.23(m,1H),0.68–0.62(m,1H),0.60–0.53(m,1H),0.41–0.31(m,2H);LC-MS:448.30[M+H]⁺.

Step 6 Synthesis of tert-butyl ((7- (5- (7 '-cyclopropyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

7' -Cyclopropyl-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclohexane-1, 3' -indolin ] -2' -one (80 mg,0.18 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (108 mg,0.27 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (12 mg,0.02 mmol) and sodium carbonate (38 mg,0.36 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL), and stirred under nitrogen protection at 80 ℃ for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (32mg,30.09％).¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝8.3Hz,1H),8.13(s,1H),8.02(s,1H),7.70(d,J＝8.0Hz,1H),7.38(d,J＝7.4Hz,1H),7.09(t,J＝7.7Hz,1H),6.93(d,J＝7.9Hz,1H),5.38–5.25(m,1H),4.49(s,2H),3.80(s,3H),2.08–1.85(m,4H),1.82–1.60(m,6H),1.47(s,9H),1.18–1.06(m,1H),0.51–0.35(m,4H);LC-MS:595.30[M+H]⁺.

Step 7 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -cyclopropylspiro [ cyclohexane-1, 3 '-indolin ] -2' -one hydrochloride

Tert-butyl ((7- (5- (7 '-cyclopropyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (15 mg, 25. Mu. Mol) was dissolved in ethanol (1 mL), and a 1, 4-dioxane solution (1 mL,4 m) of hydrogen chloride was added thereto, and stirred at room temperature for 3 hours. Concentrating under reduced pressure by rotary evaporation to obtain white solid (11mg,82.12％).¹H NMR(400MHz,CD₃OD)δ8.26(d,J＝8.4Hz,1H),8.23(s,1H),7.85(d,J＝8.4Hz,1H),7.78(s,1H),7.47(d,J＝7.4Hz,1H),7.17(t,J＝7.7Hz,1H),7.02(d,J＝7.8Hz,1H),4.23–4.11(m,2H),3.80(s,3H),3.66(s,2H),2.09–1.93(m,2H),1.90–1.53(m,8H),1.23–1.17(m,1H),0.57–0.38(m,4H);LC-MS:495.30[M+H-HCl]⁺.

EXAMPLE 24 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -chlorospiro [ cyclopropane-1, 3 '-indolin ] -2' -one hydrochloride

Step 1 Synthesis of 1-bromomethyl-3-chloro-2-iodobenzene

1-Methyl-3-chloro-2-iodobenzene (3.0 g,11.90 mmol) was dissolved in carbon tetrachloride (20 mL), N-bromosuccinimide (3.17 g,17.8 mmol) was added and reacted with benzoyl peroxide (390 mg,2.38 mmol) under stirring at 90℃for 24h. The solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane (30 mL), washed with water (30 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (eluent: PE) to give the product as a white solid (2.7 g, 68.6%).

Step 2 Synthesis of 2- (3-chloro-2-iodophenyl) acetonitrile

1-Bromomethyl-3-chloro-2-iodobenzene (2.6 g,7.85 mmol), trimethylcyanosilane (0.93 g,9.42 mmol) and potassium carbonate (1.30 g,9.42 mmol) were dissolved in acetonitrile (20 mL) and the reaction stirred at 60 ℃. The reaction was stopped, cooled to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined and washed with saturated brine (50 ml×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown liquid product (1.70 g, 78%).

Step 3 Synthesis of 1- (3-chloro-2-iodophenyl) cyclopropane-1-carbonitrile

2- (3-Chloro-2-iodophenyl) acetonitrile (1.7 g,6.13 mmol), potassium hydroxide (3.44 g,61.3 mmol) and tetrabutylammonium bromide (200 mg,0.31 mmol) were dissolved in water (10 mL), 1,2 dibromoethane (2.48 g,12.26 mmol) was added under stirring at 70℃under nitrogen protection, and the reaction was continued with stirring at temperature for 24h. The reaction was stopped, cooled to room temperature, extracted with ethyl acetate (20 ml×2), the organic phases were combined and washed with water (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =10/1) to give the product as a yellow solid (1.2 g, 65%). LC-MS 305.00[ M+H ] ⁺.

Step 4 Synthesis of 1- (3-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile

1- (3-Chloro-2-iodophenyl) cyclopropane-1-carbonitrile (500 mg,1.65 mmol), 1-methyl-5-aminopyrazole (180 mg,1.81 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (190 mg,0.33 mmol), palladium acetate (37 mg,0.17 mmol) and cesium carbonate (1.08 g,3.30 mmol) were dissolved in 1, 4-dioxane (10 mL) and reacted under stirring at 140℃under nitrogen blanket under microwave conditions for 4h. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined and washed with saturated brine (20 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give the product as a brown oil (410 mg, 91%). LC-MS 273.10[ M+H ] ⁺.

Step 5 Synthesis of 1- (3-chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid

1- (3-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carbonitrile (300 mg,1.10 mmol) and sodium hydroxide (1.32 g,33.00 mmol) were dissolved in a mixed solvent of water (10 mL) and methanol (10 mL), and reacted under stirring at 100℃under nitrogen for 24 hours. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10 mL), ph=2 adjusted with 2M hydrochloric acid, extracted with ethyl acetate (20 ml×3), the organic phases were combined and washed with saturated brine (20 ml×2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a yellow solid (250 mg, 78%). LC-MS 290.15[ M-H ] ^-.

Step 6 Synthesis of 7 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

1- (3-Chloro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopropane-1-carboxylic acid (300 mg,1.03 mmol), N-carbonyldiimidazole (250 mg,1.54 mmol) and N, N-diisopropylethylamine (270 mg,2.06 mmol) were dissolved in dichloromethane (5 mL), and the reaction was stirred at room temperature. The reaction was stopped, the reaction mixture was diluted with dichloromethane (20 mL), then washed with dilute hydrochloric acid (1M, 10 mL) and with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the product (260 mg, 92%) as a colorless oil. LC-MS 274.30[ M+H ] ⁺.

Step 7 Synthesis of 7 '-chloro-1' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indoline ] -2' -one

The compound 7 '-chloro-1' - (1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3 '-indolin ] -2' -one (108 mg,0.40 mmol) and N-iodosuccinimide (90 mg,0.40 mmol) were dissolved in acetic acid (15 mL) and the reaction was stirred at room temperature. The solvent was removed by concentration, the residue was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the product as a colourless oil (146 mg, 93%). LC-MS 400.20[ M+H ] ⁺.

Step 8 Synthesis of tert-butyl ((7- (5- (7 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

The compound 7' -chloro-1 ' - (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ cyclopropane-1, 3' -indoline ] -2' -one (100 mg,0.25 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (150 mg,0.38 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (31 mg,0.037 mmol) and sodium carbonate (53 mg,0.5 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (3 mL) and water (1 mL) and reacted under 80 ℃ microwave conditions under nitrogen protection for 3H. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a white solid (100 mg, 73%) by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =1/4). LC-MS 547.20[ M+H ] ⁺.

Step 9 Synthesis of 1'- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -7' -chlorospiro [ cyclopropane-1, 3 '-indoline ] -2' -one hydrochloride

The compound ((7- (5- (7 '-chloro-2' -oxospiro [ cyclopropan-1, 3 '-indoline ] -1' -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (20 mg,0.037 mmol) was dissolved in methanol (3 mL), and a1, 4-dioxane solution (4 m,5 mL) of hydrogen chloride was added thereto, and the reaction was stirred at room temperature for 1H. The reaction solution is decompressed and concentrated to obtain a pale yellow solid product (12mg,73.4％).¹H NMR(400MHz,DMSO-d₆)δ12.88(s,1H),8.60–8.37(m,3H),8.33(s,1H),7.72(d,J＝8.0Hz,1H),7.67(s,1H),7.30–7.18(m,2H),7.18-7.09(m,1H),4.44–4.20(m,1H),4.14–4.00(m,1H),3.72(s,3H),2.08–1.92(m,2H),1.92–1.74(m,2H);LC-MS:447.40[M-HCl+H]⁺.

EXAMPLE 25 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

Step 1 Synthesis of 2- ((1-methyl-1H-pyrazol-5-yl) amino) benzoic acid ethyl ester

Ethyl 2-iodobenzoate (1.05 g,3.82 mmol), 1-methyl-5-aminopyrazole (0.56 g,5.73 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (442 mg,0.76 mmol), palladium acetate (86 mg,0.38 mmol) and cesium carbonate (2.49 g,7.64 mmol) were dissolved in1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute it, the organic phase was washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a reddish-white viscous liquid (0.75g,84.42％).LC-MS:246.30[M+H]⁺;¹HNMR(400MHz,CDCl₃)δ9.37(s,1H),8.01–7.96(m,1H),7.48(d,J＝1.8Hz,1H),7.35–7.30(m,1H),6.82–6.73(m,2H),6.13–6.06(m,1H),4.37(q,J＝7.1Hz,2H),3.73(s,3H),1.41(t,J＝7.1Hz,3H).

Step 2 Synthesis of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopenta-1-ol

A solution of 1, 4-dibromobutane (1.87 g,8.64 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a mixture of magnesium turnings (420 mg,17.28 mmol) and iodine (109 mg,0.43 mmol), and after initiation by heating and stirring, a solution of ethyl 2- ((1-methyl-1H-pyrazol-5-yl) amino) benzoate (1.06 g,4.32 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the above reaction solution at 0℃after initiation by stirring at 25℃under heating and stirring at 2H, and a saturated ammonium chloride solution (10 mL) was added to quench the reaction solution, ethyl acetate (50 mL) was added to dilute the solution, the solution was washed with saturated brine (30 mL. Times 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =2/1) to give a yellow liquid (303mg,27.23％).LC-MS:258.20[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.60(s,1H),7.42(d,J＝1.8Hz,1H),7.28–7.24(m,1H),7.17–7.10(m,1H),6.81(td,J＝7.6,1.0Hz,1H),6.74(d,J＝8.1Hz,1H),5.96(d,J＝1.8Hz,1H),3.67(s,3H),2.23–2.14(m,4H),1.99–1.89(m,2H),1.84–1.74(m,2H).

Step3 Synthesis of 1- (1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

Triphosgene (1.16 g,3.92 mmol) was added to a solution of 1- (2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopenta-1-ol (250 mg,0.98 mmol) and triethylamine (1.19 g,11.76 mmol) in dichloromethane (5 mL) at 0℃and stirred at room temperature for 1H. Dichloromethane (50 mL) was added to the reaction solution, the organic phase was washed with water (30 ml×3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =4/1) to give a white solid (120mg,43.26％).LC-MS:284.20[M+H]⁺;¹HNMR(400MHz,CDCl₃)δ7.62(d,J＝2.0Hz,1H),7.26–7.22(m,1H),7.22–7.16(m,1H),7.15–7.09(m,1H),6.33(d,J＝7.9Hz,1H),6.31(d,J＝2.0Hz,1H),3.70(s,3H),2.45–2.33(m,2H),2.19–2.05(m,4H),1.96–1.84(m,2H).

Step 4 Synthesis of 1- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

1- (1-Methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one (110 mg,0.39 mmol) and N-iodosuccinimide (132 mg,0.58 mmol) were dissolved in acetic acid (10 mL), and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution (5 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added for dilution, the organic phase was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (150mg,94.41％).LC-MS:410.10[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.65(s,1H),7.30–7.12(m,3H),6.21(d,J＝8.1Hz,1H),3.80(s,3H),2.69–2.59(m,1H),2.40–2.27(m,2H),2.19–1.83(m,5H).

Step 5 Synthesis of tert-butyl ((7- (1-methyl-5- (2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

1- (4-Iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1 '-cyclopentane ] -2 (1H) -one (140 mg,0.34 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (205 mg,0.51 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (22 mg,34 μmol) and sodium carbonate (72 mg,0.868 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL), and stirred under nitrogen protection at 90℃for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), the organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (29mg,15.23％).LC-MS:557.30[M+H]⁺;¹HNMR(400MHz,CDCl₃)δ10.48(s,1H),8.29(d,J＝8.3Hz,1H),8.06(s,1H),7.95(s,1H),7.63(d,J＝9.4Hz,1H),7.33–7.28(m,1H),7.22–7.11(m,2H),6.30(dd,J＝7.3,1.7Hz,1H),4.53(d,J＝5.3Hz,2H),3.78(s,3H),2.44–2.23(m,3H),2.17–1.84(m,5H),1.48(s,9H).

Step 6 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

The compound ((7- (1-methyl-5- (2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (20 mg,36 umol) was dissolved in dichloromethane (1 mL), hydrogen chloride (1 mL,4M dioxane solution) was added, and stirred at room temperature for 3H. Concentrating under reduced pressure by rotary evaporation to obtain yellow solid (14mg,79.03％).LC-MS:457.30[M-HCl+H]⁺;¹H NMR(400MHz,CD₃OD)δ8.24(d,J＝8.3Hz,1H),8.20(s,1H),7.82(s,1H),7.73(d,J＝8.3Hz,1H),7.48(d,J＝7.4Hz,1H),7.32–7.21(m,2H),6.42(d,J＝7.5Hz,1H),4.38(s,2H),3.76(s,3H),2.42–2.09(m,4H),2.08–1.89(m,4H).

EXAMPLE 26 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -8-fluoro-spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

Step 1 Synthesis of 3-fluoro-2-iodobenzoic acid methyl ester

Oxalyl chloride (2.62 g,20.68 mmol) was added to a solution of 3-fluoro-2-iodobenzoic acid (5.00 g,18.80 mmol) in dichloromethane (50 mL), DMF (68 mg,0.94 mmol) was added and stirred at room temperature for 2h. Methanol (0.90 g,28.20 mmol) and potassium carbonate (7.80 g,56.4 mmol) were added thereto and stirred at room temperature for 1h. Dichloromethane (100 mL) was added to the reaction solution, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give yellow liquid (3.12 g, 59.28%). LC-MS:280.95[ m+h ] ⁺.

Step 2 Synthesis of methyl 3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) benzoate

Methyl 3-fluoro-2-iodobenzoate (3.00 g,10.71 mmol), 1-methyl-5-aminopyrazole (1.25 g,12.85 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.62 g,1.07 mmol), palladium acetate (120 mg,0.54 mmol) and cesium carbonate (5.23 g,16.07 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute it, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =3/1) to give a yellow viscous liquid (1.37g,51.31％).LC-MS:250.20[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.97(s,1H),7.79(d,J＝8.1Hz,1H),7.47(s,1H),7.21–7.12(m,1H),6.90–6.80(m,1H),6.01(s,1H),3.92(s,3H),3.80(s,3H).

Step 3 Synthesis of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-ol

A solution of 1, 4-dibromobutane (2.43 g,11.24 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a mixture of magnesium turnings (544 mg,22.48 mmol) and iodine (143 mg,0.56 mmol), and after initiation of heating and stirring, stirring was carried out at room temperature of 25℃for 2 hours.

A solution of methyl 3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) benzoate (1.40 g,5.62 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the above reaction solution at 0℃and stirred at 25℃for 12 hours.

Quenching the reaction by adding saturated ammonium chloride solution (10 mL), diluting with ethyl acetate (50 mL), washing with saturated saline (30 mL. Times.3), drying with anhydrous sodium sulfate, concentrating the solvent by rotary evaporation under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =3/1) to obtain yellow liquid (512mg,33.11％).LC-MS:276.30[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.32(s,1H),7.25(d,J＝1.9Hz,1H),7.08(d,J＝7.5Hz,1H),7.05–6.90(m,2H),3.75(s,3H),2.11–2.01(m,4H),1.98–1.87(m,2H),1.81–1.69(m,2H).

Step 4 Synthesis of 8-fluoro-1- (1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

Triphosgene (1.39 g,4.68 mmol) was added to a solution of 1- (3-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentane-1-ol (300 mg,1.17 mmol) and triethylamine (1.42 g,14.04 mmol) in dichloromethane (5 mL) at 0℃and stirred at room temperature for 1H. Dichloromethane (50 mL) was added to the reaction solution, the organic phase was washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =3/1) to give a yellow solid (192mg,57.68％).LC-MS:302.30[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.51(d,J＝1.9Hz,1H),7.15–7.08(m,1H),7.05(d,J＝7.2Hz,1H),7.02–6.95(m,1H),6.13(d,J＝1.9Hz,1H),3.84(s,3H),2.45–1.83(m,8H).

Step 5 Synthesis of 8-fluoro-1- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

8-Fluoro-1- (1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one (180 mg,0.60 mmol) and N-iodosuccinimide (203 mg,0.90 mmol) were dissolved in acetic acid (10 mL), and stirred at room temperature for 3H. The reaction was quenched with saturated sodium bisulphite solution (5 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added for dilution, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (230mg,90.12％).LC-MS:428.10[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.53(s,1H),7.17–7.10(m,1H),7.07(d,J＝7.4Hz,1H),7.03–6.95(m,1H),3.89(s,3H),2.90–2.78(m,1H),2.50–2.37(m,1H),2.34–2.23(m,1H),2.17–2.06(m,2H),2.01–1.84(m,3H).

Step 6 Synthesis of tert-butyl ((7- (5- (8-fluoro-2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

8-Fluoro-1- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1 '-cyclopentane ] -2 (1H) -one (230 mg,0.62 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (373 mg,0.93 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (40 mg, 62. Mu. Mol) and sodium carbonate (131 mg,1.24 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL), and stirred under nitrogen protection at 90℃for 3H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (62mg,19.31％).LC-MS:575.50[M+H]⁺;¹HNMR(400MHz,CDCl₃)δ10.29(s,1H),8.27(d,J＝8.3Hz,1H),7.88(s,1H),7.79(s,1H),7.54(d,J＝8.1Hz,1H),7.21–7.14(m,1H),7.13–7.01(m,2H),4.45(d,J＝5.4Hz,2H),3.86(s,3H),2.40–2.27(m,2H),2.21–2.02(m,2H),1.98–1.86(m,2H),1.83–1.68(m,2H),1.48(s,9H).

Step 7 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -8-fluoro-spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

Tert-butyl ((7- (5- (8-fluoro-2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (30 mg, 52. Mu. Mol) was dissolved in dichloromethane (1 mL), hydrogen chloride (1 mL,4M dioxane solution) was added, and stirred at room temperature for 3H. Concentrating under reduced pressure by rotary evaporation to obtain yellow solid (23mg,86.21％).LC-MS:475.40[M-HCl+H]⁺;¹HNMR(400MHz,CD₃OD)δ8.26(d,J＝8.3Hz,1H),8.03(s,1H),7.75(s,1H),7.63(d,J＝8.2Hz,1H),7.32(dd,J＝8.3,3.0Hz,2H),7.25–7.17(m,1H),4.43(d,J＝16.2Hz,1H),4.30(d,J＝16.0Hz,1H),3.83(s,3H),2.49–2.25(m,2H),2.06–1.78(m,6H).HPLC：95.23％.

EXAMPLE 27 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6-chloro-5-fluoro-spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

Step 1, synthesis of 3-chloro-2-fluorobenzoic acid

A mixture of 3-chloro-2-fluorobenzaldehyde (10.00 g,63.07 mmol), potassium permanganate (29.90 g,189.21 mmol), potassium carbonate (26.15 g,189.21 mmol) and water (100 mL) was stirred at 80℃for 12h. Cool to room temperature, add ethanol (100 mL), stir at 50 ℃ for 0.5h, adjust ph=4 with concentrated hydrochloric acid, extract with ethyl acetate (100 ml×3), combine the organic phases and spin-evaporate the concentrated solvent under reduced pressure to give a white solid (7.93 g, 72.03%). LC-MS 173.20[ M+H ] ⁺.

Step 2 Synthesis of 3-chloro-2-fluoro-6-iodobenzoic acid

A mixture of 3-chloro-2-fluorobenzoic acid (5.00 g,28.64 mmol), N-iodosuccinimide (9.67 g,42.96 mmol), pentamethylcyclopentadienyl iridium sulfate complex (410 mg,0.86 mmol) and hexafluoroisopropanol (50 mL) was stirred at 60℃for 12h under an air atmosphere. The reaction was quenched by the addition of saturated sodium bisulphite solution (50 mL), the solvent was concentrated by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added to the residue, the organic phase was adjusted to ph=4 with hydrochloric acid (4M), washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure to give a yellow solid (5.03 g, 58.45%).

Step 3 Synthesis of 3-chloro-2-fluoro-6-iodobenzoic acid methyl ester

Oxalyl chloride (2.32 g,18.30 mmol) was added to a solution of 3-chloro-2-fluoro-6-iodobenzoic acid (5.00 g,16.64 mmol) in dichloromethane (50 mL), followed by DMF (61 mg,0.83 mmol) and stirring at room temperature for 2h. Methanol (0.80 g,24.96 mmol) and potassium carbonate (6.90 g,49.92 mmol) were added and stirred at room temperature for 1h. Dichloromethane (100 mL) was added to the reaction, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow liquid (4.45 g, 85.03%).

Step 4 Synthesis of methyl 3-chloro-2-fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) benzoate

Methyl 3-chloro-2-fluoro-6-iodobenzoate (3.00 g,9.54 mmol), 1-methyl-5-aminopyrazole (1.11 g,11.45 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (552 mg,0.95 mmol), palladium acetate (107 mg,0.48 mmol) and cesium carbonate (4.66 g,14.31 mmol) were dissolved in 1, 4-dioxane (10 mL) and stirred under nitrogen at 140℃for 4h under microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution to dilute the mixture, the organic phase was washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =20/1) to give a yellow viscous liquid (1.36g,50.25％).LC-MS:284.20[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ9.11(s,1H),7.52(d,J＝2.0Hz,1H),7.32–7.27(m,1H),7.23–7.17(m,1H),6.10(d,J＝1.8Hz,1H),3.97(s,3H),3.72(s,3H).

Step 5 Synthesis of 1- (3-chloro-2-fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopentan-1-ol

A solution of methyl 3-chloro-2-fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) benzoate (1.00 g,3.53 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to a solution of 1, 4-bis (bromomagnesium) butane (1.35 g,5.10 mmol) in anhydrous tetrahydrofuran (5 mL) at 0℃and stirred at room temperature for 12H. Quenching the reaction by adding saturated ammonium chloride solution (10 mL), diluting with ethyl acetate (50 mL), washing with saturated saline (30 mL. Times.3), drying the organic phase over anhydrous sodium sulfate, concentrating the solvent by rotary evaporation under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: 60-90 petroleum ether/ethyl acetate (v/v) =3/1) to obtain yellow liquid (251mg,22.99％).LC-MS:310.10[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),7.40(d,J＝1.8Hz,1H),7.07(t,J＝8.4Hz,1H),6.40(dd,J＝8.9,1.3Hz,1H),5.94(d,J＝1.8Hz,1H),3.63(s,3H),2.35–2.21(m,4H),1.96–1.79(m,4H).

Step 6 Synthesis of 6-chloro-5-fluoro-1- (1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

Triphosgene (0.96 g,3.24 mmol) was added to a solution of 1- (3-chloro-2-fluoro-6- ((1-methyl-1H-pyrazol-5-yl) amino) phenyl) cyclopenta-1-ol (250 mg,0.81 mmol) and triethylamine (0.98 g,9.72 mmol) in dichloromethane (10 mL) at 0℃and stirred at room temperature for 1H. Dichloromethane (50 mL) was added to the reaction solution, the organic phase was washed with water (30 ml×3), dried over anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) =3/1) to give a white solid (145mg,53.17％).LC-MS:336.20[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.62(d,J＝1.9Hz,1H),7.23–7.16(m,1H),6.29(d,J＝1.9Hz,1H),6.09(dd,J＝8.9,1.2Hz,1H),3.69(s,3H),2.49–2.28(m,4H),2.14–2.00(m,2H),1.99–1.88(m,2H).

Step 7 Synthesis of 6-chloro-5-fluoro-1- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one

6-Chloro-5-fluoro-1- (1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one (130 mg,0.39 mmol) and N-iodosuccinimide (175 mg,0.78 mmol) were dissolved in acetic acid (5 mL), and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bisulphite solution (5 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added for dilution, the organic phase was washed with water (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate (v/v) =5/1) to give a yellow solid (156mg,87.27％).LC-MS:462.00[M+H]⁺;¹H NMR(400MHz,CD₃Cl)δ7.65(s,1H),7.25–7.19(m,1H),6.00–5.93(m,1H),3.79(s,3H),2.67–2.54(m,2H),2.37–2.14(m,2H),2.05(s,2H),1.97–1.90(m,2H).

Step 8 Synthesis of tert-butyl ((7- (5- (6-chloro-5-fluoro-2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate

6-Chloro-5-fluoro-1- (4-iodo-1-methyl-1H-pyrazol-5-yl) spiro [ benzo [ d ] [1,3] oxazin-4, 1 '-cyclopentane ] -2 (1H) -one (150 mg,0.33 mmol), ((4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (199mg, 0.49 mmol), 1' -bis (di-tert-butylphosphino) ferrocene dichloropalladium (22 mg, 33. Mu. Mol) and sodium carbonate (70 mg,0.66 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL) and stirred under nitrogen protection at 90℃for 2H. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 ml×3), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =50/1) to give a yellow solid (42mg,21.21％).LC-MS:609.50[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.49–8.41(m,1H),8.34(d,J＝8.3Hz,1H),8.05(s,1H),7.93–7.84(m,1H),7.59(d,J＝9.3Hz,1H),7.21–7.14(m,1H),6.01(d,J＝8.9Hz,1H),5.37(t,J＝5.4Hz,1H),4.63–4.51(m,2H),3.77(s,3H),2.59–2.49(m,1H),2.28(d,J＝30.5Hz,3H),2.13–1.91(m,4H),1.48(s,9H).

Step 9 Synthesis of 1- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -6-chloro-5-fluoro-spiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -2 (1H) -one hydrochloride

Tert-butyl ((7- (5- (6-chloro-5-fluoro-2-oxospiro [ benzo [ d ] [1,3] oxazin-4, 1' -cyclopentane ] -1 (2H) -yl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate (30 mg, 47. Mu. Mol) was dissolved in dichloromethane (1 mL), and hydrogen chloride (1 mL,4M 1, 4-dioxane solution) was added thereto and stirred at room temperature for 3H. Concentrating under reduced pressure by rotary evaporation to obtain yellow solid (20mg,74.06％).¹H NMR(400MHz,CD₃OD)δ8.29(d,J＝8.3Hz,1H),8.16(s,1H),7.85(s,1H),7.67(d,J＝8.3Hz,1H),7.35(dd,J＝9.0,4.1Hz,1H),7.02(dd,J＝10.4,9.2Hz,1H),4.45(s,2H),3.79(s,3H),2.62–2.47(m,2H),2.22–1.93(m,6H);LC-MS:537.40[M+H]⁺.

Biological Activity test examples

1. PRMT5 enzyme Activity assay

1. Experimental procedure

Compound preparation and sample addition compound was dissolved in DMSO to 10mM stock solution, corresponding dosing dilutions were prepared, initial final concentration 10 μm, 3-fold gradient dilutions were set, 10 concentration points were set, and DMSO blank wells and MRTX1719 10 μm positive control wells were additionally set. 20nl of the prepared drug dilutions were transferred to 384 well plates, 2 wells were multiplexed and centrifuged at 1000 rpm.

Enzyme and substrate working solutions are added, namely two experimental groups of adding MTA and not adding MTA are respectively arranged, 2 mu L of working solution containing MTA or not containing MTA of PRMT5/MEP50 is added to each hole, and incubation is carried out for 15min at 25 ℃. Then 2. Mu.L of Bio-H4 (1-21) & SAM working solution was added to each well and incubated at 25℃for 180min.

Adding MTase-Glo ^TM reaction solution and detection solution, adding 1 mu L of 5-X MTase-Glo ^TM reaction solution to each hole, centrifuging at 1000rpm, incubating at 25 ℃ for 30min, adding 5 mu L MTase-Glo ^TM detection solution to each hole, centrifuging at 1000rpm, and incubating at 25 ℃ for 30min.

And (3) detecting a read plate, namely placing the 384-well plate on the read plate machine to detect the chemiluminescent signal value.

2. Experimental data processing:

1) Inhibition ratio%100× (mean value of blank wells-detection value per well)/(mean value of blank wells-mean value of positive drug wells)

Mean value of the blank wells refers to mean detection value of the DMSO blank wells

Mean value of positive drug control wells refers to the mean detection value of positive control MRTX at the highest administration concentration of 10. Mu.M

2) The IC ₅₀ value calculating method is that the IC ₅₀ value is obtained through a GRAPH PAD PRISM 8.0 software nonlinear fitting formula, and the calculating formula is as follows:

Y=Bottom+(Top-Bottom)/(1+10^((LogEC50-X)×HillSlope))

x is the log value Y of the compound concentration, and the inhibition rate is%

The specific experimental results are shown in table 1.

TABLE 1 IC ₅₀ values of the compounds of the invention for PRMT 5-mediated enzymatic Activity

Conclusion the results in table 1 demonstrate that the compounds of the present invention synergistically inhibit PRMT5 enzyme activity in the presence of MTA.

In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "some implementations," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that changes, modifications, substitutions and variations may be made therein by those of ordinary skill in the art without departing from the spirit and scope of the invention, which is defined by the appended claims and their equivalents.

Claims (10)

1. A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I), in, X is N or CH; Q ¹ is N or CR ^7a ; Q ² is N or CR ^7b ; Q ³ is N or CR ^7c ; Q ⁴ is N or CR ^7d ; Q ⁵ is a bond, NH, O or CH ₂ ; n is 0 or 1; Ring A is a 5-12 membered heteroaryl or a C _6-10 aryl group, wherein the ring A is optionally substituted by 1 or 2 ^Ras ; each ^Ra is independently D, F, Cl, Br, I, CN, OH, C(=O ⁾ OH, ^-NR9R8 , _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 cyanoalkyl, _C1-6 alkoxy, _C3-6 cycloalkyl or _C1-6 haloalkyl; Ring B is a 3-7 membered cycloalkyl or a 3-7 membered heterocyclyl, wherein the ring B is optionally substituted by 1, 2 or 3 substituents independently selected from D, F, Cl, Br, I, NH ₂ , CN, OH, C(═O)OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl and C _1-6 haloalkyl; R ¹ , R ² , R ³ and R ⁴ are each independently H, D, F, Cl, Br, I, CN, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -NR ⁹ R ⁸ , -S(═O) ₂ R ⁸ , -S(═O)R ⁸ , -C(═O)OR ⁸ , -NR ⁹ C(═O)R ⁸ , -C(═O)NR ⁹ R ⁸ , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C 3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-6 membered heteroaryl or C _6-10 aryl; ^R5 and ^R6 are each independently H, D, F, Cl, Br, I, CN, OH, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 cyanoalkyl, _C1-6 alkoxy, _C3-6 cycloalkyl or _C1-6 haloalkyl; or, ^R5 , ^R6 and the carbon atom to which they are attached together form C=O; R ^7a , R ^7b , R ^7c and R ^7d are each independently H, D, F, Cl, Br, I, CN, OH, C(═O)OH, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or C _1-6 haloalkyl; and ^R8 and ^R9 are each independently H, D, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 cyanoalkyl, _C1-6 haloalkyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-6 membered heteroaryl or _C6-10 aryl. 2. The compound according to claim 1, wherein Ring A is pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, pyrazolopyridinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl or phenyl, wherein Ring A is optionally substituted with 1 or 2 ^Ra ; Each ^Ra is independently D, F, Cl, Br, I, CN, OH, C(= ^O )OH, ^-NR9R8 , _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 cyanoalkyl, _C1-4 alkoxy, _C1-4 heteroalkyl, _C3-6 cycloalkyl or _C1-4 haloalkyl. 3. The compound according to claim 1 or 2, wherein ring A is wherein the ring A is optionally substituted by 1 or 2 R ^a ; each ^Ra is independently D, F, Cl, Br, I, CN, OH, C(=O)OH, _-NH2 , _-CH3 , -CH2CH3, -(CH2) _2CH3 , _{-CH (CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3 , -CH2OH , -CH2CN , -CH2F , -CHF2 , -CF3 , - ( CH2 ) 2F , cyclopropyl} , cyclobutyl, cyclopentyl or _cyclohexyl . 4. The compound according to any one of claims 1 to 3, wherein Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein Ring B is optionally substituted by 1, 2 or 3 substituents independently selected from D, F, Cl, Br, I, _NH2 , CN, OH, C(=O)OH, _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 cyanoalkyl, _C1-4 alkoxy, _C3-6 cycloalkyl and _C1-4 haloalkyl. 5. The compound according to any one of claims 1 to 4, wherein R ¹ , R ² , R ³ and R ⁴ are each independently H, D, F, Cl, Br, I, CN, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -NR ⁹ R ⁸ , -S(＝O) ₂ R ⁸ , -S(＝O)R ⁸ , -C(＝O)OR ⁸ , -NR ⁹ C(＝O)R ⁸ , -C(＝O)NR ⁹ R ⁸ , C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C _6-10 aryl; ^R5 and ^R6 are each independently H, D, F, Cl, Br, I, CN, OH, _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 cyanoalkyl, _C1-4 alkoxy, _C3-6 cycloalkyl or _C1-4 haloalkyl; or ^R5 and ^R6 together with the carbon atom to which they are attached form C=O; R ^7a , R ^7b , R ^7c and R ^7d are each independently H, D, F, Cl, Br, I, CN, OH, C(═O)OH, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 cyanoalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or C _1-4 haloalkyl; and ^R8 and ^R9 are each independently H, D, _C1-4 alkyl, _C1-4 hydroxyalkyl, _C1-4 cyanoalkyl, _C1-4 haloalkyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-6 membered heteroaryl or _C6-10 aryl. 6. The compound according to any one of claims 1 to 5, wherein R ¹ , R ² , R ³ and R ⁴ are each independently H, D, F, Cl, Br, I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -(CH ₂ ) ₂ CH ₃ , -CH(CH ₃ ) ₂ , -(CH ₂ ) ₃ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH＝CH ₂ , -CH ₂ CH＝CH ₂ , -CH＝CHCH ₃ , -C≡CH , -C≡C(CH ₃ ), -C≡CCH ₂ CH ₃ , -CH ₂ C≡CH , -CH ₂ C≡C(CH ₃ ), -NR ⁹ R ⁸ , -S(＝O) ₂ R ⁸ , -S(=O)R ⁸ , -C(=O)OR ⁸ , -NR ⁹ C(=O)R ⁸ , -C(=O)NR ⁹ R ⁸ , -CH ₂ F, -CHF ₂ , -CF ₃ , -(CH ₂ ) ₂ F, -CHCl ₂ , -CH ₂ Cl, -CH ₂ Br, -(CH ₂ ) ₂ Cl, -CH ₂ OH, -(CH ₂ ) ₂ OH, -(CH ₂ ) ₃ OH, -(CH ₂ ) ₄ OH, -CH(OH)CH ₃ , -C(OH)(CH ₃ ) ₂ , (CH ₂ ) ₄ OH, -CH ₂ CN, -(CH ₂ ) ₂ CN, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ ,-OCF ₃ , -OCH ₂ F, -OCHF ₂ , -OCHCl ₂ , -OCH ₂ CF ₃ , -OCH ₂ CHCl ₂ , -OCH ₂ CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl or naphthyl; ^R5 and ^R6 are each independently H, D, F, Cl, Br, I, CN, OH, -CH3, _{-CH2CH3, -(CH2)2CH3 , -CH (} CH3) ₂ , -( _CH2 ) _3CH3 , -CH2CH( _CH3 ) ₂ , -C( _CH3 ) ₃ , _-CH2OH , _-CH2CN , _-OCH3 , _-OCH2CH3 , _-CH2F , _-CHF2 , _-CF3 , _- ( _CH2 ) _2F , cyclopropyl, _{cyclobutyl ,} cyclopentyl _or cyclohexyl _; or _, ^R5 , ^R6 and the carbon atom to which they are attached together form C=O; R ^7a , R ^7b , R ^7c and R ^7d are each independently H, D, F, Cl, Br, I, CN, OH, C(═O)OH, —CH ₃ , —CH ₂ CH ₃ , —(CH ₂ ) ₂ CH ₃ , —CH(CH ₃ ) ₂ , —(CH ₂ ) ₃ CH ₃ , —CH ₂ CH(CH ₃ ) ₂ , —C(CH ₃ ) ₃ , —CH ₂ OH, —CH ₂ CN, —OCH ₃ , —OCH ₂ CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , —(CH ₂ ) ₂ F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl; and ^R8 and ^R9 are each independently H, D, -CH3, _-CH2CH3 , _{- (CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 , -C ( CH3 ) 3 , -CH2OH , -CH2CN , -CH2F , -CHF2 , -CF3 , -} ( _CH2 ) _2F , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, phenyl or naphthyl. 7. A compound according to any one of claims 1 to 6, which is a compound of formula (IA) or (IB), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (IA) or (IB), wherein Ring B, n, Q ⁵ , R ¹ , R ² , R ³ , R ⁴ and ^Ra are each as defined in any one of claims 1 to 6. 8. The compound according to any one of claims 1 to 7, which is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound shown below, 9. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound; optionally, further comprising a pharmaceutically acceptable adjuvant. 10. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing, treating or treating cancer in a patient, wherein the cancer is a MTAP deficiency-related cancer.