PRMT5 inhibitor, pharmaceutical composition of PRMT5 inhibitor and application of PRMT5 inhibitor in medicine

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a PRMT5 inhibitor, a pharmaceutical composition thereof and application of the PRMT5 inhibitor in medicines. Specifically, the invention relates to a compound as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I). The compound and the pharmaceutical composition thereof can be used for preparing medicines for preventing or treating PRMT5 related diseases, and particularly can be used for preparing medicines for preventing or treating PRMT5 related cancers.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a class of PRMT5 inhibitors, pharmaceutical compositions thereof and applications thereof in medicines. Background Art

[0002] PRMT5 (protein arginine methyltransferase 5) is a protein arginine methyltransferase 5, which exists in the nucleoplasm and cytoplasm of cells. It is expressed in various tissues and organs of the human body to varying degrees, and has no significant tissue-specific distribution. Its ligand is the methyl donor SAM (S-adenosyl methionine). After binding to SAM, it catalyzes the monomethylation and symmetric dimethylation of arginine residues on histones and non-histones, and belongs to type II arginine methyltransferase. PRMT5 plays an important role in maintaining tissue stability, as well as the survival and self-renewal ability of stem cells / progenitor cells in the nervous system, muscle, reproductive and hematopoietic systems. PRMT5 is found to be highly expressed in many human solid tumors such as lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia or lymphoma and malignant glioma, and the high expression of PRMT5 is closely related to the occurrence and development of tumors and poor prognosis.

[0003] MTAP is often co-deficient with the tumor suppressor gene CDKN2A in tumors. Studies have found that compared with cells with normal MTAP, MTA accumulates in large quantities in MTAP-deficient tumor cells, while SAM synthesis decreases. MTA is a SAM analog that can competitively bind to PRMT5 with SAM to selectively weaken PRMT5 activity. At this time, MTAP-deficient tumor cells significantly rely on PRMT5 for survival. The development of PRMT5-MTA synergistic inhibitors can stabilize the structure of the PRMT5-MTA complex, inhibit the binding of SAM to PRMT5, and thus selectively kill MTAP-deficient tumor cells without affecting cells with normal MTAP.

[0004] MRTX1719 is a PRMT5-MTA synergistic inhibitor developed by Mirati therapeutics Inc., which has significant anti-tumor effects in multiple tumor cell lines (MTAP deletion) in vitro. However, new PRMT5-MTA synergistic inhibitors are still needed to prevent and treat cancers related to MTAP deletion. Summary of the invention

[0005] The present invention provides a PRMT5-MTA synergistic inhibitor, which can inhibit the binding of SAM to PRMT5, thereby selectively killing MTAP-deficient tumor cells to treat cancer. The present invention also provides a pharmaceutical composition containing such compounds, and the use of such compounds and their pharmaceutical compositions in the preparation of drugs for preventing or treating cancer.

[0006] In one aspect, the present invention provides 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),

[0007]

[0008] in,

[0009] X is N or CH;

[0010] Q 1 N or CR 7a ;

[0011] Q 2 N or CR 7b ;

[0012] Q 3 N or CR 7c ;

[0013] Q 4 N or CR 7d ;

[0014] Q 5 is a bond, NH, O or CH 2 ;

[0015] n is 0 or 1;

[0016] Ring A is a 5-12 membered heteroaryl or C 6-10 Aryl, wherein the ring A is optionally substituted by 1 or 2 R a replaced by;

[0017] Each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , 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;

[0018] 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 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 Substituted by a haloalkyl substituent;

[0019] R 1 , R 2 , R 3 and R 4 Each independently represents 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 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl;

[0020] R 5 and R 6 Each independently represents 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 , R 6 Together with the carbon atom to which they are attached, they form C=O;

[0021] R 7a , R 7b , R 7c and R7d Each independently represents 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 heterocyclic group or C 1-6 haloalkyl; and

[0022] R 8 and R 9 Each independently is 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.

[0023] In some embodiments, ring A is pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, pyrazolopyridinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl or phenyl, wherein the ring A is optionally substituted by 1 or 2 R a replaced by;

[0024] Each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , 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 Halogenated alkyl.

[0025] In other embodiments, Ring A is

[0026] wherein the ring A is optionally substituted by 1 or 2 R a replaced by;

[0027] Each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NH 2 、-CH 3 、-CH2 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、-CH 2 F, -CHF 2 , -CF 3 、-(CH 2 ) 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0028] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the ring B is optionally substituted by 1, 2 or 3 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 The alkyl group is substituted with a haloalkyl substituent.

[0029] In some embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents 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 R8 , C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Cyanoalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl;

[0030] R 5 and R 6 Each independently represents 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 atom to which they are attached, they form C=O;

[0031] R 7a , R 7b , R 7c and R 7d Each independently represents 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 heterocyclic group or C 1-4 haloalkyl; and

[0032] R 8 and R 9 Each independently is 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.

[0033] In other embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents H, D, F, Cl, Br, I, CN, OH, -CH 3 、-CH 2 CH 3 、-(CH2 ) 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、-(CH2 ) 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;

[0034] R 5 and R 6 Each independently represents 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 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 or cyclohexyl; or, R 5 , R 6 Together with the carbon atom to which they are attached, they form C=O;

[0035] R7a , R 7b , R 7c and R 7d Each independently represents 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

[0036] R 8 and R 9 are independently H, D, -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、-CH 2 F, -CHF 2 , -CF 3 、-(CH2 ) 2 F, 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.

[0037] In some embodiments, the compound of the present invention is a compound of formula (IA) or (IB) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound of formula (IA) or (IB).

[0038]

[0039] Among them, ring B, n, Q 5 , R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention.

[0040] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound; optionally, further comprising a pharmaceutically acceptable adjuvant.

[0041] In another aspect, the present invention provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating or curing cancer in a patient.

[0042] In some embodiments, the cancer is a MTAP deficiency-associated cancer; optionally, the MTAP deficiency-associated cancer is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

[0043] In another aspect, the present invention provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing, managing or treating cancer.

[0044] In another aspect, the present invention provides a method for preventing, managing or treating cancer, comprising administering to a patient a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.

[0045] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds represented by formula (I), (IA) or (IB).

[0046] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0047] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.

[0048] The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds represented by formula (I), (IA) or (IB) or separated enantiomers of the compounds represented by formula (I), (IA) or (IB), but are not necessarily pharmaceutically acceptable salts.

[0049] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.

[0050] Detailed description of the invention

[0051] Definitions and general terms

[0052] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0053] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0054] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0055] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0056] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0057] "Stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.

[0058] The stereochemical definitions and conventions used herein generally follow SP 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.

[0059] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0060] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0061] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted" or "optionally substituted" are 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 by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.

[0062] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0063] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4Alkyl, C 5 Alkyl and C 6 alkyl.

[0064] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0065] The term "alkyl" refers to 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 and is represented by C 1-6 In another embodiment, the alkyl group contains 1-4 carbon atoms and is represented by C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 )2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.

[0066] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, represented by C 2-6 In another embodiment, the alkenyl group contains 2-4 carbon atoms and is represented by C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (i.e., propenyl, -CH=CH-CH 3 ),etc.

[0067] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms, represented by C 2-6 In another embodiment, the alkynyl group contains 2-4 carbon atoms and is represented by C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propargyl (—CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 )etc.

[0068] The term "cyanoalkyl" refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted by one cyano group. In some embodiments, "cyanoalkyl" is C 1-6 Cyanoalkyl, i.e., C substituted by one or more cyano groups 1-6 In some preferred embodiments, C1-6 Cyanoalkyl is a C substituted with a cyano group. 1-6 In other embodiments, "cyanoalkyl" is C 1-4 Cyanoalkyl, i.e., C substituted by one or more cyano groups 1-4 Examples of cyanoalkyl groups include, but are not limited to, -CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH(CN)CH 2 CH 2 CN、-CH 2 CH(CN)CH 2 CH(CH 3 )CN, etc.

[0069] The term "hydroxyalkyl" refers to 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 refers to an alkyl group substituted with 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 Hydroxyalkyl, i.e. C 1-6 The alkyl group is substituted with one or more hydroxyl groups. 1-6 Hydroxyalkyl represents C 1-6 In some embodiments, hydroxyalkyl represents C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH(CH 3 )OH, etc.

[0070] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein.1-6 Haloalkyl, indicating C 1-6 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-4 Haloalkyl, indicating C 1-4 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-3 Haloalkyl, indicating C 1-3 The alkyl group is substituted with one or more halogen atoms. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0071] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, indicating C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, indicating C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, indicating C 1-3 Alkoxy. 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 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy(i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH3 ), 2-methyl-2-propoxy(t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy(-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy(-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy(-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy(-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ),etc.

[0072] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein. In some embodiments, the haloalkoxy group refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 In other embodiments, the haloalkoxy group represents a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 In other embodiments, the haloalkoxy group represents a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (-OCF 3 ), monofluoromethoxy (-OCH 2 F), 2-fluoroethoxy (-OCH 2 CH 2 F), etc.

[0073] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, wherein -CH 2 The -group may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group contains 3 to 10 ring carbon atoms, i.e., C 3-10 In another embodiment, the cycloalkyl group contains 3-6 ring carbon atoms, i.e., C 3-6 In another embodiment, the cycloalkyl group contains 3-5 ring carbon atoms, i.e., C 3-5 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydropentalenyl, and the like. 2 Examples of the - group which may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0074] The term "heterocycle" or "heterocyclyl" refers to 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 nitrogen, sulfur and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic ring. When the heterocycle is attached to the rest of the molecule through one attachment point, the heterocycle represents a monovalent heterocyclyl. Unless otherwise specified, the heterocyclyl may be a carbonyl or nitrogenyl group, and -CH 2-group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclic radical consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclic radical; in other embodiments, the heterocycle or heterocyclic radical consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membered heterocyclic radical. Examples of the heterocycle include, but are not limited to, oxirane, 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, oxirane, aziridine, azetidine, oxetanyl, thiidine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.

[0075] The term "aryl" refers to a monovalent carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system contains 3-7 ring atoms. In some embodiments, the aryl group contains 6-12 ring atoms and is represented by C 6-12 In some embodiments, the aryl group contains 6-10 ring atoms and is represented by C 6-10 Aryl or 6-10 membered aryl. Examples of the aryl group may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.

[0076] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. When the -CH 2 - group, the -CH 2-group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be connected to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable site (which can be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, expressed as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, expressed as a 5-10-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, expressed as a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolyl, and the like.

[0077] The term "composed of jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k and any natural number in between. For example, “consisting of 3-8 atoms” or “3-8 members”, “consisting of 3-6 atoms” or “3-6 members”, “consisting of 5-10 atoms” or “5-10 members”, or “consisting of 5-6 atoms” or “5-6 members” 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, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0078] As described in the present invention, the ring system formed by ring A connected to the central ring by a bond means that ring A can be substituted at any substitutable position or any reasonable position on the ring. As follows,

[0079] Expressed as

[0080] It should be further recognized that the compounds obtained by combining the groups in the embodiments of the present invention should be stable and reasonably existent structures. 1 , Q 2 , Q 3 or Q 4 When any one of them is connected, Q 1, Q 2 , Q 3 or Q 4 is not N; specifically, when ring A and Q 1 When connected, Q 1 Not for N, Q 1 is CH, ring A is Q 1 The substituents on the 2 , Q 3 or Q 4 As defined in the present invention.

[0081] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (IA) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0082] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. 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.

[0083] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -C 8 Sulfonates and aromatic sulfonates.

[0084] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association formed by a solvent molecule being water.

[0085] When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0086] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0087] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease."Therapeutically effective amount" may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.

[0088] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are encompassed within the scope of the present invention.

[0089] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

[0090] Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in methylene chloride, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or methylene chloride.

[0091] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I.

[0092] Description of the compounds of the present invention

[0093] The present invention provides a PRMT5-MTA synergistic inhibitor, which can selectively inhibit the binding of SAM to PRMT5 to treat related cancers. The present invention also provides a pharmaceutical composition containing such compounds, and the use of such compounds and their pharmaceutical compositions in the preparation of drugs for preventing or treating cancer.

[0094] The excellent properties of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can contribute to the reduction of side effects, the expansion of therapeutic index or the improvement of tolerability.

[0095] In one aspect, the present invention provides 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),

[0096]

[0097] Among them, ring A, ring B, X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q 1 , Q 2 , Q 3 , Q 4 and Q 5 Each has the definition as described in the present invention.

[0098] In some embodiments, X is N or CH.

[0099] In some embodiments, Q 1 N or CR 7a , where R 7a Has the meaning described in the present invention.

[0100] In some embodiments, Q 2 N or CR 7b , where R 7b Has the meaning described in the present invention.

[0101] In some embodiments, Q 3 N or CR 7c , where R 7c Has the meaning described in the present invention.

[0102] In some embodiments, Q 4 N or CR 7d , where R 7d Has the meaning described in the present invention.

[0103] In some preferred embodiments, Q 1 , Q 2 , Q 3 and Q 4 All are CH.

[0104] In some embodiments, Q 5 is a bond, NH, O or CH 2 .

[0105] In some embodiments, Q 5 For a key.

[0106] In some embodiments, Q 5 is O.

[0107] In some embodiments, n is 0 or 1.

[0108] In some embodiments, Ring A is a 5-12 membered heteroaryl or C 6-10 Aryl, wherein the ring A is optionally substituted by 1 or 2 R a replaced by, where R a Has the meaning described in the present invention.

[0109] In some embodiments, ring A is pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole, triazolyl, pyridazinyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, pyrazolopyridinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl or phenyl, wherein the ring A is optionally substituted by 1 or 2 R a replaced by, where R a Has the meaning described in the present invention.

[0110] In some embodiments, Ring A is

[0111] wherein the ring A is optionally substituted by 1 or 2 R a replaced by, where R a Has the meaning described in the present invention.

[0112] In some embodiments, each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0113] In some embodiments, each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , 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 Halogenated alkyl.

[0114] In some embodiments, each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NH 2 、-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、-CH 2 F, -CHF 2 , -CF 3 、-(CH 2 ) 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0115] In some preferred embodiments, Ring A is

[0116] In some embodiments, 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 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 The alkyl group is substituted with a haloalkyl substituent.

[0117] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the ring B is optionally substituted by 1, 2 or 3 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 The alkyl group is substituted with a haloalkyl substituent.

[0118] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the ring B is optionally substituted by 1, 2 or 3 independently selected from D, F, Cl, Br, I, NH 2 , 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、-OCH3 、-OCH 2 CH 3 、-CH 2 F, -CHF 2 , -CF 3 、-(CH 2 ) 2 F, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl substituents.

[0119] In some embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents 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 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl, wherein each R 8 and R 9 Has the meaning described in the present invention.

[0120] In some embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents 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)R8 、-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 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl, wherein each R 8 and R 9 Has the meaning described in the present invention.

[0121] In some embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents 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 、-CH2 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, pyridyl, pyrazinyl, pyrimidinyl, phenyl or naphthyl, wherein each R 8 and R 9 Has the meaning described in the present invention.

[0122] In some embodiments, R 5 and R 6 Each independently represents H, D, F, Cl, Br, I, CN, OH, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0123] In some embodiments, R 5 and R 6 Each independently represents 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 Halogenated alkyl.

[0124] In some embodiments, R 5 and R 6 Each independently represents 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 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 or cyclohexyl.

[0125] In some embodiments, R 5 , R 6 Together with the carbon atom to which they are attached they form C=O.

[0126] In some embodiments, R 8 and R 9 Each independently is H, D, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Cyanoalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl.

[0127] In some embodiments, R 7a , R 7b , R 7c and R 7d Each independently represents 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 heterocyclic group or C 1-6 Halogenated alkyl.

[0128] In some embodiments, R 7a , R 7b , R 7c and R 7d Each independently represents 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 heterocyclic group or C 1-4 Halogenated alkyl.

[0129] In some embodiments, R 7a , R 7b , R 7c and R 7d Each independently represents 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、-OCH3 、-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.

[0130] In some embodiments, R 8 and R 9 Each independently is 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.

[0131] In some embodiments, R 8 and R 9 are independently H, D, -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、-CH 2 F, -CHF 2 , -CF 3 、-(CH 2 ) 2 F, 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.

[0132] In some embodiments, the compound of the present invention is a compound represented by formula (IA), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (IA).

[0133]

[0134] Among them, ring B, n, R 1 , R 2 , R 3 , R 4 and R a Each has the definition described in the present invention.

[0135] In some embodiments, the compound of the present invention is a compound of formula (IB), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound of formula (IB).

[0136]

[0137] Among them, ring B, n, Q 5 , R 1 , R 2 , R 3 , R 4 and R a Each has the definition described in the present invention.

[0138] In some embodiments, the compound described in the present invention is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound shown below,

[0139]

[0140]

[0141]

[0142] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound; optionally, further comprising a pharmaceutically acceptable adjuvant.

[0143] In another aspect, the present invention provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, managing or treating cancer in a patient.

[0144] In another aspect, the present invention provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing, managing or treating cancer.

[0145] In another aspect, the present invention provides a method for preventing, managing or treating cancer, comprising administering to a patient a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.

[0146] In some embodiments, the cancer described herein is a MTAP deficiency-associated cancer.

[0147] In some embodiments, the MTAP deficiency-associated cancer described herein is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

[0148] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds represented by formula (I), (IA) or (IB).

[0149] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0150] Preparation, administration and use of the pharmaceutical composition of the compound of the present invention

[0151] The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), (IA) or (IB), a compound listed in the present invention, or a compound of the embodiments and a pharmaceutically acceptable adjuvant. The compound of the present invention exists in free form, or is suitable as a pharmaceutically acceptable derivative. 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 directly or indirectly administered according to the needs of the patient, the compounds described in other aspects of the present invention, their metabolites or their residues.

[0152] As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0153] The compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.

[0154] The compounds or pharmaceutical compositions of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or transdermally by use of transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the medication period.

[0155] The compounds or pharmaceutical compositions of the present invention can 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 phosphatidylcholine.

[0156] The dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific 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 type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect. A physician can make a decision and prescribe an effective amount of a drug to prevent, offset or arrest the development of cancer.

[0157] The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the present invention can be included in a single formulation or in a separate formulation with other therapeutic agents.

[0158] When the compounds of the invention are administered with other therapeutic agents, generally the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.

[0159] The compositions and methods provided by the present invention are particularly contemplated to be useful for inhibiting PRMT5 activity in cells in vivo. In some embodiments, cells in need of inhibiting PRMT5 activity are contacted in vivo with a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to negatively regulate the activity of PRMT5.

[0160] The compounds and compositions of the present invention can be used to treat 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 carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, bladder cancer, pancreatic cancer, liver cancer, bile duct cancer, glioblastoma.Specifically, these compounds can be used to treat the following diseases: Heart: sarcoma, myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: bronchial carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urinary Genital tract: Kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondrotic exostosis, benign cartilage Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors, glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecological: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer, granulocyte-theca tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic mole, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.

[0161] In some embodiments, the cancer is a MTAP deletion-associated cancer.

[0162] In some embodiments, the MTAP deficiency-associated cancer is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, bile duct cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

[0163] General synthesis process

[0164] To describe the present invention, the present invention will further illustrate the technical scheme of the present invention with the following examples. The following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention. In the specific implementation method of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art.

[0165] Unless otherwise specified, the substituents are as defined herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0166] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0167] In the examples described below, all temperatures are set in degrees Celsius (°C) unless otherwise indicated. The room temperature in the examples means 15°C–30°C; in some examples, the room temperature is 20°C–30°C. Unless otherwise indicated, general reagents can be purchased from the market. Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform are obtained by reflux drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried over anhydrous sodium sulfate before use.

[0168] The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0169] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectrum of CDC1 3 DMSO-d6 , CD 3 OD or acetone-d 6 is the solvent (in ppm), TMS (0 ppm) or chloroform (7.26 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet, br.s, broad singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0170] The low-resolution mass spectrometry (MS) data were measured under the following conditions: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL / min. Mobile phase: 5%-95% (CH 3 CN) in (H 2 O) using electrospray ionization (ESI) at 210 nm / 254 nm with UV detection.

[0171] The pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) at 210 nm / 254 nm with UV detection.

[0172] The following abbreviations are used throughout this invention:

[0173] NBS N-Bromosuccinimide

[0174] AIBN Azobisisobutyronitrile

[0175] XPhos G3 Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0176] Boc tert-Butyloxycarbonyl

[0177] PE Petroleum Ether

[0178] EA,EtOAc Ethyl acetate

[0179] DCM Dichloromethane

[0180] CD 3 OD Deuterated methanol

[0181] MeOH Methanol

[0182] CDCl 3 Deuterated chloroform

[0183] ℃ Celsius

[0184] h hour

[0185] mg milligram

[0186] g

[0187] mmol millimole

[0188] M,mol / L mole per liter

[0189] mL milliliters

[0190] Synthesis scheme

[0191] The following synthesis scheme lists the general experimental steps for preparing the compounds disclosed in the present invention, including that those skilled in the art can make appropriate method modifications or raw material adjustments according to actual conditions to prepare the compounds of the present invention.

[0192] Synthesis Scheme 1

[0193]

[0194] Compound (I) can be prepared by the synthesis process of Synthesis Scheme 1, wherein ring A, ring B, X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q 1 , Q 2 , Q 3 , Q 4 and Q 5 Each has the definition as described in the present invention; Hal 2is Cl, Br or I, preferably Br or I; Pg is an amino protecting group, preferably Boc. Compound (I-1) and compound (I-2) undergo coupling reaction in a suitable solvent (such as a mixed solution of 1,4-dioxane and water) under a suitable catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium) and alkaline conditions (such as sodium carbonate, etc.) to obtain compound (I-3); compound (I-3) is deprotected from the amino protecting group under acidic conditions (such as trifluoroacetic acid or hydrochloric acid, etc.) to obtain compound (I) or an acid addition salt of compound (I).

[0195] Synthesis Scheme 2

[0196]

[0197] Compound (IA) can be prepared by the synthesis process of Synthesis Scheme 2, wherein ring B, n, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Pg is an amino protecting group, preferably Boc. Compound (IA-1) reacts with N-iodosuccinimide to obtain compound (IA-2); compound (IA-2) and compound (IA-3) undergo coupling reaction in a suitable solvent (such as a mixed solution of 1,4-dioxane and water) under a suitable catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium, etc.) and alkaline conditions (such as sodium carbonate, etc.) to obtain compound (IA-4); compound (IA-4) removes the amino protecting group under acidic conditions (such as trifluoroacetic acid or hydrochloric acid, etc.) to obtain compound (IA) or an acid addition salt of compound (IA).

[0198] Synthesis Scheme 3

[0199]

[0200] Compound (IB) can be prepared by the synthesis process of Synthesis Scheme 3, wherein ring B, n, Q 5 , R 1 , R 2 , R 3 , R 4 and R aEach has the definition as described in the present invention; Pg is an amino protecting group, preferably Boc. Compound (IB-1) reacts with N-iodosuccinimide to obtain compound (IB-2); compound (IB-2) and compound (IA-3) undergo coupling reaction in a suitable solvent (such as a mixed solution of 1,4-dioxane and water) under a suitable catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium, etc.) and alkaline conditions (such as sodium carbonate, etc.) to obtain compound (IB-3); compound (IB-3) removes the amino protecting group under acidic conditions (such as trifluoroacetic acid or hydrochloric acid, etc.) to obtain compound (IB) or an acid addition salt of compound (IB).

[0201] Synthesis Scheme 4

[0202]

[0203] Compound (IC) can be prepared by the synthesis process of Synthesis Scheme 4, wherein ring B, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Pg is an amino protecting group, preferably Boc. Compound (IC-1) reacts with N-iodosuccinimide to obtain compound (IC-2); compound (IC-2) and compound (IA-3) undergo coupling reaction in a suitable solvent (such as a mixed solution of 1,4-dioxane and water) under a suitable catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium, etc.) and alkaline conditions (such as sodium carbonate, etc.) to obtain compound (IC-3); compound (IC-3) removes the amino protecting group under acidic conditions (such as trifluoroacetic acid or hydrochloric acid, etc.) to obtain compound (IC) or an acid addition salt of compound (IC).

[0204] Synthesis Scheme A

[0205]

[0206]

[0207] The synthesis of intermediate (IA-1) can be prepared by the synthesis process of synthesis scheme A, wherein ring B, n, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Hal 1 is Cl, Br or I; compound (IA-1-10) is C 2-6 Alkane chain or C 2-6A heteroalkane chain with Br substituted at both ends of the chain, where C 2-6 Heteroalkane is C 2-6 The situation where the carbon atom in the alkane is replaced by a heteroatom. Compound (IA-1-1) reacts with compound (IA-1-10) under appropriate conditions (such as potassium hydroxide and tetrabutylammonium bromide) to obtain compound (IA-1-2); compound (IA-1-2) and compound (IA-1-3) undergo coupling reaction under appropriate conditions (such as 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, palladium acetate and cesium carbonate) to obtain compound (IA-1-4); compound (IA-1-4) reacts under alkaline conditions (such as sodium hydroxide, etc.) to obtain compound (IA-1-5); compound (IA-1-5) reacts with N,N-carbonyldiimidazole and N,N-diisopropylethylamine to produce compound (IA-1).

[0208] Synthesis Scheme B

[0209]

[0210] The synthesis of intermediate (IA-1) can also be prepared by the synthesis process of synthesis scheme B, wherein ring B, n, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Hal 1 is Cl, Br or I, preferably Br or I. Compound (IA-1-6) reacts with compound (IA-1-3) under appropriate conditions (such as in the presence of cuprous iodide, potassium carbonate and 4A molecular sieves in N,N-dimethylformamide solvent) to obtain compound (IA-1).

[0211] Synthesis Scheme C

[0212]

[0213]

[0214] The synthesis of intermediate (IA-1) can also be prepared by the synthesis process of synthesis scheme C, wherein ring B, n, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Hal 1 is Cl, Br or I, preferably Br or I; compound (IA-1-10) is C 2-6 Alkane chain or C 2-6 A heteroalkane chain with Br substituted at both ends of the chain, where C2-6 Heteroalkane is C 2-6 The situation where the carbon atom in the alkane is replaced by a heteroatom. Compound (IA-1-7) reacts with compound (IA-1-3) under appropriate conditions (such as in the presence of cuprous iodide, potassium carbonate and 4A molecular sieves in N,N-dimethylformamide solvent) to obtain compound (IA-1-8); compound (IA-1-8) reacts with N,N-carbonyldiimidazole in a suitable solvent (such as dichloromethane) to obtain compound (IA-1-9); compound (IA-1-9) reacts with compound (IA-1-10) under appropriate conditions (such as potassium hydroxide and tetrabutylammonium bromide) to obtain compound (IA-1).

[0215] Synthesis Scheme D

[0216]

[0217] The synthesis of intermediate (IC-1) can also be prepared by the synthesis process of synthesis scheme D, wherein ring B, R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in the present invention; Hal 1 is Cl, Br or I, preferably Br or I; Alk represents C 1-4 The alkyl group is preferably methyl or ethyl; the compound (IA-1-10) is C 2-6 Alkane chain or C 2-6 A heteroalkane chain with Br substituted at both ends of the chain, where C 2-6 Heteroalkane is C 2-6 The situation where the carbon atom in the alkane is replaced by a heteroatom. Compound (IC-1-1) and compound (IA-1-3) are heated to react under appropriate conditions (such as in the presence of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, palladium acetate and cesium carbonate in a 1,4-dioxane solvent) to obtain compound (IC-1-2); compound (IA-1-10) is firstly reacted with a Grignard reagent under the action of iodine and magnesium, and then reacted with compound (IC-1-2) at low temperature to obtain compound (IC-1-3); compound (IC-1-3) and triphosgene are reacted under appropriate conditions (such as in the presence of triethylamine in a dichloromethane solvent) to obtain compound (IC-1). Example

[0218] Example 1 Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0219]

[0220] Step 1: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0221] Under nitrogen protection, a mixture of 1-(2-iodophenyl)cyclopropane-1-carboxylic acid (500 mg, 1.74 mmol), 1-methyl-5-aminopyrazole (340 mg, 3.48 mmol), cuprous 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 at 100°C for 2 h in a microwave. 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 obtain a brown solid (89 mg, 21.43%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0222] Step 2: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0223] 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, ethyl acetate (50 mL) was added to dilute, the organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (105 mg, 81.90%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0224] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0225] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (300 mg, 0.82 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (494 mg, 1.23 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C for 2 h under nitrogen protection and 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid (153 mg, 36.33%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0226] Step 4: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0227] The compound ((7-(1-methyl-5-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-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 3 h. The reaction solution was diluted with dichloromethane (50 mL), and water (30 mL) was added. The pH was adjusted to 9 with sodium hydroxide solution (2 M), and the organic phase was separated, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure by rotary evaporation to obtain a green solid (38 mg, 85.86%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0228] Example 2: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0229]

[0230] Step 1: Synthesis of (2-iodo-3-methylphenyl)methanol

[0231] The compound 2-iodo-3-methylbenzoic acid (3.5 g, 13.36 mmol) was dissolved in tetrahydrofuran (26 mL), and borane tetrahydrofuran complex (27 mL, 1 mol / L tetrahydrofuran solution) was added, and stirred at room temperature for 5 h. The reaction was stopped, and the reaction solution was slowly dripped into methanol (50 mL), concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (2.38 g, 100%). 1 H NMR (400 MHz, CDCl 3 )δ7.31–7.24(m,2H),7.22–7.15(m,1H),4.76–4.62(m,2H),2.50(s,3H).

[0232] Step 2: Synthesis of 1-(bromomethyl)-2-iodo-3-methylbenzene

[0233] Dissolve (2-iodo-3-methylphenyl)methanol (3.30 g, 13.30 mmol) in dichloromethane (50 mL), add triphenylphosphine (3.84 g, 14.63 mmol), stir at room temperature for 45 min, add N-bromosuccinimide (2.60 g, 14.63 mmol) in batches, and stir at room temperature for 4 h. The reaction solution was washed with saturated carbonic acid solution (50 mL) and saturated brine (50 mL) in turn, the organic phase was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 20 / 1) to obtain a colorless oily product (2.55 g, 62%).

[0234] Step 3: Synthesis of 2-(2-iodo-3-methylphenyl)acetonitrile

[0235] 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 stirred at 60°C for 5.5 h. The reaction was stopped and cooled to room temperature, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), the combined organic phases were washed with saturated brine (50 mL×2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow solid product (2.05 g, 97%). 1 H NMR (400 MHz, CDCl 3 )δ7.41–7.21(m,3H),3.90(s,2H),2.52(s,3H); LC-MS:258.20[M+H] + .

[0236] Step 4: Synthesis of 1-(2-iodo-3-methylphenyl)cyclopropane-1-carbonitrile

[0237] Dissolve 2-(2-iodo-3-methylphenyl)acetonitrile (2.00g, 7.78mmol), potassium hydroxide (4.37g, 77.80mmol) and tetrabutylammonium bromide (130mg, 0.39mmol) in water (10mL), add 1,2-dibromoethane (2.92g, 15.52mmol) under nitrogen protection and stirring at 70℃, and continue to stir and react at temperature for 22h. Stop the reaction and cool to room temperature, extract with ethyl acetate (20mL×2), wash the combined organic phases with water (20mL×2), dry the organic phases with anhydrous sodium sulfate, and then purify by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain a light yellow solid product (332mg, 15%). LC-MS: 284.10[M+H] + .

[0238] Step 5: Synthesis of 1-(3-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0239] 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(diphenylphosphino)-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 stirred under nitrogen protection and microwave conditions at 140 ° C for 4 h. Stop the reaction, concentrate under reduced pressure to remove the solvent, dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases and wash with saturated brine (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter and purify by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain a brown oily product (208 mg, 70%). LC-MS: 253.20 [M+H] + .

[0240] Step 6: Synthesis of 1-(3-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0241] 1-(3-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile (208mg, 0.82mmol) and sodium hydroxide (1.31g, 32.80mmol) were dissolved in a mixed solvent of water (3mL) and methanol (3mL), and stirred at 100°C for 16.5h under nitrogen protection. Potassium hydroxide (1.84g, 32.80mmol) was added, and the reaction was continued overnight. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The mixture was diluted with water (10mL), and the pH was adjusted to 2 with hydrochloric acid (2M). The mixture was extracted with ethyl acetate (10mL×3), and the organic phases were combined and washed with saturated brine (10mL×2). The organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily product (160mg, 72%). LC-MS: 272.20[M+H] + .

[0242] Step 7: Synthesis of 7'-methyl-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0243] 1-(3-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (160 mg, 0.59 mmol), N,N-carbonyldiimidazole (140 mg, 0.89 mmol) and N,N-diisopropylethylamine (150 mg, 1.18 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature overnight. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1M, 10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain a yellow oily product (34 mg, 46%). LC-MS: 254.40 [M+H] + .

[0244] Step 8: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-7'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0245] 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 stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the residue was diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a colorless oily product (52 mg, 99%). LC-MS: 380.30 [M+H]+ .

[0246] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0247] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-7'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (52 mg, 0.14 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (84 mg, 0.21 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the reaction was stirred at 80 °C for 3 h under nitrogen protection and microwave conditions. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (20 mL), the organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 4) to obtain a light yellow solid product (18 mg, 25%). LC-MS: 527.25 [M+H] + .

[0248] Step 10: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-methylspiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0249] Dissolve tert-butyl ((7-(1-methyl-5-(7'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (18 mg, 0.03 mmol) in methanol (3 mL), add a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M), and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain a light yellow solid product (13 g, 82%). LC-MS: 428.20 [M+H-HCl] + .

[0250] Example 3: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0251]

[0252] Step 1: Synthesis of 2-bromo-1-bromomethyl-3-fluorobenzene

[0253] 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 stirred at 90°C for 2 h. The reaction was stopped and cooled to room temperature, and petroleum ether (50 mL) was added to dilute, and the organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a red solid (5.06 g, 71.40%). 1 H NMR (400 MHz, CDCl 3 )δ7.29–7.23(m,2H),7.10–7.05(m,1H),4.61(s,2H); GC-MS:267.9[M] + .

[0254] Step 2: Synthesis of 2-(2-bromo-3-fluorophenyl)acetonitrile

[0255] 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 stirred at 80 ° C for 6 h. The reaction was stopped and cooled to room temperature, the reaction solution 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), and the organic phases were dried with 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 obtain a colorless transparent liquid (2.91 g, 70.05%). GC-MS: 212.96 [M] + .

[0256] Step 3: Synthesis of 1-(2-bromo-3-fluorophenyl)cyclopropane-1-carbonitrile

[0257] Sodium hydride (2.34 g, 58.4 mmol, 60% content) was dissolved in N, N-dimethylformamide (50 mL), and compound 2-(2-bromo-3-fluorophenyl)acetonitrile (2.50 g, 11.68 mmol) was slowly added under ice bath, and stirred for 30 min. 1,2-dibromoethane (3.29 g, 17.52 mmol) was added, and stirred at room temperature for 3 h. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 3), and 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: PE / EtOAc (v / v) = 5 / 1) to obtain a white solid (1.62 g, 57.77%). 1 HNMR (400MHz, CDCl 3 )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] + .

[0258] Step 4: Synthesis of 1-(3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0259] 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(diphenylphosphino)-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 stirred at 140°C under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow oil (113 mg, 21.17%). LC-MS: 257.15[M+H] + ; 1 H NMR (599 MHz, CDCl 3 )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).

[0260] Step 5: Synthesis of 1-(3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0261] 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°C for 12 h. The pH was adjusted to 4 with a 1,4-dioxane solution of hydrogen chloride (4 M), and 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 by rotary evaporation under reduced pressure to obtain a yellow liquid (68 mg, 63.31%). LC-MS: 276.40 [M+H] + ; 1 H NMR (600 MHz, CDCl 3 )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).

[0262] Step 6: Synthesis of 7'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0263] Dissolve 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) in dichloromethane (5 mL) and stir at room temperature for 2 h. Dilute with dichloromethane (50 mL), wash with water (30 mL×3), dry with anhydrous sodium sulfate, concentrate the solvent by rotary evaporation under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=5 / 1) to obtain a red solid (80 mg, 77.82%). LC-MS: 258.20[M+H] + ; 1 H NMR (599 MHz, CDCl 3 )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).

[0264] Step 7: Synthesis of 7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0265] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, ethyl acetate (50 mL) was added to dilute, the organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (110 mg, 92.32%). 1 H NMR (599 MHz, CDCl 3 )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] + .

[0266] Step 8: Synthesis of tert-butyl (7-(5-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0267] 7'-Fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolino]-2'-one (119 mg, 0.31 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (187 mg, 0.46 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (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 at 80 °C for 2 h under nitrogen protection and 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to give a yellow solid (80 mg, 48.55%). 1 H NMR (599 MHz, 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),5.4 0(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] + .

[0268] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0269] Dissolve tert-butyl (7-(5-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (70 mg, 0.13 mmol) in dichloromethane (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4.0 mmol, 4 M), and stir at room temperature for 3 h. The reaction solution was diluted with dichloromethane (50 mL), and water (30 mL) was added. The pH was adjusted to 9 with sodium hydroxide solution (2 M), and the organic phase was separated, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure by rotary evaporation to obtain a yellow solid (50 mg, 88.04%). 1 H NMR (599 MHz, CDCl 3 )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] + .

[0270] Example 4: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0271]

[0272] Step 1: Synthesis of 1-(bromomethyl)-4-fluoro-2-iodobenzene

[0273] Dissolve 4-fluoro-2-iodo-1-toluene (0.1 g, 0.42 mmol) in carbon tetrachloride (5 mL), add azobisisobutyronitrile (34.48 mg, 0.21 mmol) and N-bromosuccinimide (0.12 g, 0.67 mmol), replace nitrogen, and stir at 80 ° C for 2 h. After cooling to room temperature, concentrate under reduced pressure, add water (20 mL), extract the water layer with dichloromethane, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is purified by column chromatography (eluent: PE) to obtain a colorless liquid (80 mg, 59.96%).

[0274] Step 2: Synthesis of 2-(4-fluoro-2-iodophenyl)acetonitrile

[0275] 1-(Bromomethyl)-4-fluoro-2-iodobenzene (2.02 g, 6.41 mmol) was dissolved in acetonitrile (20 mL), and trimethylsilyl cyanide (0.76 g, 7.69 mmol) and potassium carbonate (1.77 g, 12.82 mmol) were added, and then the temperature was raised to 80°C and stirred for 5.5 h. The reaction system was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE (v / v) = 15 / 85) to obtain a colorless liquid (1.08 g, 64.50%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0276] Step 3: Synthesis of 1-(4-fluoro-2-iodophenyl)cyclopropane-1-carbonitrile

[0277] Dissolve 2-(4-fluoro-2-iodophenyl)acetonitrile (1.08 g, 4.14 mmol) in water (8 mL), add 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), and stir at 70 ° C for 24 h. Cool to room temperature, extract with ethyl acetate (20 mL × 2), combine the organic phases and wash with water (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 10 / 90) to obtain a yellow solid (0.7 g, 58.94%). 1 H NMR (400 MHz, CDCl 3 )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).

[0278] Step 4: Synthesis of 1-(4-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0279] 1-(4-Fluoro-2-iodophenyl)cyclopropane-1-carbonitrile (0.3 g, 1.05 mmol) was dissolved in 1,4-dioxane (10 mL), and then 1-methyl-5-aminopyrazole (110 mg, 1.16 mmol), 4,5-bis(diphenylphosphino)-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 for 4 h under microwave conditions at 140°C. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL×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 obtain a yellow oil (0.27 g, 100%). 1 H 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] + .

[0280] Step 5: Synthesis of 1-(4-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0281] Dissolve 1-(4-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile (270 mg, 1.05 mmol) in a mixed solution of methanol (5 mL) and water (2 mL), then add sodium hydroxide (1.68 mg, 42.00 mmol), replace nitrogen, and stir at 100°C for 24 hours. Cool to room temperature, adjust pH to 6 with dilute hydrochloric acid (2.0 M), extract with ethyl acetate (20 mL×2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow viscous substance (150 mg, 51.57%). LC-MS: 276.30 [M+H] + .

[0282] Step 6: Synthesis of 6'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0283] 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, and the reaction was stirred at room temperature for 23 h. The reaction system was concentrated under reduced pressure, water (10 mL) was added, and the mixture was 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 obtain a light yellow solid (45 mg, 32.10%). LC-MS: 258.30 [M+H] + .

[0284] Step 7: Synthesis of 6'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0285] Dissolve 6'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (45 mg, 0.17 mmol) in acetic acid (5 mL), add N-iodosuccinimide (76.49 mg, 0.34 mmol), and stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure, dissolve with EA, and then wash with saturated sodium bicarbonate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a yellow viscous substance (67 mg, 100%). LC-MS: 384.05[M+1] + .

[0286] Step 8: Synthesis of tert-butyl ((7-(5-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0287] 6'-Fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (0.100 g, 0.26 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (17 mg, 0.026 mmol) and sodium carbonate (36 mg, 0.34 mmol) were added, and the reaction was stirred at 80 ° C in a microwave for 4 h. The reaction system was then 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×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 (45 mg, 48.51%). 1 H NMR (400 MHz, CDCl 3 )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=8.3,2.1 Hz,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.

[0288] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-fluorospiro[cyclopropyl-1,3'-indolyl]-2'-one hydrochloride

[0289] Tert-butyl ((7-(5-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 0.057 mmol) was dissolved in methanol (3 mL), and then a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 mol / L) was added, and then stirred at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain a white solid (26 mg, 98.49%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[0290] Example 5: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0291]

[0292] Step 1: Synthesis of (4-chloro-2-iodophenyl)methanol

[0293] Dissolve 4-chloro-2-iodobenzoic acid (2.5 g, 8.85 mmol) in tetrahydrofuran (15 mL), add a tetrahydrofuran solution of borane tetrahydrofuran complex (27 mL, 1 mol / L), and stir at 50°C for 2 h. Stop the reaction and cool to room temperature, slowly drop the reaction solution into methanol (10 mL), concentrate under reduced pressure, dissolve the residue in ethyl acetate (20 mL), wash the organic phase with saturated brine (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid product (2.38 g, 100%).

[0294] Step 2: Synthesis of 4-chloro-1-(chloromethyl)-2-iodobenzene

[0295] Dissolve (4-chloro-2-iodophenyl)methanol (2.4 g, 8.94 mmol) in dichloromethane (20 mL), add thionyl chloride (3.2 mL) and N,N-dimethylformamide (1 mL), stir the reaction at room temperature for 3 h, concentrate under reduced pressure to remove the solvent, dissolve the residue with ethyl acetate (20 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL×2), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a brown liquid product (2.56 g, 100%).

[0296] Step 3: Synthesis of 2-(4-chloro-2-iodophenyl)acetonitrile

[0297] 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 stirred at 80°C for 10 h. The reaction was stopped and cooled to room temperature, the reaction solution 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 phases were 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 obtain a yellow solid product (1.10 g, 44%).

[0298] Step 4: Synthesis of 1-(4-chloro-2-iodophenyl)cyclopropane-1-carbonitrile

[0299] 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), and 1,2-dibromoethane (1.5 g, 7.92 mmol) was added under nitrogen protection and stirring at 70°C, and the reaction was continued at 70°C for 24 h. The reaction was stopped and 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 with anhydrous sodium sulfate, and then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a yellow solid product (619 mg, 51%). 1 H NMR (600 MHz, DMSO-d 6 )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] + .

[0300] Step 5: Synthesis of 1-(4-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0301] 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(diphenylphosphino)-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), stirred and reacted at 140°C for 4 h under nitrogen protection and microwave conditions. The reaction was stopped, concentrated under reduced pressure to remove the solvent, 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, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH=20:1) to obtain a brown oily product (380 mg, 94%). LC-MS: 273.30 [M+H] + .

[0302] Step 6: Synthesis of 1-(4-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0303] 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 stirred at 100 ° C for 14 h under nitrogen protection. Sodium hydroxide (560 mg, 13.90 mmol) was added, and the reaction was continued overnight. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The mixture was diluted with water (10 mL), and the pH was adjusted to 2 with hydrochloric acid (2 M). It was extracted with ethyl acetate (20 mL × 3), and 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 obtain a brown oil product (255 mg, 63%). LC-MS: 292.30 [M+H] + .

[0304] Step 7: Synthesis of 6'-chloro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0305] Dissolve 1-(4-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (255 mg, 0.87 mmol), N,N-carbonyldiimidazole (210 mg, 1.30 mmol) and N,N-diisopropylethylamine (220 mg, 1.74 mmol) in dichloromethane (8 mL) and stir at room temperature overnight. Stop the reaction, dilute with dichloromethane (20 mL), wash with dilute hydrochloric acid (1M, 10 mL), wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter and purify by column chromatography (eluent: PE / EA (v / v) = 3 / 1) to obtain a colorless oily product (134 mg, 56%). LC-MS: 274.15 [M+H] + .

[0306] Step 8: 6'-Chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0307] Dissolve 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) in acetic acid (16 mL) and stir at room temperature for 1 h. Concentrate to remove the solvent, dilute the residue with ethyl acetate (20 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL), dry the organic phase with anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain a colorless oily product (128 mg, 100%). LC-MS: 400.00 [M+H] + .

[0308] Step 9: Synthesis of tert-butyl ((7-(5-(6'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0309] 6'-Chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (128 mg, 0.32 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (190 mg, 0.48 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the mixture was stirred under nitrogen protection at 100°C for reaction. Stop the reaction, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases and wash with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure and purify by column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 4) to obtain a white solid product (55 mg, 31%). LC-MS: 547.15 [M+H] + .

[0310] Step 10: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0311] Dissolve tert-butyl ((7-(5-(6'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (55 mg, 0.10 mmol) in methanol (3 mL), add a solution of hydrogen chloride in 1,4-dioxane (4 M, 4 mL), and stir at room temperature for 1 h. Concentrate under reduced pressure to obtain a light yellow solid product (40 mg, 82%). 1 H NMR (600 MHz, DMSO-d 6 )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]+ .

[0312] Example 6: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0313]

[0314] Step 1: Synthesis of (2-iodo-4-(trifluoromethyl)phenyl)methanol

[0315] Dissolve 2-iodo-4-(trifluoromethyl)benzoic acid (2g, 6.33mmol) in THF (10mL), replace nitrogen, and slowly add borane tetrahydrofuran solution (20mL, 1mol / L). Then stir and react at room temperature for 14h. Slowly add the reaction solution dropwise into methanol to quench the reaction, then concentrate under reduced pressure, add water (10mL), extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a colorless liquid product (1.91g, 99.92%). 1 H NMR (400 MHz, CDCl 3 )δ8.04(s,1H),7.65–7.57(m,2H),4.69(s,2H).

[0316] Step 2: Synthesis of 1-(bromomethyl)-2-iodo-4-(trifluoromethyl)benzene

[0317] Dissolve (2-iodo-4-(trifluoromethyl)phenyl)methanol (0.3g, 0.99mmol) in dichloromethane (5mL), add triphenylphosphine (0.39g, 1.49mmol), stir at room temperature for 45min, then add N-bromosuccinimide (0.26g, 1.49mmol) in batches, and then stir at room temperature to react. Wash the reaction solution with saturated sodium bicarbonate solution (10mL), wash with saturated brine (10mL), dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 20 / 1) to obtain a colorless oily product (0.15g, 41.38%). LC-MS: 364.93[M+H] + .

[0318] Step 3: Synthesis of 2-(2-iodo-4-(trifluoromethyl)phenyl)acetonitrile

[0319] Dissolve 1-(bromomethyl)-2-iodo-4-(trifluoromethyl)benzene (1.15 g, 3.15 mmol) in acetonitrile (10 mL), add trimethylsilyl cyanide (0.38 g, 3.78 mmol) and potassium carbonate (0.87 g, 6.3 mmol), then heat to 80°C and stir for 7 h. Concentrate the reaction solution under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 15 / 85) to obtain a colorless liquid (0.52 g, 53.05%). GC-MS: 311.0 [M] + .

[0320] Step 4: Synthesis of 1-(2-iodo-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile

[0321] Dissolve 2-(2-iodo-4-(trifluoromethyl)phenyl)acetonitrile (0.52 g, 1.67 mmol) in water (8 mL), add potassium hydroxide (0.94 g, 16.7 mmol) and tetrabutylammonium bromide (27 mg, 0.084 mmol), replace nitrogen, add 1,2-dibromoethane (0.63 g, 3.34 mmol), stir and react at 70°C for 24 h. Cool to room temperature, extract with ethyl acetate (20 mL × 2), combine the organic phases and wash with water (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter and purify by column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a light yellow solid (303 mg, 53.77%).

[0322] Step 5: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile

[0323] 1-(2-iodo-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (0.3 g, 0.89 mmol) was dissolved in 1,4-dioxane (10 mL), and then 1-methyl-5-aminopyrazole (95 mg, 0.98 mmol), 4,5-bis(diphenylphosphino)-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 the reaction was stirred for 4 h at 140 ° C under microwave conditions. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 9 to obtain a brown solid (0.27 g, 99.05%). LC-MS: 307.15 [M+H] + .

[0324] Step 6: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)-4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid

[0325] Dissolve 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (50 mg, 0.16 mmol) in a mixed solution of methanol (3 mL) and water (1 mL), add sodium hydroxide (128 mg, 3.2 mmol), replace nitrogen, and stir at 100°C for 24 hours. Cool to room temperature, adjust pH to 6 with dilute hydrochloric acid (2.0 M), extract with ethyl acetate (20 mL×2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid (53.1 mg, 100%). LC-MS 326.00[M+H] + .

[0326] Step 7: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0327] Dissolve 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)-4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (286 mg, 0.88 mmol) in dichloromethane (10 mL), add N,N'-carbonyldiimidazole (0.42 g, 2.64 mmol) and N,N'-diisopropylethylamine (0.46 g, 3.52 mmol), and stir at room temperature for 21.5 h. Concentrate the reaction system under reduced pressure, add water (10 mL), extract with dichloromethane (10 mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain a light yellow solid (74 mg, 27.39%). LC-MS: 308.10 [M+H] + .

[0328] Step 8: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6'-(trifluoromethyl)spiro[cyclopropyl-1,3'-indolin]-2'-one

[0329] Dissolve 1'-(1-methyl-1H-pyrazol-5-yl)-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolin]-2'-one (74 mg, 0.24 mmol) in acetic acid (5 mL), add N-iodosuccinimide (54 mg, 0.24 mmol), and stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure, dissolve with ethyl acetate, and then wash with saturated sodium bicarbonate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a light yellow solid (104.32 mg, 100%). LC-MS: 434.30 [M+H]+ .

[0330] Step 9: Synthesis of tert-butyl ((7-(1-methyl-5-(2'-oxo-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolyl]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0331] 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), and tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (0.14 g, 0.36 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (23 mg, 0.036 mmol) and sodium carbonate (51 mg, 0.48 mmol) were added, and the reaction was stirred at 80 °C in a microwave for 4 h. The reaction solution was then 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×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 (16 mg, 11.48%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0332] Step 10: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0333] Dissolve tert-butyl ((7-(1-methyl-5-(2'-oxo-6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indolin]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (16 mg, 0.028 mmol) in methanol (2 mL), add a solution of hydrogen chloride in 1,4-dioxane (1.5 mL, 4 mol / L), and then stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure to obtain 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] + .

[0334] Example 7: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chloro-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0335]

[0336] Step 1: Synthesis of 4-chloro-3-fluoro-2-iodobenzoic acid

[0337] Under nitrogen protection, at -78°C, a solution of n-butyl lithium in n-hexane (57 mL, 143 mmol, 2.5 M) was slowly dripped into a solution of 4-chloro-3-fluorobenzoic acid (10.00 g, 57.29 mmol) in anhydrous tetrahydrofuran (150 mL), and the mixture was stirred for 1.5 h. A solution of iodine (36.35 g, 143.22 mmol) in anhydrous tetrahydrofuran (70 mL) was dripped into the mixture, and the reaction solution was slowly warmed to room temperature and stirred for 2 h. Saturated ammonium chloride solution was added to quench the reaction, most of the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added to dilute the mixture, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a brown solid (11.19 g, 65.01%). 1 H NMR (400 MHz, CDCl 3 )δ7.80(dd,J=8.4,1.3Hz,1H),7.51(dd,J=8.4,7.0Hz,1H); LC-MS:299.00[MH] - .

[0338] Step 2: Synthesis of (4-chloro-3-fluoro-2-iodophenyl)methanol

[0339] Borane tetrahydrofuran complex (74mL, 73.88mmol, 1M tetrahydrofuran solution) was slowly dripped into anhydrous tetrahydrofuran (100mL) solution of 4-chloro-3-fluoro-2-iodobenzoic acid (11.10g, 36.94mmol), and stirred at room temperature for 1h. Methanol was added to quench the reaction, most of the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100mL) and water (100mL) were added to dilute, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (8.47g, 80.03%). 1 H NMR (400 MHz, CDCl 3 )δ7.43–7.37(m,1H),7.24(d,J=8.3Hz,1H),4.68(s,2H); GC-MS:285.9[M] + .

[0340] Step 3: Synthesis of 1-(bromomethyl)-4-chloro-3-fluoro-2-iodobenzene

[0341] At 0°C, methanesulfonyl chloride (5.04 g, 43.98 mmol) was slowly dripped into 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), and stirred at room temperature for 0.5 h. The solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (100 mL) was added to the residue, stirred for 5 min, the solid was filtered off through diatomaceous earth, lithium bromide (15.28 g, 175.92 mmol) was added to the filtrate, and stirred at room temperature for 3 h. The reaction solution was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain a yellow liquid (7.15 g, 69.79%). 1 H NMR (400 MHz, CDCl 3 )δ7.37–7.33(m,1H),7.24–7.21(m,1H),4.59(s,2H); GC-MS:349.8[M] + .

[0342] Step 4: Synthesis of 2-(4-chloro-3-fluoro-2-iodophenyl)acetonitrile

[0343] A mixture of 1-(bromomethyl)-4-chloro-3-fluoro-2-iodobenzene (7.10 g, 20.32 mmol), trimethylsilyl cyanide (2.42 g, 24.38 mmol), potassium carbonate (5.62 g, 40.64 mmol) and acetonitrile (70 mL) was stirred at 80°C for 3 h. The mixture was heated and stirred, cooled to room temperature, and the solvent was concentrated by rotary evaporation under reduced pressure. Ethyl acetate (50 mL) was added to the residue, washed with saturated brine (30 mL × 3), and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 20 / 1) to obtain a colorless transparent liquid (3.92 g, 65.28%). 1 H NMR (400 MHz, CDCl 3 )δ7.45(t,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H),3.84(s,2H); GC-MS:294.9[M] + .

[0344] Step 5: Synthesis of 1-(4-chloro-3-fluoro-2-iodophenyl)cyclopropane-1-carbonitrile

[0345] 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 at 50°C for 1 h. Ethyl acetate (100 mL) was added to the reaction solution for dilution, 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 obtain a yellow solid (202 mg, 37.13%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0346] Step 6: Synthesis of 1-(4-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0347] 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(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a brown solid (96 mg, 53.09%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0348] Step 7: Synthesis of 1-(4-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0349] 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°C for 4 h. The pH was adjusted to 4 with a dioxane solution of hydrogen chloride (4 M), and 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 obtain a yellow liquid (80 mg, 83%). LC-MS: 310.10 [M+H] + .

[0350] Step 8: Synthesis of 6'-chloro-7'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0351] Dissolve 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) in dichloromethane (5 mL) and stir at room temperature for 2 h. Dilute with dichloromethane (50 mL), wash with water (30 mL×3), dry with anhydrous sodium sulfate, concentrate the solvent by rotary evaporation under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a yellow solid (122 mg, 61.68%). 1 H NMR (400 MHz, CDCl 3 )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),6.66–6.6 0(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] + .

[0352] Step 9: Synthesis of 6'-chloro-7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0353] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a gray viscous liquid (132 mg, 76.84%). 1 HNMR (400MHz, CDCl 3 )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] + .

[0354] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0355] Compound 6'-chloro-7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (120 mg, 0.29 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (175 mg, 0.43 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C for 4 h under nitrogen protection and 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (32 mg, 19.71%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0356] Step 11: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chloro-7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0357] Dissolve 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-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 0.05 mmol) in ethanol (1 mL), add a solution of hydrogen chloride in dioxane (1 mL, 4 M), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a white solid (24 mg, 90.16%). 1 H NMR (400MHz, CD 3 OD)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] + .

[0358] Example 8: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0359]

[0360] Step 1: Synthesis of 2-(bromomethyl)-4-fluoro-1-iodobenzene

[0361] Dissolve 4-fluoro-1-iodo-2-toluene (5.00 g, 21.18 mmol) in carbon tetrachloride (40 mL), add N-bromosuccinimide (4.52 g, 25.42 mmol) and azobisisobutyronitrile (1.04 g, 6.35 mmol), and stir at 80°C for 21.5 h. Concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane (30 mL), wash with water (30 mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify by silica gel column chromatography (eluent: PE) to obtain a white solid product (2.00 g, 30%). 1 H NMR (400 MHz, CDCl 3 )δ7.85–7.77(m,1H),7.27–7.22(m,1H),6.83–6.74(m,1H),4.58–4.53(m,2H).

[0362] Step 2: Synthesis of 2-(5-fluoro-2-iodophenyl)acetonitrile

[0363] 2-(Bromomethyl)-4-fluoro-1-iodobenzene (3.12 g, 9.91 mmol), trimethylsilyl cyanide (1.28 g, 12.88 mmol) and potassium carbonate (1.78 g, 12.88 mmol) were dissolved in acetonitrile (30 mL) and stirred at 60°C. The reaction was stopped and cooled to room temperature, the reaction solution 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, the organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1) to obtain a white solid product (1.70 g, 66%).

[0364] Step 3: Synthesis of 1-(5-fluoro-2-iodophenyl)cyclopropane-1-carbonitrile

[0365] Dissolve 2-(5-fluoro-2-iodophenyl)acetonitrile (1.70g, 6.51mmol), potassium hydroxide (3.65g, 65.10mmol) and tetrabutylammonium bromide (100mg, 0.33mmol) in water (10mL), add 1,2-dibromoethane (2.45g, 13.02mmol) under nitrogen protection and stirring at 70℃, and continue to stir and react at the temperature for 20h. Stop the reaction, cool the reaction solution to room temperature, extract with ethyl acetate (20mL×2), combine the organic phases and wash with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify it by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain a yellow solid product (1.59g, 85%). LC-MS: 288.00[M+H] + .

[0366] Step 4: Synthesis of 1-(5-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0367] 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(diphenylphosphino)-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 stirred at 140 ° C under nitrogen protection and microwave conditions for 4 h. Stop the reaction, concentrate under reduced pressure to remove the solvent, dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases and wash with saturated brine (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure and purify by column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain a brown oily product (420 mg, 94%). LC-MS: 257.20 [M+H] + .

[0368] Step 5: Synthesis of 1-(5-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0369] 1-(5-Fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile (420mg, 1.64mmol) and potassium hydroxide (1.84g, 32.80mmol) were dissolved in a mixed solvent of water (8mL) and ethylene glycol (8mL), and stirred at 140°C for 4h under nitrogen protection. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The mixture was diluted with water (10mL), adjusted to pH=6 with hydrochloric acid (2M), extracted with ethyl acetate (20mL×3), and the organic phases were combined and washed with saturated brine (10mL). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a yellow solid product (280mg, 62%). LC-MS: 276.20[M+H] + .

[0370] Step 6: Synthesis of 5'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0371] 1-(5-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (280 mg, 1.02 mmol), N,N-carbonyldiimidazole (250 mg, 1.53 mmol) and N,N-diisopropylethylamine (260 mg, 2.04 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature. The reaction was stopped, the reaction solution was diluted with dichloromethane (20 mL), and washed with dilute hydrochloric acid (1M, 10 mL) and saturated brine (10 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain a colorless oily product (162 mg, 62%). LC-MS: 258.15 [M+H] + .

[0372] Step 7: Synthesis of 5'-fluoro-1'-(4-iodo-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0373] Dissolve 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) in acetic acid (20 mL) and stir the reaction at room temperature. Concentrate to remove the solvent, dilute the residue with ethyl acetate (20 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a yellow solid product (200 mg, 83%). LC-MS: 384.30 [M+H] + .

[0374] Step 8: Synthesis of tert-butyl ((7-(5-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0375] 5'-Fluoro-1'-(4-iodo-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (100 mg, 0.26 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridazin-1-yl)methyl)carbamate (160 mg, 0.39 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the mixture was stirred under nitrogen protection at 80 °C for overnight. 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 obtain a white solid product (45 mg, 33%). LC-MS: 531.30 [M+H] + .

[0376] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0377] Dissolve tert-butyl ((7-(5-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (45 mg, 0.09 mmol) in methanol (4 mL), add a solution of hydrogen chloride in 1,4-dioxane (4M, 5 mL), and stir at room temperature for 1 h. Concentrate under reduced pressure to obtain a light yellow solid product (39 mg, 98%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[0378] Example 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0379]

[0380] Step 1: Synthesis of 2-(bromomethyl)-4-chloro-1-iodobenzene

[0381] Dissolve 4-chloro-1-iodo-2-methylbenzene (5.00 g, 19.80 mmol) in carbon tetrachloride (50 mL), add N-bromosuccinimide (4.23 g, 23.76 mmol) and azobisisobutyronitrile (0.98 g, 5.94 mmol), and stir at 80°C for 40 h. Concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane (30 mL), wash with water (30 mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify by column chromatography (eluent: PE) to obtain a purple oily product (1.60 g, 24%).

[0382] Step 2: Synthesis of 2-(5-chloro-2-iodophenyl)acetonitrile

[0383] 2-(Bromomethyl)-4-chloro-1-iodobenzene (1.60 g, 4.83 mmol), trimethylsilyl cyanide (0.62 g, 6.28 mmol) and potassium carbonate (0.87 g, 6.28 mmol) were dissolved in acetonitrile (20 mL) and stirred at 65°C for 5.5 h. The reaction was stopped and cooled to room temperature, the reaction solution 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 phases were dried over anhydrous sodium sulfate, filtered and purified by column chromatography (PE / EA (v / v)=10 / 1) to obtain a white solid product (0.80 g, 60%). 1 H NMR (400 MHz, CDCl 3 )δ7.81(d,J=8.4Hz,1H),7.56(q,J=3.0Hz,1H),7.12–7.04(m,1H),3.81(s,2H).

[0384] Step 3: Synthesis of 1-(5-chloro-2-iodophenyl)cyclopropane-1-carbonitrile

[0385] Dissolve 2-(5-chloro-2-iodophenyl)acetonitrile (0.75g, 2.70mmol), potassium hydroxide (1.51g, 27.00mmol) and tetrabutylammonium bromide (44mg, 0.14mmol) in water (10mL). Add 1,2-dibromoethane (1.01g, 5.40mmol) to the reaction solution under nitrogen protection and stirring at 70°C. Continue stirring and reacting at the temperature for 34h. Stop the reaction, cool the reaction solution to room temperature, extract with ethyl acetate (20mL×2), combine the organic phases and wash with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify it by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain a yellow solid product (643mg, 78%). LC-MS: 304.00[M+H] + .

[0386] Step 4: Synthesis of 1-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0387] 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(diphenylphosphino)-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 the reaction was stirred at 100 ° C under nitrogen protection overnight. Stop the reaction, concentrate under reduced pressure to remove the solvent, dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), combine the organic phases and wash with saturated brine (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure and purify by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain a brown oily product (372 mg, 64%). LC-MS: 273.30 [M+H] + .

[0388] Step 5: Synthesis of 1-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0389] Dissolve 1-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile (372mg, 1.36mmol) and potassium hydroxide (1.53g, 27.20mmol) in a mixed solvent of water (8mL) and ethylene glycol (8mL), and stir under nitrogen protection at 140°C for 4h. Stop the reaction, concentrate under reduced pressure to remove the solvent, dilute with water (10mL), adjust pH to 6 with hydrochloric acid (2M), extract with ethyl acetate (20mL×3), combine the organic phases and wash with saturated brine (10mL), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid product (358mg, 90%). LC-MS: 292.30[M+H] + .

[0390] Step 6: Synthesis of 5'-chloro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0391] Dissolve 1-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (358 mg, 1.23 mmol), N,N-carbonyldiimidazole (300 mg, 1.84 mmol) and N,N-diisopropylethylamine (320 mg, 2.46 mmol) in dichloromethane (10 mL) and stir at room temperature to react. Stop the reaction, dilute with dichloromethane (20 mL), wash with dilute hydrochloric acid (1M, 10 mL), wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter and purify by column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain a yellow oily product (281 mg, 84%). LC-MS: 274.30 [M+H] + .

[0392] Step 7: Synthesis of 5'-chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0393] 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 stirred at room temperature for reaction. The solvent was removed by concentration, and 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 with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a yellow solid product (387 mg, 96%). LC-MS: 400.20 [M+H] + .

[0394] Step 8: Synthesis of tert-butyl ((7-(5'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0395] 5'-Chloro-1'-(4-iodo-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (300 mg, 0.75 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridazin-1-yl)methyl)carbamate (450 mg, 1.13 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the mixture was stirred at 80 °C under nitrogen protection for overnight. 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 obtain a light yellow solid product (221 mg, 54%). LC-MS: 547.20 [M+H] + .

[0396] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0397] The compound ((7-(5'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (221 mg, 0.40 mmol) was dissolved in methanol (8 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 14 mL) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid product (180 mg, 100%). 1 H NMR (400 MHz, DMSO-d 6)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] + .

[0398] Example 10: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0399]

[0400] Step 1: Synthesis of 2-(bromomethyl)-1-chloro-3-iodobenzene

[0401] Dissolve 1-chloro-3-iodo-2-methylbenzene (2.50 g, 9.90 mmol) in carbon tetrachloride (20 mL), add N-bromosuccinimide (1.94 g, 10.89 mmol) and benzoyl peroxide (320 mg, 0.99 mmol), and stir at 90°C for 37 h. Concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane (30 mL), wash with water (30 mL×2), dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography (eluent: PE) to obtain a white solid product (2.17 g, 56%).

[0402] Step 2: Synthesis of 2-(2-chloro-6-iodophenyl)acetonitrile

[0403] 2-(Bromomethyl)-1-chloro-3-iodobenzene (2.17 g, 6.55 mmol), trimethylsilyl cyanide (0.78 g, 7.86 mmol) and potassium carbonate (1.09 g, 7.86 mmol) were dissolved in acetonitrile (20 mL) and stirred at 60°C. The reaction was stopped and cooled to room temperature, the reaction solution 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, filtered and concentrated under reduced pressure to obtain a brown liquid product (1.70 g, 94%).

[0404] Step 3: Synthesis of 1-(2-chloro-6-iodophenyl)cyclopropane-1-carbonitrile

[0405] Dissolve 2-(2-chloro-6-iodophenyl)acetonitrile (1.72g, 6.20mmol), potassium hydroxide (3.48g, 62.00mmol) and tetrabutylammonium bromide (100mg, 0.31mmol) in water (5mL), add 1,2-dibromoethane (2.33g, 12.40mmol) under nitrogen protection and stirring at 70℃, and continue to stir and react at temperature for 19h. Stop the reaction, cool the reaction solution to room temperature, extract with ethyl acetate (20mL×2), combine the organic phases and wash with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify by column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain a yellow solid product (1.24g, 66%). LC-MS: 304.25[M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0406] Step 4: Synthesis of 1-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0407] 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(diphenylphosphino)-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 stirred at 140 ° C under nitrogen protection and microwave conditions for 4 h. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The 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), and the organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was purified by column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a brown oily product (320 mg, 71%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0408] Step 5: Synthesis of 1-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0409] 1-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile (300mg, 1.10mmol) and sodium hydroxide (1.32g, 33.00mmol) were dissolved in a mixed solvent of water (6mL) and methanol (9mL), and stirred at 100°C under nitrogen protection for 20.5h. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The residue was diluted with water (10mL), and the pH was adjusted to 2 with 2M hydrochloric acid. It was extracted with ethyl acetate (20mL×3), and the organic phases were combined and washed with saturated brine (20mL×2). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a yellow solid product (320mg, 100%). LC-MS: 292.10[M+H] + .

[0410] Step 6: Synthesis of 4'-chloro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0411] Dissolve 1-(2-chloro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (320 mg, 1.10 mmol), N,N-carbonyldiimidazole (270 mg, 1.65 mmol) and N,N-diisopropylethylamine (280 mg, 2.20 mmol) in dichloromethane (5 mL) and stir at room temperature to react. Stop the reaction, dilute with dichloromethane (20 mL), wash with dilute hydrochloric acid (1M, 10 mL), wash with saturated brine (10 mL), dry the organic phase with anhydrous sodium sulfate, filter and purify by column chromatography (eluent: PE / EA (v / v) = 5 / 1) to obtain a colorless oily product (52 mg, 17%). LC-MS: 274.30 [M+H] + .

[0412] Step 7: Synthesis of 4'-chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0413] Dissolve 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) in acetic acid (15 mL) and stir the reaction at room temperature. Concentrate to remove the solvent, dilute the residue with ethyl acetate (20 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a colorless oily product (73 mg, 93%). LC-MS: 400.30 [M+H] + .

[0414] Step 8: Synthesis of tert-butyl ((7-(5-(4'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0415] 4'-Chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (73 mg, 0.18 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (110 mg, 0.27 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the reaction was stirred at 80 °C for 3 h under nitrogen protection and microwave conditions. 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 obtain a white solid product (49 mg, 49%). LC-MS: 547.18 [M+H] + .

[0416] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0417] The compound ((7-(5-(4'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (49 mg, 0.09 mmol) was dissolved in methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (4M, 5 mL) was added, and the reaction was stirred at room temperature for 1 h. The product was concentrated under reduced pressure to obtain a light yellow solid product (40 mg, 92%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[0418] Example 11: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-fluorospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0419]

[0420] Step 1: Synthesis of (2-fluoro-6-iodophenyl)methanol

[0421] Dissolve 2-fluoro-6-iodobenzoic acid (4.0 g, 15.40 mmol) in borane tetrahydrofuran complex (38 mL, 1 mol / L THF) and stir at room temperature overnight. Stop the reaction, slowly drip the reaction solution into methanol (50 mL), concentrate under reduced pressure, dissolve the residue in ethyl acetate (50 mL), wash the organic phase with saturated brine (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid (3.79 g, 100%). Step 2: Synthesis of 2-fluoro-6-iodobenzyl methanesulfonate

[0422] Dissolve (2-fluoro-6-iodophenyl)methanol (1.50 g, 5.95 mmol) and N,N-diisopropylethylamine (2.31 g, 17.80 mmol) in dichloromethane (20 mL), add methylsulfonyl chloride (0.89 g, 7.74 mmol) under ice bath, transfer to room temperature and stir to react for 3 h. Dilute the reaction solution with water (10 mL), adjust pH to 6 with dilute hydrochloric acid (1 M), wash with saturated brine (10 mL) after separation, dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography (PE / EA (v / v) = 10 / 1) to obtain a white solid product (1.10 g, 56%).

[0423] Step 3: Synthesis of 2-(2-fluoro-6-iodophenyl)acetonitrile

[0424] 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 stirred at 50°C overnight. The reaction was stopped and cooled to room temperature, the reaction solution 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), the organic phases were dried over anhydrous sodium sulfate, filtered and purified by column chromatography (PE / EA (v / v)=10 / 1) to obtain a white solid product (0.87 g, 100%).

[0425] Step 4: Synthesis of 1-(2-fluoro-6-iodophenyl)cyclopentane-1-carbonitrile

[0426] Sodium hydrogen (270 mg, 6.69 mmol) was dissolved in N, N-dimethylformamide (12 mL), and the compound 2-(2-fluoro-6-iodophenyl)acetonitrile (583 mg, 2.23 mmol) was slowly added under ice bath, and stirred for 30 min, and then 1,4-dibromobutane (580 mg, 2.68 mmol) was added, and stirred for 2 h at room temperature. The reaction was stopped and water (20 mL) was added to quench the reaction, and then extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL), and the organic phases were dried with anhydrous sodium sulfate, filtered, and purified by column chromatography (eluent: PE / EA (v / v) = 20 / 1) to obtain a colorless oily product (405 mg, 58%). LC-MS: 316.05 [M+H] + .

[0427] Step 5: Synthesis of 1-(2-fluoro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentane-1-carbonitrile

[0428] 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(diphenylphosphino)-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), stirred and reacted overnight at 100 ° C under nitrogen protection. 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, filtered and purified by column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain a brown oily product (474 ​​mg, 81%). LC-MS: 285.20 [M+H] + .

[0429] Step 6: Synthesis of 4'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0430] 1-(2-Fluoro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentane-1-carbonitrile (470mg, 1.67mmol) and sodium hydroxide (1.87g, 33.40mmol) were dissolved in a mixed solvent of water (8mL) and methanol (8mL), and stirred at 140°C for 4h under nitrogen protection. The reaction was stopped, and the solvent was removed by concentration under reduced pressure. The mixture was diluted with water (10mL), and the pH was adjusted to 6 with hydrochloric acid (2M). The mixture was extracted with ethyl acetate (10mL×3), and the organic phases were combined and washed with saturated brine (10mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily product (330mg, 70%). LC-MS: 286.10[M+H] + .

[0431] Step 7: Synthesis of 4'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0432] Dissolve 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) in acetic acid (20 mL) and stir at room temperature for 1.5 h. Concentrate under reduced pressure to remove the solvent, dilute the residue with ethyl acetate (20 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a colorless oily product (400 mg, 84%). LC-MS: 412.05 [M+H] + .

[0433] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0434] 4'-Fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (200 mg, 0.49 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridazin-1-yl)methyl)carbamate (290 mg, 0.73 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the mixture was stirred at 80 °C under nitrogen protection for overnight. 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 / 3) to obtain a light yellow solid product (129 mg, 47%). LC-MS: 559.25 [M+H] + .

[0435] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-fluorospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0436] Dissolve tert-butyl ((7-(5-(4'-fluoro-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (100 mg, 0.18 mmol) in methanol (4 mL), add a solution of hydrogen chloride in 1,4-dioxane (4M, 10 mL), and stir at room temperature for 1.5 h. Concentrate under reduced pressure to obtain a light yellow solid product (89 mg, 100%). 1 H NMR (400 MHz, DMSO-d 6 )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),7.0 0(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] + .

[0437] Example 12: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one hydrochloride

[0438]

[0439] Step 1: Synthesis of 2-(2-iodophenyl)acetonitrile

[0440] 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 stirred at 60°C for 6 h. The reaction was stopped and cooled to room temperature, the reaction solution 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, filtered and concentrated under reduced pressure to obtain a brown liquid product (3.17 g, 97%).

[0441] Step 2: Synthesis of 1-(2-iodophenyl)cyclobutane-1-carbonitrile

[0442] Sodium hydrogen (1.3g, 32.60mmol) was dissolved in N,N-dimethylformamide (30mL), 2-(2-iodophenyl)acetonitrile (3.2g, 13.04mmol) was slowly added under ice bath, and the reaction was stirred for 30 minutes, and then 1,3-dibromopropane (2.63g, 13.04mmol) was added, and the reaction was stirred at room temperature. The reaction was stopped, and water (100mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50mL×2), and the organic phases were combined and washed with saturated brine (50mL×2). The organic phase was dried with 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 obtain a white solid product (0.6g, 16%). LC-MS: 284.00[M+H] + .

[0443] Step 3: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclobutane-1-carbonitrile

[0444] 1-(2-iodophenyl)cyclobutane-1-carbonitrile (220 mg, 0.78 mmol), 1-methyl-5-aminopyrazole (83 mg, 0.86 mmol), 4,5-bis(diphenylphosphino)-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 stirred under nitrogen protection and microwave conditions at 140°C. The reaction was stopped, the solvent was removed by concentration under reduced pressure, the 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 phases were dried over anhydrous sodium sulfate, the organic phases were concentrated under reduced pressure and purified by column chromatography (eluent: DCM / MeOH (v / v)=20 / 1) to obtain a brown oily product (188 mg, 96%). 1 H NMR (599 MHz, DMSO-d 6 )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] + .

[0445] Step 4: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclobutane-1-carboxylic acid

[0446] 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclobutane-1-carbonitrile (188mg, 0.75mmol) and sodium hydroxide (600mg, 15.00mmol) were dissolved in a mixed solvent of water (4mL) and methanol (6mL), and stirred under nitrogen protection at 100°C. The reaction was stopped, the solvent was removed by concentration under reduced pressure, diluted with water (10mL), adjusted to pH=2 with hydrochloric acid (2M), extracted with ethyl acetate (20mL×3), the combined organic phases were washed with saturated brine (20mL×2), the organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily product (166mg, 82%). LC-MS272.15[M+H] + .

[0447] Step 5: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0448] 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclobutane-1-carboxylic acid (166 mg, 0.61 mmol), N,N-carbonyldiimidazole (150 mg, 0.92 mmol) and N,N-diisopropylethylamine (160 mg, 1.22 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1M, 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 obtain a colorless oily product (166 mg, 82%). LC-MS: 254.35 [M+H] + .

[0449] Step 6: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one

[0450] 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-dihydroindole]-2'-one (60 mg, 0.24 mmol) and N-iodosuccinimide (54 mg, 0.24 mmol) were dissolved in acetic acid (12 mL) and stirred at room temperature for reaction. The solvent was removed by concentration, and 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 obtain a colorless oily product (90 mg, 100%). LC-MS: 380.30 [M+H] + .

[0451] 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

[0452] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (88 mg, 0.23 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridazin-1-yl)methyl)carbamate (140 mg, 0.35 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the reaction was stirred at 80 °C under nitrogen protection and microwave conditions. Stop the reaction, dilute the reaction solution with water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases and wash with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (eluent: PE / EA (v / v) = 1 / 4) to obtain a colorless oily product (45 mg, 37%). LC-MS527.50 [M+H] + .

[0453] Step 8: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one hydrochloride

[0454] Dissolve 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 (45 mg, 0.09 mmol) in methanol, add a solution of hydrogen chloride in 1,4-dioxane (4M, 4 mL), and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain a light yellow solid product (30 mg, 82%). 1 H NMR (600 MHz, DMSO-d 6)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] + .

[0455] Example 13: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0456]

[0457] Step 1: Synthesis of 2-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)acetic acid

[0458] Dissolve 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) in DMF (10 mL) and stir for 1 h at 100 °C under nitrogen protection and microwave conditions. Add ethanol (50 mL) to dilute, filter out the solid through diatomaceous earth, adjust the filtrate to pH = 4 with a solution of hydrogen chloride in 1,4-dioxane (4 M), filter out the solid, and concentrate the filtrate under reduced pressure to obtain a yellow oil (1.94 g, 81.48%). LC-MS: 232.20 [M+H] + .

[0459] Step 2: Synthesis of 1-(1-methyl-1H-pyrazol-5-yl)indolin-2-one

[0460] 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 12 h. The reaction solution was diluted with dichloromethane (50 mL), washed with water (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to obtain a yellow solid (0.32 g, 69.62%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0461] Step 3: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0462] Dissolve 1-(1-methyl-1H-pyrazol-5-yl)indolin-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) in water (5 mL) and stir at 50°C for 1 h. Dilute with ethyl acetate (50 mL), wash with saturated brine (30 mL×3), dry with anhydrous sodium sulfate, concentrate the solvent by rotary evaporation under reduced pressure, and purify the residue by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to obtain a yellow solid (0.15 g, 47.86%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0463] Step 4: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0464] 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-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 1 h. The reaction was quenched with saturated sodium bisulfite solution, concentrated under reduced pressure to remove acetic acid, and the concentrate was diluted with ethyl acetate (50 mL). The organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (170 mg, 77.05%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0465] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0466] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (100 mg, 0.25 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (150 mg, 0.38 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 and microwave conditions at 80 °C for 4 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 30 / 1) to give a yellow solid (61 mg, 44.37%). 1H NMR (400 MHz, CDCl 3 )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] + .

[0467] Step 6: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0468] Dissolve tert-butyl ((7-(1-methyl-5-(2'-oxospiro[cyclopentane-1,3'-indolin]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (60 mg, 0.11 mmol) in dichloromethane (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was diluted with dichloromethane (50 mL) and water (30 mL), and the pH was adjusted to 9 with sodium hydroxide (1 M) solution. The organic phase was separated, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure by rotary evaporation to obtain a yellow solid (31 mg, 63.41%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0469] Example 14: 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chloro-7'-fluorospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0470]

[0471] Step 1: Synthesis of 1-(4-chloro-3-fluoro-2-iodophenyl)cyclopentane-1-carbonitrile

[0472] 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°C for 1 h. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the mixture was washed with saturated brine (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: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a yellow solid (567 mg, 47.93%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0473] Step 2: Synthesis of 1-(4-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentane-1-carbonitrile

[0474] 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(diphenylphosphino)-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 for 4 h at 140 ° C under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow viscous liquid (203 mg, 40.47%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0475] Step 3: Synthesis of 1-(4-chloro-3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentane-1-carboxylic acid

[0476] Dissolve 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) in a mixed solvent of ethanol (2 mL) and water (2 mL), and stir at 140°C for 4 h. Adjust pH to 4 with a solution of hydrogen chloride in 1,4-dioxane (4 M), and concentrate the solvent by rotary evaporation under reduced pressure. Add ethanol (20 mL) to the residue, filter out the solid, and concentrate the solvent by rotary evaporation under reduced pressure to obtain a yellow liquid (202 mg, 100%). LC-MS: 338.20 [M+H] + .

[0477] Step 4: Synthesis of 6'-chloro-7'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0478] Dissolve 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) in dichloromethane (5 mL) and stir at room temperature for 2 h. The reaction solution was diluted with dichloromethane (50 mL) and 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 obtain a yellow solid (127 mg, 78.92%). 1 HNMR (400MHz, CDCl 3 )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]+ .

[0479] Step 5: Synthesis of 6'-chloro-7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0480] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (156 mg, 89.54%). 1 HNMR (400MHz, CDCl 3 )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] + .

[0481] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0482] 6'-Chloro-7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolino]-2'-one (160 mg, 0.36 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (217 mg, 0.54 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C under nitrogen protection and microwave conditions for 4 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (28 mg, 13.11%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0483] Step 7: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6'-chloro-7'-fluorospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0484] Dissolve 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-dihydrophthalazin-1-yl)methyl)carbamate (26 mg, 0.04 mmol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a white solid (24 mg, 90.48%). 1 H NMR (400MHz, CD 3OH)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] + .

[0485] Example 15: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0486]

[0487] Step 1: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0488] Dissolve 1-(1-methyl-1H-pyrazol-5-yl)indolin-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) in water (5 mL) and stir at 50 °C for 1 h. Dilute with ethyl acetate (50 mL) and wash with saturated brine (30 mL × 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (185 mg, 70.11%). 1 H NMR (400 MHz, CDCl 3 )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=7.7H z,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] + .

[0489] Step 2: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0490] 1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (50 mL) was added to dilute, the organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (218 mg, 81.41%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0491] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0492] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (200 mg, 0.49 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (295 mg, 0.73 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (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 the mixture was stirred at 80 °C under nitrogen protection and microwave conditions for 4 h. 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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (93 mg, 34.14%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0493] Step 4: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0494] Dissolve tert-butyl ((7-(1-methyl-5-(2'-oxospiro[cyclohexane-1,3'-indolin]-1'-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (60 mg, 0.11 mmol) in dichloromethane (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a brown solid (48 mg, 90.37%). 1 H NMR (400 MHz, Methanol-d 4 )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] + .

[0495] Example 16: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one hydrochloride

[0496]

[0497] Step 1: Synthesis of 1-(2-iodobenzyl)cyclopropane-1-carbonitrile

[0498] Dissolve the tetrahydrofuran solution of lithium diisopropylamide (1.5 mL, 2M) in tetrahydrofuran (10 mL), add the tetrahydrofuran solution of cyclopropanenitrile (170 mg, 2.53 mmol) (5 mL) at -78 °C, stir for 1 h, add 2-iodobenzyl bromide (900 mg, 3.04 mmol), transfer to room temperature and stir for 2 h. Stop the reaction, dilute with water (40 mL), wash with ethyl acetate (40 mL × 3), combine the organic phases and wash with saturated brine (40 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify the concentrate by silica gel column chromatography (eluent: PE) to obtain a colorless oily product (400 mg, 56%). LC-MS: 284.20 [M+H] + .

[0499] Step 2: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)benzyl)cyclopropane-1-carbonitrile

[0500] 1-(2-iodobenzyl)cyclopropane-1-carbonitrile (372 mg, 1.31 mmol), 1-methyl-5-aminopyrazole (140 mg, 1.44 mmol), 4,5-bis(diphenylphosphino)-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), stirred and reacted for 4 h at 140 ° C under nitrogen protection and microwave conditions. The reaction was stopped, concentrated under reduced pressure to remove the solvent, 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), and the organic phase was dried over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, it was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v)=20 / 1) to obtain a brown oil product (89 mg, 27%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0501] Step 3: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)benzyl)cyclopropane-1-carboxylic acid

[0502] 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)benzyl)cyclopropane-1-carbonitrile (92mg, 0.36mmol) and sodium hydroxide (430mg, 10.80mmol) were dissolved in a mixed solvent of water (4mL) and methanol (6mL), and stirred at 100°C for 17.5h under nitrogen protection. The reaction was stopped, the reaction solution was concentrated under reduced pressure to remove the solvent, diluted with water (10mL), and adjusted to pH=2 with hydrochloric acid (2M), extracted with ethyl acetate (20mL×3), the organic phases were combined and washed with saturated brine (20mL×2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a brown oily product (90mg, 91%). LC-MS: 272.40[M+H] + .

[0503] Step 4: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinolin]-2'-one

[0504] 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)benzyl)cyclopropane-1-carboxylic acid (90 mg, 0.33 mmol), N,N-carbonyldiimidazole (80 mg, 0.49 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature overnight. The reaction was stopped, diluted with dichloromethane (20 mL), washed with dilute hydrochloric acid (1M, 10 mL), washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA (v / v) = 5 / 1) to obtain a colorless oily product (34 mg, 46%). LC-MS: 254.20 [M+H] + .

[0505] 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

[0506] 1'-(1-methyl-1H-pyrazol-5-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one (38 mg, 0.15 mmol) and N-iodosuccinimide (34 mg, 0.15 mmol) were dissolved in acetic acid (12 mL) and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and 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 obtain a colorless oily product (50 mg, 88%). LC-MS: 380.10 [M+H] + .

[0507] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0508] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one (50 mg, 0.13 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (78 mg, 0.20 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the reaction was stirred at 80 °C for 3 h under nitrogen protection and microwave conditions. 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 obtain a white solid product (17 mg, 24%). LC-MS: 527.65 [M+H] + .

[0509] Step 7: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-2'-one hydrochloride

[0510] Dissolve 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-dihydrophthalazin-1-yl)methyl)carbamate (17 mg, 0.03 mmol) in methanol (3 mL), add a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 mL), and stir at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid product (10 mg, 67%). LC-MS: 427.50 [M+H-HCl] + ; HRMS: 427.1825 [M+H-HCl] + .

[0511] Example 17: Synthesis of 1'-(5-(1-(aminomethyl)-4-oxo-3,4-dihydrophthalazin-6-yl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0512]

[0513] Step 1: Synthesis of 1-(2-iodophenyl)cyclopropane-1-carboxylic acid

[0514] The title compound was obtained as a yellow solid (2.27 g, 31.95%) by referring to the synthesis of I-10 on page 62 of the specification of CN 104736533 B. 1 H NMR (400 MHz, CDCl 3 )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] + .

[0515] Step 2: Synthesis of 1'-(5-bromopyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0516] Under nitrogen protection, a mixture of 1-(2-iodophenyl)cyclopropane-1-carboxylic acid (500 mg, 1.74 mmol), 5-bromo-3-aminopyridine (450 mg, 2.61 mmol), cuprous iodide (33 mg, 0.17 mmol), potassium carbonate (480 mg, 3.48 mmol) and N,N-dimethylformamide (10 mL) was stirred at 100 ° C for 1 h in a microwave. N,N'-carbonyldiimidazole (1.13 g, 6.96 mmol) was added and stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate (100 mL), the organic phase was washed with water (50 mL × 3), and 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 obtain a yellow solid (90 mg, 16.45%). 1 H NMR (400 MHz, CDCl 3 )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,1 H),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] + .

[0517] Step 3: Synthesis of tert-butyl ((4-oxo-6-(5-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)pyridin-3-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0518] 1'-(5-Bromopyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (80 mg, 0.25 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (151 mg, 0.38 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (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 at 80 °C under nitrogen protection and microwave conditions for 2 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a white solid (43 mg, 33.24%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0519] Step 4: Synthesis of 1'-(5-(1-(aminomethyl)-4-oxo-3,4-dihydrophthalazin-6-yl)pyridin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0520] Dissolve tert-butyl ((4-oxo-6-(5-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)pyridin-3-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (45 mg, 0.09 mmol) in dichloromethane (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was diluted with dichloromethane (50 mL) and water (30 mL), and the pH was adjusted to 9 with sodium hydroxide solution (1 M). The organic phase was separated, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (31 mg, 85.73%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[0521] Example 18: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-cyclopropylspiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0522]

[0523] Step 1: Synthesis of 4'-cyclopropyl-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0524] 4'-Bromo-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (100 mg, 0.29 mmol, see Step 6 of Example 20), 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 at 110 °C for 1 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the mixture was washed with saturated brine (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to give a yellow solid (56 mg, 63.07%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0525] Step 2: Synthesis of 4'-cyclopropyl-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0526] Dissolve 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) in acetic acid (10 mL) and stir at room temperature for 3 h. Quench the reaction with saturated sodium bisulfite solution (10 mL), concentrate under reduced pressure to remove acetic acid, add dichloromethane (100 mL) to dilute the concentrate, wash the organic phase with water (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (eluent: PE / EtOAc (v / v)=4 / 1) to obtain a yellow solid (78 mg, 100%). LC-MS: 434.10[M+H] + .

[0527] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0528] 4'-Cyclopropyl-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (75 mg, 0.17 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (102 mg, 0.26 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80°C under nitrogen protection and microwave conditions for 2 h. The reaction solution was diluted with ethyl acetate (100 mL) and washed with water (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (30 mg, 29.85%). 1 H 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),2.00–1.9 4(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] + .

[0529] Step 4: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-cyclopropylspiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0530] Dissolve tert-butyl ((7-(5-(4'-cyclopropyl-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (20 mg, 34 μmol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a white solid (16 mg, 96.67%). 1 H NMR (400 MHz, Methanol-d 4 )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] + .

[0531] Example 19: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2'-oxospiro[cyclopentane-1,3'-indoline]-4'-carbonitrile hydrochloride

[0532]

[0533] Step 1: Synthesis of 1'-(1-methyl-1H-pyrazol-5-yl)-2'-oxospiro[cyclopentane-1,3'-indoline]-4'-carbonitrile

[0534] 4'-Bromo-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (100 mg, 0.29 mmol), potassium ferrocyanide (267 mg, 0.72 mmol), XPhos G3 (25 mg, 0.03 mmol), 2-dicyclohexylphosphino-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 at 110 °C for 6 h under nitrogen protection. Ethyl acetate (50 mL) was added to the reaction solution for dilution, and the mixture was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to give a yellow solid (60 mg, 71.06%). 1 H NMR (400 MHz, CDCl 3 )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),6.3 1(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] + .

[0535] Step 2: Synthesis of 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2'-oxospiro[cyclopentane-1,3'-indoline]-4'-carbonitrile

[0536] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, and dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to obtain a yellow solid (85 mg, 99.02%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0537] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0538] 1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2'-oxospiro[cyclopentane-1,3'-indoline]-4'-carbonitrile (80 mg, 0.19 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (114 mg, 0.29 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (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 °C for 4 h 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (23 mg, 21.26%). 1 H NMR (400 MHz, CDCl 3 )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,1 H),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] + .

[0539] Step 4: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2'-oxospiro[cyclopentane-1,3'-indoline]-4'-carbonitrile hydrochloride

[0540] Dissolve tert-butyl ((7-(5-(4'-cyano-2'-oxospiro[cyclohexane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (20 mg, 35 μmol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a yellow solid (17 mg, 95.77%). 1 H NMR (400MHz, CD 3 OD)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] + .

[0541] Example 20: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-bromospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0542]

[0543] Step 1: Synthesis of (2-bromo-6-iodophenyl)methanol

[0544] The tetrahydrofuran solution of borane tetrahydrofuran complex (31 mL, 31 mmol, 1 M) was slowly dripped into the anhydrous tetrahydrofuran solution (50 mL) of 2-bromo-6-iodobenzoic acid (5.00 g, 15.29 mmol), and stirred at 70 ° C for 12 h. Methanol was added to quench the reaction, and 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 for dilution, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and 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 silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain a white solid (4.11 g, 85.87%).1 HNMR (400MHz, CDCl 3 )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).

[0545] Step 2: Synthesis of 2-bromo-6-iodobenzyl methanesulfonate

[0546] At 0°C, methanesulfonyl chloride (3.14 g, 27.38 mmol) was slowly dripped into 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), and stirred at room temperature for 1 h. DCM (50 mL) was added to dilute the reaction solution, and then washed with water (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a yellow liquid (5.12 g, 100%). 1 H NMR (400 MHz, CDCl 3 )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).

[0547] Step 3: Synthesis of 2-(2-bromo-6-iodophenyl)acetonitrile

[0548] A mixture of 2-bromo-6-iodobenzyl methanesulfonate (5.10 g, 13.04 mmol), trimethylsilyl cyanide (1.55 g, 15.65 mmol), potassium carbonate (3.60 g, 26.08 mmol) and acetonitrile (60 mL) was stirred at 80°C for 5 h. The heating and stirring were stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, and washed with saturated brine (30 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain a colorless transparent liquid (3.32 g, 79.07%). 1 H NMR (400 MHz, CDCl 3 )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).

[0549] Step 4: Synthesis of 1-(2-bromo-6-iodophenyl)cyclopentane-1-carbonitrile

[0550] 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 at 50°C for 1 h. Ethyl acetate (100 mL) was added to the reaction solution for dilution, 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: PE / EtOAc (v / v) = 10 / 1) to obtain a yellow solid (1.34 g, 38.24%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0551] Step 5: Synthesis of 1-(2-bromo-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentane-1-carbonitrile

[0552] 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(diphenylphosphino)-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 at 140 ° C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a wine red viscous liquid (0.67 g, 72.98%). 1 H NMR (400 MHz, CDCl 3 )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]+ .

[0553] Step 6: Synthesis of 4'-bromo-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0554] 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°C for 6 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (453 mg, 72.35%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0555] Step 7: Synthesis of 4'-bromo-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one

[0556] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution, acetic acid was removed by rotary evaporation under reduced pressure, and dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (125 mg, 91.67%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0557] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0558] 4'-Bromo-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one (100 mg, 0.21 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (151 mg, 0.38 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C for 2 h under nitrogen protection and 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain a yellow solid (33 mg, 20.96%); 1 H NMR (400 MHz, CDCl 3 )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] + .

[0559] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-bromospiro[cyclopentane-1,3'-indolin]-2'-one hydrochloride

[0560] Dissolve tert-butyl ((7-(5-(4'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (10 mg, 17 umol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (8 mg, 89.16%). 1 H NMR (400MHz, CD 3 OD)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] + .

[0561] Example 21: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-(difluoromethyl)spiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0562]

[0563] Step 1: Synthesis of 1-(2-(difluoromethyl)-6-iodophenyl)cyclohexane-1-carbonitrile

[0564] At 0°C, add NaH (0.50 g, 12.30 mmol, 60% content) to a solution of 2-(2-(difluoromethyl)-6-iodophenyl)acetonitrile (0.60 g, 2.05 mmol) in N,N-dimethylformamide (20 mL), stir at room temperature for 0.5 h, add 1,5-dibromopentane (0.71 g, 3.07 mmol), and stir at room temperature for 4 h. Stop stirring, add water to quench the reaction, concentrate under reduced pressure, add ethyl acetate (100 mL) to the residue to dilute, and wash with water (50 mL×3). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a yellow liquid (0.60 g, 80.87%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0565] Step 2: Synthesis of 1-(2-(difluoromethyl)-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclohexane-1-carbonitrile

[0566] 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(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid (320 mg, 69.96%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0567] Step 3: Synthesis of 4'-(difluoromethyl)-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0568] 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°C for 6 h. 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×3) and dried over anhydrous sodium sulfate. 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) = 5 / 1) to obtain a yellow solid (142 mg, 47.19%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0569] Step 4: Synthesis of 4'-(difluoromethyl)-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0570] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution (10 mL), and the acetic acid was removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added to dilute, and the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (181 mg, 93.69%). LC-MS: 458.10 [M+H] + .

[0571] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0572] 4'-(Difluoromethyl)-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one (100 mg, 0.22 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (132 mg, 0.33 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 and microwave conditions at 80 °C for 2 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (20 mg, 15.12%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0573] Step 6: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4'-(difluoromethyl)spiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0574] Dissolve tert-butyl ((7-(5-(4'-(difluoromethyl)-2'-oxospiro[cyclohexane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (10 mg, 17 umol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a yellow solid (8 mg, 89.41%). 1 H NMR (400 MHz, DMSO-d 6 )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] + .

[0575] Example 22: 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-fluorospiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0576]

[0577] Step 1: Synthesis of (3-fluoro-2-iodophenyl)methanol

[0578] The tetrahydrofuran solution of borane tetrahydrofuran complex (38mL, 38mmol) was slowly dripped into the anhydrous tetrahydrofuran (50mL) solution of 3-fluoro-2-iodobenzoic acid (5.00g, 18.80mmol), and stirred at room temperature for 1h. Methanol was added to quench the reaction, and most of the solvent was removed by rotary evaporation under reduced pressure. Ethyl acetate (100mL) and water (100mL) were added to dilute, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (4.61g, 97.32%). 1 H NMR (400 MHz, CDCl 3 )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] +

[0579] Step 2: Synthesis of 3-fluoro-2-iodobenzyl methanesulfonate

[0580] At 0°C, 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), and stirred at room temperature for 0.5 h. DCM (50 mL) was added to dilute, and the reaction solution was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure to obtain a yellow liquid (6.26 g, 100%). 1 H NMR (400 MHz, CDCl 3 )δ7.31–7.24(m,2H),7.02–6.96(m,1H),4.69(s,2H),2.76(s,3H).

[0581] Step 3: Synthesis of 2-(3-fluoro-2-iodophenyl)acetonitrile

[0582] A mixture of 3-fluoro-2-iodobenzyl methanesulfonate (6.00 g, 18.18 mmol), trimethylsilyl cyanide (2.16 g, 21.82 mmol), potassium carbonate (5.03 g, 36.36 mmol) and acetonitrile (60 mL) was stirred at 80 °C for 3 h. The mixture was stopped and cooled to room temperature. The solvent was concentrated by rotary evaporation under reduced pressure. Ethyl acetate (50 mL) was added to the residue and washed with saturated brine (30 mL × 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 obtain a colorless transparent liquid (2.86 g, 65.28%). 1 H NMR (400 MHz, CDCl 3 )δ7.40–7.32(m,2H),7.07–7.02(m,1H),3.87(s,2H); GC-MS:260.9[M] + .

[0583] Step 4: Synthesis of 7-bromo-2-(3-fluoro-2-iodophenyl)heptanenitrile

[0584] 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 °C for 1 h. Ethyl acetate (100 mL) was added to the reaction solution to dilute it, and the mixture was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain a yellow solid (0.89 g, 56.65%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0585] Step 5: Synthesis of 1-(3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclohexane-1-carbonitrile

[0586] 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(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a brown solid (184 mg, 50.58%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0587] Step 6: Synthesis of 1-(3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclohexane-1-carboxylic acid

[0588] Dissolve 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) in a mixed solvent of ethanol (5 mL) and water (5 mL) and stir at 140°C for 4 h. Adjust pH to 4 with a solution of hydrogen chloride in 1,4-dioxane (4 M), concentrate the solvent under reduced pressure, add ethanol (20 mL) to the residue, and filter out the solid. Concentrate the solvent under reduced pressure to obtain a yellow liquid (201 mg, 100%). LC-MS: 318.20 [M+H] + .

[0589] Step 7: Synthesis of 7'-fluoro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0590] Dissolve 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) in dichloromethane (10 mL) and stir at room temperature for 2 h. Dilute with dichloromethane (50 mL), wash with water (30 mL×3), dry over anhydrous sodium sulfate, concentrate the solvent by rotary evaporation under reduced pressure, and purify the residue by silica gel column chromatography (eluent: PE / EtOAc (v / v)=4 / 1) to obtain a yellow solid (77 mg, 42.74%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0591] Step 8: Synthesis of 7'-fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0592] Dissolve 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) in acetic acid (10 mL) and stir at room temperature for 3 h. Quench the reaction with saturated sodium bisulfite solution (10 mL), then concentrate the mixture under reduced pressure to remove acetic acid, and add dichloromethane (100 mL) to the concentrate to dilute it. Wash the organic phase with water (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a gray viscous liquid (110 mg, 91.10%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0593] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0594] 7'-Fluoro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one (110 mg, 0.26 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (156 mg, 0.39 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C under nitrogen protection and microwave conditions for 2 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to give a yellow solid (13 mg, 8.78%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0595] Step 10: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-fluorospiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0596] Dissolve tert-butyl ((7-(5-(7'-fluoro-2'-oxospiro[cyclohexane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (13 mg, 23 μmol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain a brown solid (11 mg, 95.20%). 1 H NMR (400MHz, CD 3 OD)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] + .

[0597] Example 23: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-cyclopropylspiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0598]

[0599] Step 1: Synthesis of 1-(3-bromo-2-iodophenyl)cyclohexane-1-carbonitrile

[0600] At 0°C, NaH (0.45 g, 18.66 mmol, 60% content) was added to a solution of 2-(3-bromo-2-iodophenyl)acetonitrile (1.00 g, 3.11 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred for 0.5 h at room temperature, and then 1,5-dibromopentane (1.07 g, 4.67 mmol) was added and stirred at room temperature for 4 h. Stirring was stopped, water was added to quench the reaction, the solvent was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue to dilute, and washed with water (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a yellow solid (843 mg, 69.58%). 1 H NMR (400 MHz, CDCl 3)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] + .

[0601] Step 2: Synthesis of 1-(3-bromo-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclohexane-1-carbonitrile

[0602] 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(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow viscous liquid (283 mg, 61.45%). 1 HNMR (400MHz, CDCl 3 )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] + .

[0603] Step 3: Synthesis of 7'-bromo-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0604] 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°C for 6 h. The solvent was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue for dilution, and the residue was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (386 mg, 76.99%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0605] Step 4: Synthesis of 7'-cyclopropyl-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0606] 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 at 110 °C for 1 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a yellow solid (63 mg, 70.61%). 1 HNMR (400MHz, CDCl 3)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] + .

[0607] Step 5: Synthesis of 7'-cyclopropyl-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one

[0608] 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 3 h. The reaction was quenched with saturated sodium bisulfite solution (10 mL), acetic acid was removed by rotary evaporation under reduced pressure, dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a yellow solid (83 mg, 99.40%). 1 H NMR (400 MHz, CDCl 3 )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] + .

[0609] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0610] 7'-Cyclopropyl-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclohexane-1,3'-indolin]-2'-one (80 mg, 0.18 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (108 mg, 0.27 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 at 80 °C under nitrogen protection and microwave conditions for 2 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow solid (32 mg, 30.09%). 1 H NMR (400 MHz, CDCl 3 )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,6 H),1.47(s,9H),1.18–1.06(m,1H),0.51–0.35(m,4H); LC-MS:595.30[M+H] + .

[0611] Step 7: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-cyclopropylspiro[cyclohexane-1,3'-indolin]-2'-one hydrochloride

[0612] Dissolve tert-butyl ((7-(5-(7'-cyclopropyl-2'-oxospiro[cyclohexane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (15 mg, 25 μmol) in ethanol (1 mL), add a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a white solid (11 mg, 82.12%). 1 H NMR (400MHz, CD3 OD)δ8.26(d,J=8.4Hz,1H),8.23(s,1H),7.85(d,J=8.4Hz,1H),7.78(s,1 H),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),1.90–1.5 3(m,8H),1.23–1.17(m,1H),0.57–0.38(m,4H); LC-MS:495.30[M+H-HCl] + .

[0613] Example 24: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0614]

[0615] Step 1: Synthesis of 1-bromomethyl-3-chloro-2-iodobenzene

[0616] Dissolve 1-methyl-3-chloro-2-iodobenzene (3.0 g, 11.90 mmol) in carbon tetrachloride (20 mL), add N-bromosuccinimide (3.17 g, 17.8 mmol) and benzoyl peroxide (390 mg, 2.38 mmol), and stir at 90°C for 24 h. Concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane (30 mL), wash with water (30 mL×2), dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography (eluent: PE) to obtain a white solid product (2.7 g, 68.6%).

[0617] Step 2: Synthesis of 2-(3-chloro-2-iodophenyl)acetonitrile

[0618] 1-Bromomethyl-3-chloro-2-iodobenzene (2.6 g, 7.85 mmol), trimethylsilyl cyanide (0.93 g, 9.42 mmol) and potassium carbonate (1.30 g, 9.42 mmol) were dissolved in acetonitrile (20 mL) and stirred at 60°C. The reaction was stopped and cooled to room temperature, the reaction solution 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, filtered and concentrated under reduced pressure to obtain a brown liquid product (1.70 g, 78%).

[0619] Step 3: Synthesis of 1-(3-chloro-2-iodophenyl)cyclopropane-1-carbonitrile

[0620] Dissolve 2-(3-chloro-2-iodophenyl)acetonitrile (1.7g, 6.13mmol), potassium hydroxide (3.44g, 61.3mmol) and tetrabutylammonium bromide (200mg, 0.31mmol) in water (10mL), add 1,2-dibromoethane (2.48g, 12.26mmol) under nitrogen protection and stirring at 70°C, and continue to stir and react at temperature for 24h. Stop the reaction and cool to room temperature, extract with ethyl acetate (20mL×2), combine the organic phases and wash with water (20mL×2), and dry the organic phase with anhydrous sodium sulfate. After the organic phase is concentrated under reduced pressure, it is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=10 / 1) to obtain a yellow solid product (1.2g, 65%). LC-MS: 305.00[M+H] + .

[0621] Step 4: Synthesis of 1-(3-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carbonitrile

[0622] 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(diphenylphosphino)-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), stirred and reacted at 140°C for 4 h under nitrogen protection and 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), and the organic phases were 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 obtain a brown oily product (410 mg, 91%). LC-MS: 273.10 [M+H] + .

[0623] Step 5: Synthesis of 1-(3-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[0624] Dissolve 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) in a mixed solvent of water (10 mL) and methanol (10 mL), and stir the reaction at 100 ° C for 24 h under nitrogen protection. Stop the reaction, concentrate under reduced pressure to remove the solvent, dilute with water (10 mL), adjust pH to 2 with 2M hydrochloric acid, extract with ethyl acetate (20 mL×3), combine the organic phases and wash with saturated brine (20 mL×2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid product (250 mg, 78%). LC-MS: 290.15[MH] - .

[0625] Step 6: Synthesis of 7'-chloro-1'-(1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0626] 1-(3-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopropane-1-carboxylic acid (300 mg, 1.03 mmol), N,N-carbonyldiimidazole (250 mg, 1.54 mmol) and N,N-diisopropylethylamine (270 mg, 2.06 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature. The reaction was stopped, and the reaction solution was diluted with dichloromethane (20 mL), then washed with dilute hydrochloric acid (1 M, 10 mL), and washed 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 obtain a colorless oily product (260 mg, 92%). LC-MS: 274.30 [M+H] + .

[0627] Step 7: Synthesis of 7'-chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

[0628] 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 stirred at room temperature for reaction. The solvent was removed by concentration, and the residue was diluted with ethyl acetate (20 mL). The organic phase was washed with saturated sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a colorless oily product (146 mg, 93%). LC-MS: 400.20 [M+H] + .

[0629] Step 8: Synthesis of tert-butyl ((7-(5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0630] Compound 7'-chloro-1'-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (100 mg, 0.25 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (150 mg, 0.38 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 the reaction was stirred at 80 °C for 3 h under nitrogen protection and microwave conditions. 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 obtain a white solid product (100 mg, 73%). LC-MS: 547.20 [M+H] + .

[0631] Step 9: Synthesis of 1'-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one hydrochloride

[0632] The compound ((7-(5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (20 mg, 0.037 mmol) was dissolved in methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid product (12 mg, 73.4%). 1 H NMR (400 MHz, DMSO-d 6)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] + .

[0633] Example 25: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0634]

[0635] Step 1: Synthesis of ethyl 2-((1-methyl-1H-pyrazol-5-yl)amino)benzoate

[0636] Ethyl 2-iodobenzoate (1.05 g, 3.82 mmol), 1-methyl-5-aminopyrazole (0.56 g, 5.73 mmol), 4,5-bis(diphenylphosphino)-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 in 1,4-dioxane (10 mL) and stirred at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a wine red viscous liquid (0.75 g, 84.42%). LC-MS: 246.30 [M+H] + ; 1 HNMR (400MHz, CDCl 3 )δ9.37(s,1H),8.01–7.96(m,1H),7.48(d,J=1.8Hz,1H),7.35–7.30(m,1H),6.82–6.7 3(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).

[0637] Step 2: Synthesis of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentan-1-ol

[0638] A solution of 1,4-dibromobutane (1.87 g, 8.64 mmol) in anhydrous tetrahydrofuran (10 mL) was dropped into a mixture of magnesium chips (420 mg, 17.28 mmol) and iodine (109 mg, 0.43 mmol), and the mixture was heated and stirred for 2 h at room temperature at 25 °C. 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 dropped into the above reaction solution at 0 °C, and the mixture was stirred for 12 h at room temperature at 25 °C. A saturated ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (50 mL) was added to dilute the mixture, and the mixture was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a yellow liquid (303 mg, 27.23%). LC-MS: 258.20 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0639] Step 3: Synthesis of 1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0640] At 0°C, triphosgene (1.16 g, 3.92 mmol) was added to a solution of 1-(2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentan-1-ol (250 mg, 0.98 mmol) and triethylamine (1.19 g, 11.76 mmol) in dichloromethane (5 mL), and stirred at room temperature for 1 h. Dichloromethane (50 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain a white solid (120 mg, 43.26%). LC-MS: 284.20 [M+H] + ;1 HNMR (400MHz, CDCl 3 )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).

[0641] Step 4: Synthesis of 1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0642] 1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-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 3 h. The reaction was quenched with saturated sodium bisulfite solution (5 mL), and the acetic acid was removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added to dilute the mixture, and the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (150 mg, 94.41%). LC-MS: 410.10 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0643] Step 5: Synthesis of tert-butyl ((7-(1-methyl-5-(2-oxospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-1(2H)-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0644] 1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one (140 mg, 0.34 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (205 mg, 0.51 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (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 and microwave conditions at 90 °C for 2 h. 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 and 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 obtain a yellow solid (29 mg, 15.23%). LC-MS: 557.30 [M+H] + ; 1 HNMR (400MHz, CDCl 3 )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).

[0645] Step 6: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0646] Dissolve the compound ((7-(1-methyl-5-(2-oxospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-1(2H)-yl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (20 mg, 36 umol) in dichloromethane (1 mL), add hydrogen chloride (1 mL, 4M dioxane solution), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a yellow solid (14 mg, 79.03%). LC-MS: 457.30 [M-HCl+H] + ; 1H NMR (400MHz, CD 3 OD)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),7.3 2–7.21(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).

[0647] Example 26: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-8-fluorospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0648]

[0649] Step 1: Synthesis of methyl 3-fluoro-2-iodobenzoate

[0650] Add oxalyl chloride (2.62g, 20.68mmol) to a dichloromethane solution (50mL) of 3-fluoro-2-iodobenzoic acid (5.00g, 18.80mmol), then add DMF (68mg, 0.94mmol) and stir at room temperature for 2h. Then add methanol (0.90g, 28.20mmol) and potassium carbonate (7.80g, 56.4mmol) and stir at room temperature for 1h. Add dichloromethane (100mL) to the reaction solution, wash the organic phase with water (50mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure by rotary evaporation. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow liquid (3.12g, 59.28%). LC-MS: 280.95[M+H] + .

[0651] Step 2: Synthesis of methyl 3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)benzoate

[0652] Methyl 3-fluoro-2-iodobenzoate (3.00 g, 10.71 mmol), 1-methyl-5-aminopyrazole (1.25 g, 12.85 mmol), 4,5-bis(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow viscous liquid (1.37 g, 51.31%). LC-MS: 250.20 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0653] Step 3: Synthesis of 1-(3-fluoro-2-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentan-1-ol

[0654] Add a solution of 1,4-dibromobutane (2.43 g, 11.24 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise into a mixture of magnesium turnings (544 mg, 22.48 mmol) and iodine (143 mg, 0.56 mmol), heat and stir, and stir at room temperature for 2 h.

[0655] 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 reaction mixture at 0°C and stirred at room temperature (25°C) for 12 h.

[0656] Add saturated ammonium chloride solution (10 mL) to quench the reaction, add ethyl acetate (50 mL) to dilute, wash with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate the solvent by rotary evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow liquid (512 mg, 33.11%). LC-MS: 276.30 [M+H] + ; 1 H NMR (400 MHz, 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).

[0657] Step 4: Synthesis of 8-fluoro-1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0658] At 0°C, 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), and stirred at room temperature for 1 h. Dichloromethane (50 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow solid (192 mg, 57.68%). LC-MS: 302.30 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0659] Step 5: Synthesis of 8-fluoro-1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0660] 8-Fluoro-1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-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 3 h. The reaction was quenched with saturated sodium bisulfite solution (5 mL), acetic acid was removed by rotary evaporation under reduced pressure, and dichloromethane (100 mL) was added to dilute the mixture. The organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (230 mg, 90.12%). LC-MS: 428.10[M+H] + ; 1 HNMR (400MHz, CDCl 3 )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).

[0661] Step 6: Synthesis of tert-butyl ((7-(5-(8-fluoro-2-oxospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-1(2H)-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0662] 8-Fluoro-1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one (230 mg, 0.62 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (373 mg, 0.93 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (40 mg, 62 μmol) 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 at 90 °C for 3 h under nitrogen protection and microwave conditions. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain a yellow solid (62 mg, 19.31%). LC-MS: 575.50 [M+H] + ; 1 HNMR (400MHz, CDCl 3 )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).

[0663] Step 7: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-8-fluorospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0664] Dissolve tert-butyl ((7-(5-(8-fluoro-2-oxospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-1(2H)-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 52 μmol) in dichloromethane (1 mL), add hydrogen chloride (1 mL, 4M dioxane solution), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a yellow solid (23 mg, 86.21%). LC-MS: 475.40 [M-HCl+H] +; 1 HNMR (400MHz, CD 3 OD)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%.

[0665] Example 27: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0666]

[0667] Step 1: Synthesis of compound 3-chloro-2-fluorobenzoic acid

[0668] Place 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) at 80 °C and stir for 12 h. Cool to room temperature, add ethanol (100 mL), stir at 50 °C for 0.5 h, adjust pH to 4 with concentrated hydrochloric acid, extract with ethyl acetate (100 mL × 3), combine the organic phases, and concentrate the solvent under reduced pressure to obtain a white solid (7.93 g, 72.03%). LC-MS: 173.20 [M+H] + .

[0669] Step 2: Synthesis of 3-chloro-2-fluoro-6-iodobenzoic acid

[0670] Under air atmosphere, a mixture of 3-chloro-2-fluorobenzoic acid (5.00 g, 28.64 mmol), N-iodosuccinimide (9.67 g, 42.96 mmol), pentamethylcyclopentadienyl sulfate iridium complex (410 mg, 0.86 mmol) and hexafluoroisopropanol (50 mL) was stirred at 60°C for 12 h. Saturated sodium bisulfite solution (50 mL) was added to quench the reaction, 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 (4 M), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure to obtain a yellow solid (5.03 g, 58.45%).

[0671] Step 3: Synthesis of methyl 3-chloro-2-fluoro-6-iodobenzoate

[0672] Add oxalyl chloride (2.32g, 18.30mmol) to a dichloromethane solution (50mL) of 3-chloro-2-fluoro-6-iodobenzoic acid (5.00g, 16.64mmol), then add DMF (61mg, 0.83mmol), and stir at room temperature for 2h. Then add methanol (0.80g, 24.96mmol) and potassium carbonate (6.90g, 49.92mmol), and stir at room temperature for 1h. Add dichloromethane (100mL) to the reaction solution, wash the organic phase with water (50mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure by rotary evaporation. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow liquid (4.45g, 85.03%).

[0673] Step 4: Synthesis of methyl 3-chloro-2-fluoro-6-((1-methyl-1H-pyrazol-5-yl)amino)benzoate

[0674] 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(diphenylphosphino)-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 at 140°C for 4 h under nitrogen protection and microwave conditions. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow viscous liquid (1.36 g, 50.25%). LC-MS: 284.20 [M+H] + ; 1H NMR (400 MHz, CDCl 3 )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).

[0675] Step 5: Synthesis of 1-(3-chloro-2-fluoro-6-((1-methyl-1H-pyrazol-5-yl)amino)phenyl)cyclopentan-1-ol

[0676] At 0°C, 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), and stirred at room temperature for 12 h. Saturated ammonium chloride solution (10 mL) was added to quench the reaction, ethyl acetate (50 mL) was added to dilute, and the mixture was washed with saturated brine (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a yellow liquid (251 mg, 22.99%). LC-MS: 310.10 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ8.16(s,1H),7.40(d,J=1.8Hz,1H),7.07(t,J=8.4Hz,1H),6.40(dd,J=8.9,1.3 Hz,1H),5.94(d,J=1.8Hz,1H),3.63(s,3H),2.35–2.21(m,4H),1.96–1.79(m,4H).

[0677] Step 6: Synthesis of 6-chloro-5-fluoro-1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0678] At 0°C, 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)cyclopentan-1-ol (250 mg, 0.81 mmol) and triethylamine (0.98 g, 9.72 mmol) in dichloromethane (10 mL), and stirred at room temperature for 1 h. Dichloromethane (50 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a white solid (145 mg, 53.17%). LC-MS: 336.20 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0679] Step 7: Synthesis of 6-chloro-5-fluoro-1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one

[0680] Dissolve 6-chloro-5-fluoro-1-(1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one (130 mg, 0.39 mmol) and N-iodosuccinimide (175 mg, 0.78 mmol) in acetic acid (5 mL) and stir at room temperature for 3 h. Quench the reaction with saturated sodium bisulfite solution (5 mL), remove acetic acid by rotary evaporation under reduced pressure, add dichloromethane (100 mL) to dilute, wash the organic phase with water (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v)=5 / 1) to obtain a yellow solid (156 mg, 87.27%). LC-MS: 462.00[M+H] + ; 1 H NMR (400MHz, CD 3 Cl)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).

[0681] 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-dihydrophthalazin-1-yl)methyl)carbamate

[0682] 6-Chloro-5-fluoro-1-(4-iodo-1-methyl-1H-pyrazol-5-yl)spiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one (150 mg, 0.33 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (199 mg, 0.49 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (22 mg, 33 μmol) 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 °C under microwave conditions for 2 h. 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. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to obtain a yellow solid (42 mg, 21.21%). LC-MS: 609.50 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0683] Step 9: Synthesis of 1-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-2(1H)-one hydrochloride

[0684] Dissolve tert-butyl ((7-(5-(6-chloro-5-fluoro-2-oxospiro[benzo[d][1,3]oxazine-4,1'-cyclopentane]-1(2H)-yl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 47 μmol) in dichloromethane (1 mL), add hydrogen chloride (1 mL, 4M 1,4-dioxane solution), and stir at room temperature for 3 h. Concentrate under reduced pressure by rotary evaporation to obtain a yellow solid (20 mg, 74.06%). 1 H NMR (400MHz, CD 3 OD)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] + .

[0685] Biological Activity Test Example

[0686] 1. PRMT5 enzyme activity assay

[0687] 1. Experimental operation steps

[0688] Compound preparation and sample addition: Dissolve the compound in DMSO to 10mM stock solution, prepare the corresponding dosing dilution, start with a 10μM concentration, dilute 3 times, set 10 concentration points, set up DMSO blank control wells and MRTX1719 10μM positive control wells. Take 20nl of the prepared drug dilution and transfer it to a 384-well plate, duplicate 2 wells, and centrifuge at 1000rpm.

[0689] Add enzyme and substrate working solution: Two experimental groups were set up, one with MTA and one without MTA. 2 μL of PRMT5 / MEP50 working solution with or without MTA was added to each well and incubated at 25°C for 15 min. Then, 2 μL of Bio-H4(1-21)&SAM working solution was added to each well and incubated at 25°C for 180 min.

[0690] Add MTase-Glo TM Reaction solution and detection solution: add 1 μL 5X MTase-Glo to each well TM The reaction solution was centrifuged at 1000 rpm and incubated at 25°C for 30 min. Then 5 μL of MTase-Glo was added to each well. TM The test solution was centrifuged at 1000 rpm and incubated at 25°C for 30 min.

[0691] Plate reading detection: Place the 384-well plate on a plate reader to detect the chemiluminescent signal value.

[0692] 2. Experimental data processing:

[0693] 1) Inhibition rate % = 100 × (average value of blank control wells – detection value of each well) / (average value of blank control wells – average value of positive drug control wells)

[0694] Average value of blank control wells: refers to the average detection value of DMSO blank control wells

[0695] Average value of positive drug control wells: refers to the average detection value of the positive control MRTX1719 at the highest drug concentration of 10μM

[0696] 2) IC 50 IC value calculation method: IC value was obtained by nonlinear fitting formula using Graph Pad Prism 8.0 software. 50 The value is calculated as follows:

[0697] Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)×HillSlope))

[0698] X: log value of compound concentration Y: inhibition rate %

[0699] The specific experimental results are shown in Table 1.

[0700] Table 1 IC values ​​of the compounds of the present invention on PRMT5-mediated enzyme activity 50 value

[0701]

[0702] Conclusion: The results in Table 1 illustrate that the compounds of the present invention synergistically inhibit PRMT5 enzyme activity in the presence of MTA.

[0703] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of the different embodiments, implementation schemes or examples, without contradiction.

[0704] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, substitute and vary the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

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 N or CR 7a ; Q 2 N or CR 7b ; Q 3 N or CR 7c ; Q 4 N or CR 7d ; Q 5 is a bond, NH, O or CH2; n is 0 or 1; Ring A is a 5-12 membered heteroaryl or C 6-10 Aryl, wherein the ring A is optionally substituted by 1 or 2 R a replaced by; Each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , 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 heterocyclic group, wherein the ring B is optionally substituted by 1, 2 or 3 independently selected from D, F, Cl, Br, I, NH2, 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 Substituted by a haloalkyl substituent; R 1 , R 2 , R 3 and R 4 Each independently represents 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)2R 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 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl; R 5 and R 6 Each independently represents 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 , R 6 Together with the carbon atom to which they are attached, they form C=O; R 7a , R 7b , R 7c and R 7d Each independently represents 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 heterocyclic group or C 1-6 haloalkyl; and R 8 and R 9 Each independently is 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.

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 the ring A is optionally substituted by 1 or 2 R a replaced by; Each R a are independently D, F, Cl, Br, I, CN, OH, C(=O)OH, -NR 9 R 8 , 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 Halogenated alkyl.

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 replaced by; Each R a and are 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 the ring B is optionally substituted by 1, 2 or 3 independently selected from D, F, Cl, Br, I, NH2, 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 The alkyl group is substituted with a haloalkyl substituent.

5. The compound according to any one of claims 1 to 4, wherein R 1 , R 2 , R 3 and R 4 Each independently represents 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)2R 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 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6-10 Aryl; R 5 and R 6 Each independently represents 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 atom to which they are attached, they form C=O; R 7a , R 7b , R 7c and R 7d Each independently represents 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 heterocyclic group or C 1-4 haloalkyl; and R 8 and R 9 Each independently is 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.

6. The compound according to any one of claims 1 to 5, wherein R 1 , R 2 , R 3 and R 4 Each independently represents 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), -NR 9 R 8 、-S(=O)2R 8 、-S(=O)R 8 、-C(=O)OR 8 、-NR 9 C(=O)R 8 、-C(=O)NR 9 R 8 , -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br, -(CH2)2Cl, -CH2OH, -(CH2)2OH, -(CH2)3 OH, -(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, pyridyl, pyrazinyl, pyrimidinyl, phenyl or naphthyl; R 5 and R 6 each independently represents 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 , R 6 Together with the carbon atom to which they are attached, they form C=O; R 7a , R 7b , R 7c and R 7d each independently represents 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 Each is 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, pyridyl, 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), in, Ring B, n, Q 5 , R 1 , R 2 , R 3 , R 4 and R a Each has the definition as described in any one of the preceding claims 1-6.

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 an MTAP deficiency-associated cancer.

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