WO2022228515A1 - 甲硫氨酸腺苷转移酶抑制剂、其制备方法及应用 - Google Patents

甲硫氨酸腺苷转移酶抑制剂、其制备方法及应用 Download PDF

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WO2022228515A1
WO2022228515A1 PCT/CN2022/089900 CN2022089900W WO2022228515A1 WO 2022228515 A1 WO2022228515 A1 WO 2022228515A1 CN 2022089900 W CN2022089900 W CN 2022089900W WO 2022228515 A1 WO2022228515 A1 WO 2022228515A1
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cancer
pharmaceutically acceptable
isomers
prodrugs
hydrates
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PCT/CN2022/089900
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English (en)
French (fr)
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阳安乐
张德伟
董理进
何权鸿
易韬
孟江
田林
梁杰
冯泽
胡凯
张晓东
张毅
胡希
候亚男
唐军
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赛诺哈勃药业（成都）有限公司
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Priority to US18/557,795 priority Critical patent/US20240228491A1/en
Priority to JP2023566848A priority patent/JP2024516429A/ja
Priority to EP22794985.6A priority patent/EP4332101A1/en
Priority to CN202280031963.0A priority patent/CN117295734A/zh
Publication of WO2022228515A1 publication Critical patent/WO2022228515A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a methionine adenosyl transferase inhibitor, a preparation method thereof and its application in the pharmaceutical field.
  • Loss-of-function mutations in tumor suppressor genes are very common, but there are few selectively targeted therapies based on tumor suppressor gene deletion mutations. Targeted therapy of tumor suppressor genes inactivated by homozygous deletion is particularly difficult because the lack of residual proteins renders therapeutic strategies that directly activate, stabilize or repair tumor suppressor genes ineffective.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP , considered to be the rate-limiting step of the methionine cycle.
  • SAM is the propylamino donor in polyamine biosynthesis and is the major methyl donor for DNA methylation, which is involved in gene transcription and cell proliferation and the generation of secondary metabolites.
  • MAT gene can be divided into MAT1A gene and MAT2a gene, encoding the only enzyme that can catalyze the synthesis of SAM-MAT.
  • MAT has three isoenzymes, namely MATI, MATIII and MATII, the first two are the products encoded by the MAT1a gene, and the latter is the product encoded by the MAT2a gene.
  • the MAT1a gene is mainly expressed in the adult liver, while the MAT2a gene is widely expressed in human tissues other than the liver. More and more studies have found that MAT2a protein is also highly expressed in other cancer tissues or cells, such as breast cancer, intestinal cancer, leukemia and lymphoma, etc., and the silencing of MAT2a gene leads to the death of corresponding cancer cells, indicating that MAT2a protein has potential as a therapeutic target.
  • Methylthioadenosine phosphorylase is an enzyme expressed in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methyl thioglycoside-1-phosphate.
  • MTAP activity has also been detected in a large number of primary lesions such as ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, and non-Hodgkin's lymphoma.
  • MTA When MTAP is depleted, MTA will accumulate in cells to about 100 [mu]M, and cells will begin to excrete MTA.
  • PRMT5 Protein Arginine Methyltransferase 5
  • SAM Protein Arginine Methyltransferase 5
  • One of the objects of the present invention is to provide a compound with MAT2a inhibitory activity.
  • the present invention provides the compound represented by the following formula I structure, its pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures:
  • R 1 is selected from 5-10-membered aryl group or aromatic heterocyclic group
  • R 2 is selected from -CF 3 or cyclopropyl
  • R is selected from hydrogen, alkyl, aryl, aromatic heterocyclyl, cycloalkyl, alicyclic heterocyclyl, bridged ring and spiro;
  • A is an aryl group or an aromatic heterocyclic group
  • R 1 in the present invention is selected from imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
  • the R 1 of the present invention may be further substituted with 0-2 R a groups, and each of the R a groups may be independently selected from alkyl, halogen, haloalkyl, alkane Oxy group, haloalkoxy group, hydroxyl group, amino group, amine group, carboxyl group, amido group, cycloalkyl group, deuterium.
  • the R 1 may be further substituted with 0-2 R a groups, each of the R a groups may be independently selected from C 1 -C 3 alkyl, fluorine, chlorine , bromine, iodine, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, hydroxyl, amino, amino, carboxyl, acyl, C 3 -C 6 cycloalkyl ,deuterium.
  • the R 1 is phenyl, which may be further substituted with 0-2 Ra groups, each of which may be independently selected from C 1 - C 3 alkyl, fluorine, chlorine, bromine, iodine, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, hydroxyl, amino, amino, carboxyl, acyl, C 3 -C 6 cycloalkyl, deuterium.
  • Ra groups each of which may be independently selected from C 1 - C 3 alkyl, fluorine, chlorine, bromine, iodine, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, hydroxyl, amino, amino, carboxyl, acyl, C 3 -C 6 cycloalkyl, deuterium.
  • the R 1 is phenyl, which can be further substituted with 0-2 Ra groups, each of which can be independently selected from C 1 - C3 alkyl, fluorine, chlorine, bromine and iodine.
  • the R 1 is selected from the group consisting of phenyl, 4-chlorophenyl, 4-bromophenyl, and 4-methylphenyl, and the phenyl may be further substituted with fluorine.
  • R 3 described in the present invention is selected from hydrogen, C 1 -C 3 alkyl, 6- to 10-membered aryl, 5- to 10-membered aromatic heterocyclyl, C 3 -C 6 cycloalkane base, 3- to 6-membered alicyclic heterocyclic group, 4- to 10-membered bridged ring group, spirocyclic group;
  • said R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl , tetrahydropyranyl, thiacyclohexyl, piperidinyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1, 2,4-oxadiazolyl, 4- to 10-membered bridged ring group, spirocyclic group;
  • the R 3 in the present invention is not hydrogen, the R 3 can be optionally selected from one or more halogen, alkyl, alkoxy, cyano, hydroxyl, amino, deuterium, sulfone, sulfone Group substitution of acyl, haloalkyl, cycloalkyl, alicyclic heterocyclyl;
  • the R 3 of the present invention when the R 3 of the present invention is not hydrogen, the R 3 can be optionally selected from one or more halogens, C 1 -C 3 alkyl, C 1 -C 3 alkane Group substitution of oxy, cyano, hydroxyl, amino, deuterium, sulfone, sulfonyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered alicyclic heterocyclic group;
  • the R 3 of the present invention when the R 3 of the present invention is not hydrogen, the R 3 can be selected by one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiacyclohexyl, piperidinyl, pyrrolidinyl, trifluoromethyl, Group substitution of hydroxyl, amino, cyano, deuterium, sulfone, sulfonyl.
  • R3 is selected from hydrogen and C1 - C3 alkyl.
  • a ring of the present invention is selected from a 6- to 10-membered aromatic ring group and a 5- to 10-membered aromatic heterocyclic group.
  • the A ring of the present invention is selected from phenyl, naphthyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, furyl, pyrrolyl, thienyl, oxazolyl, Isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, benzodioxin azolyl, imidazopyridyl, benzisoxazolyl, naphthyridinyl, quinolyl, isoquinolyl, quinoxalinyl, pyrazolopyridyl, triazolopyridyl, pyridone, quinoline oxazolinyl, cinnolinyl, pyridopyrazin
  • the A ring of the present invention is selected from phenyl, naphthyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, furyl, pyrrolyl, thienyl, oxazolyl, Isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, quinolinyl, quinoxaline pyridyl, pyrazolopyridyl, triazolopyridyl, pyridone, quinazolinyl, cinnolinyl, pyridopyrazinyl, benzotriazolyl and benzoxadiazolyl.
  • the A ring of the present invention may be further selected from one or more groups selected from methyl, methoxy, -CF 3 , -CH 2 CF 3 , -NH 2 , F, cyano, -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 SO 2 CH 3 , -(CH 2 ) 2 N(CH 3 ) 2 are substituted.
  • the substituents on the A ring can further form a ring and form a co-cyclic ring with the A ring, such as
  • the A ring of the present invention is selected from the following groups:
  • Another object of the present invention is to provide a compound of the following formula II or formula III structure, its pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures:
  • R 1 , R 3 and A are as described above.
  • the compound of formula I described in the present invention has the following structure:
  • Another object of the present invention is to provide compounds of formula I or formula II or formula III, and pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof, for use in the preparation of medicaments for the treatment of MAT2a-related diseases use.
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a therapeutically effective dose of a compound of formula I or formula II or formula III, or a pharmaceutically acceptable salt or hydrate of the compound of formula I or formula II or formula III , isomers, prodrugs or mixtures, and pharmaceutically acceptable carriers.
  • the present invention further provides the use of the above-mentioned pharmaceutical composition for preparing a medicine for treating MAT2a-related diseases.
  • the MAT2a-related disease is cancer or tumor
  • the cancer or tumor includes neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer Cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer Body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, Medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hod
  • the cancer is lung cancer, non-small cell lung cancer (NSLC), bronchoalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer Cancer, Anal Cancer, Stomach Cancer, Stomach Cancer, Colon Cancer, Breast Cancer, Uterine Cancer, Fallopian Tube Cancer, Endometrial Cancer, Cervical Cancer, Vaginal Cancer, Vulvar Cancer, Hodgkin's Disease, Esophageal Cancer, Small Intestine Cancer, Endocrine System Cancer , Thyroid, parathyroid, adrenal, soft tissue sarcoma, urethral, penile, prostate, bladder, kidney or ureter, renal cell carcinoma, renal pelvis, mesothelioma, hepatocellular carcinoma, biliary tract cancer , chronic or acute leukemia, lymphocytic lymphoma Homas, central nervous system (CNS) tumor, spinal cord axis tumor, brain stem cells, and
  • Another object of the present invention is to provide a method for treating cancer or tumor diseases, comprising administering to a patient in need one or more of the aforementioned pharmaceutical compositions or compounds of formula I or pharmaceutically acceptable salts, hydrates, Isomers, prodrugs or mixtures.
  • pharmaceutically acceptable means suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions or other problems or complications, and with reasonable benefit / risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric or atropisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, all of which fall within the scope of the "isomers" described in the present invention within.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, for example: C 1 -C 3 alkyl refers to a saturated aliphatic hydrocarbon group containing 1 to 3 carbon atoms, including but not limited to methyl, ethyl base, propyl, isopropyl, etc. and their various isomers.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms
  • typical C 3 -C 6 cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentane cyclopentenyl, cyclohexyl, cyclohexenyl, etc.
  • Aliphatic heterocyclyl refers to a saturated monocyclic hydrocarbon substituent wherein one or more ring atoms are substituted with a heteroatom selected from N, O, S and the remaining ring atoms are carbon.
  • 3-6 membered alicyclic heterocycle refers to a saturated cyclic hydrocarbon substituent containing 3-6 ring atoms, wherein one or more ring atoms are substituted by heteroatoms selected from N, O, S, and the rest of the rings Atom is carbon.
  • Specific examples include, but are not limited to: oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, and the like.
  • “Bridged ring group” refers to a cyclic structural group formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other.
  • Spirocyclyl refers to a cyclic structural group formed by two rings sharing a carbon atom.
  • Aryl means an aromatic ring group, and examples of the aryl moiety include phenyl, naphthyl, and the like.
  • Aromatic heterocyclyl refers to an aromatic cyclic substituent wherein one or more ring atoms are substituted with a heteroatom selected from N, O, S, and the remaining ring atoms are carbon.
  • “5-10 membered aromatic heterocyclic ring” refers to an aromatic heterocyclic group containing 5 to 10 ring atoms, wherein one or more ring atoms are replaced by heteroatoms selected from N, O, S, and the remaining ring atoms for carbon.
  • Examples of specific "5-10 membered aromatic heterocycles” include, but are not limited to, imidazolyl, pyrazolyl, triazolyl, thiazolyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, oxazolyl oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, benzobisoxazolyl, imidazopyridine base, benzisoxazolyl, naphthyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrazolopyridyl, triazolopyridyl, pyridone, quinazolinyl, cinnoline base, pyridopyrazinyl, be
  • Amino refers to -NH2 ;
  • Amino refers to -NH-Rx, where Rx is any substituent such as alkyl, cycloalkyl, aryl, heterocyclyl, and the like.
  • the compound of the present invention has excellent MAT2a enzyme inhibitory activity, has excellent inhibitory effect on the growth of cancer cells, and has good safety and good druggability. Therefore, the compound of the present invention will be used in MAT2a-related cancer or tumor diseases. has excellent application prospects.
  • Step 2 Preparation of 4-hydroxy-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester
  • 2-(phenylamino)-6-(trifluoromethyl)nicotinic acid 500mg was dissolved in tetrahydrofuran, N,N-diisopropylcarbodiimide (670mg) and 1-hydroxybenzotriazole ( 718 mg), reacted at room temperature for one hour.
  • diethyl malonate 567 mg was dissolved in tetrahydrofuran (10 mL), and then sodium hydride (355 mg) was added in portions under an ice bath.
  • Step 3 Preparation of 4-chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester
  • Step 4 4-(Methylamino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester preparation
  • Step 5 Preparation of 4-(methylamino)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • Step 6 Preparation of 3-bromo-4-(methylamino)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • the compound of this preparation example was prepared by referring to a method similar to that in the aforementioned preparation example 1.
  • the compound of this preparation example was prepared by referring to a method similar to that in the aforementioned preparation example 2.
  • Step 1 Preparation of 6-bromo-1-methyl-1H-benzo[d]imidazol-2-amine.
  • 6-bromo-1-methyl-1H-benzo[d]imidazol-2-amine 100 mg was dissolved in 1,4-dioxane (15 mL), 1,1'-bis (Diphenylphosphino)ferrocene palladium chloride (65 mg), bispinacol borate (223 mg) and potassium acetate (122 mg) were heated and reacted at 90° C. for 4 hours. After the disappearance of the raw materials was monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the residue was purified by normal phase column chromatography to obtain 100 mg of the target compound.
  • Step 2 Preparation of ethyl 2-(1-methyl-1H-benzo[d]imidazol-6-yl)acetate
  • Step 1 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazole and 6-bromo-1-(tetrahydro- Preparation of 2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazole
  • Step 2 1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)- 1H-benzo[d][1,2,3]triazole and 1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaboran-2-yl)-1H-benzo[d][1,2,3]triazole
  • the target compound (350 mg) obtained in the previous step was dissolved in 1,4-dioxane (10 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (45 mg) was added, and double Alcohol borate (630 mg) and potassium acetate (245 mg) were heated to 90° C. for 4 hours under nitrogen protection. After the disappearance of the raw materials was monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the residue was purified by normal phase column chromatography to obtain 270 mg of the target compound.
  • Step 3 Preparation of 1H-benzo[d][1,2,3]triazol-1-yl 2-((4-bromophenyl)amino)-6-(trifluoromethyl)nicotinate
  • the compound of this preparation example was prepared by referring to a method similar to that in the aforementioned preparation example 11.
  • Example 1 4-(Methylamino)-3-(oxazol-5-yl)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one preparation
  • Step 1 Preparation of 4-(methylamino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbaldehyde
  • Step 2 Reduction of 4-(methylamino)-3-(oxazol-5-yl)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one preparation
  • Step 1 Preparation of 4-hydroxy-1-phenyl-3-(thiazol-2-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • Step 2 Preparation of 4-chloro-1-phenyl-3-(thiazol-2-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • Step 3 Preparation of 4-(methylamino)-1-phenyl-3-(thiazol-2-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • N-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)acetamide 200 mg was dissolved in tetrahydrofuran, and sodium hydride (68 mg) was added under ice-water bath conditions at 0°C, and the reaction was carried out for 30 minutes.
  • 2-Chloro-6-(trifluoromethyl)nicotinonitrile (352 mg) was added to react for 1 hour, and the disappearance of the starting material was monitored by LCMS.
  • Step 1 4-((tert-Butoxycarbonyl)(methyl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8- Preparation of naphthyridine-3-carboxylic acid ethyl ester
  • Step 2 4-((tert-Butoxycarbonyl)(methyl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8- Preparation of naphthyridine-3-carboxylic acid
  • the pH of the system was adjusted to weakly acidic with oxalic acid, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain 210 mg of the target compound.
  • Step 4 (3-(((dimethylamino)methylene)carbamoyl)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1, Preparation of tert-butyl 8-naphthyridin-4-yl)(methyl)carbamate
  • Step 5 (2-oxo-1-phenyl-3-(4H-1,2,4-triazol-3-yl)-7-(trifluoromethyl)-1,2-dihydro-1 Preparation of tert-butyl ,8-naphthyridin-4-yl)(methyl)carbamate
  • Step 6 4-(Methylamino)-1-phenyl-3-(4H-1,2,4-triazol-3-yl)-7-(trifluoromethyl)-1,8-naphthyridine Preparation of -2(1H)-one
  • Step 1 (3-(1,3,4-oxadiazol-2-yl)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1, Preparation of tert-butyl 8-naphthyridin-4-yl)(methyl)carbamate
  • Step 2 4-(Methylamino)-3-(1,3,4-oxadiazol-2-yl)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridine- Preparation of 2(1H)-ketones
  • the system was concentrated to remove dichloromethane, the pH was adjusted to weakly alkaline with saturated aqueous sodium carbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse preparative HPLC to obtain 7 mg of the target compound.
  • Step 3 Reduction of 4-(methylamino)-3-(oxazol-2-yl)-1-phenyl-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one preparation
  • Step 1 Preparation of 4-hydroxy-1-phenyl-3-(1H-pyrazol-1-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • the reaction was terminated by adding (5 mL) aqueous ammonium chloride solution, extracted with ethyl acetate three times, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the obtained crude product was purified by column chromatography to obtain the title Compound 250.0 mg.
  • Step 2 Preparation of 4-chloro-1-phenyl-3-(1H-pyrazol-1-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one
  • Step 1 1-(4-Chlorophenyl)-3-(furan-2-yl)-4-hydroxy-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one preparation
  • Step 2 1-(4-Chlorophenyl)-3-(furan-2-yl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine Preparation of -4-ylmethanesulfonate
  • Step 3 1-(4-Chlorophenyl)-4-((2,4-dimethoxybenzyl)amino)-3-(furan-2-yl)-7-(trifluoromethyl)- Preparation of 1,8-Naphthyridin-2(1H)-one
  • Step 4 Reduction of 4-amino-1-(4-chlorophenyl)-3-(furan-2-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one preparation
  • Example 62 4-Amino-3-(1H-benzo[d][1,2,3]triazol-6-yl)-1-(4-chlorophenyl)-7-(trifluoromethyl) Preparation of )-1,8-naphthyridin-2(1H)-one
  • Step 1 4-Amino-1-(4-chlorophenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3] Triazol-5-yl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one and 4-amino-1-(4-chlorophenyl)-3-(1- (Tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazol-6-yl)-7-(trifluoromethyl)-1,8-naphthalene Preparation of pyridin-2(1H)-one
  • Step 2 4-Amino-3-(1H-benzo[d][1,2,3]triazol-6-yl)-1-(4-chlorophenyl)-7-(trifluoromethyl) Preparation of -1,8-Naphthyridin-2(1H)-one
  • the system was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography to obtain 120 mg of the target compound.
  • the IC 50 value of MAT2a was detected by the method of Colorimetric assay to detect the test compound.
  • the initial concentration of the compound test is 1 ⁇ M or 10 ⁇ M
  • the 3-fold gradient dilution is made into 10 concentration points.
  • the substrate mixed solution (containing 400 ⁇ M ATP and 600 ⁇ M L-Methionine) with Assay buffer, add 10 ⁇ L of the substrate mixed solution to the positive control well, the test compound well, and the negative control well, respectively, and start the reaction.
  • the reaction time is 150 minutes.
  • 50 ⁇ L of stop reaction solution (BIOMOL Green TM Reagent, Enzo lifesciences, product number BML-AK111-1000) was added to stop the reaction, and the reaction was centrifuged at 1000 rpm for 60 seconds and incubated for 15 minutes. Read the OD620 and process the data.
  • Inhibition% (OD620 positive control well- OD620 test compound well )/(OD620 positive control well- OD620 negative control well ) ⁇ 100
  • Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) 1 NA 2 26.1 3 12.7 4 20.2 5 NA 6 40.5 7 37.9 8 8.7 9 21.4 10 20.9 11 21.4 12 25.8 13 32 14 22.9 15 23.2 16 41.9 17 NA 18 51.4 19 12.3 20 11.5 twenty one 16.2 twenty two 15 twenty three 16.5 twenty four 15.6 25 13.3 26 17.8 27 17.5 28 25.3 29 25.2 30 13.4 31 15.4 32 14.9 33 20.2 34 NA 35 14.9 36 13.6 37 20.2 38 18.1 39 19.8 40 26.3 41 18.4 42 15.0 43 twenty two 44 13.4 45 14.8 46 15.1 47 13.6 48 16.1 49 15.8 50 17.2 51 16.2 52 16.2 53 14.4 54 16.2 55 16.3 56 14.5 57 17.1 58 17.4 59 25.4 60 17.0 61 17.0 62 16.1 63 17.8 64 15.4 65 15.2 66 16 67 18.1 68 16.0 69 16.6 70 30.5 71 1
  • cell plating After trypsinization of cells, they were plated with complete medium (RPMI-1640 containing 10% FBS. The cells were resuspended to the required density, mixed evenly, 100 ⁇ L/well was added to a 96-well plate, the cell density was 1000-3000 cells per well, and then returned to the incubator to allow the cells to adhere and grow.
  • complete medium RPMI-1640 containing 10% FBS.
  • the cells were resuspended to the required density, mixed evenly, 100 ⁇ L/well was added to a 96-well plate, the cell density was 1000-3000 cells per well, and then returned to the incubator to allow the cells to adhere and grow.
  • add the test compound starve the cells with serum-free medium for 4 hours before adding the compound, then add the complete medium containing the compound of the corresponding concentration, and incubate for 120 hours at 37°C, 5% CO 2 .
  • %Inhibition 100-(signal from well to be tested - signal from well without cells only containing medium)/(well signal with cells but no compound added - well signal without cells only containing medium) ⁇ 100.
  • a dose-response curve was fitted with the analysis software GraphPad Prism 5 to obtain the IC50 value of each compound on cellular activity.
  • the experimental results show that the compounds of the present invention have outstanding activity of inhibiting cancer cells, and the compounds of the present invention generally have IC 50 values lower than 1000 nM.
  • the compounds of the present invention have excellent effects of inhibiting the activity of MAT2a enzyme, and have excellent effects of inhibiting the growth of cancer cells, especially for cancer cells with MTAP gene deletion, and will have excellent effects in MAT2a-related cancers or tumor diseases the therapeutic effect.
  • cell plating After trypsinization of cells, resuspend the cells to 1*10 4 cells/mL in RPMI1640 complete medium (HyClone, Cat. No. SH30809.01) containing 10% FBS (Gibco, 10099141C). Mix evenly, add 100 ⁇ L/well to a 96-well plate, and put it back into the incubator to allow cells to adhere and grow.
  • Add the compound to be tested add 100 ⁇ L of complete medium containing the compound (the concentration of the compound in the medium is as follows: 3-fold gradient dilution from 60 ⁇ M down, a total of 10 concentration gradients), 37°C, 5% CO 2 , cultured for 144 hours.
  • %Inhibition 100-(signal from well to be tested - signal from well without cells only containing medium)/(well signal with cells but no compound added - well signal without cells only containing medium) ⁇ 100.
  • the KP-4 cell inhibitory activity test shows that the compounds of the preferred embodiments of the present invention have strong inhibitory activity on KP-4 cells, usually with an inhibitory activity of ⁇ 20 ⁇ M, such as 0.001-10 ⁇ M, especially 0.01-10 ⁇ M inhibitory activity, It has obvious advantages over existing compounds ( IC50 is generally higher than 30 ⁇ M).
  • cell plating Resuspend the cells to the desired density in DMEM complete medium (Gibico, Cat. No. 10569010) containing 10% FBS (Gibco, 10099141C), mix well, and add 30 ⁇ L/well to a 384-well plate , the cell density was 800 cells/well.
  • Add the compound to be tested add 30nL of the DMSO solution containing the compound (the compound concentration is configured as: 3-fold gradient dilution from 10mM down, a total of 10 concentration points), 37°C, 5% CO 2 , and incubated for 120 hours.
  • remove the compound-treated cells and equilibrate to room temperature add 30 ⁇ L of CellTiter-Glo (Promega, Cat. No. G7573) reagent to each well, shake at room temperature to fully lyse the cells, and then incubate at 37°C in the dark under 5% CO 2 . After 30 minutes, the fluorescence intensity was detected.
  • %Inhibition 100-(signal from well to be tested - signal from well without cells only containing medium)/(well signal with cells but no compound added - well signal without cells only containing medium) ⁇ 100.
  • Example IC50 /nM 20 48 twenty one 507 25 507 31 430 36 7 44 495 46 251 47 559 48 518 68 200 69 663
  • the DOHH-2 cell inhibitory activity test shows that the compounds of the preferred embodiments of the present invention have strong inhibitory activity on DOHH-2 cells, usually with an inhibitory activity of ⁇ 1 ⁇ M, such as 0.1-100 nM, preferably 0.1-50 nM, which is significantly better than the current There are compounds with great development prospects.
  • test sample 1.1 Accurately weigh an appropriate amount of the test sample, add 5% DMSO, 10% polyethylene glycol-15 hydroxystearate, and 85% normal saline (all by volume) in turn, and mix thoroughly by vortexing or ultrasonication. A dosing solution with a concentration of 0.2 mg/mL of the test substance was obtained for intravenous administration.
  • Pharmacokinetic parameters were calculated using the non-compartmental model in Pharsight Phoenix 8.0.
  • test sample 2.1 Accurately weigh an appropriate amount of the test sample, add 5% DMSO, 10% polyethylene glycol-15 hydroxystearate, and 85% normal saline (all by volume) in turn, and mix thoroughly by vortexing or ultrasonication. A dosing solution with a concentration of 0.4 mg/mL of the test substance was obtained for intravenous administration.
  • test substance concentration 1 mg/mL was obtained for oral gavage administration.
  • Blood was collected through the submandibular vein or other suitable methods, each sample was collected about 0.03mL, heparin sodium was anticoagulated, the blood samples were placed on ice after collection, and centrifuged within 1 hour to separate the plasma (centrifugation conditions: centrifugal force 6800g, 6 minutes, 2-8°C).
  • the collected plasma samples were stored in a -80°C refrigerator before analysis, and the remaining plasma samples were kept in a -80°C refrigerator for temporary storage after analysis.
  • the BLQ lower limit of detection
  • the concentration before administration is calculated as 0; the BLQ before Cmax (including "No peak") is calculated as 0; the BLQ (including "No peak") after Cmax is not involved in the calculation.
  • WinNonlin to calculate the pharmacokinetic parameters, such as AUC(0-t), T 1/2 , Cmax, etc., through the plasma concentration data at different time points.

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Abstract

公开了式(I)的甲硫氨酸腺苷转移酶抑制剂、其制备方法及其在制药领域的应用，其中R1、R2、R3和A如说明书和权利要求中所定义。

Description

甲硫氨酸腺苷转移酶抑制剂、其制备方法及应用 技术领域
本发明涉及医药化学领域，具体涉及一种甲硫氨酸腺苷转移酶抑制剂、其制备方法及在制药领域的应用。
背景技术
肿瘤抑制基因的功能缺失突变非常普遍，但却很少有根据肿瘤抑制基因缺失突变来实现选择性靶向的疗法，这很容易理解，即缺失的蛋白很难被直接抑制来获得疗效。由纯合缺失而失活的抑癌基因的靶向治疗尤为困难，因为缺乏残留蛋白，使得直接激活、稳定或修复抑癌基因的治疗策略失效。
甲硫氨酸腺苷转移酶(MAT)也称为S-腺苷甲硫氨酸合成酶，是催化甲硫氨酸和ATP合成S-腺苷甲硫氨酸(SAM或AdoMet)的细胞酶，被认为是甲硫氨酸循环的限速步骤。SAM是多胺生物合成中的丙氨基供体，并且是用于DNA甲基化的主要甲基供体，其参与基因转录和细胞增殖以及次级代谢产物的生成。MAT基因可以分为MAT1A基因与MAT2a基因，编码唯一能催化合成SAM的酶——MAT。MAT有三种同工酶，分别是MATⅠ、MATⅢ和MATⅡ，前两种是MAT1a基因编码的产物，后一种是MAT2a基因编码的产物。MAT1a基因主要在成人肝脏中表达，而MAT2a基因在除肝脏外的人体组织中广泛表达。越来越多的研究发现，MAT2a蛋白在其他癌症组织或细胞中也存在高表达，如乳腺癌、肠癌、白血病及淋巴瘤等，而MAT2a基因的沉默导致相应癌细胞死亡，表明MAT2a蛋白具有作为治疗靶点的潜力。
甲基硫代腺苷磷酸化酶(Methylthioadenosine phosphorylase，MTAP)是一种在所有正常组织均有表达的酶，它催化甲基硫代腺苷(Methylthioadenosine，MTA)转化为腺嘌呤和5-甲基硫代糖苷-1-磷酸。许多恶性肿瘤细胞系缺乏MTAP活性，同时，在神经胶质瘤、黑色素瘤、胰腺癌、非小细胞肺癌、膀胱癌、星形细胞瘤、骨肉瘤、头部和颈部癌症、黏液样软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤及非霍奇金淋巴瘤等大量原发病灶中也检测到了MTAP的活性丢失。当MTAP缺失时，细胞中MTA将累积到约100μM，并且细胞会开始排出MTA。MTA的异常积累导致了蛋白精氨酸甲基转移酶-5(Protein Arginine Methyltransferase 5，PRMT5)的脆弱性。由于PRMT5利用SAM作为甲基供体底物，因此抑制MAT2a活性降低了细胞内SAM的浓度，从而使MTAP缺失细胞中的PRMT5甲基化活性选择性降低，低于 生长所需的阈值水平。因此抑制MAT2a活性可通过抑制PRMT5活性在MTAP缺失的细胞中产生联合杀伤力，可为多种癌症提供治疗益处。
发明内容
本发明的目的之一是提供一种具有MAT2a抑制活性的化合物。
具体的，本发明提供下式Ⅰ结构所示的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物：
Figure PCTCN2022089900-appb-000001
其中，R 1选自5-10元芳基或芳杂环基；
R 2选自-CF 3或环丙基；
R 3选自氢、烷基、芳基、芳杂环基、环烷基、脂杂环基、桥环基和螺环基；
A为芳基或芳杂环基，
条件是所述化合物不包括下式化合物：
Figure PCTCN2022089900-appb-000002
进一步，本发明所述R 1选自咪唑基、噻唑基、吡唑基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
在某些具体的实施方案中，本发明所述R 1可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自烷基、卤素、卤代烷基、烷氧基、卤代烷氧基、羟基、氨基、胺基、羧基、酰胺基、环烷基、氘。
在某些具体的实施方案中，所述R 1可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自C 1-C 3烷基、氟、氯、溴、碘、C 1-C 3卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、羟基、氨基、胺基、羧基、酰基、C 3-C 6环烷基、氘。
在某些具体的实施方案中，所述R 1是苯基，所述苯基可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自C 1-C 3烷基、氟、氯、溴、碘、C 1-C 3卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、羟基、氨基、胺基、羧基、酰基、C 3-C 6环烷基、氘。
在某些具体的实施方案中，所述R 1是苯基，所述苯基可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自C 1-C 3烷基、氟、氯、溴和碘。
在某些具体的实施方案中，所述R 1选自苯基、4-氯苯基、4-溴苯基和4-甲基苯基，并且所述苯基可以进一步被氟取代。
在某些具体的实施方式中，本发明所述R 3选自氢、C 1-C 3烷基、6至10元芳基、5至10元芳杂环基、C 3-C 6环烷基、3至6元脂杂环基、4至10元桥环基、螺环基；
在某些具体的实施方案中，所述R 3选自氢、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、氧杂环丁基、四氢呋喃基、四氢吡喃基、硫杂环己基、哌啶基、吡咯烷基、苯基、吡啶基、嘧啶基、咪唑基、吡唑基、噻唑基、噁唑基、异噁唑基、1,2,4-噁二唑基，4至10元桥环基、螺环基；
进一步的，本发明所述R 3不为氢时，所述R 3可选择的被一个或多个选自卤素、烷基、烷氧基、氰基、羟基、氨基、氘、砜基、磺酰基、卤代烷基、环烷基、脂杂环基的基团取代；
在某些具体的实施方案中，本发明所述R 3不为氢时，所述R 3可选择的被一个或多个选自卤素、C 1-C 3烷基、C 1-C 3烷氧基、氰基、羟基、氨基、氘、砜基、磺酰基、C 1-C 3卤代烷基、C 3-C 6环烷基、3至6元脂杂环基的基团取代；
在某些具体的实施方案中，本发明所述R 3不为氢时，所述R 3可选择的被一个或多个选自氟、氯、溴、碘、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、氧杂环丁基、四氢呋喃基、四氢吡喃基、硫杂环己基、哌啶基、吡咯烷基、三氟甲基、羟基、氨基、氰基、氘、砜基、磺酰基的基团取代。
在某些具体的实施方案中，R 3选自氢和C 1-C 3烷基。
进一步的，本发明所述A环选自6至10元芳环基、5至10元芳杂环基。
在某些具体的实施方案中，本发明所述A环选自苯基、萘基、咪唑基、吡唑基、***基、噻唑基、呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噁唑基、苯并二噁唑基、咪唑并吡啶基、苯并异噁唑基、萘啶基、喹啉基、异喹啉基、喹喔啉基、吡唑并吡啶基、***并吡啶基、吡啶酮基、喹唑啉基、噌啉基、吡啶并吡嗪基、苯并***基、苯并噁二唑基。
在某些具体的实施方案中，本发明所述A环选自苯基、萘基、咪唑基、吡唑基、***基、噻唑基、呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、噁二唑基、吡啶基、嘧啶基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噁唑基、咪唑并吡啶基、喹啉基、喹喔啉基、吡唑并吡啶基、***并吡啶基、吡啶酮基、喹唑啉基、噌啉基、吡啶并吡嗪基、苯并***基和苯并噁二唑基。
在某些具体的实施方案中，本发明所述A环可进一步被一个或多个选自烷基、环烷基、脂杂环基、卤素、烷氧基、氨基、胺基、羟基、氰基、卤代烷基、卤代烷氧基、-(CH 2) nOCH 3、-(CH 2) nSO 2CH 3、-(CH 2) nN(CH 3) 2的基团取代，其中n＝1、2、或3。
在某些具体的实施方案中，本发明所述A环可进一步被一个或多个选自C 1-C 3烷基、C 1-C 3烷氧基、卤素、C 1-C 3卤代烷基、氨基、氰基、-(CH 2) nOCH 3、-(CH 2) nSO 2CH 3、-(CH 2) nN(CH 3) 2的基团取代，其中n＝1、2或3。
在某些具体的实施方案中，本发明所述A环可进一步被一个或多个选自甲基、甲氧基、-CF 3、-CH 2CF 3、-NH 2、F、氰基、-(CH 2) 2OCH 3、-(CH 2) 2SO 2CH 3、-(CH 2) 2N(CH 3) 2的基团取代。
在某些具体的实施方案中，所述A环上的取代基可进一步成环，并与A环形成并环，例如
Figure PCTCN2022089900-appb-000003
在某些具体的实施方案中，本发明所述A环选自如下基团：
Figure PCTCN2022089900-appb-000004
本发明的另一目的是提供一种如下式II或式III所示结构的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物：
Figure PCTCN2022089900-appb-000005
其中，R 1、R 3、A的定义如前所述。
在某些具体的实施方式中，本发明所述式Ⅰ化合物具有如下结构：
Figure PCTCN2022089900-appb-000006
Figure PCTCN2022089900-appb-000007
Figure PCTCN2022089900-appb-000008
Figure PCTCN2022089900-appb-000009
Figure PCTCN2022089900-appb-000010
Figure PCTCN2022089900-appb-000011
Figure PCTCN2022089900-appb-000012
本发明的另一目的是提供式I或式II或式III的化合物，及其药学上可接受的盐、水合物、异构体、前药或混合物，用于制备治疗MAT2a相关疾病的药物的用途。
本发明的另一目的是提供一种药物组合物，其中含有治疗有效剂量的式I或式II或式III化合物，或包含式I或式II或式III化合物药学上可接受的盐、水合物、异构体、前药或混合物，以及药学上可接受的载体。
本发明进一步提供上述药物组合物用于制备治疗MAT2a相关疾病的药物的用途。
本发明中所述MAT2a相关疾病为癌症或肿瘤，进一步，所述癌症或肿瘤包括成神经细胞瘤、肠癌如直肠癌、结肠癌、家族性腺瘤性息肉病癌和遗传性非息肉病结肠直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、乳腺癌、泌尿***癌、黑素瘤、脑肿瘤如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-细胞白血病、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。在一个实施方案中，癌症是肺癌、非小细胞肺癌(NSLC)、支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、***癌、胃癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子***、***癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌***癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、***癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆道癌、慢性或急性白血病、淋巴细胞淋巴瘤霍马斯、中枢神经***(CNS)肿瘤、脊髓轴肿瘤、脑干神经胶质瘤、多形性胶质母细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、成神经管细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤，包括任何上述癌症的难治性形式，或一种或多种上述癌症的组合。
本发明的另一目的是提供一种治疗癌症或肿瘤疾病的方法，包括给予所需要的患者一种或多种前述的药物组合物或式Ⅰ化合物或其药学上可接受的盐、水合物、异构体、前药或混合物。
术语定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是指适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。
本发明的化合物可以存在特定的几何或立体异构体或阻转异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，所有这些异构体及其混合物都属于本发明所述的“异构体”的范围之内。
“烷基”是指直链或含支链的饱和脂族烃基，例如：C 1-C 3烷基是指含有1到3个碳原子的饱和脂肪族烃基，包括但不限于甲基、乙基、丙基、异丙基等及他们的各种异构体。
“环烷基”是指饱和或部分不饱和的单环或多环环状烃取代基。例如，“C 3-C 6环烷基”指包含3至6个碳原子的环烷基，典型的C 3-C 6环烷基包括但不限于：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基等。
“脂杂环基”指饱和的单环烃取代基，其中一个或多个环原子被选自N、O、S的杂原子取代，其余环原子为碳。例如：“3-6元脂杂环”是指包含3-6个环原子的饱和环状烃取代基，其中一个或多个环原子被选自N、O、S的杂原子取代，其余环原子为碳。具体的示例包括但不限于：氧杂环丁基、吡咯烷基、四氢呋喃基、吗啉基等。
“桥环基”是指由两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的环状结构基团。
“螺环基”是指两个环共用一个碳原子形成的环状结构基团。
“芳基”是指芳香族环基，芳基部分的例子包括苯基、萘基等。
“芳杂环基”是指芳香族环状取代基，其中一个或多个环原子被选自N、O、S的杂原子取代，其余环原子为碳。例如：“5-10元芳杂环”是指包含5到10个环原子的芳香族杂环基，其中一个或多个环原子被选自N、O、S的杂原子取代，其余环原子为碳。具体的“5-10元芳杂环”的示例包括但不限于咪唑基、吡唑基、***基、噻唑基、呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噁唑基、苯并二噁唑基、咪唑并吡啶基、苯并异噁唑基、萘啶基、喹啉基、异喹啉基、喹喔啉基、吡唑并吡啶基、***并吡啶基、吡啶酮基、喹唑啉基、噌啉基、吡啶并吡嗪基、苯并***基、苯并噁二唑基等。
“砜基”是指-S(＝O) 2-基团；
“磺酰基”是指-S(＝O) 2-NR bR c，其中R b、R c分别为任意取代基，如氢、烷基、环烷基、芳基、杂环基等。
“氨基”是指-NH 2；
“胺基”是指-NH-R x，其中R x为任意取代基，如烷基、环烷基、芳基、杂环基等。
“酰基”是指-C(＝O)-R d，其中R d为任意取代基，如烷基、环烷基、氨基、芳基、杂环基、卤代烷基等。
“可选择地”是指随后描述的事件或状况可能但不是必需出现。
当任何变量在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。
本发明中的缩写均为本领域技术人员已知的，除另有说明外，均代表本领域所通知的含义。例如：DMF是指N,N-二甲基甲酰胺；THF是指四氢呋喃；Me是指甲基。
试验证明，本发明化合物具有优异的MAT2a酶抑制活性，对癌症细胞的生长具有优异的抑制作用，且安全性良好，具有较好的成药性，因此本发明化合物将在MAT2a相关的癌症或肿瘤疾病中具有优异的应用前景。
具体实施方式
下面通过举例说明本发明的化合物和中间体的合成方法，下述举例仅作为本发明的示例，而不应作为对本发明范围的限制。除特殊说明外，本发明中所涉及的原料和试剂均可通过商业化渠道获得，具体渠道来源并不影响本发明技术方案的实施。
制备例1：3-溴-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000013
步骤1：2-(苯氨基)-6-(三氟甲基)烟酸的制备
Figure PCTCN2022089900-appb-000014
将2-氯-6-(三氟甲基)烟酸(1.0g)溶于1,4-二氧六环(10mL)，加入苯胺(2.0g)，120℃下由微波引发反应5小时，LCMS显示大部分原料反应完全。体系减压浓缩，残留物于搅拌下加入石油醚中，过滤，滤液减压浓缩，所得粗品经柱层析纯化，得标题化合物1.0g。
MS(ESI)m/z(M+H) +＝283.0.
1H NMR(400MHz,DMSO-d 6)δ14.14(brs,1H),10.59(s,1H),8.47(d,J＝7.8Hz,1H),7.82-7.63(m,2H),7.37(dd,J＝8.5,7.3Hz,2H),7.29(d,J＝7.9Hz,1H),7.07(td,J＝7.3,1.1Hz,1H).
步骤2：4-羟基-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯的制备
Figure PCTCN2022089900-appb-000015
将2-(苯氨基)-6-(三氟甲基)烟酸(500mg)溶于四氢呋喃，加入N,N-二异丙基碳二亚胺(670mg)和1-羟基苯并***(718mg)，室温反应一小时。另取丙二酸二乙酯(567mg)溶于四氢呋喃(10mL)，然后于冰浴下分批加入氢化钠(355mg)，室温反应1小时后，然后将2-(苯氨基)-6-(三氟甲基)烟酸体系滴加到丙二酸二乙酯体系中，加毕，室温继续反应2小时，LC-MS显示反应完全。体系加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物250mg。
MS(ESI)m/z(M+H) +＝379.1.
步骤3：4-氯-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯的制备
Figure PCTCN2022089900-appb-000016
将4-羟基-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(250mg)溶于三氯氧磷(1mL)，90℃加热反应2小时，LC-MS显示反应完全。将体系滴加到适量冰水中，饱和碳酸钠溶液调节pH至弱碱性，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物180mg。
MS(ESI)m/z(M+H) +＝397.0.
步骤4：4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯的制备
Figure PCTCN2022089900-appb-000017
将4-氯-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(160mg)溶于甲胺(2M in THF,1mL)，室温反应1小时，LC-MS显示反应完全。体系减压浓缩，无需进一步纯化，即可直接用于下一步。
MS(ESI)m/z(M+H) +＝392.1.
1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝8.3Hz,1H),7.79(d,J＝8.2Hz,1H),7.71(d,J＝5.4Hz,1H),7.49(t,J＝7.3Hz,2H),7.45-7.39(m,1H),7.28-7.19(m,2H),4.23(q,J＝7.1Hz,2H),2.92(d,J＝4.8Hz,3H),1.27(t,J＝7.1Hz,3H).
步骤5：4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000018
将4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(100mg)溶于乙醇/水(8mL,4:2)，加入氢氧化钠溶液(1.3mL,1M)，60℃加热反应过夜。TLC显示反应完全，将体系减压浓缩除去乙醇，加入适量水，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗三次，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物70mg。
步骤6：3-溴-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000019
将4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(370.0mg)溶于二氯甲烷(4mL)，体系降温至0℃，加入液溴(186mg)，体系自然恢复至室温反应1h，TLC显示反应完全。将体系倒入水(20mL)，饱和碳酸氢钠溶液调pH约至8，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩。所得粗品用层析柱分离得到标题化合物270.0mg。
MS(ESI)m/z(M+H) +＝398.0,400.0.
制备例2：3-溴-1-(4-氯苯基)-4-(甲基氨基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000020
参考前述制备例1中类似的方法制备得到本制备例的化合物。
MS(ESI)m/z(M+H) +＝432.0,434.0.
制备例3：4-氨基-3-溴-1-(4-氯苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000021
参考前述制备例2中类似的方法制备得到本制备例的化合物。
MS(ESI)m/z(M+H) +＝417.9,419.9.
1H NMR(400MHz,DMSO-d 6)δ8.88(d,J＝8.2Hz,1H),7.80(d,J＝8.2Hz,1H),7.59–7.53(m,2H),7.37(s,2H),7.34–7.29(m,2H).
制备例4：2-(呋喃-2-基)-N-(对甲苯基)乙酰胺的制备
Figure PCTCN2022089900-appb-000022
将对甲苯胺(500mg)、2-(呋喃-2-基)乙酸(700mg)、三乙胺(1.9mL)和1-丙基磷酸酐(5.89mL,50％in EA)溶于1,2-二氯乙烷(15mL)，65℃下反应2小时，LCMS显示原料反应完毕。反应液降至室温，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物800mg。
MS(ESI)m/z(M+H) +＝216.0。
制备例5：6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d]咪唑-2-胺的制备
Figure PCTCN2022089900-appb-000023
步骤1：6-溴-1-甲基-1H-苯并[d]咪唑-2-胺的制备.
Figure PCTCN2022089900-appb-000024
将4-溴-2-甲基氨基苯胺(600mg)溶于甲醇(30mL)，加入溴化氰(630mg)，室温反应2小时。LCMS监测原料消失后，反应液减压浓缩，残留物经柱层析纯化得目标化合物486mg。
MS(ESI)m/z(M+H) +＝225.9.
步骤2：6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d]咪唑-2-胺的制备
Figure PCTCN2022089900-appb-000025
氮气氛中，将6-溴-1-甲基-1H-苯并[d]咪唑-2-胺(100mg)溶于1,4-二氧六环(15mL)，加入1,1'-双(二苯膦基)二茂铁合氯化钯(65mg)、双联频哪醇硼酸酯(223mg)和乙酸钾(122mg)，90℃加热反应4小时。LCMS监测原料消失后，反应液减压浓缩，残留物经正相柱色谱纯化得目标化合物100mg。
MS(ESI)m/z(M+H) +＝274.1.
制备例6：2-(1-甲基-1H-苯并[d]咪唑-6-基)乙酸乙酯的制备
Figure PCTCN2022089900-appb-000026
步骤1：2-(1-甲基-1H-苯并[d]咪唑-6-基)丙二酸二乙酯的制备
Figure PCTCN2022089900-appb-000027
将6-溴-1-甲基-1H-苯并[d]咪唑(300mg)，丙二酸二乙酯(450mg)，三[二亚苄基丙酮]二钯(65mg)，2-二环己基膦-2',4',6'-三异丙基联苯(35mg)和碳酸铯(700mg)加入到甲苯中，氮气保护下升温至100℃搅拌反应6小时。LCMS显示反应完全，减压浓缩，残留物经柱层析纯化得目标化合物300mg。
MS(ESI)m/z(M+H) +＝291.1.
步骤2：2-(1-甲基-1H-苯并[d]咪唑-6-基)乙酸乙酯的制备
Figure PCTCN2022089900-appb-000028
将2-(1-甲基-1H-苯并[d]咪唑-6-基)丙二酸二乙酯(300mg)溶于无水乙醇(10mL)，加入乙醇钠(680mg)，氮气保护下升温回流搅拌反应4小时。LCMS显示反应完全，用乙酸终止反应，减压浓缩，残留物经柱层析纯化得目标化合物200mg。
MS(ESI)m/z(M+H) +＝219.1.
制备例7：1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d][1,2,3]***和1-(四氢-2H-吡喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d][1,2,3]***的制备
Figure PCTCN2022089900-appb-000029
步骤1：5-溴-1-(四氢-2H-吡喃-2-基)-1H-苯并[d][1,2,3]***和6-溴-1-(四氢-2H-吡喃-2-基)-1H-苯并[d][1,2,3]***的制备
将5-溴-1H-苯并***(300mg)溶于乙腈(10mL)，加入3,4-二氢-2H-吡喃(150mg)和2,3-二氯-5,6-二氰基苯醌(35mg)，氮气保护下室温搅拌反应6小时。LCMS显示反应完全，减压浓缩，残留物经柱层析纯化得目标化合物350mg。
MS(ESI)m/z(M-84+H) +＝198.1.
步骤2：1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d][1,2,3]***和1-(四氢-2H-吡喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-苯并[d][1,2,3]***的制备
将上步所得目标化合物(350mg)溶于1,4-二氧六环(10mL)，加入1,1'-双(二苯膦基)二茂铁合氯化钯(45mg)、双联频哪醇硼酸酯(630mg)和乙酸钾(245mg)，氮气保护下升温至90℃加热反应4小时。LCMS监测原料消失后，反应液减压浓缩，残留物经正相柱色谱纯化得目标化合物270mg。
MS(ESI)m/z(M-84+H) +＝246.1.
制备例8：4-氨基-3-溴-1-(4-氯-3-氟苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000030
参考前述制备例2&3中类似的方法制备得到本制备例的化合物。
MS(ESI)m/z(M+H) +＝435.9,437.9.
制备例9：4-氨基-3-溴-1-(4-氯-2-氟苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000031
参考前述制备例2&3中类似的方法制备得到本制备例的化合物。
MS(ESI)m/z(M+H) +＝435.9,437.9.
制备例10：4-氨基-3-溴-1-(4-甲基苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000032
参考前述制备例2&3中类似的方法制备得到本制备例的化合物。
MS(ESI)m/z(M+H) +＝398.0,400.0.
制备例11：1H-苯并[d][1,2,3]***-1-基2-((4-溴苯基)氨基)-6-(三氟甲基)烟酸酯的制备
Figure PCTCN2022089900-appb-000033
步骤1：2-(4-溴苯氨基)-6-(三氟甲基)烟腈的制备
Figure PCTCN2022089900-appb-000034
将2-氯-6-(三氟甲基)烟腈(1.0g)溶于1,4-二氧六环(5mL)，加入4-溴苯胺(1.1g)，120℃下由微波引发反应5小时，LCMS显示大部分原料反应完全。体系减压浓缩，残留物经柱层析纯化，得标题化合物1.5g。
MS(ESI)m/z(M+H) +＝342.0,344.0.
步骤2：2-(4-溴苯氨基)-6-(三氟甲基)烟酸的制备
Figure PCTCN2022089900-appb-000035
将2-(4-溴苯氨基)-6-(三氟甲基)烟腈(1.5g)溶于乙醇/水，一次性加入氢氧化钾(1.2g)，体系回流反应6h。LCMS显示原料消耗完毕，用2N盐酸调节pH约为5，乙酸乙酸萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经柱层析纯化得产物1.4g。
MS(ESI)m/z(M+H) +＝361.0,363.0。
步骤3：1H-苯并[d][1,2,3]***-1-基2-((4-溴苯基)氨基)-6-(三氟甲基)烟酸酯的制备
Figure PCTCN2022089900-appb-000036
将2-(4-溴苯氨基)-6-(三氟甲基)烟酸(1.4g)溶于四氢呋喃，加入N,N-二异丙基碳二亚胺(730mg)和1-羟基苯并***(790mg)，室温反应2小时。TLC显示反应完全，减压浓缩，残留物经柱层析纯化得目标化合物1.6g。
制备例12：1H-苯并[d][1,2,3]***-1-基2-((4-甲苯基)氨基)-6-(三氟甲基)烟酸酯的制备
Figure PCTCN2022089900-appb-000037
参考前述制备例11中类似的方法制备得到本制备例的化合物。
实施例1：4-(甲基氨基)-3-(噁唑-5-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000038
步骤1：4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲醛的制备
Figure PCTCN2022089900-appb-000039
将4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(70mg)溶于N,N–二甲基甲酰胺(1mL)，0℃下缓慢加入三氯氧磷(321μL)。体系恢复至室温反应3h。TLC显示原料消耗完毕，加入水(100mL)淬灭体系，饱和碳酸氢钠溶液调节pH约至8，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗三次，无水硫酸钠干燥，过滤，浓缩。所得粗品经制备TLC纯化得目标物50mg。
步骤2：4-(甲基氨基)-3-(噁唑-5-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000040
将4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲醛(30mg)溶于甲醇(2mL)，加入对甲基苯磺酰甲基异腈(50mg)和碳酸钾(36mg)，室温反应30min。TLC显示原料反应完全，体系经制备HPLC纯化，冷冻干燥得标题化合物0.81mg。
MS(ESI)m/z(M+H) +＝387.0.
1H NMR(400MHz,DMSO-d 6)δ8.85(d,J＝8.3Hz,1H),8.42(s,1H),7.72(dd,J＝8.3,1.7Hz,1H),7.54(t,J＝7.5Hz,2H),7.46(dd,J＝8.2,6.3Hz,1H),7.30–7.24(m,2H),6.77(d,J＝2.9Hz,1H),4.03(s,3H).
实施例2：4-(甲基氨基)-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000041
步骤1：4-羟基-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000042
将2-(苯氨基)-6-(三氟甲基)烟酸(220.0mg)溶于四氢呋喃(10mL)，依次加入1-羟基苯并***(105.0mg)和N,N'-二异丙基碳二亚胺(120.0mg)，室温反应1小时，反应液备用；将氢化钠(204.0mg)置于100mL茄形瓶，氩气置换三次，0℃下缓慢加入2-乙酸乙酯-噻唑(290.0mg)的四氢呋喃溶液(2mL)，体系自然恢复至室温反应1h，再缓慢加入上述备用反应液于此体系中，室温继续反应2h，TLC显示原料反应完全。将体系倒入水(50mL)，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物250.0mg。
MS(ESI)m/z(M+H) +＝390.0.
步骤2：4-氯-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000043
将4-羟基-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(260.0mg)溶于三氯氧磷(5.0mL)，90℃加热反应1h，TLC显示原料反应完全。体系冷却至室温，将反应液缓慢滴入水中，饱和碳酸氢钠溶液调pH约至9，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩。所得粗品经柱层析纯化得标题化合物230.0mg。
MS(ESI)m/z(M+H) +＝408.0.
步骤3：4-(甲基氨基)-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000044
将4-氯-1-苯基-3-(噻唑-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(50.0mg)溶于N-甲基吡咯烷酮(2mL)，加入甲胺(0.3mL,2.0mol/L in THF)。体系于150℃由微波引发反应1小时，TLC显示原料消耗完全。加入水(10mL)，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗一次， 无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC纯化，冷冻干燥得标题化合物12.6mg。
MS(ESI)m/z(M+H) +＝403.0.
1H NMR(400MHz,DMSO-d 6)δ12.07(s,1H),9.07(d,J＝8.4Hz,1H),7.98(d,J＝3.4Hz,1H),7.74–7.66(m,2H),7.57–7.46(m,3H),7.34–7.28(m,2H),3.56(d,J＝5.5Hz,3H).
实施例3：4-氨基-1-(4-氯苯基)-3-(1H-吡咯-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000045
步骤1：2-(1H-吡咯-1-基)乙酸乙酯的制备
Figure PCTCN2022089900-appb-000046
将吡咯(1.03mL)、2-溴乙酸乙酯(1.6mL)和碳酸钾(4g)溶于乙腈，80℃下反应3h。LCMS监测原料消失后，加入饱和氯化铵水溶液(5mL)终止反应，乙酸乙酯(10mL*3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物600mg。
步骤2：N-(4-氯苯基)-2-(1H-吡咯-1-基)乙酰胺的制备
Figure PCTCN2022089900-appb-000047
将2-(1H-吡咯-1-基)乙酸乙酯(5g)、对氯苯胺(14.2g)和三甲基铝(2M,16mL)溶于甲苯，100℃反应1小时。LCMS监测原料消失后，冷却至室温，加入甲醇：二氯甲烷＝1:1(50mL)加热回流15分钟，过滤，浓缩，残留物经柱层析纯化得到目标化合物1.5g。
步骤3：4-氨基-1-(4-氯苯基)-3-(1H-吡咯-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000048
将N-(4-氯苯基)-2-(1H-吡咯-1-基)乙酰胺(200mg)溶于四氢呋喃，0℃冰水浴条件下，加入氢化钠(68mg)，反应30分钟。加入2-氯-6-(三氟甲基)烟腈(352mg)反应1小时，LCMS监 测原料消失。加入水(5mL)终止反应，乙酸乙酯(10mL*3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经反相制备HPLC纯化得到目标化合物15mg。
MS(ESI)m/z(M+H) +＝404.9。
1H NMR(400MHz,DMSO-d 6)δ8.91(d,J＝8.2Hz,1H),7.81(d,J＝8.2Hz,1H),7.60-7.50(m,2H),7.37-7.28(m,2H),6.74(t,J＝2.1Hz,2H),6.70(s,2H),6.23(t,J＝2.1Hz,2H).
实施例4：4-(甲基氨基)-1-苯基-3-(噻吩-3-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000049
氮气氛中，将3-溴-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(30.0mg)、噻吩-3-基硼酸(50.0mg)和碳酸钾(53.0mg)溶于1,4-二氧六环/水(1.0mL/0.2mL)，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(27mg)，体系于100℃反应1小时，TLC显示原料消耗完全。加入水(10mL)，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC纯化，冷冻干燥得标题化合物13.0mg。
MS(ESI)m/z(M+H) +＝402.1.
1H NMR(400MHz,DMSO-d6)δ8.76(d,J＝8.2Hz,1H),7.76(d,J＝8.3Hz,1H),7.53–7.36(m,5H),7.27–7.14(m,3H),7.00(q,J＝5.0Hz,1H),2.42(d,J＝4.9Hz,3H).
实施例5：4-(甲胺基)-1-苯基-3-(4H-1,2,4-***-3-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000050
步骤1：4-((叔丁氧基羰基)(甲基)氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯的制备
Figure PCTCN2022089900-appb-000051
将4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(770mg)溶于二氯甲烷(30mL)，加入三乙胺(398mg)、二碳酸二叔丁酯(859mg)和4-二甲氨基吡啶(120mg)，室温反应一小时后，体系由浑浊变澄清。LC-MS显示反应完全。体系减压浓缩，残留物经柱层析纯化得目标化合物900mg。
MS(ESI)m/z(M+H) +＝492.1.
步骤2：4-((叔丁氧基羰基)(甲基)氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸的制备
Figure PCTCN2022089900-appb-000052
将4-((叔丁氧基羰基)(甲基)氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(300mg)溶于四氢呋喃/水的混合溶液(8mL/2mL)，加入氢氧化锂(88mg)，加热至55℃反应4小时，LC-MS显示反应完全。体系用草酸调节pH至弱酸性，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物210mg。
MS(ESI)m/z(M+H) +＝464.1.
步骤3：(3-氨基甲酰基-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯的制备
Figure PCTCN2022089900-appb-000053
将4-((叔丁氧基羰基)(甲基)氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸(210mg)溶于四氢呋喃(20mL)，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(862mg)和甲酸铵(171mg)，室温反应过夜。LC-MS显示反应完全。体系加水适量，乙酸乙酯萃取，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩，所得粗品无需进一步纯化，即可直接用于下一步反应。
MS(ESI)m/z(M+H) +＝463.1.
步骤4：(3-(((二甲氨基)亚甲基)氨基甲酰基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯的制备
Figure PCTCN2022089900-appb-000054
将(3-氨基甲酰基-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯粗品(200mg)溶于乙腈(10mL)，加入N,N-二甲基甲酰胺二甲基缩醛(103mg)，室温反应1小时。LC-MS显示反应完全。体系减压浓缩，所得粗品无需进一步纯化，即可直接用于下一步反应。
MS(ESI)m/z(M+H) +＝518.2.
步骤5：(2-氧代-1-苯基-3-(4H-1,2,4-***-3-基)-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯的制备
Figure PCTCN2022089900-appb-000055
将(3-(((二甲氨基)亚甲基)氨基甲酰基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯粗品(210mg)溶于醋酸(6mL)，加入水合肼(51mg)，升温至90℃反应2小时。LC-MS显示反应完全。体系减压浓缩，所得粗品无需进一步纯化，即可直接用于下一步反应。
MS(ESI)m/z(M+H) +＝487.2.
步骤6：4-(甲胺基)-1-苯基-3-(4H-1,2,4-***-3-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000056
将(2-氧代-1-苯基-3-(4H-1,2,4-***-3-基)-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯粗品(180mg)溶于三氟乙酸/二氯甲烷(2mL/2mL)的混合溶剂，室温反应5小时。LC-MS显示反应完全。体系减压浓缩，残留物经反向制备HPLC纯化得到目标化合物6mg。
MS(ESI)m/z(M+H) +＝387.1.
1H NMR(400MHz,DMSO-d 6)δ13.88(s,1H),10.15(s,1H),8.98(d,J＝8.4Hz,1H),8.12(s,1H),7.74(d,J＝8.3Hz,1H),7.52(t,J＝7.5Hz,2H),7.45(t,J＝7.4Hz,1H),7.29(d,J＝7.6Hz,2H),3.22(s,3H).
实施例6：4-(甲胺基)-3-(1,3,4-噁二唑-2-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000057
步骤1：(3-(1,3,4-噁二唑-2-基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯的制备
Figure PCTCN2022089900-appb-000058
将4-((叔丁氧基羰基)(甲基)氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸(40mg)溶于二氯甲烷(20mL)，缓慢加入(异氰亚氨基)三苯基膦(52mg)的二氯甲烷溶液，室温反应过夜。LC-MS显示反应完全。将体系减压浓缩，残留物经柱层析纯化得目标化合物20mg。
MS(ESI)m/z(M-55) +＝432.1.
步骤2：4-(甲胺基)-3-(1,3,4-噁二唑-2-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000059
将(3-(1,3,4-噁二唑-2-基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基)(甲基)氨基甲酸叔丁酯(20mg)溶于三氟乙酸/二氯甲烷的混合溶液(1mL/2mL)，室温反应4小时。LC-MS显示反应完全。体系浓缩除去二氯甲烷，饱和碳酸钠水溶液调节pH至弱碱性，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经反向制备HPLC纯化得到目标化合物7mg。
MS(ESI)m/z(M+H) +＝388.1.
1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.85(d,J＝8.3Hz,1H),8.12(d,J＝5.4Hz,1H),7.85(d,J＝8.3Hz,1H),7.49(dd,J＝8.2,6.6Hz,2H),7.45-7.39(m,1H),7.30-7.23(m,2H),2.42(d,J＝4.9Hz,3H).
实施例7：4-(甲基氨基)-3-(噁唑-2-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000060
步骤1：N-(2-羟乙基)-4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酰胺的制备
Figure PCTCN2022089900-appb-000061
氮气氛中，将4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酸乙酯(220mg)溶于甲苯，0℃下加入三甲基铝(61mg)和乙醇胺(51mg)，加毕，体系恢复至室温，80℃继续加热反应2小时。加水淬灭反应，加入适量二氯甲烷和甲醇回流15分钟，过滤，浓缩得目标化合物粗品200mg。
步骤2：3-(4,5-二氢噁唑-2-基)-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000062
将N-(2-羟乙基)-4-(甲基氨基)-2-氧代-1-苯基-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲酰胺(20mg)溶于三氯氧磷，80℃反应1小时。LCMS监测反应完全，浓缩除去三氯氧磷，饱和碳酸氢钠溶液调节pH约为碱性，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经制备HPLC纯化得目标化合物10mg。
MS(ESI)m/z(M+H) +＝389.1.
1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝8.3Hz,1H),7.78(d,J＝8.1Hz,2H),7.62–7.31(m,3H),7.21(d,J＝7.1Hz,2H),4.29(t,J＝9.5Hz,2H),3.89(t,J＝9.5Hz,2H),2.97(d,J＝4.8Hz,3H).
步骤3：4-(甲基氨基)-3-(噁唑-2-基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000063
将3-(4,5-二氢噁唑-2-基)-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(100mg)溶于氯仿(3mL)，加入二氧化锰(224mg)，100℃加热条件下由微波引发反应3小时。LCMS监测原料消失，过滤，体系减压浓缩，残留物经反相制备HPLC纯化得到目标化合物0.57mg。
MS(ESI)m/z(M+H) +＝387.1。
实施例8：3-(1H-咪唑-2-基)-4-(甲基氨基)-1-苯基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000064
参考前述实施例7中类似的方法制备得到本实施例的化合物。
MS(ESI)m/z(M+H) +＝386.1.
1H NMR(400MHz,DMSO-d 6)δ14.63(s,1H),9.21(d,J＝8.3Hz,1H),8.73(d,J＝5.2Hz,1H),7.87(d,J＝8.3Hz,1H),7.77(s,2H),7.50(d,J＝7.7Hz,2H),7.45(t,J＝7.3Hz,1H),7.25(d,J＝7.6Hz,2H),2.41(d,J＝4.6Hz,3H).
实施例15：4-(甲基氨基)-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000065
步骤1：4-羟基-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000066
将2-(苯氨基)-6-(三氟甲基)烟酸(220.0mg)溶于四氢呋喃(10mL)，依次加入1-羟基苯并***(105.0mg)和N,N'-二异丙基碳二亚胺(120.0mg)，室温反应1小时，加入2-(1H-吡唑-1-基)乙酸乙酯(115mg)。体系移至冰水浴中，氮气保护下加入双三甲基硅基胺基锂(3mL,4.0mmol)，反应0.5h。TLC显示原料反应完全。加入(5mL)氯化铵水溶液终止反应，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液反洗一次，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物250.0mg。
步骤2：4-氯-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000067
将4-羟基-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(250mg)溶于三氯氧磷，90℃反应2小时。LCMS监测原料消失后，加入饱和碳酸氢钠水溶液调pH至弱碱性，乙酸乙酯(10mL*3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物78mg。
步骤3：4-(甲基氨基)-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000068
将4-氯-1-苯基-3-(1H-吡唑-1-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(40mg)溶于N-甲基吡咯烷酮(2mL)，滴加甲胺(6.2mg)和N,N-二异丙基乙胺(0.1mL)，150℃加热条件下由微波引发反应0.5小时。LCMS监测原料消失后，加入水(5mL)终止反应，乙酸乙酯(10mL*3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物经反相制备HPLC纯化得到目标化合物20mg。
MS(ESI)m/z(M+H) +＝386.0。
1H NMR(400MHz,DMSO-d 6)δ8.85(d,J＝8.3Hz,1H),7.88-7.80(m,2H),7.63(d,J＝1.8Hz,1H),7.57(q,J＝5.0Hz,1H),7.50(dd,J＝8.3,6.6Hz,2H),7.46-7.39(m,1H),7.31-7.20(m,2H),6.42(t,J＝2.1Hz,1H),2.27(d,J＝4.9Hz,3H)。
实施例30：4-氨基-1-(4-氯苯基)-3-(呋喃-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000069
步骤1：1-(4-氯苯基)-3-(呋喃-2-基)-4-羟基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000070
氩气氛中，将2-呋喃乙酸乙酯(225mg)溶于无水四氢呋喃(6mL)，将反应体系降温到-78℃后加入双(三甲基硅基)氨基锂的四氢呋喃溶液(3.0mL,3.0mmol)，反应1小时备用。将2-((4-氯苯基)氨基)-6-(三氟甲基)烟酸(400mg)溶于四氢呋喃，依次加入1-羟基苯并***(105.0mg)和N,N'-二异丙基碳二亚胺(120.0mg)，室温反应1小时。将此反应液加入上述备用体系，移至室温反应过夜。LCMS显示原料反应完毕，加入饱和氯化铵溶液淬灭反应，粗品浓缩后柱色谱纯化得到标题化合物120mg。
MS(ESI)m/z(M+H) +＝406.9。
步骤2：1-(4-氯苯基)-3-(呋喃-2-基)-2-氧代-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基甲磺酸酯的制备
Figure PCTCN2022089900-appb-000071
将1-(4-氯苯基)-3-(呋喃-2-基)-4-羟基-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(30mg)溶于二氯甲烷(5mL)，加入三乙胺(0.1mL)和甲基磺酰氯(0.4mL)，室温反应1小时，LCMS显示原料反应完毕。将反应液浓缩得到标题化合物35mg。
MS(ESI)m/z(M+H) +＝484.9。
步骤3：1-(4-氯苯基)-4-((2,4-二甲氧基苄基)氨基)-3-(呋喃-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000072
将(2,4-二甲氧基苯基)甲胺(0.4mL)溶于乙腈(5mL)，加入1-(4-氯苯基)-3-(呋喃-2-基)-2-氧代-7-(三氟甲基)-1,2-二氢-1,8-萘啶-4-基甲磺酸酯(80mg)的乙腈溶液，室温反应过夜。TLC显示原料反应完全。浓缩反应液，粗品经柱层析纯化得标题化合物44mg。
MS(ESI)m/z(M+H) +＝555.9。
步骤4：4-氨基-1-(4-氯苯基)-3-(呋喃-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000073
将1-(4-氯苯基)-4-((2,4-二甲氧基苄基)氨基)-3-(呋喃-2-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(44mg)溶于1,4-二氧六环(5mL)，加入氯化氢的1,4-二氧六环溶液(1mL)，室温反应15分钟，TLC显示原料反应完全。加入饱和碳酸氢钠溶液调pH呈弱碱性，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经制备HPLC纯化得标题化合物2mg。
MS(ESI)m/z(M+H) +＝405.9。
1H NMR(400MHz,DMSO-d 6)δ8.93(d,J＝8.2Hz,1H),7.83–7.75(m,2H),7.60–7.54(m,2H),7.46(s,2H),7.39–7.29(m,2H),7.03(d,J＝3.4Hz,1H),6.63(dd,J＝3.4,1.8Hz,1H).
实施例62：4-氨基-3-(1H-苯并[d][1,2,3]***-6-基)-1-(4-氯苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000074
步骤1：4-氨基-1-(4-氯苯基)-3-(1-(四氢-2H-吡喃-2-基)-1H-苯并[d][1,2,3]***-5-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮和4-氨基-1-(4-氯苯基)-3-(1-(四氢-2H-吡喃-2-基)-1H-苯并[d][1,2,3]***-6-基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
氮气氛中，将3-溴-4-氨基-1-(4-氯苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(50mg)、制备例7所得产物(60mg)和碳酸钾(33.0mg)溶于1,4-二氧六环/水(1.0mL/0.2mL)，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8mg)，体系于100℃反应1小时，LCMS显示原料消耗完全。反应液减压浓缩，残留物经正相柱色谱纯化得目标化合物60mg。
MS(ESI)m/z(M+H) +＝541.1.
步骤2：4-氨基-3-(1H-苯并[d][1,2,3]***-6-基)-1-(4-氯苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
将上步所得产物(60mg)溶于甲醇(4mL)，加入盐酸-1,4-二氧六环溶液(1mL,4M)，室温搅拌2小时。LCMS监测原料消失后，饱和碳酸氢钠溶液调节pH约为8，减压浓缩，残留物经反相制备HPLC纯化，得标题化合物20mg。
MS(ESI)m/z(M+H) +＝457.1.
1H NMR(400MHz,DMSO-d 6)δ15.71(s,1H),8.87(d,J＝8.2Hz,1H),7.96(s,1H),7.82-7.69(m,2H),7.55(d,J＝8.6Hz,2H),7.36-7.33(m,3H),6.65(s,2H).
实施例79：4-氨基-1-(4-溴苯基)-3-(4-甲氧基苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000075
步骤1：1-(4-溴苯基)-4-羟基-3-(4-甲氧基苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000076
将4-甲氧基苯乙酸乙酯(200mg)溶于四氢呋喃，于-70℃下滴加双三甲基硅基胺基锂(5mL，1M in THF)，搅拌0.5小时，再加入1H-苯并[d][1,2,3]***-1-基2-((4-溴苯基)氨基)-6-(三氟甲基)烟酸酯(200mg)，缓慢升至室温反应1小时，LC-MS显示反应完全。体系加入饱和 氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物经柱层析纯化得目标化合物120mg。
MS(ESI)m/z(M+H) +＝491.1,493.1.
步骤2：1-(4-溴苯基)-3-(4-甲氧基苯基)-4-(2,2,2-三氟乙氧基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000077
将1-(4-溴苯基)-4-羟基-3-(4-甲氧基苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(120mg)溶于N,N-二甲基甲酰胺中，室温下加入碳酸钾(70mg)和甲磺酸-(2,2,2)-三氟乙酯(200mg)，室温搅拌过夜，LC-MS显示反应完全。体系经反相柱层析纯化得目标化合物90mg。
MS(ESI)m/z(M+H) +＝573.1.575.1.
步骤3：4-氨基-1-(4-溴苯基)-3-(4-甲氧基苯基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮的制备
Figure PCTCN2022089900-appb-000078
将1-(4-溴苯基)-3-(4-甲氧基苯基)-4-(2,2,2-三氟乙氧基)-7-(三氟甲基)-1,8-萘啶-2(1H)-酮(90mg)溶于N-甲基吡咯烷酮，加入氨的乙醇溶液(1mL,2M in EtOH)，150℃下由微波引发反应5小时，LCMS显示大部分原料反应完全。体系经反相制备HPLC纯化，得标题化合物20mg。
MS(ESI)m/z(M+H) +＝490.0,492.0.
1H NMR(400MHz,DMSO-d 6)δ8.82(d,J＝8.2Hz,1H),7.74(d,J＝8.2Hz,1H),7.67(d,J＝8.6Hz,2H),7.25(t,J＝8.1Hz,4H),7.02(d,J＝8.7Hz,2H),6.42(s,2H),3.80(s,3H).
参照前述制备例中类似的方法制备起始原料，同时参考前述实施例中类似的方法制备得到下表中实施例的化合物：
Figure PCTCN2022089900-appb-000079
Figure PCTCN2022089900-appb-000080
Figure PCTCN2022089900-appb-000081
Figure PCTCN2022089900-appb-000082
Figure PCTCN2022089900-appb-000083
Figure PCTCN2022089900-appb-000084
Figure PCTCN2022089900-appb-000085
Figure PCTCN2022089900-appb-000086
Figure PCTCN2022089900-appb-000087
Figure PCTCN2022089900-appb-000088
Figure PCTCN2022089900-appb-000089
Figure PCTCN2022089900-appb-000090
Figure PCTCN2022089900-appb-000091
Figure PCTCN2022089900-appb-000092
Figure PCTCN2022089900-appb-000093
Figure PCTCN2022089900-appb-000094
Figure PCTCN2022089900-appb-000095
Figure PCTCN2022089900-appb-000096
Figure PCTCN2022089900-appb-000097
Figure PCTCN2022089900-appb-000098
Figure PCTCN2022089900-appb-000099
Figure PCTCN2022089900-appb-000100
Figure PCTCN2022089900-appb-000101
Figure PCTCN2022089900-appb-000102
Figure PCTCN2022089900-appb-000103
Figure PCTCN2022089900-appb-000104
生物试验
相关生物试验研究表明，本发明化合物具有优异的MAT2a抑制活性，在MTAP缺失工程细胞增殖抑制试验中明显优于现有同靶点化合物，并具有潜在肝毒性低、溶解度高等有益性。
实验例1：酶学活性测试
利用Colorimetric assay的方法检测受试化合物对MAT2a的IC 50值进行检测。
具体步骤为：化合物测试起始浓度为1μM或10μM，3倍梯度稀释成10个浓度点。分别取10个不同浓度的待测化合物溶液250nL，加入384孔板备用。用Assay buffer(50mM Tris,50mM KCl,10mM MgCl 2,0.05％聚氧乙烯月桂醇醚,pH 8.0)配制20μg/mL的MAT2a酶溶液，在不同浓度的待测化合物孔中分别加入20μg/mL的MAT2a酶溶液15μL；在阴性对照孔中加15μL的Assay buffer。振荡混匀后孵育15分钟。用Assay buffer配制底物混合溶液(含400μM ATP及600μM L-Methionine)，在阳性对照孔、待测化合物孔、阴性对照孔中分别加入10μL的底物混合溶液，开始反应，反应时间150分钟。随后加入50μL终止反应液(BIOMOL Green TM Reagent，Enzo lifesciences，货号BML-AK111-1000)终止反应，1000rpm离心60秒后孵育15分钟。读取OD620，处理数据。
计算公式：
Inhibition％＝(OD620 阳性对照孔-OD620 待测化合物孔)/(OD620 阳性对照孔-OD620 阴性对照孔)×100
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。实验结果如下表所示：
表1 本发明化合物对MAT2a的IC 50值
实施例 IC 50(nM) 实施例 IC 50(nM) 实施例 IC 50(nM)
1 NA 2 26.1 3 12.7
4 20.2 5 NA 6 40.5
7 37.9 8 8.7 9 21.4
10 20.9 11 21.4 12 25.8
13 32 14 22.9 15 23.2
16 41.9 17 NA 18 51.4
19 12.3 20 11.5 21 16.2
22 15 23 16.5 24 15.6
25 13.3 26 17.8 27 17.5
28 25.3 29 25.2 30 13.4
31 15.4 32 14.9 33 20.2
34 NA 35 14.9 36 13.6
37 20.2 38 18.1 39 19.8
40 26.3 41 18.4 42 15.0
43 22 44 13.4 45 14.8
46 15.1 47 13.6 48 16.1
49 15.8 50 17.2 51 16.2
52 16.2 53 14.4 54 16.2
55 16.3 56 14.5 57 17.1
58 17.4 59 25.4 60 17.0
61 17.0 62 16.1 63 17.8
64 15.4 65 15.2 66 16
67 18.1 68 16.0 69 16.6
70 30.5 71 18.5 72 16.5
73 18.8 74 16.4 75 13.8
76 16.3 77 13.9 78 14.0
79 18.0 80 15.5 81 17.0
82 16.0 83 17.2 84 28.2
85 15.2 86 15.9 87 15.4
88 16.0 89 16.5 90 16.9
91 18.0 92 17.4 93 16.3
NA代表未检测
结论：上述试验表明本发明化合物具有优异的MAT2a酶抑制活性。
实验例2：HCT116 MTAP基因纯合缺失细胞(来源：Horizon公司)活性测试
第1天，细胞铺板：胰蛋白酶消化下细胞后，用完全培养基(含10％FBS的RPMI-1640。FBS品牌为EXCELL，货号FND500；RPMI-1640品牌为ATCC，货号30-2001。)将细胞重悬成所需的密度，混合均匀，100μL/孔加入到96孔板中，细胞密度1000～3000个细胞每孔，放回培养箱待细胞贴壁生长。第2天，加入待测化合物：加化合物前先用无血清培养基饥饿处理细胞4小时，然后加入含相应浓度化合物的完全培养基，37℃，5％CO 2，培养120小时。第7天，取出化合物处理后的细胞平衡至室温，每孔加入50μL的CellTiter-Glo(Promega公司，货号G7571)试剂，室温振荡2分钟使细胞充***解，再孵育60分钟，检测荧光强度。计算公式：
％Inhibition＝100-(待测化合物孔信号-无细胞仅含培养基孔信号)/(有细胞但不加化合物孔信号-无细胞仅含培养基孔信号)×100。
采用分析软件GraphPad Prism 5的拟合量效曲线，从而得出各个化合物对细胞活性的IC 50值。实验结果表明，本发明化合物具有突出的抑制癌细胞的活性，本发明化合物普遍具有低于1000nM的IC 50值。
表2 HCT116 MTAP基因纯合缺失(HCT116 MTAP-/-)细胞抑制活性
Figure PCTCN2022089900-appb-000105
Figure PCTCN2022089900-appb-000106
通过试验证明，本发明化合物具有优异的抑制MAT2a酶活性的作用，且具有优异的抑制癌细胞生长的作用，尤其是对MTAP基因缺失的癌症细胞，将在MAT2a相关的癌症或肿瘤疾病中具有优异的治疗效果。
实验例3：KP-4细胞(来源：南京科佰生物科技有限公司)抑制活性试验
第1天，细胞铺板：胰蛋白酶消化细胞后，用含10％FBS(Gibco，10099141C)的RPMI1640完全培养基(HyClone公司，货号SH30809.01)将细胞重悬成1*10 4个/mL，混合均匀，100μL/孔加入到96孔板中，放回培养箱待细胞贴壁生长。第2天，加待测化合物：加入含化合物的的完全培养基100μL(培养基中化合物浓度配置如下：从60μM往下3倍梯度稀释，共10个浓度梯度)，37℃，5％CO 2，培养144小时。第8天，取出化合物处理后的细胞平衡至室温，吸出孔内多余培养基，使其保留50μL上清液，每孔加入50μL的CellCounting-Lite 2.0(南京诺唯赞生物科技有限公司，货号DD1101)试剂，室温振荡10分钟使细胞充***解，孵育5分钟，检测荧光强度。
％Inhibition＝100-(待测化合物孔信号-无细胞仅含培养基孔信号)/(有细胞但不加化合物孔信号-无细胞仅含培养基孔信号)×100。
以浓度的log值作为X轴，％Inhibition为Y轴，在分析软件GraphPad Prism 8中采用nonlinear regression(dose response–variable slope)拟合量效曲线并计算IC50值。结果见下表3。
表3 KP-4细胞抑制活性
Figure PCTCN2022089900-appb-000107
KP-4细胞抑制活性试验显示，本发明化合物优选实施例化合物对KP-4细胞有较强的抑制活性，通常具有<20μM的抑制活性，例如0.001-10μM，特别地0.01-10μM的抑制活性，相对于现有化合物(IC 50普遍高于30μM)有明显优势。
实验例4：DOHH-2细胞(来源：Creative Bioarray公司)抑制活性试验
第1天，细胞铺板：用含10％FBS(Gibco，10099141C)的DMEM完全培养基(Gibico公司，货号10569010)将细胞重悬成所需的密度，混合均匀，30μL/孔加入到384孔板中，细胞密度为800个/孔。加待测化合物：加入含有化合物的DMSO溶液30nL(其中化合物浓度配置为：从10mM往下3倍梯度稀释，共10浓度点)，37℃，5％CO 2，培养120小时。第6天，取出化合物处理后的细胞平衡至室温，每孔加入30μL的CellTiter-Glo(Promega公司，货号G7573)试剂，室温振荡使细胞充***解，再避光于37℃，5％CO 2孵育30分钟，检测荧光强度。
％Inhibition＝100-(待测化合物孔信号-无细胞仅含培养基孔信号)/(有细胞但不加化合物孔信号-无细胞仅含培养基孔信号)×100。
以浓度的log值作为X轴，％Inhibition为Y轴，在分析软件GraphPad Prism 8中采用nonlinear regression(dose response–variable slope)拟合量效曲线并计算IC50值。试验结果见下表4。
表4 DOHH-2细胞抑制活性
实施例 IC 50/nM
20 48
21 507
25 507
31 430
36 7
44 495
46 251
47 559
48 518
68 200
69 663
DOHH-2细胞抑制活性试验显示，本发明化合物优选实施例化合物对DOHH-2细胞有较强的抑制活性，通常具有<1μM，例如0.1-100nM，优选0.1-50nM的抑制活性，明显优于现有化合物，具有极大的开发前景。
实验例5：SD大鼠体内药代动力学研究
1.试验动物
种属：SD大鼠。来源：维通利华实验动物技术有限公司。数量：每种剂型3只。
供试品配制：
1.1准确称取适量的供试品，依次加入5％DMSO、10％聚乙二醇-15羟基硬脂酸酯、85％生理盐水(均为体积百分比)，涡旋或超声使充分混匀，得到供试品浓度为0.2mg/mL的给药溶液，用于静脉注射给药。
1.2准确称取适量的供试品，依次加入5％DMSO、10％聚乙二醇-15羟基硬脂酸酯、85％生理盐水(均为体积百分比)，涡旋或超声使充分混匀，得到供试品浓度为0.5mg/mL的给药溶液，用于口服灌胃给药。
2.实验设计
Figure PCTCN2022089900-appb-000108
3.给药方式
给药前称重，根据体重，计算给药量。通过静脉或灌胃口服给药。
4.采血时间点
给药前及给药后0.083h，0.25h，0.5h，0.75h，1h，2h，4h，8h，24h。
5.样品采集和处置
实验当天，分别于各设定时间点经由颈静脉窦采血100μL，全血样品置于含EDTA-K 2的抗凝管中。全血样品于1500g条件下离心10分钟分离血浆，收集上层血浆样品至样品管中。生物样品于-40至-20℃条件保存待分析。
6.生物分析和数据处理
根据苏州圣苏新药开发有限公司SOP-BA-002(液质联用法生物样品分析)的要求，建立测定大鼠血浆中化合物浓度的LC-MS/MS分析方法，并用于测定本实验获得的生物样品中化合物的浓度。
采用Pharsight Phoenix 8.0中的非房室模型计算药代动力学参数。
表5：SD大鼠静脉和口服给予受试化合物的体内药代动力学研究数据
Figure PCTCN2022089900-appb-000109
实验例6：ICR小鼠体内药代动力学研究
1.试验动物
种属：ICR小鼠，SPF级。来源：上海西普尔-必凯实验动物有限公司。数量：每种剂型3只。
2.供试品配制
2.1准确称取适量的供试品，依次加入5％DMSO、10％聚乙二醇-15羟基硬脂酸酯、85％生理盐水(均为体积百分比)，涡旋或超声使充分混匀，得到供试品浓度为0.4mg/mL的给药溶液，用于静脉注射给药。
2.2准确称取适量的供试品，依次加入5％DMSO、10％聚乙二醇-15羟基硬脂酸酯、85％生理盐水(均为体积百分比)，涡旋或超声使充分混匀，得到供试品浓度为1mg/mL的给药溶液，用于口服灌胃给药。
3.实验设计
Figure PCTCN2022089900-appb-000110
4.给药方式
给药前称重，根据体重，计算给药量。通过静脉或灌胃口服给药。
5.采血时间点
给药前及给药后0.083h，0.25h，0.5h，1h，2h，4h，6h，8h，24h。
6.样品采集和处置
经颌下静脉或其它合适方式采血，每个样品采集约0.03mL，肝素钠抗凝，血液样本采集后放置于冰上，并于1小时内离心分离血浆(离心条件：离心力6800g，6分钟，2-8℃)。采集的血浆样本在分析前存放于-80℃冰箱内，分析后剩余血浆样本继续存放于-80℃冰箱暂存。
7.生物分析和数据处理
检测受试物血药浓度，进行血浆药物浓度-时间曲线绘制时，BLQ(最低检测限)均记为0。进行药代参数计算时，给药前的浓度按照0计算；C max之前的BLQ(包括“No peak”)按照0计算；Cmax之后出现的BLQ(包括“No peak”)一律不参与计算。通过不同时间点的血药浓度数据，运用WinNonlin计算药代动力学参数，如AUC(0-t)，T 1/2，Cmax等。
表6：ICR小鼠鼠静脉和口服给予受试化合物的体内药代动力学研究数据
Figure PCTCN2022089900-appb-000111

Claims (23)

  1. 式Ⅰ结构所示的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物：
    Figure PCTCN2022089900-appb-100001
    其中，R 1选自5-10元芳基或芳杂环基；
    R 2选自-CF 3或环丙基；
    R 3选自氢、烷基、芳基、芳杂环基、环烷基、脂杂环基、桥环基和螺环基；
    A为芳基或芳杂环基，
    条件是所述化合物不包括下式化合物：
    Figure PCTCN2022089900-appb-100002
  2. 根据权利要求1所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 1选自咪唑基、噻唑基、吡唑基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
  3. 根据权利要求1或2所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 1可进一步被0-2个R a基团取代，每个所述Ra基团可独立的选自烷基、卤素、卤代烷基、烷氧基、卤代烷氧基、羟基、氨基、胺基、羧基、酰胺基、环烷基、氘。
  4. 根据权利要求3所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 1可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自C 1-C 3烷基、氟、氯、溴、碘、C 1-C 3卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、羟基、氨基、胺基、羧基、酰基、C 3-C 6环烷基、氘。
  5. 根据权利要求1所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 1是苯基，所述苯基可进一步被0-2个R a基团取代，每个所述R a基团可独立的选自C 1-C 3烷基、氟、氯、溴和碘，优选所述R 1选自苯基、4-氯苯基、4-溴苯基和4-甲基苯基，并且所述苯基可以进一步被氟取代。
  6. 根据权利要求1-5中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 3选自氢、C 1-C 3烷基、6至10元芳基、5至10元芳杂环基、C 3-C 6环烷基、3至6元脂杂环基、4至10元桥环基、螺环基。
  7. 根据权利要求6所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 3选自氢、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、氧杂环丁基、四氢呋喃基、四氢吡喃基、硫杂环己基、哌啶基、吡咯烷基、苯基、吡啶基、嘧啶基、咪唑基、吡唑基、噻唑基、噁唑基、异噁唑基、1,2,4-噁二唑基，4至10元桥环基、螺环基。
  8. 根据权利要求1-7中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 3不为氢时，所述R 3可选择的被一个或多个选自卤素、烷基、烷氧基、氰基、羟基、氨基、氘、砜基、磺酰基、卤代烷基、环烷基、脂杂环基的基团取代。
  9. 根据权利要求8所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 3不为氢时，所述R 3可选择的被一个或多个选自卤素、C 1-C 3烷基、C 1-C 3烷氧基、氰基、羟基、氨基、氘、砜基、磺酰基、C 1-C 3卤代烷基、C 3-C 6环烷基、3至6元脂杂环基的基团取代。
  10. 根据权利要求9所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述R 3不为氢时，所述R 3可选择的被一个或多个选自氟、氯、溴、碘、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、氧杂环丁基、四氢呋喃基、四氢吡喃基、硫杂环己基、哌啶基、吡咯烷基、三氟甲基、羟基、氨基、氰基、氘、砜基、磺酰基的基团取代。
  11. 根据权利要求1-10中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环选自6至10元芳环基、5至10元芳杂环基。
  12. 根据权利要求11所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环选自苯基、萘基、咪唑基、吡唑基、***基、噻唑基、呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并噁唑基、苯并二噁唑基、咪唑并吡啶基、苯并异噁唑基、萘啶基、喹啉基、异喹啉基、喹喔啉基、吡唑并吡啶基、***并吡啶基、吡啶酮基、喹唑啉基、噌啉基、吡啶并吡嗪基、苯并***基、苯并噁二唑基。
  13. 根据权利要求12所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环可进一步被一个或多个选自烷基、环烷基、脂杂环基、卤素、烷氧基、氨基、胺基、羟基、氰基、卤代烷基、卤代烷氧基、-(CH 2) nOCH 3、-(CH 2) nSO 2CH 3、-(CH 2) nN(CH 3) 2的基团取代，其中n＝1、2、或3。
  14. 根据权利要求13所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环可进一步被一个或多个选自C 1-C 3烷基、C 1-C 3烷氧基、卤素、C 1-C 3卤代烷基、氨基、氰基、-(CH 2) nOCH 3、-(CH 2) nSO 2CH 3、-(CH 2) nN(CH 3) 2的基团取代，其中n＝1、2或3。
  15. 根据权利要求13所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环可进一步被一个或多个选自甲基、甲氧基、-CF 3、-CH 2CF 3、-NH 2、F、氰基、-(CH 2) 2OCH 3、-(CH 2) 2SO 2CH 3、-(CH 2) 2N(CH 3) 2的基团取代。
  16. 根据权利要求13所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环上的取代基可进一步成环，并与A环形成并环。
  17. 根据权利要去1-16中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述A环选自如下基团：
    Figure PCTCN2022089900-appb-100003
  18. 根据权利要求1-17中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述化合物具有如下式II或式III所示的结构：
    Figure PCTCN2022089900-appb-100004
  19. 根据权利要求1-18中任一项所述的化合物，其药学上可接受的盐、水合物、异构体、前药及混合物，其特征在于所述式Ⅰ化合物选自：
    Figure PCTCN2022089900-appb-100005
    Figure PCTCN2022089900-appb-100006
    Figure PCTCN2022089900-appb-100007
    Figure PCTCN2022089900-appb-100008
    Figure PCTCN2022089900-appb-100009
    Figure PCTCN2022089900-appb-100010
    Figure PCTCN2022089900-appb-100011
  20. 权利要求1-19中任一项所述的化合物，及其药学上可接受的盐、水合物、异构体、前药或混合物，用于制备治疗MAT2a相关疾病的药物的用途。
  21. 一种药物组合物，其中含有治疗有效剂量的权利要求1-19中任一项所述的化合物，或其药学上可接受的盐、水合物、异构体、前药或混合物，以及药学上可接受的载体。
  22. 权利要求21的药物组合物用于制备治疗MAT2a相关疾病的药物的用途。
  23. 根据权利要求20或22所述的用途，其特征在于所述MAT2a相关疾病为癌症或肿瘤，进一步，所述癌症或肿瘤包括成神经细胞瘤、肠癌如直肠癌、结肠癌、家族性腺瘤性息肉病癌和遗传性非息肉病结肠直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、乳腺癌、泌尿***癌、黑素瘤、脑肿瘤如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-细胞白血病、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。在一个实施方案中，癌症是肺癌、非小细胞肺癌(NSLC)、支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、***癌、胃癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子***、***癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌***癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、***癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆道癌、慢性或急性白血病、淋巴细胞淋巴瘤霍马斯、中枢神经***(CNS)肿瘤、脊髓轴肿瘤、脑干神经胶质瘤、多形性胶质母细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、成神经管细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤，包括任何上述癌症的难治性形式，或一种或多种上述癌症的组合。
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