WO2024012507A1 - 二并环类mat2a抑制剂及其用途 - Google Patents
二并环类mat2a抑制剂及其用途 Download PDFInfo
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- WO2024012507A1 WO2024012507A1 PCT/CN2023/107109 CN2023107109W WO2024012507A1 WO 2024012507 A1 WO2024012507 A1 WO 2024012507A1 CN 2023107109 W CN2023107109 W CN 2023107109W WO 2024012507 A1 WO2024012507 A1 WO 2024012507A1
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- substituted
- group
- unsubstituted
- halogen
- cycloalkyl
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- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
- A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/495—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- 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
-
- 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 present invention relates to MAT2A inhibitors, specifically to a class of dicyclic compounds represented by the following formula I, pharmaceutical compositions containing said compounds, and their use in the preparation of drugs for treating and/or preventing MAT2A-related diseases, especially tumors. uses in.
- Cancer treatment is a huge challenge facing the world today.
- Synthetic lethality is defined as cell death caused by the deletion of two or more genes, whereas the deletion of any one gene alone has no effect.
- Synthetic lethality is defined as cell death caused by the deletion of two or more genes, whereas the deletion of any one gene alone has no effect.
- a large number of studies have shown that there are multiple genetic mutations in cancer cells that make them more sensitive to synthetic lethal treatments. These tumor-specific genetic mutations can prompt us to use appropriate targeted therapies to kill cancer cells without affecting normal cells.
- Methionine adenosyltransferase 2A is an enzyme that can catalyze the reaction of methionine (Met) and ATP to generate S-adenosyl-methionine (S-Adenosyl-L-methionine). , SAM) enzyme.
- SAM is the main methyl donor in the body. It can regulate gene expression through transmethylation reactions on DNA, RNA and proteins, thereby having an important impact on cell differentiation, growth and death.
- Arginine N-methyltransferase 5 PRMT5 is a methylase that uses SAM as a methyl donor.
- MTA 5’methylthioadenosine
- SAM is crucial for the activity of PRMT5
- 5’methylthioadenosine (MTA) can inhibit the activity of PRMT5.
- MTA is the product of the methionine compensation pathway. It is catalyzed by methylthioadenosine phosphorylase (MTAP) in cells to generate 5-methylthioribose-1-phosphate and adenine to maintain it at a low level. level.
- MTAP methylthioadenosine phosphorylase
- the MTAP gene is located on chromosome 9, which is deleted in cells of various cancer patients, including pancreatic cancer, esophageal cancer, bladder cancer and lung cancer (cBioPortal database).
- pancreatic cancer esophageal cancer
- bladder cancer esophageal cancer
- lung cancer cBioPortal database
- the loss of MTAP will lead to the enrichment of MTA in cells, making these cells more dependent on SAM production and MAT2A activity than normal cells.
- Studies have shown that inhibiting MAT2A expression in MTAP-deficient cancer cells can selectively inhibit cell activity compared to cancer cells with normal MTAP (McDonald et.al., 2017 Cell 170, 577-592).
- reducing MAT2A expression can selectively inhibit tumor growth in MTAP-deficient tumor cell mouse xenograft tumor models (Marjon et.al., 2016 Cell Reports 15(3), 574-587). These results indicate that MAT2A inhibitors can provide a new and effective treatment for cancer patients, especially those whose tumors contain MTAP deletions.
- An object of the present invention is to provide a dicyclic compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropase thereof Isomers, polymorphs, solvates, isotopically labeled compounds,
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount selected from the group consisting of compounds represented by formula (I) or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, One or more of racemates, atropisomers, polymorphs, solvates, isotopically labeled compounds, and at least one pharmaceutically acceptable carrier.
- Another object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, or polymorph thereof. Forms, solvates, isotope-labeled compounds, and uses of the pharmaceutical compositions in the preparation of drugs for inhibiting MAT2A activity.
- Another object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, or polymorph thereof.
- the first aspect of the present invention provides a dicyclic compound represented by formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, Racemates, atropisomers, polymorphs, solvates or isotopically labeled compounds,
- R 1 is selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylsulfonyl, C 3 -C 7 cycloalkyl, 3 -6-membered heterocycloalkyl, cyano, nitro, carboxyl, -NR a R a2 , -NHCOR a , -OR a , -SR a , the C 1 -C 6 alkyl, C 2 -C 6 alkene Base, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 3-6 membered heterocycloalkyl are unsubstituted or optionally substituted by one or more substituents selected from D and halogen;
- R a and R a2 are each independently selected from H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-6 membered hetero Cycloalkyl, C 1 -C 10 alkyl substituted by one or more substituents selected from group A, C 3 -C 10 cycloalkyl substituted by one or more substituents selected from group A;
- a Group substituents include: D, halogen, C 1 -C 3 alkoxy, hydroxyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, unsubstituted or substituted by one or more selected from group A2 C 3 -C 10 cycloalkyl group substituted; the A2 group substituents include: D, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 10 alkoxy;
- R 2 and R 3 are each independently selected from unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted 4-6 membered heterocycloalkyl , unsubstituted or substituted 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by one or more substituents selected from group B.
- Group C substituents include: D, halogen, hydroxyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, C 1 - C 4 alkoxy;
- R b is selected from H, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 6 -C 10 aryl, wherein C 1 - in R b C 4 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, and C 6 -C 10 aryl are unsubstituted or substituted with one or more selected from halogen, hydroxyl, and cyano. ;
- Ring A is a five-membered heteroaromatic ring, in which at most one of X, Y, and Z is CR 4 , and the others are independently selected from N, NR 5 , O, and S;
- R 4 and R 5 are each independently selected from H, D, halogen, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; or, R 4 and R 5 are each independently selected from H, D , halogen, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are unsubstituted or substituted by hydroxyl.
- R 1 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-6 membered heterocycloalkyl, -OR a , NR a R a2 ; the C 1 - C 6 alkyl, C 3 -C 7 cycloalkyl, and 3-6-membered heterocycloalkyl are unsubstituted or substituted by one or more substituents selected from D and halogen; R a and R a2 are each independently Selected from H, C 3 -C 7 cycloalkyl, unsubstituted or C 1 -C 6 alkyl substituted by one or more substituents selected from group A, the substituents of group A include: D, halogen, C 1 -C 3 alkoxy, hydroxyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 ring unsubstituted or substituted by one or more substituents
- R 1 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3-6 membered heterocycloalkyl, -OR a , -SR a , NR a R a2 ;
- the C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, and 3-6 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents selected from D and halogen;
- R a , R a2 is each independently selected from H, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl which is unsubstituted or substituted by one or more substituents selected from group A, which group A substituents include: D.
- R 2 and R 3 are each independently selected from unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted 5- 10-membered heteroaryl, the substitution refers to being substituted by one or more substituents selected from group B;
- the substituents of group B include: halogen, cyano, hydroxyl, mercapto, nitro, amino, oxo group, unsubstituted or substituted 4-6 membered heterocycloalkyl, unsubstituted or substituted C 1 -C 4 alkyl with one or more substituents selected from group C, unsubstituted or halogen substituted C 3 - C 7 cycloalkyl, unsubstituted or halogen substituted C 1 -C 4 alkoxy;
- Group C substituents include: D, halogen, hydroxyl, C 3 -C 6 cyclo
- R 1 is selected from C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, -OR a , NR a R a2 ; wherein said C 2 -C 6 alkyl, C 3 - C 6 cycloalkyl is unsubstituted or substituted by one or more substituents selected from D and halogen; R a and R a2 are each independently selected from H, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 2 -C 6 alkyl substituted by one or more substituents selected from Group A.
- the substituents of Group A include: D, halogen, methoxy, hydroxyl, C 3 -C 6 cycloalkyl.
- R 1 is selected from C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, -OR a , -SR a , NR a R a2 ; wherein said C 2 -C 6 alkyl , C 3 -C 6 cycloalkyl is unsubstituted or substituted by one or more substituents selected from D and halogen; R a and R a2 are each independently selected from H, C 3 -C 6 cycloalkyl, A C 2 -C 6 alkyl group that is unsubstituted or substituted by one or more substituents selected from Group A.
- the substituents of Group A include: D, halogen, methoxy, hydroxyl, C 3 -C 6 cycloalkyl.
- R 2 and R 3 are each independently selected from unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-10 membered heteroaryl, said 5-10
- the heteroaryl group is selected from the following structures: Substitution in the unsubstituted or substituted phenyl and unsubstituted or substituted 5-10-membered heteroaryl refers to being substituted by one or more substituents selected from group B.
- the substituents of group B include: halogen, cyanide group, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, unsubstituted or C 1 -C 4 alkyl substituted by one or more substituents selected from group C, unsubstituted or halogen substituted C 3 -C 7 cycloalkyl, unsubstituted or halogen substituted C 1 -C 4 alkoxy; group C substituents include: D, halogen, C 3 -C 6 cycloalkyl, hydroxyl, 4-6 yuan Heterocycloalkyl, C 1 -C 4 alkoxy.
- R 2 and R 3 are each independently selected from unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-10 membered heteroaryl, said 5-10
- the heteroaryl group is selected from the following structures: Substitution in the unsubstituted or substituted phenyl and unsubstituted or substituted 5-10-membered heteroaryl refers to being substituted by one or more substituents selected from group B.
- the substituents of group B include: halogen, cyanide group, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, unsubstituted or C 1 -C 4 alkyl substituted by one or more substituents selected from group C, unsubstituted or halogen substituted C 3 -C 7 cycloalkyl, unsubstituted or halogen substituted C 1 -C 4 alkoxy; group C substituents include: D, halogen, C 3 -C 6 cycloalkyl, hydroxyl, 4-6 yuan Heterocycloalkyl, C 1 -C 4 alkoxy.
- R 5 at each occurrence is independently H, D, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; or R 5 at each occurrence is independently H, D. C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, the C 1 -C 3 alkyl and C 3 -C 6 cycloalkyl are unsubstituted or substituted by hydroxyl.
- R 1 is selected from -OR a and NHR a .
- R 1 is selected from C 2 -C 6 alkyl, -OR a and NHR a .
- R a is selected from C 3 -C 6 cycloalkyl, unsubstituted or C 2 -C 6 alkyl substituted with one or more substituents selected from Group A;
- Group A substituents include : D, halogen, methoxy group, hydroxyl group, C 3 -C 6 cycloalkyl group.
- R 2 and R 3 are each independently selected from:
- R 2 and R 3 are each independently selected from:
- R 7 m means that there are m identical or different R 7 substituents on the ring; m is 1, 2 or 3; R 6 and each R 7 are independently selected from; H, halogen, cyanide group, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, unsubstituted or C 1 -C 4 alkyl substituted by one or more substituents selected from group C, unsubstituted or halogen substituted C 3 -C 7 cycloalkyl, unsubstituted or halogen substituted C 1 -C 4 alkoxy; group C substituents include: D, halogen, C 3 -C 6 cycloalkyl, hydroxyl, 4-6 yuan Heterocycloalkyl, C 1 -C 4 alkoxy; preferably, m is 1 or 2; R 6 and each R 7 are each independently selected from; H, halogen, cyano, hydroxyl,
- each occurrence of R5 is independently H or methyl.
- each occurrence of R5 is independently H, methyl, or hydroxyethyl.
- R 1 is selected from -OR a , NHR a ;
- R a is selected from C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 4 alkyl, halogen substituted C 2 -C 4 alkyl group, cyclopropyl-substituted C 2 -C 4 alkyl, methoxy-substituted C 2 -C 4 alkyl, hydroxyl-substituted C 2 -C 4 alkyl.
- R 1 is selected from C 2 -C 6 alkyl, -OR a , -SR a , NHR a ;
- R a is selected from C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 4 Alkyl, halogen-substituted C 2 -C 4 alkyl, cyclopropyl-substituted C 2 -C 4 alkyl, methoxy-substituted C 2 -C 4 alkyl, hydroxyl-substituted C 2 -C 4 alkyl .
- R 2 and R 3 are each independently selected from:
- R 2 and R 3 are each independently selected from:
- m is 1, 2 or 3;
- R 6 and R 7 are each independently selected from; H, halogen, cyano, hydroxyl, mercapto, nitro, amino, 4-6 membered heterocycloalkyl, Unsubstituted or substituted C 1 -C 4 alkyl with one or more substituents selected from group C, unsubstituted or halogen substituted C 3 -C 7 cycloalkyl, unsubstituted or halogen substituted C 1 -C 4 alkoxy; group C substituents include: D, halogen, C 3 -C 6 cycloalkyl, hydroxyl, 4-6 membered heterocycloalkyl, C 1 -C 4 alkoxy.
- m is 1, 2 or 3;
- R 6 and R 7 are each independently selected from: H, halogen, cyano, hydroxyl, thiol, nitro, amino, Unsubstituted or substituted C 1 -C 3 alkyl group with one or more substituents selected from group C, unsubstituted or halogen substituted cyclopropyl group, unsubstituted or halogen substituted C 1 -C 2 alkoxy group;
- Group C substituents include: D, halogen, C 3 -C 6 cycloalkyl, hydroxyl, methoxy,
- R 1 is selected from -OC 2 H 5 , -OCH 2 CF 3 , -NHCH 3 , -NHC 2 H 5 ,
- R 1 is selected from propyl, -OC 2 H 5 , -SC 2 H 5 , -OCH 2 CF 3 , -NHCH 3 , -NHC 2 H 5 ,
- R is selected from Alternatively, R 2 is selected from Wherein, m is 1, 2 or 3; R 8 and R 9 are each independently selected from H, halogen, CN, methoxy, methyl substituted by one or more halogens, methyl substituted by one or more halogens Oxygen group, cyclopropyl group; preferably, R 2 is selected from Alternatively, R 2 is selected from Wherein, R 8 and R 9 are each independently selected from H, halogen, cyano, methoxy, methyl substituted by one or more halogens, methoxy substituted by one or more halogens, cyclopropyl;
- R 3 is selected from Alternatively, R 3 is selected from Wherein, m is 1, 2 or 3; R 10 and R 11 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyano, methoxy, hydroxyl substitution ethyl, methoxy substituted ethyl, cyclopropyl,
- the compound of formula (I) is selected from the following structures:
- R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
- the compound of formula (I) is selected from the following structures:
- R 1 , R 2 , R 3 and R 5 are as defined above.
- the compound represented by formula (I) is selected from the following structures:
- a second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts thereof, enantiomers, and diastereomers.
- a therapeutically effective dose selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts thereof, enantiomers, and diastereomers.
- the pharmaceutical composition may optionally also include one or more other therapeutic agents.
- the present invention provides a combination, especially a pharmaceutical combination, which contains a therapeutically effective dose selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts thereof, enantiomers, non- Enantiomers, racemates, atropisomers one or more of a conformation, a polymorph, a solvate, an isotopically labeled compound, and one or more other therapeutic agents.
- a therapeutically effective dose selected from the group consisting of compounds represented by formula (I), pharmaceutically acceptable salts thereof, enantiomers, non- Enantiomers, racemates, atropisomers one or more of a conformation, a polymorph, a solvate, an isotopically labeled compound, and one or more other therapeutic agents.
- the compounds of the invention may be used alone, in combination with other compounds of the invention or in combination with one or more, preferably one or two, other therapeutic agents simultaneously or sequentially.
- the third aspect of the present invention provides the compound described in formula (I) or a pharmaceutically acceptable salt thereof, its enantiomers, diastereomers, racemates, atropisomers, The use of the pharmaceutical composition in a polymorph, solvate or isotopically labeled compound or in the preparation of a medicament for inhibiting MAT2A activity.
- the fourth aspect of the present invention provides the compound described in formula (I) or a pharmaceutically acceptable salt thereof, its enantiomers, diastereomers, racemates, atropisomers, Use of one or more polymorphs, solvates or isotopically labeled compounds or the pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of MTAP-related diseases, especially tumors.
- the tumors include: tumors lacking MTAP; tumors with low expression of MTAP; tumors with abnormal expression of MAT2A; and other MAT2A-dependent tumors.
- the tumors include: breast cancer, lung cancer, glioblastoma, brain cancer and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, Rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline tract carcinomas, and carcinomas of unknown primary.
- the present invention provides a method for treating or preventing MAT2A-related diseases, especially tumors, which method comprises administering to an individual in need an effective amount of a compound selected from the present invention, a pharmaceutically acceptable One or more of salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, isotopically labeled compounds, or this Pharmaceutical compositions of the invention.
- the method further includes administering to the individual in need thereof an effective amount of a second therapeutic agent that is one or more other therapeutic agents.
- the invention provides a product or kit comprising a compound selected from the invention as defined above, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, One or more of a conformation, a polymorph, a solvate, an isotopically labeled compound, or a pharmaceutical composition of the invention.
- the kit may also contain one or more other therapeutic agents, thereby constituting a combination formulation for simultaneous, separate or sequential use in anti-cancer therapy.
- a dash ("-") not between two letters or symbols indicates the attachment site of the substituent.
- -O(C 1 -C 3 alkyl) means that the group is connected to the rest of the molecule through an oxygen atom.
- the "-" may be omitted.
- heteroatom refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, including their oxidized forms.
- halogen refers to fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.
- alkyl refers to a fully saturated linear or branched monovalent hydrocarbon group.
- the alkyl group preferably contains 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms or 1- 3 carbon atoms.
- the number before the alkyl group indicates the number of carbon atoms.
- C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms
- C 1 -C 4 alkyl means an alkyl group having 1 to 4 carbon atoms
- C 1 -C 3 "Alkyl” means an alkyl group having 1 to 3 carbon atoms, and so on.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl base, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.
- This definition applies whether the term "alkyl" appears alone or as part of other groups such as haloalkyl, alkoxy, etc.
- alkenyl refers to a straight or branched monovalent hydrocarbon group containing at least one double bond.
- the alkenyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms.
- the number before the alkenyl group indicates the number of carbon atoms.
- Representative examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.
- alkynyl refers to a straight or branched monovalent hydrocarbon group containing at least one triple bond.
- the alkynyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms. The number before the alkynyl group indicates the number of carbon atoms.
- alkynyl groups include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isopentenyl, hexynyl, heptynyl, octynyl Key et al.
- alkoxy refers to an alkyl group as defined herein linked through an oxygen bridge, ie, an alkyl-O- group, the number before the alkoxy group indicating the number of carbon atoms.
- C 1- C 6 alkoxy means an alkoxy group with 1-6 carbon atoms, that is, -OC 1-6 alkyl
- C 1- C 4 alkoxy means an alkoxy group with 1-4 carbon atoms Alkoxy group of carbon atoms, namely -OC 1-4 alkyl group
- C 1- C 3 alkoxy group means an alkoxy group of 1 to 3 carbon atoms, namely -OC 1-3 alkyl group.
- Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
- cycloalkyl refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi- or tricyclic rings, preferably having 3 to 12 ring carbon atoms, more preferably 3 to 10 ring carbon atoms , such as 3-8, 3-7, 3-6, 4-10, or 4-8 ring carbon atoms.
- C 3 -C 8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl groups;
- C 3 -C 6 cycloalkyl is intended to include C 3 , C 4 , C 5 and C 6 cycloalkyl groups.
- Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
- Exemplary bicyclic cycloalkyl groups include bornyl, tetrahydronaphthyl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptene base, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, etc.
- Exemplary tricyclic cycloalkyl groups include adamantyl and the like.
- haloalkyl refers to a group in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by halogen. alkyl group as defined, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other.
- C 1 -C 4 haloalkyl is intended to include C 1 , C 2 , C 3 and C 4 haloalkyl groups
- C 1 -C 3 haloalkyl is intended to include C 1 , C 2 and C 3 haloalkyl groups. group.
- Halogenated alkyl examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl, and 1,1,1 -Trifluoropropyl.
- haloalkyl groups also include "fluoroalkyl groups,” which is intended to include alkyl groups as defined herein in which one or more hydrogen atoms are replaced by fluorine atoms.
- Haloalkyl herein is preferably an alkyl group in which up to three hydrogen atoms are replaced by halogen.
- haloalkoxy means a haloalkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge, with one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 Hydrogen atoms, for example 1, 2 or 3 hydrogen atoms, are replaced by halogens.
- hydrogen atoms such as 1, 2, 3, 4, 5, 6 or 7
- Hydrogen atoms for example 1, 2 or 3 hydrogen atoms, are replaced by halogens.
- C 1 -C 6 haloalkoxy or “C 1 to C 6 haloalkoxy” is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 haloalkoxy groups.
- haloalkoxy examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy. Examples of haloalkoxy also include "fluoroalkoxy”.
- aryl is composed of one ring or multiple fused rings and has 6-20, preferably 6-14, more preferably 6-12, most preferably 6-10.
- Aryl groups with 6 to 10 ring carbon atoms include: monocyclic aryl groups (such as phenyl); or fused bicyclic systems in which one ring is an aromatic ring and The other ring is aromatic (eg in naphthalene, biphenyl) or non-aromatic (eg in indene, tetralin).
- aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl or anthracenyl, and the like.
- heteroaryl refers to a 5-14-membered, preferably 5-10-membered, more preferably 5-7-membered ring heteroatom containing 1-4, preferably 1-3 ring heteroatoms selected from N, O or S.
- 5-6 membered aromatic ring system including monocyclic or bicyclic or fused polycyclic rings, and the remaining ring atoms are carbon atoms.
- heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazine base, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-color En, benzopyranyl, benzothienyl, indolyl, indazolyl, benzopyrazole, benzimidazolyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, 7-nitrogen Heteroindolyl, 6-azaindolyl, 5-azaindo
- heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated ring having 3 to 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 8 ring atoms, such as 3 to 6 ring atoms. and partially unsaturated nonaromatic rings.
- the heterocycloalkyl group is preferably a 4- to 12-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 4- to 8-membered heterocycloalkyl group, More preferred are 4- to 7-membered, 4- to 6-membered or 5- to 6-membered heterocycloalkyl, wherein the heteroatoms are substituted or unsubstituted, for example substituted by C 1 -C 4 alkyl.
- heterocycloalkyl examples include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, azetidinyl (pyrrolidinyl), Tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl-2-one , imidazolinyl, piperidinyl (hexahydropyridinyl), N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl , piperidinyl (piperidinylone), 1,4-diox
- optionally substituted alkyl includes “unsubstituted alkyl” and “substituted alkyl” as defined herein.
- Optionally substituted by halogen includes the case of "substituted by halogen” and the case of "not substituted by halogen", for example, substituted by 0 to 3 halogens.
- substituted means that one or more hydrogen atoms on a given atom or group are replaced by one or more hydrogen atoms selected from a given group of substituents Base substitution, provided that the normal valency of the given atom is not exceeded.
- two hydrogen atoms on a single atom are replaced by oxygen.
- a ring system eg, a carbocyclic or heterocyclic ring
- carbonyl group or double bond is part of the ring (ie, within the ring).
- substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds.
- a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from the reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that has at least practical utility.
- substituted means one or more hydrogen atoms on a given atom or group Independently substituted by one or more, for example 1, 2, 3 or 4 substituents.
- substituents may be the same or different.
- the term "compound of the present invention” or “compound of the present invention” refers to one or more formula (I) or subformulas thereof as defined herein, such as formula (I-1), ( Compounds of I-2), (I-1-1), (I-2-1), (I-3-1), etc., or pharmaceutically acceptable salts thereof, and all isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, isomers Internal addition products of conformations, prodrugs, and isotopically labeled compounds (including deuterium substitution) and intrinsically formed moieties (eg, polymorphs, solvates, and/or hydrates).
- Salts especially pharmaceutically acceptable salts, are also included when moieties capable of forming salts are present.
- the presence of tautomers or internal addition products of isomers can be identified by one skilled in the art using tools such as NMR.
- the compounds of formula (I) of the present invention are capable of readily forming tautomers and internal addition products of isomers as depicted herein.
- enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to refer to racemic mixtures.
- a single stereoisomer with known relative and absolute configurations of two chiral centers e.g., (1S,2S)
- Single stereoisomers whose relative configuration is known but whose absolute configuration is unknown are marked with an asterisk (e.g. (1R*, 2R*)); racemates with two letters (e.g.
- (1RS, 2RS)) are ( 1R, 2R) and (1S, 2S) racemic mixture; (1RS, 2SR) is the racemic mixture of (1R, 2S) and (1S, 2R)).
- "Diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-lngold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be rotated according to their rotation of plane polarized light at the wavelength of the sodium D line. Direction (right-handed or left-handed) is specified as (+) or (-). Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers/diastereomers via chiral HPLC.
- Some of the compounds described herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereomers and compounds that can be defined in absolute stereochemistry as (R)- or (S)- Other stereoisomers.
- Geometric isomers can occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. If the compound contains a double bond, the substituent can be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration.
- Conformational isomers are isomers that differ by rotation about one or more valence bonds. Rotamers are conformers that differ by the rotation of only a single valence bond.
- Atropisomer refers to a structural isomer based on axial or planar chirality resulting from restricted rotation in the molecule.
- the compounds of the invention are intended to include all such possible isomers, including racemic mixtures, optically active forms and intermediate mixtures.
- Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds of the present invention can be isolated into optically active forms or racemic forms.
- Optically active forms can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All methods for preparing the compounds of the invention and the intermediates prepared therein are considered to be part of the invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, such as by chromatography or fractional crystallization.
- the final product of the invention is obtained in free (neutral) or salt form.
- the free and salt forms of these end products are within the scope of this invention.
- one form of a compound can be converted into other forms. Free bases or acids can be converted into salts; salts can be converted into free compounds or other salts; mixtures of isomeric compounds of the invention can be separated into individual isomers.
- salts refer to salts that retain the biological effects and properties of the compounds of the invention and which are not biologically or otherwise undesirable.
- Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the compounds of the invention.
- the compounds of the invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
- Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like; ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred.
- Organic bases from which salts may be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and the like, in particular such as isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.
- salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods.
- the salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (eg hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K ) reaction or reacting the free base form of the compound with a stoichiometric amount of an appropriate acid.
- This type of reaction is usually carried out in water or organic solvents or a mixture of the two.
- non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where feasible.
- Other suitable salts can be found in Remington's Pharmaceutical Sciences, Vol. 20th edition, Mack Publishing Company, Easton, Pa., (1985), which is incorporated by reference.
- pharmaceutically acceptable excipients include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, Absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, said similar substances and combinations thereof, are well known to those of ordinary skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference) . Unless any conventional carrier is incompatible with the active ingredient, it is contemplated for use in the therapeutic or pharmaceutical compositions.
- isotopically labeled compound has the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.
- isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H (i.e., D), 3 H (i.e., T), 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I.
- the invention includes different isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as 3H , 13C and 14C are present.
- Such isotopically labeled compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (e.g. using 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computers.
- PET positron emission tomography
- PET positron emission tomography
- SPECT single photon emission computers.
- 18 F or labeled compounds may be particularly desirable for PET or SPECT studies.
- Isotopically labeled compounds of the present invention can generally be prepared by carrying out those procedures described in the schemes described below or in the Examples and Preparations, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.
- isotopes especially deuterium (i.e. 2 H or D) may also result in certain therapeutic benefits resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements or improved therapeutic index.
- deuterium in this context may be regarded as a substituent for the compounds of the invention.
- concentration of these heavier isotopes, especially deuterium can be defined by the isotope enrichment factor.
- An “isotopic enrichment factor" represents the ratio between the isotopic abundance and the natural abundance of a given isotope.
- a “therapeutically effective amount” of a compound of the present invention refers to an amount of a compound of the present invention that elicits a biological or medical response in an individual or ameliorates symptoms, slows or delays the progression of a disease, prevents a disease, or the like.
- the "therapeutically effective amount” may be determined by the participating physician or veterinary practitioner and will vary with the compound, the disease state treated, the severity of the disease treated, the age and related health conditions of the individual, the route and form of administration, the attending physician It varies depending on factors such as the judgment of the physician or veterinary practitioner.
- individual refers to an animal.
- the animal is a mammal.
- Individuals also refer to, for example, primates (eg, humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
- the individual is a human.
- inhibition refers to the alleviation or inhibition of a particular condition, symptom or condition or disease, or a significant reduction in the baseline activity of a biological activity or process.
- any disease or condition in one embodiment refers to ameliorating the disease or condition (i.e., preventing or slowing the progression of the disease or at least one clinical symptom thereof).
- “treating” or “treating” refers to improving at least one physical parameter, which may not be noticeable to the patient.
- “treating” or “treating” refers to modulating a disease or disorder physically (e.g., stabilizing perceived symptoms) or physiologically (e.g., stabilizing parameters of the body) or both.
- prevention refers to the administration of one or more pharmaceutical substances, specific In particular, the compounds of the present invention and/or pharmaceutically acceptable salts thereof are used to prevent an individual from suffering from the disease.
- the term "about” is used herein to adjust a given numerical value to 20%, such as 10%, such as 5%, above or below that value.
- the sources and trade names of the reagents and equipment used are all indicated when they first appear. Unless otherwise specified, the same reagents used thereafter are the same as those first indicated. Conventional unlabeled reagents are purchased from Sinopharm Chemical Reagent Co., Ltd. company.
- DIPEA N,N-diisopropylethylamine
- SEMCl 2-(trimethylsilyl)ethoxymethyl chloride
- TBAF tetrabutylammonium fluoride
- NBS N-bromosuccinimide
- Tf Trifluoromethanesulfonyl
- FA formic acid
- BSA bovine serum albumin
- Brij 35 polyoxyethylene lauryl ether
- Pd(dppf)Cl 2 1,1'-bisdiphenylphosphine ferrocene palladium dichloride
- NBS N-bromosuccinimide
- PE petroleum ether
- EA ethyl acetate.
- intermediate 2-1 (3.8 g, 28.1 mmol) was dissolved in acetic acid (72.0 mL), liquid bromine (18.0 g, 112.5 mmol) was added under stirring at room temperature, and the reaction was completed for 3 hours. Filter, collect the filter cake, and wash the filter cake twice with PE to obtain intermediate 3-1 (4.0 g, yield: 66.7%), a light yellow solid.
- 1 H NMR 400MHz, DMSO) ⁇ 12.14(s,1H),9.82(s,2H),8.29(s,1H),8.03(s,1H).
- reaction solution was concentrated to dryness and purified through silica gel flash column (0-3% methanol (MEOH)/dichloromethane (DCM)) to obtain intermediate 6-1 (21 mg, yield: 38.9%) as a white solid.
- LCMS(ESI)m/z 502.4[M+H] + .
- intermediate 3-2 (50 g, 141 mmol) was dissolved in 15% sodium hydroxide aqueous solution (350 mL), and the temperature was raised to 105°C for 15 hours.
- LCMS(ESI)m/z 282.1[M+H] + .
- intermediate 9-2 (100 mg, 1.83 mmol) was dissolved in 4M HCl/1,4-dioxane solution (15 mL), and the reaction was carried out at room temperature for 2 h.
- the reaction solution was poured into ice water, and the pH was adjusted to neutral with sodium bicarbonate aqueous solution. Extract with DCM/methanol (10/1), combine the organic phases, wash once with water and saturated brine, dry with anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure and purified by prep-HPLC (H 2 O/CAN, 0.1 % FA), freeze-drying to obtain compound 2 (31.77 mg, yield: 41.8%), a white solid.
- intermediate 5-4 (75 mg, 0.14 mmol) was dissolved in 4 mol/L hydrogen chloride dioxane solution (5 mL), and stirred at room temperature for 2 h. Pour the reaction solution into 10 mL of water, and adjust the pH to neutral with sodium bicarbonate aqueous solution. Extract with 50 mL DCM/methanol (10/1), combine the organic layers, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated to dryness under reduced pressure, and purified by prep-HPLC (water/acetonitrile, 0.1% NH 3 .H 2 O). After freeze-drying, compound 4 (6.83 mg, yield: 12.1%) was obtained as a white solid.
- intermediate 5-3 (100 mg, 0.183 mmol) was dissolved in 4 mol/L hydrogen chloride dioxane solution (5 mL), and stirred at room temperature for 2 h. Pour the reaction solution into 10 mL of water, and adjust the pH to neutral with sodium bicarbonate aqueous solution. Extract with 50 mL DCM/methanol (10/1), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. Purify by prep-HPLC (water/acetonitrile, 0.1% FA), and freeze-dry to obtain 3( 9.0 mg, yield: 11.84%), white solid.
- Adopt the synthesis method of Example 4 replace the 4-methoxyphenylboronic acid pinacol ester in the third step with 4-chlorophenylboronic acid pinacol ester, and the 5-bromo-2-methyl in the fourth step -2H-indazole was replaced with 1-(azetidin-3-yl)-6-iodo-1H-benzo[d]imidazole, and the mobile phase FA purified by prep-HPLC in the fifth step was replaced with trifluoro Acetic acid gave the trifluoroacetate salt of compound 35.
- intermediate 5-12 (80 mg, 0.133 mmol) was dissolved in 4M hydrogen chloride 1,4-dioxane (6 mL), and stirred at room temperature for 4 h. Pour the reaction solution into water, and adjust the pH to neutral with sodium bicarbonate aqueous solution. Extract with 50 mL DCM/methanol (10/1), combine the organic layers, dry and filter over anhydrous sodium sulfate, collect the filtrate, concentrate to dryness under reduced pressure, perform prep-HPLC (water/acetonitrile, 0.1% FA), and freeze-dry to obtain Compound 12 (31.53 mg, yield: 50.4%), white solid.
- 4M hydrogen chloride 1,4-dioxane 6 mL
- intermediate 4-67 (3.2 g, 9.1 mmol) was dissolved in 15% sodium hydroxide aqueous solution (30 mL), and reacted at 105°C for 5 hours.
- LCMS(ESI)m/z 282.1[M+H] + .
- Compound 44 was prepared using the synthetic method of Example 9.
- intermediate 5-63 (40 mg, 0.07 mmol) was dissolved in TBAF tetrahydrofuran solution (6 mL), and the reaction was carried out under reflux at 60°C for 2 hours.
- intermediate 4-55 (7.5 g, 21.22 mmol) was added to the 15% NaOH solution, the temperature was raised to 105°C, and the reaction was refluxed for 6 hours. The pH of the reaction solution was adjusted to about 4 with 2M hydrochloric acid, and a solid was precipitated and filtered to obtain intermediate 5-55 (6.1 g, yield: 95.31%), a yellow solid.
- LCMS(ESI)m/z 282.10[M+H] + .
- intermediate 9-55 (150 mg, 0.27 mmol) was dissolved in TBAF (10 mL), and the temperature was raised to 60°C and refluxed for 1 hour.
- the reaction solution was concentrated, washed with water to remove TBAF, extracted with EA, and the organic phase was concentrated and purified by Prep-HPLC (water/acetonitrile, 0.1% FA). After freeze-drying, compound 55 (77.75 mg, yield: 68.2%) was obtained as a white solid. .
- reaction solution was concentrated, and the crude product was purified by silica gel Flash column (0-2% methanol/DCM) to obtain the crude product, which was further purified by prep-HPLC (water/acetonitrile, 0.1% FA) and freeze-dried to obtain compound 100 (16.26 mg , Yield: 19%), white solid.
- MAT2A can catalyze the conversion of L-methionine and ATP into SAM, inorganic phosphate and inorganic diphosphate.
- a chromogenic reagent added to the enzymatic reaction system, the content of inorganic phosphate in the sample can be quantitatively detected, thereby characterizing the enzymatic activity of MAT2A.
- Test materials Tris(Life science#0497); BSA(Sigma#); MAT2A his-tag(BPS#71401-1); 384-well plate (Corning#3765); L-methionine(Admas#1100469); ATP(Sigma) #A7699); MgCl 2 (Sigma#M8266); KCl (Sigma#7447-40-7); Brij35 (Sigma#B4184); EDTA (Sigma#E1644)
- 1xAssaybuffer buffer composition: Tris, KCl, MgCl 2 , BSA, Brij35 and EDTA; solvent is ultrapure water.
- 1xAssaybuffer to prepare MAT2A his-tag enzyme solution (containing 1.3 ⁇ L MAT2A enzyme and 998.7 ⁇ L 1xAssaybuffer per 1000 ⁇ L) and substrate mixed solution (containing 5 ⁇ L ATP, 1.3 ⁇ L L-methionine and 993.7 ⁇ L 1xAssaybuffer per 1000 ⁇ L).
- test compound concentration gradient The test compound is tested with 10 ⁇ M as the starting concentration, and 10 equal concentrations are set according to 3-fold dilution. Specifically, first, gradient dilutions were made into 10 series solutions of different concentrations in a 384-well plate (so that the final detection concentrations of the compounds were 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.0137, 0.0046, 0.0015 and 0.0005 ⁇ M), Then use the sonic pipetting system Echo550 to transfer 250nL of the above series of solutions to a 384-well reaction plate for later use. Add 250 nL of 100% DMSO to the negative control well and positive control well respectively. Repeat hole test.
- compound inhibition rate (%) (OD620_max-OD620_sample)/(OD620_max-OD620_min) ; OD620_max is the absorbance value of the negative control well, indicating the reading of the well without compound inhibition.
- test results Under the conditions of this test, the inhibitory effect of the test compound on MAT2A enzyme activity can be expressed by the IC 50 value of the inhibition of phosphate production during the enzymatic reaction.
- the MAT2A inhibitory activity of the compounds to be tested is shown in Table 1. The results show that using compound 1 with a similar structure as a control, the compound of the present invention has a significant MAT2A enzyme inhibitory effect.
- Test principle After the MAT2A inhibitor to be tested is incubated with KP-4 cells for a period of time, a cell activity measurement method based on ATP content is used to characterize the effect of the compound to be tested on cell activity.
- Test materials KP-4 cells (JCRB#JCRB0182); IMDM (Gibco#12440061); Fetal bovine serum (EXCELL#FND500); Penicillin-Streptomycin (Gibco#15140- 122); 0.25% Typsin-EDTA (Gibco#25200-072); DMSO (Sigma#D2650); 96-well plate (Corning#3610); CellTiter-Glo (Promega#G7571)
- KP-4 cells are cultured in IMDM containing 10% fetal calf serum and 1% penicillin-streptomycin in a cell culture incubator at 37°C and 5% CO2 . Cells in the logarithmic growth phase can only be used. for subsequent testing.
- DMSO DMSO to dissolve the compound and dilute it with culture medium to 10 different concentrations (about 10000, 3333.3, 1111.1, 370, 123, 41.2, 13.7, 4.6, 1.5 and 0.5nM), then add it to the cell plate and incubate at 37°C. Continue culturing for 5 days under 5% CO2 conditions.
- compound inhibition rate (%) (Signal_max-Signal_sample)/(Signal_max-Signal_min) ⁇ 100, where: Signal_sample is the sample well reading, indicating the cell activity of the compound inhibited well; Signal_min is the positive control well reading, Indicates no background activity of cells; Signal_max is the negative control well reading, indicating that no compound inhibits cell activity in the well.
- Compound 13 and AG-270, a MAT2A inhibitor were evaluated using human B-cell lymphoma DOHH-2 cell subcutaneous xenograft tumor models. )’s anti-tumor efficacy in vivo.
- the female CB-17SCID mice used were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.
- Tumor cell culture and subcutaneous inoculation Human B-cell lymphoma DOHH-2 cells (DSMZ) were cultured in vitro in RPMI-1640 medium containing 10% fetal calf serum and 1% double antibody, and cultured in a 37°C 5% CO 2 incubator . When the number of cells reaches the required number, collect the cells, count them, and inoculate 0.2mL (10 ⁇ 10 6 ) DOHH-2 cells (plus Matrigel, volume ratio 1:1) subcutaneously into the right back of each mouse. When the average tumor volume reached 100-150 mm, random groups were started, with 5 mice in each group.
- the administration group (Compound 13 or Compound AG-270) was administered intragastrically twice a day (see Table 3 for dosage), and the negative control group was intragastrically administered the same volume of blank vehicle every day.
- the tumor inhibitory effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%).
- TRTV and CRTV take the same day data.
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Abstract
提供了式(I)所示的二并环类化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物。所述式(I)所示化合物具有MAT2A酶抑制活性,可作为良好的MAT2A抑制剂,进一步用于制备治疗和/或预防MTAP相关疾病,特别是肿瘤的药物。
Description
本申请要求2022年7月13日提交的申请号为202210828873.6,发明名称均为“二并环类MAT2A抑制剂及其用途”的中国专利申请的优先权,其全部内容通过引用整体并入本文。
本发明涉及MAT2A抑制剂,具体涉及一类下面式I所示的二并环类化合物,包含所述化合物的药物组合物,以及其在制备治疗和/或预防MAT2A相关疾病,特别是肿瘤的药物中的用途。
癌症治疗是当今世界面对的巨大挑战,对于现有的常用疗法,比如化疗和免疫治疗,最大的问题是细胞杀伤效果往往不仅针对癌症细胞,对于正常细胞和组织也会产生很大的副作用。因此,迫切需要开发新型治疗手段以更好的靶向癌症细胞。
合成致死被定义为两个或多个基因的缺失导致细胞死亡,而其中任何一个基因的单独缺失不会有影响。近年来,大量的研究显示在癌症细胞中存在着多种基因突变导致它们对于合成致死的治疗手段更加敏感。这些肿瘤特异性的基因突变可以促使我们使用合适的靶向治疗药物杀伤癌症细胞,而对于正常细胞没有影响。
甲硫氨酸腺苷转移酶2A(methionine adenosyltransferase 2A,MAT2A)是一种能够催化甲硫氨酸(methionine,Met)与ATP反应生成S-腺苷甲硫氨酸(S-Adenosyl-L-methionine,SAM)的酶。SAM是体内主要的甲基供体,能够通过对DNA、RNA和蛋白的转甲基反应,调控基因的表达,进而对细胞的分化、生长和死亡产生重要影响。精氨酸甲基转移酶5(arginine N-methyltransferase 5,PRMT5)是一种以SAM为甲基供体的甲基化酶。SAM对于PRMT5的活性至关重要,同时甲硫腺苷(5’methylthioadenosine,MTA)可以抑制PRMT5的活性。MTA是甲硫氨酸补偿途径的产物,其在细胞内通过甲硫腺苷转化酶(methylthioadenosine phosphorylase,MTAP)催化生成5-甲基硫代核糖-1-磷酸及腺嘌呤而维持在较低的水平。
MTAP基因位于9号染色体,该染色体在多种癌症病人的细胞中存在缺失,包括胰腺癌、食管癌、膀胱癌和肺癌等(cBioPortal数据库)。MTAP的缺失会导致细胞内MTA的富集,进而使这些细胞相比于正常细胞更加依赖于SAM的产量和MAT2A的活性。研究表明,在MTAP缺失的癌细胞中抑制MAT2A的表达相较于MTAP正常的癌细胞可以选择性的抑制细胞活性(McDonald et.al.,2017Cell 170,577-592)。同时,降低MAT2A表达可以选择性的抑制MTAP缺失的肿瘤细胞小鼠异种移植瘤模型中的肿瘤生长(Marjon et.al.,2016Cell Reports 15(3),574-587)。这些结果表明MAT2A抑制剂可以为癌症病人,尤其是肿瘤含有MTAP缺失的病人,提供一种新型有效的治疗手段。
发明内容
发明人出人意料地发现,本发明所述式(I)化合物具有MAT2A酶活性抑制作用,并通过细胞实验验证了其肿瘤细胞活性抑制效果。因此式(I)化合物可作为良好的MAT2A抑制剂。
本发明的一个目的是提供一种如式(I)所示的二并环类化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物,
本发明的另一目的是提供一种药物组合物,包含治疗有效量的选自式(I)所示的化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,和至少一种药学上可接受的载体。
本发明的又一目的是提供式(I)所示的化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物、所述药物组合物在制备用于抑制MAT2A活性的药物中的用途。
本发明的又一目的是提供式(I)所示的化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物,所述药物组合物在制备治疗和/或预防MAT2A相关疾病,特别是肿瘤的药物中的用途。
为了实现上述目的,本发明的第一个方面,提供一种如式(I)所示的二并环类化合物或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,
其中,
R1选自卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基磺酰基、C3-C7环烷基、3-6元杂环烷基、氰基、硝基、羧基、-NRaRa2、-NHCORa、-ORa、-SRa,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、3-6元杂环烷基为无取代或任选地被一个或多个选自D、卤素的取代基所取代;
Ra、Ra2各自独立地选自H、C1-C10烷基、C3-C10环烷基、C6-C10芳基、5-10元杂芳基、3-6元杂环烷基、被一个或多个选自A组的取代基取代的C1-C10烷基、被一个或多个选自A组的取代基取代的C3-C10环烷基;A组取代基包括:D、卤素、C1-C3烷氧基、羟基、C6-C10芳基、5-10元杂芳基、无取代或被一个或多个选自A2组的取代基取代的C3-C10环烷基;所述A2组取代基包括:D、卤素、羟基、C1-C6烷基、C1-C10烷氧基;
R2、R3各自独立地选自无取代或取代的C3-C10环烷基、无取代或取代的C6-C10芳基、无取代或取代的4-6元杂环烷基、无取代或取代的5-10元杂芳基;其中,所述取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基(-CN)、羟基(-OH)、氧代(=O)、巯基(-SH)、氨基(-NH2)、硝基(-NO2)、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基、
-COOH、-CONHRb、-NHCORb、-NHSO2Rb;C组取代基包括:D、卤素、羟基、C3-C6环烷基、4-6元杂环烷基,C1-C4烷氧基;
Rb选自H、C1-C4烷基、C3-C10环烷基、C1-C10烷氧基、C6-C10芳基,其中所述Rb中的C1-C4烷基、C3-C10环烷基、C1-C10烷氧基、C6-C10芳基为无取代或被选自卤素、羟基、氰基中的一个或多个取代;
环A为五元杂芳环,其中,X、Y、Z中至多一个为CR4,其余各自独立地选自N、NR5、O、S;
R4、R5各自独立地选自H、D、卤素、氨基、C1-C6烷基、C3-C6环烷基;或者,R4、R5各自独立地选自H、D、卤素、氨基、C1-C6烷基、C3-C6环烷基;所述C1-C6烷基、C3-C6环烷基为无取代或被羟基取代。
在一些实施方式中,R1选自C1-C6烷基、C3-C7环烷基、3-6元杂环烷基、-ORa、NRaRa2;所述C1-C6烷基、C3-C7环烷基、3-6元杂环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C7环烷基、无取代或被一个或多个选自A组的取代基取代的C1-C6烷基,所述A组取代基包括:D、卤素、C1-C3烷氧基、羟基、C6-C10芳基、5-10元杂芳基、无取代或被一个或多个选自A2组的取代基取代的C3-C10环烷基;所述A2组取代基包括:D、卤素、羟基、C1-C6烷基、C1-C6烷氧基。
在一些实施方式中,R1选自C1-C6烷基、C3-C7环烷基、3-6元杂环烷基、-ORa、-SRa、NRaRa2;所述C1-C6烷基、C3-C7环烷基、3-6元杂环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C7环烷基、无取代或被一个或多个选自A组的取代基取代的C1-C6烷基,所述A组取代基包括:D、卤素、C1-C3烷氧基、羟基、C6-C10芳基、5-10元杂芳基、无取代或被一个或多个选自A2组的取代基取代的C3-C10环烷基;所述A2组取代基包括:D、卤素、羟基、C1-C6烷基、C1-C6烷氧基。
在一些实施方式中,R2、R3各自独立地选自无取代或取代的C3-C10环烷基、无取代或取代的C6-C10芳基、无取代或取代的5-10元杂芳基,所述取代是指被一个或多个选自B组的取代基所取代;所述B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、氧代基、无取代或取代的4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、羟基、C3-C6环烷基、4-6元杂环烷基、C1-C4烷氧基;特别地,所述5-10元杂芳基选自苯并5元杂芳基、苯并6元杂芳基、6元杂芳基并5元杂芳基、6元杂芳基并6元杂芳基、
在一些实施方式中,R1选自C2-C6烷基、C3-C6环烷基、-ORa、NRaRa2;其中所述C2-C6烷基、C3-C6环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C6环烷基、无取代或被一个或多个选自A组的取代基取代的C2-C6烷基,A组取代基包括:D、卤素、甲氧基、羟基、C3-C6环烷基。
在一些实施方式中,R1选自C2-C6烷基、C3-C6环烷基、-ORa、-SRa、NRaRa2;其中所述C2-C6烷基、C3-C6环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C6环烷基、无取代或被一个或多个选自A组的取代基取代的C2-C6烷基,A组取代基包括:D、卤素、甲氧基、羟基、C3-C6环烷基。
在一些实施方式中,R2和R3各自独立地选自无取代或取代的环己基、无取代或取代的苯基、无取代或取代的5-10元杂芳基,所述5-10元杂芳基选自如下结构:
所述无取代或取代的苯基、无取代或取代的5-10元杂芳基中取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基。
所述无取代或取代的苯基、无取代或取代的5-10元杂芳基中取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基。
在一些实施方式中,R2和R3各自独立地选自无取代或取代的环己基、无取代或取代的苯基、无取代或取代的5-10元杂芳基,所述5-10元杂芳基选自如下结构:
所述无取代或取代的苯基、无取代或取代的5-10元杂芳基中取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基。
所述无取代或取代的苯基、无取代或取代的5-10元杂芳基中取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基。
在一些实施方式中,R5在每次出现时独立地为H、D、C1-C3烷基或C3-C6环烷基;或者R5在每次出现时独立地为H、D、C1-C3烷基或C3-C6环烷基,所述C1-C3烷基、C3-C6环烷基为无取代或被羟基取代。
在一些实施方式中,R1选自-ORa和NHRa。
在一些实施方式中,R1选自C2-C6烷基、-ORa和NHRa。
在一些实施方式中,Ra选自C3-C6环烷基、无取代或被一个或多个选自A组的取代基所取代的C2-C6烷基;A组取代基包括:D、卤素、甲氧基、羟基、C3-C6环烷基。
在一些实施方式中,R2和R3各自独立地选自:
或者,R2和R3各自独立地选自:
其中,(R7)m表示在所在环上有m个相同或不同的R7取代基;m为1、2或3;R6和每个R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基,C1-C4烷氧基;优选地,m为1或2;R6和每个R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C2烷基、无取代或卤素取代的环丙基、无取代或卤素取代的C1-C2烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基,C1-C4烷氧基。
在一些实施方式中,R5在每次出现时独立地为H或甲基。
在一些实施方式中,R5在每次出现时独立地为H、甲基或羟乙基。
在一些实施方式中,R1选自-ORa、NHRa;Ra选自C3-C6环烷基、无取代的C2-C4烷基、卤素取代的C2-C4烷基、环丙基取代的C2-C4烷基、甲氧基取代的C2-C4烷基、羟基取代的C2-C4烷基。
在一些实施方式中,R1选自C2-C6烷基、-ORa、-SRa、NHRa;Ra选自C3-C6环烷基、无取代的C2-C4烷基、卤素取代的C2-C4烷基、环丙基取代的C2-C4烷基、甲氧基取代的C2-C4烷基、羟基取代的C2-C4烷基。
在一些实施方式中,R2和R3各自独立地选自:
在一些实施方式中,R2和R3各自独立地选自:
在一些实施方式中,m为1、2或3;R6和R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基。
在一些实施方式中,m为1、2或3;R6和R7各自独立地选自:H、卤素、氰基、羟基、巯基、硝基、氨基、无取代或被一个或多个选自C组的取代基取代的C1-C3烷基、无取代或卤素取代的环丙基、无取代或卤素取代的C1-C2烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、甲氧基、
在一些实施方式中,R1选自-OC2H5、-OCH2CF3、-NHCH3、-NHC2H5、
在一些实施方式中,R1选自丙基、-OC2H5、-SC2H5、-OCH2CF3、-NHCH3、-NHC2H5、
在一些实施方式中,R2选自
或者,R2选自
其中,m为1、2或3;R8和R9各自独立地选自H、卤素、CN、甲氧基、被一个或多个卤素取代的甲基、被一个或多个卤素取代的甲氧基、环丙基;优选地,R2选自或者,R2选自其中,R8和R9各自独立地选自H、卤素、氰基、甲氧基、被一个或多个卤素取代的甲基、被一个或多个卤素取代的甲氧基、环丙基;
R3选自
或者,R3选自
其中,m为1、2或3;R10和R11各自独立地选自氢、甲基、乙基、异丙基、氰基、甲氧基、羟基取代
的乙基、甲氧基取代的乙基、环丙基、
在一些实施方式中,所述的式(I)化合物选自如下结构:
其中,R1、R2、R3、R4、R5同前所定义。
在一些实施方式中,所述的式(I)化合物选自如下结构:
其中,R1、R2、R3、R5同前所定义。
在一些实施方式中,式(I)所示的化合物选自如下结构:
本发明的第二个方面,提供了一种药物组合物,包含治疗有效剂量的选自式(I)所示的化合物、其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,和至少一种药学上可接受的载体。所述药物组合物还可以任选地包含一种或多种其它治疗剂。
在本发明的一个实施方案中,本发明提供组合,尤其是药物组合,其包含治疗有效剂量的选自式(I)所示的化合物、其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异
构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,及一种或多种其它治疗剂。
本发明的化合物可以单独地、与其它的本发明的化合物组合地或与一种或多种、优选一种或两种其它治疗剂组合地同时或依次使用。
本发明的第三个方面,提供式(I)所述的化合物或其可药用的盐、其对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物中、或所述药物组合物在制备用于抑制MAT2A活性的药物中的用途。
本发明的第四个方面,提供式(I)所述的化合物或其可药用的盐、其对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物中的一种或多种或所述药物组合物在制备治疗和/或预防MTAP相关疾病,特别是肿瘤的药物中的用途。
优选地,所述肿瘤包括:MTAP缺失的肿瘤;MTAP低表达的肿瘤;MAT2A异常表达的肿瘤;其他MAT2A依赖的肿瘤。
具体地,所述肿瘤包括:乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
在本发明的一个实施方案中,本发明提供了治疗或预防MAT2A相关疾病,特别是肿瘤的方法,该方法包括给有需要的个体施用有效量的选自本发明的化合物、其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,或者本发明的药物组合物。在一些实施方案中,该方法还包括给有需要的个体施用有效量的第二种治疗剂,所述第二种治疗剂是一种或多种其它治疗剂。
另外,本发明提供了产品或试剂盒,其包含选自如上定义的本发明的化合物、其可药用盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,或本发明的药物组合物。所述试剂盒还可以包含一种或多种其它治疗剂,从而构成在抗癌疗法中同时、分开或依次使用的联合制剂。
术语说明
在本发明中,除非另外明确地说明,本发明所使用的术语具有下面所定义的含义。本发明未明确定义的术语具有本领域技术人员所普遍理解的一般含义。
在本发明的上下文中(尤其在权利要求的上下文中)使用的单数术语应被理解为包括复数含义,除非文中另外特别指出或根据上下文明显矛盾。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如,-O(C1-C3烷基)表示该基团通过氧原子与分子的其余部分连接。然而,当取代基的连接位点对本领域技术人员来说是显而易见的时候,例如对于卤素、羟基等取代基而言,“-”可以省略。
如本文所用,“杂原子”指氮(N)、氧(O)或硫(S)原子,特别是氮或氧,其各自可以是取
代或未取代的,包括其氧化形式。杂原子的实例包括但不限于-O-、-N=、-NR-、-S-、-S(O)-和-S(O)2-,其中R是氢、C1-C4烷基或氮保护基(例如苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。任何具有未满足的价键的杂原子被认为具有足以满足价键的氢原子,另有指示除外。
如本文所用,“卤素”或“卤代”指氟、氯、溴和碘。优选的作为取代基的卤素是氟和氯。
如本文所用,“烷基”指完全饱和的直链或支链的一价烃基团。烷基优选包含1-20个碳原子,更优选1-16个碳原子、1-10个碳原子、1-8个碳原子、1-6个碳原子、1-4个碳原子或1-3个碳原子。烷基前的数字表示碳原子的个数。例如,“C1-C6烷基”表示具有1-6个碳原子的烷基,“C1-C4烷基”表示具有1-4个碳原子的烷基,“C1-C3烷基”表示具有1-3个碳原子的烷基,依此类推。烷基的代表性示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。无论术语“烷基”单独出现,还是作为其它基团如卤代烷基、烷氧基等的一部分出现,均适用该定义。
如本文所用,“烯基”指包含至少一个双键的直链或支链的一价烃基团。烯基优选包含2-20个碳原子,更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。烯基前的数字表示碳原子的个数。烯基的代表性示例包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、庚烯基、辛烯基等。
如本文所用,“炔基”指包含至少一个叁键的直链或支链的一价烃基团。炔基优选包含2-20个碳原子,更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。炔基前的数字表示碳原子的个数。炔基的代表性示例包括但不限于乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基、异戊炔基、己炔基、庚炔基、辛炔基等。
如本文所用,“烷氧基”指通过氧桥连接的如本文所定义的烷基,即,烷基-O-基团,烷氧基前的数字表示碳原子的个数。例如,“C1-C6烷氧基”表示具有1-6个碳原子的烷氧基,即-O-C1-6烷基;“C1-C4烷氧基”表示具有1-4个碳原子的烷氧基,即-O-C1-4烷基;“C1-C3烷氧基”表示具有1-3个碳原子的烷氧基,即-O-C1-3烷基。烷氧基的代表性示例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。
如本文所用,“环烷基”指饱和或部分饱和的非芳香族碳环,包括单-、双-或三环,优选具有3-12个环碳原子,更优选3-10个环碳原子,例如3-8个、3-7个、3-6个、4-10个、或4-8个环碳原子。"C3-C8环烷基"意欲包括C3、C4、C5、C6、C7和C8环烷基基团;"C3-C6环烷基"意欲包括C3、C4、C5和C6环烷基基团。示例性的单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。示例性的二环环烷基包括冰片基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。示例性的三环环烷基包括金刚烷基等。
如本文所用,“卤代烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素替代的如本文所定义的烷基,并且当超过一个氢原子被卤素原子替代时,所述卤素原子可以彼此相同或不同。例如“C1-C4卤代烷基”意欲包括C1、C2、C3和C4卤代烷基基团,“C1-C3卤代烷基”意欲包括C1、C2和C3卤代烷基基团。卤代烷
基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、1,1-二氟乙基、1,1,-二氟丙基和1,1,1-三氟丙基。卤代烷基的实例还包括“氟烷基”,后者意欲包括其中一个或多个氢原子被氟原子取代的如本文定义的烷基。本文“卤代烷基”优选为烷基中至多三个氢原子被卤素替代。
如本文所用,“卤代烷氧基”表示通过氧桥连接的具有指定碳原子数的如上定义的卤代烷基,其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素替代。例如,“C1-C6卤代烷氧基”或“C1至C6卤代烷氧基”意欲包括C1、C2、C3、C4、C5和C6卤代烷氧基基团。卤代烷氧基的实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2,2,2-三氟乙氧基。卤代烷氧基的实例还包括“氟烷氧基”。
如本文所用,“芳基”是由一个环或多个环稠合构成的具有6-20个、优选6-14个、更优选6-12个、最优选6-10个。具有6-10个环碳原子的芳基,即C6-C10芳基,其包括:单环芳基(例如苯基);或稠合二环系统,其中一个环是芳族环、而另一个环是芳族(例如在萘、联苯基中)或非芳族环(例如在二氢茚、四氢萘中)。芳基的非限制性示例包括苯基、联苯基、萘基、四氢萘基、茚基、二氢茚基或蒽基等。
如本文所用,“杂芳基”指含有1-4个、优选1-3个选自N、O或S的环杂原子的5-14元、优选5-10元、更优选5-7元或5-6元芳香族环系,包括单环或二环或稠合多环,其余环原子为碳原子。杂芳基的实例包括但不限于:吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、三唑基、噻唑基、异噻唑基、噁唑基、吡啶基、吡喃基、吡嗪基、哒嗪基、嘧啶基、噁嗪基、噁二嗪基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、2H-色烯、苯并吡喃基、苯并噻吩基、吲哚基、吲唑基、苯并吡唑、苯并咪唑基、咪唑并吡啶基、苯并噁唑基、苯并噻唑基、7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基、1H-苯并[d][1,2,3]三唑基、[1,2,4]三唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶、吡唑并[1,5-a]吡啶等。
如本文所用,“杂环烷基”指如本申请中所定义的环烷基中的一个或多个环碳被选自N、O或S的杂原子替换所得的基团,所述杂原子例如是-O-、-N=、-NR-、-S-、-S(=O)-和-S(=O)2-,其中R是氢、C1-4烷基或氮保护基(例如,苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。优选地,杂环烷基是具有3-20个环原子、例如3-12个环原子、例如3-8个环原子、例如3-6个环原子的单环、二环或三环的饱和和部分不饱和非芳族环。更优选地,杂环烷基优选含有1、2或3个选自N、O或S的杂原子的4-至12-元杂环烷基,优选4-至8-元杂环烷基、更优选是4-至7-元、4-至6元或5-至6-元杂环烷基,其中所述杂原子是取代或未取代的,例如被C1-C4烷基取代。例如,杂环烷基的实例包括但不限于:环氧乙烷基、氮丙啶基、氮杂环丁烷基、氧杂环丁烷基、氮杂环戊烷基(吡咯烷基)、四氢呋喃基、四氢噻吩基、四氢噻吩基1,1-二氧化物、吡唑烷基、咪唑烷基、噁唑烷基、噻唑烷基、异噻唑烷基、吡咯烷基-2-酮、咪唑酮基、哌啶基(六氢吡啶)、N-甲基哌啶基、四氢吡喃基、噁嗪烷基、1,3-噁嗪烷基、六氢嘧啶基、哌嗪基、哌啶酮基(piperidinylone)、1,4-二氧杂-8-氮杂-螺[4.5]癸烷-8-基、吗啉代基、硫吗啉代基、硫代吗啉代-S-单氧化物(sulfanomorpholino)、硫代吗啉代-S,S-二氧化物(sulfonomorpholino)、八氢吡咯并[3,2-b]吡咯基等。
如本文所用,术语“氧代基”是指氧原子通过双键与其它原子连接,可表示为“=O”。
术语“-C(=O)”为羰基,“-S(=O)”为亚砜基、“-S(=O)2”为砜基。
本文所用的“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生,并且该描述包括所述事件发生的情形以及所述事件不发生的情形。例如,“任选被取代的烷基”包括本文定义的“未取代的烷基”和“被取代的烷基”。“任选被卤素取代”包括“被卤素取代”的情形和“未被卤素取代”的情形,例如被0-3个卤素取代。本领域技术人员应当理解的是,对于含有一个或多个取代基的任意基团而言,所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
本文所用的术语“取代”、“取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换,条件是不超过该给定原子的正常化合价。当取代基是氧代(即=O)时,则单个原子上的两个氢原子被氧替换。在芳香族部分上不存在氧代取代基。当环系(例如碳环或杂环)被羰基基团或双键取代时,意欲羰基基团或双键是环的一部分(即,在环内)。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时,这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定,以至于能从反应混合物中被分离出来并能确定化合物的化学结构,并且随后能被配制成至少具有实际效用的制剂。例如,在没有明确列出取代基的情况下,本文所用的术语“取代”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。
除非另有指出,否则术语“本发明化合物”或“本发明的化合物”指包括本发明的一种或多种本文定义的式(I)或其亚式,如式(I-1)、(I-2)、(I-1-1)、(I-2-1)、(I-3-1)等的化合物,或其可药用盐,以及所有异构体如立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、互变异构体、异构体的内部加成产物、前药以及同位素标记的化合物(包括氘取代)和固有形成的部分(例如多晶型物、溶剂合物和/或水合物)。当存在能够形成盐的部分时,则也包括盐、特别是可药用盐。互变异构体或异构体的内部加成产物的存在可由本领域技术人员使用诸如NMR的工具来鉴别。本发明的式(I)化合物能够容易地形成如本文所描绘的互变异构体和异构体的内部加成产物。
本领域技术人员将认可,本发明的化合物可以含有手性中心,照此可以存在不同的异构形式。如本文所用的“异构体”指具有相同分子式、但是原子的排列和构型有区别的不同化合物。
如本文所用,“对映异构体”是相互为不可重叠的镜像的一对立体异构体。一对对映异构体的1:1混合物是"外消旋”混合物。合适时,该术语用于指外消旋混合物。当指示本发明的化合物的立体化学时,采用常规的RS系统指定了具有两个手性中心的已知的相对和绝对构型的单一立体异构体(例如(1S,2S));具有已知的相对构型、但是绝对构型未知的单一立体异构体标示了星号(例如(1R*,2R*));具有两个字母的外消旋物(例如(1RS,2RS)为(1R,2R)和(1S,2S)的外消旋混合物;(1RS,2SR)为(1R,2S)和(1S,2R))的外消旋混合物。"非对映异构体”是具有至少两个不对称原子、但是相互不为镜像的立体异构体。根据Cahn-lngold-Prelog R-S系统指明绝对立体化学。当化合物是纯的对映异构体时,各手性碳处的立体化学可以通过R或S说明。绝对构型未知的被拆分的化合物可以根据它们在钠D线波长处旋转平面偏振光的
方向(右旋或左旋)指定为(+)或(-)。或者,被拆分的化合物可以通过相应的对映异构体/非对映异构体经由手性HPLC的各自的保留时间来定义。
本文所述的一些化合物含有一个或多个不对称中心或轴,因此可以产生对映异构体、非对映异构体和可以以绝对立体化学定义为(R)-或(S)-的其它立体异构体。
当化合物含有双键或一些其它的使得分子具有一定量结构刚性的特征时,可以发生几何异构体。如果化合物含有双键,则取代基可以是E或Z构象。如果化合物含有二取代的环烷基,则环烷基取代基可以具有顺式或反式构型。
构象异构体是通过有关一个或多个价键的旋转而不同的异构体。旋转异构体是通过仅单个价键的旋转而不同的构象异构体。
"阻转异构体"指基于分子中的旋转受限所产生的轴向或平面手性的结构异构体。
除非另有说明,否则本发明的化合物意欲包括所有这类可能的异构体,包括外消旋混合物、具有旋光活性的形式和中间体混合物。具有旋光活性的(R)-和(S)-异构体可以采用手性合成子或手性试剂进行制备,或者采用常规技术进行拆分。
本发明的化合物可以分离为具有旋光活性的形式或外消旋形式。用旋光活性的形式可以通过外消旋形式的拆分或通过由具有旋光活性的原料合成来制备。用于制备本发明的化合物的所有方法和其中制备的中间体被认为是本发明的一部分。当制备对映体或非对映异构体产物时,它们可以通过常规方法如通过色谱法或分步结晶来进行分离。
根据方法条件,本发明的终产物以游离(中性)或盐形式获得。这些终产物的游离形式和盐形式在本发明的范围内。如果期望的话,则化合物的一种形式可以转化为其它形式。游离碱或酸可以转化为盐;盐可以转化为游离化合物或其它盐;本发明的同分异构化合物的混合物可以分离为单独异构体。
如本文所用,“可药用盐”指保持本发明化合物的生物学效应和性能的盐,并且该盐在生物学上或其它方面不是不被期望的。所述盐的非限制性示例包括本发明化合物的无毒的、无机或有机碱或酸的加成盐。在许多情况下,由于氨基和/或羧基或与之相似的基团的存在,本发明化合物能够形成酸盐和/或碱盐。可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。可以用无机和有机碱形成药学上可接受的碱加成盐。可以由其衍生得到盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等;特别优选的是铵、钾、钠、钙和镁盐。可以由其衍生得到盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状的胺、碱性离子交换树脂等,尤其例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。通过常规化学方法,可以从母体化合物(碱性或酸性部分)合成本发明可药用盐。一般来讲,可以如下制备所述的盐:使所述化合物的游离酸形式与化学计算量的适当的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或使所述化合物的游离碱形式与化学计算量的适当的酸反应。这类反应通常在水或有机溶剂或两者的混合溶剂中进行。一般来讲,在可行时,非水介质例如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。其它合适的盐可以见于Remington氏药物科学(Remington's Pharmaceutical Sciences),第
20版,Mack出版公司(Mack Publishing Company),Easton,Pa.,(1985),将其引入文中作为参考。
如本文所用,“药学上可接受的赋形剂”包括任何和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料、所述类似的物质和其组合,其是本领域普通技术人员所公知的(见,例如,Remington氏药物科学(Remington's Pharmaceutical Sciences),第18版,Mack出版公司(Mack Printing Company),1990,pp.1289-1329,引入文中作为参考)。除非任何常规载体是与活性成分不能共存的,可以考虑在治疗或药物组合物中使用它。
本文所给的任意式还意欲代表化合物的未标记的形式以及同位素标记的形式。除了一个或多个原子被具有所选原子质量或质量数的原子所代替外,同位素标记的化合物具有本文所给的式所描述的结构。可以掺入到本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别有2H(即D)、3H(即T)、11C、13C、14C、15N、18F31P、32P、35S、36Cl、125I。本发明包括如本文定义的不同的同位素标记的化合物,例如其中存在放射性同位素如3H、13C和14C的那些。这类同位素标记的化合物可用于代谢研究(用14C)、反应动力学研究(例如用2H或3H)、检测或显像技术、例如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)、包括药物或底物组织分布测定,或者可用于个体的放射性治疗。特别地,18F或标记的化合物可以特别希望用于PET或SPECT研究。通常可以通过进行下文所述的流程中或实施例和制备例中所述的那些方法、用容易获得的同位素标记的试剂代替未同位素标记的试剂来制备同位素标记的本发明的化合物。
而且,被较重同位素、特别是氘(即2H或D)所取代还可以获得由更大的代谢稳定性引起的某些治疗益处,例如延长体内半衰期或降低剂量要求或改善治疗指数。可以理解,上下文中的氘可被看作是本发明的化合物的取代基。这类较重同位素、特别是氘的浓度可由同位素富集因子来定义。“同位素富集因子”表示指定同位素的同位素丰度和天然丰度之间的比值。
如本文所用,本发明化合物的“治疗有效量”指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本发明化合物的量。“治疗有效量”可以由参与医师或兽医执业者来确定,并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。
如本文所用,“个体”指动物。优选地,动物是哺乳动物。个体还指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一优选实施方案中,个体是人。
如本文所用,“抑制”指特定的病患、症状或病症或疾病的减轻或抑制,或者生物学活性或过程基线活性的显著降低。
如本文所用,在一个实施方案中术语"治疗"任何疾病或病症指改善疾病或病症(即阻止或减缓疾病或其至少一种临床症状的发展)。在另一个实施方案中,“治疗”指改善至少一种身体参数,其可能不为患者所察觉。在另一个实施方案中,“治疗"指身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。
如本文所用,“预防”指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特
别是本发明的化合物和/或其可药用盐,用以防止个体罹患该疾病。
一般而言,术语“约”在本文中用于将所给出的数值调整至高于或低于该数值20%、例如10%、例如5%。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
实施例
以下实施例说明上述本发明,然而其不以任何方式限制本发明的范围。本发明的组合的有益效果也可以通过本领域技术人员已知的其他测试模型确定。
本发明中,所用试剂、设备的来源和商品名,均在首次出现时标明,其后所用相同试剂如无特殊说明,均与首次标明的内容相同,常规未标注试剂购自国药集团化学试剂有限公司。
缩写含义:
DIPEA:N,N-二异丙基乙胺;SEMCl:2-(三甲硅烷基)乙氧甲基氯;TBAF:四丁基氟化铵;NBS:N-溴代琥珀酰亚胺;Tf:三氟甲磺酰基;FA:甲酸;BSA:牛血清白蛋白;Brij 35:聚氧乙烯月桂醚;Pd(dppf)Cl2:1,1'-双二苯基膦二茂铁二氯化钯;NBS:N-溴代丁二酰亚胺;PE:石油醚;EA:乙酸乙酯。
实施例1:化合物1的合成
第一步:中间体2-1的合成
在100mL单口瓶中,将5-氨基吡唑1-1(8.3g,100mmol)溶于冰乙酸(AcOH)(80mL),常温搅拌下加入丙炔酸甲酯(8.4g,100mmol),回流反应过夜。将反应液浓缩至干,向反应液中加入EA(150ml),继续搅拌1.5h,过滤,得到中间体2-1(4.5g,收率:33.3%),黄色固体。LCMS(ESI)m/z=136.2[M+H]+.
第二步:中间体3-1的合成
在100mL单口瓶中,将中间体2-1(3.8g,28.1mmol)溶于乙酸(72.0mL),常温搅拌下加入液溴(18.0g,112.5mmol),反应3小时,反应完全。过滤,收集滤饼,滤饼用PE冲洗两次,得中间体3-1(4.0g,收率:66.7%),淡黄色固体。1H NMR(400MHz,DMSO)δ12.14(s,1H),9.82(s,2H),8.29(s,1H),8.03(s,1H).
第三步:中间体4-1的合成
在100mL单口瓶中,将中间体3-1(2.14g,100mmol)、DIPEA(2.84g,220mmol)溶于四氢呋喃(THF)(50mL),常温搅拌滴加SEMCl(2.0g,120mmol)后反应16h,将反应液倒入水中,用EA(100mL)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液浓缩,经硅胶快速柱纯化(0-30%
PE/EA),得中间体4-1(0.8g,收率:23.3%),蜡状固体。LCMS(ESI)m/z=346.0[M+H]+.
第四步:中间体5-1的合成
将中间体4-1(0.8g,2.32mmol)、4-甲氧基苯硼酸频哪醇酯(1.085g,4.64mmol)、Pd(PPh3)4(536mg,0.464mmol)、碳酸钾(640mg,4.64mmol)、1,4-二氧六环(25ml)、水(5ml)依次投入50mL单口瓶中,N2保护下110℃搅拌16h。将反应液过滤,滤液浓缩后经硅胶快速柱纯化(0-50%PE/EA),得800mg中间体5-1粗品,白色固体。取400mg经prep-HPLC分离纯化(H2O/ACN,0.1%甲酸),得中间体5-1(50mg,收率:11.6%)。LCMS(ESI)m/z=372.1[M+H]+.
第五步:中间体6-1的合成
将中间体5-1(40mg,0.10mmol)、5-溴-2-甲基-2H-吲唑(44mg,0.2mmol)、反式N,N’-二甲基环己二胺(3mg,0.02mmol)、碘化亚铜(4mg,0.02mmol)、磷酸钾(44mg,0.2mmol)、二甲亚砜(DMSO)(5ml)依次投入50mL单口瓶中,氮气保护下110℃搅拌16h。将反应液浓缩至干,经硅胶快速柱纯化(0-3%甲醇(MEOH)/二氯甲烷(DCM)),得中间体6-1(21mg,收率:38.9%),白色固体。LCMS(ESI)m/z=502.4[M+H]+.
第六步:化合物1的合成
将中间体6-1(21mg,0.057mmol)、TBAF四氢呋喃溶液(5ml,5mmol)依次投入25mL单口瓶中,N2保护下60℃搅拌16h。将反应液浓缩至干,经prep-TLC制备(DCM/THF=1/1),得到化合物1(3mg,收率:19.4%),白色固体。1H NMR(400MHz,DMSO)δ12.07(s,1H),8.77(s,1H),8.46(s,1H),8.14(s,1H),7.85(s,1H),7.81(d,J=9.4Hz,1H),7.75(d,J=9.1Hz,1H),7.60(d,J=8.1Hz,2H),6.97(d,J=7.8Hz,2H),4.20(s,3H),3.79(s,3H).LCMS(ESI)m/z=372.2[M+H]+.
实施例2:化合物2的合成
第一步:中间体2-2的合成
在100mL单口瓶中,将3-氨基-4-乙氧羰基吡唑(40g,258mmol)用THF(500mL)溶解,温度降至0℃,加入DIPEA(40g,310mmol),搅拌15min,向反应液中滴加SEMCl(51.5g,310mmol),滴完室温搅拌12h。将反应液倒入1L冰水混合物中,用EA萃取,合并有机相,用水、饱和食盐水依次洗涤一次(200mL/次),无水硫酸钠干燥、过滤,滤液浓缩后用硅胶快速柱纯化(EA/PE=1/2),得到中间体2-2(55g,收率:74.8%),淡黄色油状液体。LCMS(ESI)m/z=286.2[M+H]+.
第二步:中间体3-2的合成
在500mL单口瓶中,将中间体2-2(54g,189.5mmol)溶于乙醇(250mL),室温搅拌同时加入丙二酸二乙酯(113.6g,709.5mmol),加完降至0℃,缓慢滴加20%乙醇钠(NaOEt)的乙醇溶液(192.9g,567mmol),滴加完毕,N2保护下升温至95℃,搅拌18小时。将反应液减压浓缩干,加入200mL冰水,用甲醇/DCM(1/10)萃取,合并有机相,用水、饱和食盐水依次洗涤,无水硫酸钠干燥、过滤,滤液浓缩干,用硅胶柱纯化(DCM/MeOH=30/1),得到中间体3-2(50g,收率:75.9%),淡黄色固体。LCMS(ESI)m/z=354.2[M+H]+.
第三步:中间体4-2的合成
在500mL单口瓶中,将中间体3-2(50g,141mmol)溶于15%氢氧化钠水溶液(350mL),升温至105℃反应15小时。将反应液用冰水浴降至0℃,用4M稀盐酸将pH调至5左右,过滤,得到白色的固体,硅胶快速柱纯化(DCM/MeOH=10:1),得到中间体4-2(30.8g,收率:77.4%),白色固体。LCMS(ESI)m/z=282.1[M+H]+.
第四步:中间体5-2的合成
在100mL单口瓶中,将中间体4-2(30.8g,109.5mmol)溶于二甲基甲酰胺(DMF)(200mL),加入三乙胺(TEA)(33.2g,328.5mmol),接着分批加入N-苯基双三氟甲基磺酰亚胺(46.9g,131.4mmol),室温反应16小时。将反应液倒入1L冰水,EA萃取,合并有机相,用水、饱和食盐水各洗涤一次(100mL/次),无水硫酸钠干燥、过滤,滤液减压浓缩后经硅胶快速柱纯化(PE/EA=2:1),得到中间体5-2(10.1g,收率:22.3%),白色固体。1H NMR(400MHz,DMSO)δ12.41(s,1H),8.60(s,1H),6.41(s,1H),5.55(s,2H),3.66-3.55(m,2H),0.93-0.84(m,2H),0.01-0.02(m,9H).
第五步:中间体6-2的合成
在25mL单口瓶中,将中间体5-2(5.0g,12.1mmol)溶于DMF(25mL),加入TEA(1.35g,13.3mmol),再缓慢滴加乙胺四氢呋喃溶液(13.3ml,26.6mmol,2M),滴完室温搅拌过夜。将反应液倒入250mL冰水,EA萃取,合并有机相,用水、饱和食盐水各洗涤一次(50mL/次),无水硫酸钠干燥、过滤,滤液减压浓缩后经硅胶快速柱纯化(DCM/MeOH=40/1),得到中间体6-2(1.1g,收率:29.5%),白色固体。1H NMR(400MHz,DMSO)δ10.63(s,1H),8.21(s,1H),6.90(t,J=5.2Hz,1H),5.43(d,J=4.0Hz,2H),4.88(d,J=5.6Hz,1H),3.57(t,J=8.2Hz,2H),3.15(d,J=4.4Hz,2H),1.24(t,J=7.2Hz,3H),0.89(t,J=8.0Hz,2H),0.02(s,9H).
第六步:中间体7-2的合成
在25mL单口瓶中,将中间体6-2(1.1g,3.57mmol)溶于THF(15mL),加入NBS(634mg,3.57mmol),室温反应2h。将反应液倒入冰水中,用DCM/甲醇(10/1)萃取,合并有机层,用水、饱和食盐水各洗涤一次(20mL/次),无水硫酸钠干燥、过滤,滤液减压浓缩得粗品,经硅胶快速柱纯化(DCM/MeOH=25/1),得中间体7-2(1.1g,收率:79.6%),白色固体。1H NMR(400MHz,DMSO)δ11.31(s,1H),8.62(s,1H),6.36(t,J=6.0Hz,1H),5.48(s,2H),3.67-3.55(m,4H),1.27(t,J=7.2Hz,3H),0.90(t,J=8.0Hz,2H),0.01(s,9H).
第七步:中间体8-2的合成
将中间体7-2(1.0g,2.58mmol)、4-甲氧基苯硼酸频哪醇酯(1.2g,5.16mmol)、Pd(dppf)Cl2(209mg,0.258mmol)、碳酸钾(712mg,5.16mmol)、1,4-二氧六环(25ml)、水(5ml)依次投入50mL单口瓶中,N2保护下升温至100℃搅拌16h。将反应液浓缩至干,粗品经硅胶快速柱纯化(DCM/甲醇=30/1),得中间体8-2(550mg,收率:51.4%),白色固体。1H NMR(400MHz,DMSO)δ10.90(s,1H),8.49(s,1H),7.12(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,2H),5.45(s,2H),5.21(t,J=6.0Hz,1H),3.80(s,3H),3.60(dd,J=10.8,5.3Hz,2H),3.33-3.28(m,2H),1.07(t,J=7.2Hz,3H),0.92-0.87(m,2H),0.01(s,9H).
第八步:中间体9-2的合成
将中间体8-2(200mg,0.48mmol)、5-溴-2-甲基-2H-吲唑(204mg,0.96mmol)、反式N,N’-二甲基环己二胺(7mg,0.048mmol)、碘化亚铜(9mg,0.048mmol)、磷酸钾(204.5mg,1mmol)、DMSO(25ml)依次投入50mL单口瓶中,N2保护下升温至130℃搅拌16h。将反应液倒入冰水中,用DCM/甲醇(10/1)萃取,合并有机层,用水、饱和食盐水各洗涤一次(25mL/次),无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶快速柱纯化(DCM/MeOH=30/1),得中间体9-2(100mg,收率:38.3%),白色固体。LCMS(ESI)m/z=545.2[M+H]+.
第九步:化合物2的合成
在25mL单口瓶中,将中间体9-2(100mg,1.83mmol)溶于4M的HCl/1,4-二氧六环溶液(15mL),室温反应2h。将反应液倒入冰水中,用碳酸氢钠水溶液将pH调至中性。用DCM/甲醇(10/1)萃取,合并有机相,用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,滤液减压浓缩后经prep-HPLC纯化(H2O/CAN,0.1%FA),冷冻干燥得化合物2(31.77mg,收率:41.8%),白色固体。1H NMR(400MHz,DMSO)δ13.03(s,1H),8.35(s,2H),7.60(d,J=13.2Hz,2H),7.16(d,J=8.8Hz,2H),7.07(dd,J=9.2,2.0Hz,1H),6.95(d,J=8.8Hz,2H),5.27(s,1H),4.19(s,3H),3.77(s,3H),3.36(m,2H),1.09(t,J=7.2Hz,3H).LCMS(ESI)m/z=415.2[M+H]+.
采用实施例2的合成方法,制备化合物5、6、7、9、10、11、16。
实施例3:化合物4的合成
第一步:中间体2-4的合成
在25mL高压釜中,将4-2(2.5g,8.9mmol)溶于甲胺的THF溶液(25mL,2M),升温至100℃反应过夜。将反应液直接浓缩得粗品,经硅胶快速柱纯化(0-2%甲醇/DCM),得中间体2-4(1.0g,收率:38.3%),白色固体。1H NMR(400MHz,DMSO)δ10.64(s,1H),8.14(s,1H),7.05(d,J=4.8Hz,1H),5.44(s,2H),4.86(s,1H),3.61-3.54(m,2H),2.78(d,J=4.8Hz,3H),0.93-0.85(m,2H),-0.00(s,9H).
第二步:中间体3-4的合成
在25mL单口瓶中,将中间体2-4(1.0g,3.4mmol)溶于THF(15mL),加入NBS(604mg,3.4mmol),室温搅拌2h。将反应液浓缩干得粗品,经硅胶快速柱纯化(0-3%甲醇/DCM),得中间体3-4(760mg,收率:60.3%),白色固体。LCMS(ESI)m/z=373.1[M+H]+.
第三步:中间体4-4的合成
将中间体3-4(373mg,1.0mmol)、4-甲氧基苯硼酸频那醇酯(468mg,2mmol)、Pd(dppf)Cl2(81mg,0.1mmol)、碳酸钾(276mg,2mmol)、1,4-二氧六环(15ml)、水(3ml)依次投入50mL单口瓶中,N2保护下90℃搅拌16h。将反应液过滤,滤液浓缩得粗品,经硅胶快速柱纯化(0-3%甲醇/DCM),得中间体4-4(180mg,收率:45%),白色固体。LCMS(ESI)m/z=401.2[M+H]+.
第四步:中间体5-4的合成
将中间体4-4(80mg,0.2mmol)、5-溴-2-甲基-2H-吲唑(84mg,0.4mmol)、反式N,N’-甲基环己二胺(3mg,0.02mmol)、碘化亚铜(8mg,0.04mmol)、磷酸钾(55mg,0.4mmol)、DMSO(6
ml)依次投入10mL微波管中,氮气保护下110℃微波反应3h。将反应液倒入水中,用50mL甲醇/DCM(1/10)萃取,合并有机层,用水、饱和食盐水洗涤,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶快速柱纯化(0-2%甲醇/DCM),得中间体5-4(75mg,收率:75.5%),白色固体。LCMS(ESI)m/z=531.3[M+H]+.
第五步:化合物4合成
在25mL单口瓶中,将中间体5-4(75mg,0.14mmol)溶于4mol/L的氯化氢二氧六环溶液(5mL),室温搅拌2h。将反应液倒入10mL水中,用碳酸氢钠水溶液调pH至中性。用50mLDCM/甲醇(10/1)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液减压浓缩至干,经prep-HPLC纯化(水/乙腈,0.1%NH3.H2O),冷冻干燥后得化合物4(6.83mg,收率:12.1%),白色固体。1H NMR(400MHz,DMSO)δ13.02(s,1H),8.36(s,2H),7.61(d,J=12.0Hz,2H),7.15(d,J=8.4Hz,2H),7.06(dd,J1=9.2Hz,J2=2.0Hz,1H),6.94(d,J=8.4Hz,2H),5.61(s,1H),4.19(s,3H),3.77(s,3H),2.99(d,J=4.4Hz,3H).LCMS(ESI)m/z=401.1[M+H]+.
实施例4:化合物3的合成
第一步:中间体2-3的合成
在25mL单口瓶中,将4-2(2.0g,7.1mmol)溶于DMF(25mL),加入碳酸氢钠(1.2g,14.2mmol)、碘乙烷(EtI)(1.66g,10.7mmol),45℃反应过夜。将反应液倒入冰水中,用EA(100mL)萃取,合并有机层,用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶快速柱纯化(0-80%EA/PE),得到中间体2-3(0.2g,收率:9.1%),白色固体。1HNMR(400MHz,DMSO)δ11.37(s,1H),8.30(s,1H),5.52(s,1H),5.44(s,2H),4.17(q,J=7.2Hz,2H),3.62-3.55(m,2H),1.41(t,J=7.2Hz,3H),0.91-0.85(m,2H),-0.00(s,9H).
第二步:中间体3-3的合成
在25mL单口瓶中,将中间体2-3(0.2g,0.645mmol)溶于THF(15mL),加入NBS(120mg,0.677mmol),室温搅拌2h。将反应液倒入到水中,用50mL DCM/甲醇(10/1)萃取,有机层合并,用无水硫酸钠干燥、过滤,滤液浓缩干得粗品,经硅胶快速柱纯化(0-4%甲醇/DCM),得到中间体3-3(205mg,收率:82.3%),白色固体。1HNMR(400MHz,DMSO)δ12.01(s,1H),8.77(s,1H),5.49(s,2H),4.63(q,J=7.2Hz,2H),3.67-3.59(m,2H),1.44(t,J=7.2Hz,3H),0.94-0.85(m,2H),0.02--0.04(m,9H).
第三步:中间体4-3的合成
将中间体3-3(205mg,0.53mmol)、4-甲氧基苯硼酸频哪醇酯(247mg,1.06mmol)、Pd(dppf)Cl2(43mg,0.053mmol)、碳酸钾(146mg,1.06mmol)、1,4-二氧六环(15ml)、水(3ml)
依次投入50mL单口瓶中,N2保护下升温至100℃搅拌16h。将反应液过滤,收集滤液,减压浓缩得粗品,经硅胶快速柱纯化(0-2%甲醇/DCM),得中间体4-3(150mg,收率:68.5%),白色固体。1H NMR(400MHz,DMSO)11.62(s,1H),8.61(s,1H),7.24(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),5.47(s,2H),4.32(q,J=7.2Hz,2H),3.79(s,3H),3.65-3.57(m,2H),1.21(t,J=7.2Hz,3H),0.93-0.86(m,2H),-0.00(s,9H).LCMS(ESI)m/z=416.2[M+H]+.
第四步:中间体5-3的合成
将中间体4-3(130mg,0.31mmol)、5-溴-2-甲基-2H-吲唑(131mg,0.62mmol)、反式N,N’-甲基环己二胺(4.4mg,0.03mmol)、碘化亚铜(9mg,0.048mmol)、磷酸钾(131.0mg,0.62mmol)、DMSO(8ml)依次投入20mL微波管中,氮气保护下110℃微波反应3h。将反应液倒入水中,用50mL甲醇/DCM(1/10)萃取,合并有机层,水、饱和食盐水洗涤,无水硫酸钠干燥、过滤,滤液浓缩,经硅胶快速柱纯化(0-3%甲醇/DCM),得到中间体5-3(100mg,收率:58.8%),白色固体。LCMS(ESI)m/z=546.2[M+H]+.
第五步:化合物3的合成
在25mL单口瓶中,将中间体5-3(100mg,0.183mmol)溶于4mol/L的氯化氢二氧六环溶液(5mL),室温搅拌2h。将反应液倒入10mL水中,用碳酸氢钠水溶液调pH至中性。用50mLDCM/甲醇(10/1)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液减压浓缩至干,经prep-HPLC纯化(水/乙腈,0.1%FA),冷冻干燥得3(9.0mg,收率:11.84%),白色固体。1H NMR(400MHz,DMSO)δ13.29(s,1H),8.48(s,1H),8.40(s,1H),7.76-7.57(m,2H),7.27(d,J=8.8Hz,2H),7.10(dd,J1=9.2Hz,J2=2.0Hz,1H),6.89(d,J=8.8Hz,2H),4.40(q,J=6.8Hz,2H),4.21(s,3H),3.76(s,3H),1.23(t,J=7.2Hz,3H).LCMS(ESI)m/z=416.1[M+H]+.
采用实施例4的合成方法,制备化合物13、14、15、17-26、33-34、37-38、40-41、46-48、54、57-58、60、62、65-66、84、86-87、90、92、101-102、111、114、116-118、124-128、131-133、137、139、141、142。
化合物35的三氟醋酸盐:
采用实施例4的合成方法,将第三步中的4-甲氧基苯硼酸频哪醇酯替换为4-氯苯硼酸频哪醇酯,第四步中的5-溴-2-甲基-2H-吲唑替换为1-(氮杂环丁烯-3-基)-6-碘-1H-苯并[d]咪唑,第五步经prep-HPLC纯化的流动相FA替换为三氟醋酸,得到化合物35的三氟醋酸盐。1H NMR(400MHz,MeOD)δ8.83(s,1H),8.46(d,J=9.1Hz,1H),7.92-7.82(dd,J=23.1,14.3Hz,2H),7.46-7.25(m,5H),5.90-5.63(m,1H),4.81-4.58(m,4H),4.51(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H).LCMS(ESI)m/z=460.85[M+H]+.
实施例5:化合物12的合成
第一步:中间体2-12的合成
在25mL单口瓶中,将4-2(2.0g,7.1mmol),碳酸钾(1.96g,14.2mmol),用DMF(25mL)溶解,向反应液中加入2,2,2-三氟乙基三氟甲烷磺酸酯溶液(3.3g,14.2mmol),室温搅拌6h。将反应液倒入水中,用EA(100mL)萃取,合并有机层,用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,滤液浓缩后经硅胶快速柱纯化(0-60%EA),得中间体2-12(0.6g,收率:51.9%),白色固体。1HNMR(400MHz,DMSO)δ11.53(s,1H),8.35(s,1H),5.70(s,1H),5.41(s,2H),4.91(q,J=8.8Hz,2H),3.54(t,J=8.0Hz,2H),0.83(t,J=8.0Hz,2H),-0.05(s,9H).LCMS(ESI)m/z=363.9[M+H]+.
第二步:中间体3-12的合成
在25mL单口瓶中,将中间体2-12(0.6g,1.36mmol)溶于THF(15mL),加入NBS(0.24g,1.36mmol),室温搅拌2h。将反应液缓慢滴加到冰水中,有大量固体析出,抽滤。滤饼经硅胶快速柱纯化(0-4%甲醇/DCM),得中间体3-12(600mg,收率:93.7%),白色固体。1HNMR(400MHz,DMSO)δ12.23(s,1H),8.76(s,1H),5.50(s,2H),5.26(q,J=8.5Hz,2H),3.68-3.57(m,2H),0.89(dd,J1=10.6Hz,J2=5.6Hz,2H),-0.00(s,9H).LCMS(ESI)m/z=441.9[M+H]+.
第三步:中间体4-12的合成
将中间体3-12(200mg,0.426mmol)、4-甲氧基苯硼酸频哪醇酯(200mg,0.852mmol)、Pd(dppf)Cl2(34.5mg,0.043mmol)、碳酸钾(117mg,0.852mmol)、1,4-二氧六环(15ml)、水
(3ml)依次投入50mL单口瓶中,N2保护下100℃搅拌16h。过滤,滤液浓缩后经硅胶快速柱纯化(0-3%甲醇/DCM),得中间体4-12(95mg,收率:47.5%),白色固体。LCMS(ESI)m/z=470.0[M+H]+.
第四步:中间体5-12的合成
将中间体4-12(95mg,0.2mmol)、5-溴-2-甲基-2H-吲唑(85mg,0.4mmol)、反式N,N’-二甲基环己二胺(6mg,0.04mmol)、碘化亚铜(8mg,0.04mmol)、磷酸钾(85mg,0.4mmol)、DMSO(8ml)依次投入20mL微波管中,氮气保护下110℃微波反应3h。将反应液倒入水中,用50mL甲醇/DCM(1/10)萃取,合并有机层,用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,收集滤液,硅胶快速柱纯化(0-3%甲醇/DCM),得中间体5-12(80mg,收率:65.8%),白色固体。LCMS(ESI)m/z=600.2[M+H]+.
第五步:化合物12的合成
在25mL单口瓶中,将中间体5-12(80mg,0.133mmol)溶于4M氯化氢1,4-二氧六环(6mL),室温搅拌4h。将反应液倒入水中,用碳酸氢钠水溶液调pH至中性。用50mLDCM/甲醇(10/1)萃取,合并有机层,无水硫酸钠干燥、过滤,收集滤液,减压浓缩至干,经prep-HPLC(水/乙腈,0.1%FA),冷冻干燥后得到化合物12(31.53mg,收率:50.4%),白色固体。1H NMR(400MHz,DMSO)δ13.38(s,1H),8.51(s,1H),8.41(s,1H),7.72(s,1H),7.67(d,J=9.2Hz,1H),7.28(d,J=8.8Hz,2H),7.11(dd,J1=9.2Hz,J2=2.0Hz,1H),6.91(d,J=8.8Hz,2H),4.98(q,J=8.8Hz,2H),4.21(s,3H),3.77(s,3H).LCMS(ESI)m/z=470.1[M+H]+.
采用实施例5的合成方法,制备化合物27-29、46-47、49、52-54、89、93、99。
实施例6:化合物31和45的合成
在25mL单口瓶中,将化合物14(50mg,0.011mmol)、碳酸铯(7mg,0.022mmol)用3mL丙酮溶解,加入碘甲烷(4mg,0.03mmol),加完室温搅拌1h。将反应液浓缩干,得粗品,经prep-TLC纯化(DCM/MeOH=20/1),冷冻干燥后分别得到化合物31(15mg,收率:29.1%),白色固体;和化合物45(35mg,收率:67.9%),白色固体。
化合物31:1H NMR(400MHz,DMSO)δ8.49(s,1H),8.14(s,1H),7.86(d,J=1.3Hz,1H),7.74(d,J=9.0Hz,1H),7.40(d,J=8.8Hz,2H),7.26(t,J=76.0Hz,1H),7.24(dd,J=9.0,2.0
Hz,1H),7.13(d,J=8.7Hz,2H),4.46(q,J=7.0Hz,2H),4.22(s,3H),3.05(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m/z=466.0[M+H]+.
化合物45:1H NMR(400MHz,DMSO)δ8.57(s,1H),8.40(s,1H),7.68(d,J=1.4Hz,1H),7.65(d,J=9.0Hz,1H),7.40(d,J=8.7Hz,2H),7.26(t,J=76.0Hz,1H),7.13(d,J=8.6Hz,2H),7.10(d,J=1.9Hz,1H),4.42(d,J=7.0Hz,2H),4.20(s,3H),3.83(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m/z=466.0[M+H]+.
实施例7:化合物50的合成
第一步:中间体2-50的合成
在250mL单口瓶中,将4-2(4g,14.2mol)溶于DMF(50mL),加入碳酸钠(3g,28.4mol),溴甲基环丙烷(6.72g,49.7mol),升温至90℃搅拌3h。反应结束,将反应液倒入水中,析出固体,抽滤得粗品,粗品用硅胶Flash柱纯化(0-2%甲醇),得到中间体2-50(1.5g,收率:31.5%),白色固体。LCMS(ESI)m/z=336.1[M+H]+.
第二步:中间体3-50的合成
在50mL单口瓶中,将中间体2-50(1.5g,4.47mmol)溶于THF(20mL),常温下分批加入NBS(0.84g,4.7mmol),室温反应2h。将反应液倒入冰水中,用EA(50mL)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶Flash柱纯化(0-100%EA),得到中间体3-50(1.35g,收率:73.6%),淡黄色固体。LCMS(ESI)m/z=414.0[M+H]+.
第三步:中间体4-50的合成
将中间体3-50(1.25g,3mmol)、4-氯苯硼酸频哪醇酯(1.43g,11.6mmol)、Pd(dppf)Cl2(0.24g,0.58mmol)、碳酸钾(0.83g,11.6mmol)、1,4-二氧六环(15mL)、水(3ml)依次投入100mL单口瓶中,N2保护下升温至100℃反应16h。将反应液浓缩经硅胶Flash柱纯化(PE:EA=1:1),得到中间体4-50(0.55g,收率:41%),淡黄色固体。LCMS(ESI)m/z=446.1[M+H]+.
第四步:中间体5-50的合成
将中间体4-50(550mg,1.23mmol)、5-溴-2-甲基-2H-吲唑(516mg,2.46mmol)、反式N,N’-二甲基环己二胺(20mg,0.12mmol)、碘化亚铜(47mg,0.246mmol)、磷酸钾(524mg,2.46mmol)、DMSO(10ml)依次投入50mL单口瓶中,N2保护下升温至130℃反应过夜。将反应液浓缩至干,浓缩得粗品,经硅胶Flash柱纯化(3%甲醇/DCM),得到中间体5-50(420mg,收率:59.1%),为白色固体。LCMS(ESI)m/z=576.2[M+H]+.
第五步:化合物50的合成
在50mL单口瓶中,将中间体5-50(420mg,0.73mmol)溶于4M的盐酸/1,4-二氧六环(10mL),室温反应4h。将反应液倒入水中,用氨水溶液调pH至碱性。用50mLDCM/甲醇(10/1)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液减压浓缩至干,经prep-HPLC纯化(水/乙腈,0.1%NH3.H2O),冷冻干燥后得到终产物化合物50(164.39mg,收率:50.5%),白色固体。1H NMR(400MHz,DMSO)δ13.33(s,1H),8.52(s,1H),8.40(s,1H),7.74-7.61(m,2H),7.45-7.33(m,4H),7.11(d,J=8.9Hz,1H),4.28(d,J=6.6Hz,2H),4.20(s,3H),1.18-1.04(m,1H),0.50(d,J=7.3Hz,2H),0.29(d,J=4.0Hz,2H).LCMS(ESI)m/z=446.0[M+H]+.
采用实施例7的合成方法,制备化合物32、39、51、95、96、104.
实施例8:化合物59的合成
第一步:中间体2-59的合成
在50mL单口瓶中,将中间体4-2(1.2g,4.27mmol),2-(2-溴乙氧基)四氢吡喃(1.0g,4.7mmol),碳酸钠(0.9g,8.54mmol)用DMF(15mL)溶解,90℃反应2h。加入水(50mL)猝灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash分离(PE/EA=1/4),得中间体2-59(640mg,收率:36.64%),黄色固体。LCMS(ESI)m/z=410.2[M+H]+.
第二步:中间体3-59的合成
在25mL单口瓶中,将中间体2-59(600mg,1.46mmol),5-溴-2-甲基-2H-吲唑(462mg,2.20mmol),(1R,2R)-二甲基环己烷-1,2-二胺(207mg,1.46mmol),碘化亚铜(277mg,1.46mmol)和磷酸钾(403mg,2.92mmol)用DMSO(10mL)溶解,氮气保护下110℃反应16h。加水淬灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩后经硅胶Flash分离(EA/PE=9/1)得中间体3-59(600mg,收率:76.24%),黄色固体。LCMS(ESI)m/z=540.2[M+H]+.
第三步:中间体4-59的合成
在50mL单口瓶中,将中间体3-59(500mg,0.928mmol)用THF(20mL)溶解,再分批加入NBS(173mmol,0.974mmol),室温反应2h。加饱和硫代硫酸钠溶液淬灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash纯化(EA/PE=90/10),得中间体4-59(400mg,收率:69.82%),淡黄色固体。LCMS(ESI)m/z=618.0[M+H]+.
第四步:中间体5-59的合成
将中间体4-59(100mg,0.162mmol),4-氯苯硼酸频哪醇酯(77.1mg,0.324mmol),Pd(dppf)Cl2(11.8mg,0.016mmol),碳酸钾(44.7mg,0.324mmol)和1,4-二氧六环/水=5/1(2mL)依次加入25mL单口瓶,氮气保护下100℃反应16h。加水(10mL)淬灭反应,DCM萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash纯化(甲醇/DCM=2/98),得中间体5-59(94mg,收率:89.40%),淡黄色固体。LCMS(ESI)m/z=650.1[M+H]+.
第五步:化合物59的合成
在25mL单口瓶中,将中间体5-59(80mg,0.123mmol)用氯化氢/1,4-二氧六环溶液(4M,2mL)溶解,室温反应4h。加冰水(10mL)淬灭反应,用氨水调节反应液pH至8~9,DCM/甲醇=10/1萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得粗品,经prep-HPLC(ACN/water-0.1%NH3H2O)分离,冻干后得到终产物59(16.68mg,收率:31.17%),白色固体。1H NMR(400MHz,DMSO)δ13.35(s,1H),8.55(s,1H),8.39(s,1H),7.70(s,1H),7.65(d,J=8.8Hz,1H),7.46-7.41(m,2H),7.39-7.34(m,2H),7.11(d,J=8.8Hz,1H),4.84(t,J=5.2Hz,1H),4.41(s,2H),4.21(s,3H),3.64(dd,J=9.6,4.8Hz,2H).LCMS(ESI)m/z=436.0[M+H]+.
实施例9:化合物67的合成
第一步:中间体2-67的合成
将4-氨基-5-咪唑甲酰胺1-67(10g,79mmol),甲基磺酸(20mL)和乙醇(100mL)依次加入200mL反应釜中,密封好之后将体系置于120℃下反应16h。加氨水中和反应液pH至8~9,甲醇/DCM=1/10(50mL×5)萃取,浓缩得粗品,经硅胶Flash分离(甲醇/DCM=20/80)得中间体2-67(6.4g,收率:52.03%),白色固体。LCMS(ESI)m/z=156.0[M+H]+.
第二步:中间体3-67的合成
在250mL三口瓶中,将中间体2-67(6.0g,38.7mmol),二异丙基乙胺(7.5g,58.1mmol)用THF(100mL)溶解,缓慢滴加2-(三甲基硅烷基)乙氧甲基氯(9.6g,58.1mmol),加完室温反应2h。除去溶剂,加水稀释,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash分离(EA/PE=1/1),得到中间体3-67粗品(3.0g,收率:27.3%),为无色粘稠油状物。LCMS(ESI)m/z=285.9[M+H]+.
第三步:中间体4-67的合成
在100mL三口瓶中,将中间体3-67粗品(3.0g,10.5mmol),丙二酸二乙酯(9.2g,57.7mmol)用乙醇(20mL)溶解。冰水浴下滴加乙醇钠(20%)(17.8g,52.5mmol),滴完95℃反应16h。除去大部分溶剂,加入冰水(100mL),EA萃取,饱和食盐水(200mL)洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash分离(甲醇/DCM=15/85),得到中间体4-67(3.2g,收率:86.3%),白色固体。LCMS(ESI)m/z=354.0[M+H]+.
第四步:中间体5-67的合成
在100mL单口瓶中,将中间体4-67(3.2g,9.1mmol)溶于15%氢氧化钠水溶液(30mL),105℃下反应5h。体系降温至0℃,用4M盐酸调节pH=5,过滤得到中间体5-67(1.5g,收率:58.68%),白色固体。LCMS(ESI)m/z=282.1[M+H]+.
第五步:中间体6-67的合成
在50mL单口瓶中,将中间体5-67(1.0g,3.56mmol),碳酸钾(982mg,7.12mmol)溶于DMF(5mL)。滴加碘乙烷(833mg,5.34mmol),加完在40℃反应16h。加水(20mL)淬灭反应,EA萃取,饱和食盐水(50mL)洗涤,无水硫酸钠干燥。浓缩后得到粗品,经硅胶Flash分离(甲醇/DCM=7/93),得到中间体6-67(310mg,收率:28.18%)。1H NMR(400MHz,DMSO)δ11.72(s,1H),8.14(s,1H),5.71(s,1H),5.59(s,2H),4.21(q,J=6.8Hz,2H),3.59(t,J=7.8Hz,2H),
1.46(t,J=6.8Hz,3H),0.91(t,J=8.0Hz,2H),-0.00(s,9H).
第六步:中间体7-67的合成
在100mL单口瓶中,将中间体6-67(280mg,0.906mmol),5-溴-2-甲基吲唑(285mg,1.35mmol),(1R,2R)-二甲基环己烷-1,2-二胺(128.6mg,0.906mmol),碘化亚铜(172mg,0.906mmol)和磷酸钾(384mg,1.81mmol)用DMSO(5mL)溶解,氮气保护下110℃反应16h。加水淬灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩后经硅胶Flash纯化(甲醇/DCM=6/94),得到中间体7-67(190mg,收率:47.77%),淡黄色固体。LCMS(ESI)m/z=440.1[M+H]+.
第七步:中间体8-67的合成
在25mL单口瓶中,将中间体7-67(170mg,0.36mmol)用THF(3mL)溶解,向其中分批加入NBS(61.6mg,0.36mmol),室温反应1h。加饱和硫代硫酸钠溶液淬灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩,粗品经硅胶Flash纯化(甲醇/DCM=5/95),得中间体8-67(120mg,收率:64.44%),淡黄色固体。LCMS(ESI)m/z=518.0[M+H]+.
第八步:中间体9-67的合成
将中间体8-67(50mg,0.0967mmol),4-氯苯硼酸频哪醇酯(46mg,0.193mmol),Pd(dppf)Cl2(8.1mg,0.00967mmol),碳酸钾(26.6mg,0.193mmol)和1,4-二氧六环/水=5/1(2mL)依次投入25mL单口瓶,氮气保护下100℃反应16h。加水淬灭反应,DCM萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经prep-TLC纯化(甲醇/DCM=1/10),得到中间体9-67(50mg,收率:94.18%),白色固体。LCMS(ESI)m/z=550.1[M+H]+.
第九步:化合物67的合成
在50mL单口瓶中,将中间体9-67(50mg,0.091mmol)用氯化氢/1,4-二氧六环溶液溶解(4M,3mL),室温反应4h。加冰水(10mL)淬灭反应,用氨水调节反应液pH至8~9,DCM/甲醇=10/1萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经prep-TLC分离(甲醇/DCM=1/10),浓缩冻干后得67(12.70mg,收率33.30%),白色固体。1H NMR(400MHz,DMSO)δ13.06(s,1H),8.42(s,1H),7.92(s,1H),7.73(s,1H),7.67(d,J=8.4Hz,1H),7.40(s,4H),7.14(d,J=8.4Hz,1H),4.21(s,5H),1.23(m,3H).LCMS(ESI)m/z=420.0[M+H]+.
采用实施例9的合成方法,制备化合物44.
实施例10:化合物61的合成
第一步:中间体2-61的合成
将中间体2-3(6.0g,19.4mmol)、5-溴-2-甲基-2H-吲唑(8.2g,38.8mmol)、反式N,N’-二甲基环己二胺(551mg,3.88mmol)、碘化亚铜(739mg,3.88mmol)、磷酸钾(8.2g,38.8mmol)、DMSO(80ml)依次投入250mL三口瓶中,N2保护下升温至120℃反应过夜。将反应液浓缩至干,加入冰水,用50mL(甲醇/DCM=1/10)萃取,合并有机层,用水、饱和食盐水依次洗涤,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶Flash柱纯化(0-3%甲醇/DCM),得到中间体化合物2-61(7.0g,收率:82.0%),白色固体。1H NMR(400MHz,DMSO)δ8.47(d,J=3.2Hz,2H),7.75(d,J=9.6Hz,2H),7.15(dd,J1=8.8Hz,J2=1.6Hz,1H),5.81(s,1H),5.41(s,2H),4.36-4.22(m,5H),3.58(t,J=8.0Hz,2H),1.49(t,J=7.2Hz,3H),0.91-0.80(m,2H),-0.00(s,9H).LCMS(ESI)m/z=440.2[M+H]+.
第二步:中间体3-61的合成
在25mL单口瓶中,将中间体2-61(4.0g,9.1mmol)溶于THF(120mL),常温搅拌下分批加入NBS(1.46g,8.2mmol),室温反应2h。将反应液倒入冰水中,用EA(50mL)萃取,合并有机层,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶Flash柱纯化(0-100%EA),得中间体3-61(3.5g,收率:74.2%),淡黄色固体。LCMS(ESI)m/z=518[M+H]+.
第三步:中间体4-61的合成
将中间体3-61(100mg,0.19mmol)、环己基-1-烯-1-基硼酸(49mg,0.38mmol)、Pd(dppf)Cl2(30mg,0.04mmol)、碳酸钾(53mg,0.38mmol)和二氧六环:水=5:1(5mL)加入50mL单口瓶中,N2保护下于100℃搅拌16h。将反应液过滤,浓缩,粗品经Flash纯化(DCM/MeOH=98/2),得到中间体4-61(80mg,收率:79.2%),黄色固体。LCMS(ESI)m/z=520.3[M+H]+.
第四步:中间体5-61的合成
将中间体4-61(80mg,0.15mmol)、Pd/C(10mg)、EtOH(3ml)依次投入50ml单口瓶中,氢气气氛下常温搅拌72h。将反应液浓缩得到中间体5-61粗品(70mg,收率:87.5%),黄色固体。LCMS(ESI)m/z=522.2[M+H]+.
第五步:化合物61的合成
在25mL单口瓶中,将中间体5-61(120mg,0.13mmol)溶于4M的HCl/1,4-二氧六环溶液(5mL),室温反应3h。将反应液倒入冰水中,用氨水溶液将pH调至9-10。用DCM/甲醇(10/1)萃取,有机相用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,滤液减压浓缩至干,经Prep-HPLC纯化(H2O/ACN,0.1%NH3.H2O),冷冻干燥后得到化合物61(10mg,收率:19.2%),白色固体。1H NMR(400MHz,DMSO)δ13.14(s,1H),8.38(s,2H),7.63(d,J=3.2Hz,2H),7.04(dd,J1=9.1Hz,J2=1.7Hz,1H),4.47(d,J=6.9Hz,2H),4.21(s,3H),3.09(t,J=12.0Hz,1H),2.11-2.00(m,2H),1.74(d,J=12.3Hz,2H),1.66(d,J=11.1Hz,1H),1.47(d,J=11.9Hz,
2H),1.42(t,J=7.0Hz,3H),1.22(td,J=25.0,12.6Hz,3H).LCMS(ESI)m/z=392.0[M+H]+.
实施例11:化合物63的合成
第一步:中间体2-63的合成
将4-2(1.05g,3.39mmol),2,2,2-三氟乙烷-1-胺(2mL)和THF(5mL)加入到50mL反应釜中,升温至110℃反应16h。反应液浓缩后,粗品经硅胶Flash柱纯化(DCM/MeOH=97/3)得到中间体2-63(175mg,收率:24.72%),黄色固体。LCMS(ESI)m/z=363.10[M+H]+.
第二步:中间体3-63的合成
将中间体2-63(175mg,0.48mmol)、5-溴-2-甲基吲唑(203mg,0.97mmol)、反式N,N’-二甲基环己二胺(69mg,0.48mmol)、碘化亚铜(92mg,0.48mmol)、磷酸钾(205mg,0.97mmol)、DMSO(3ml)依次投入25mL单口瓶中,N2保护下110℃反应16h。将反应液浓缩,粗品经硅胶Flash柱纯化(DCM/MeOH=97/3),得中间体3-63(200mg,收率:84.03%),黑色固体。LCMS(ESI)m/z=493.10[M+H]+.
第三步:中间体4-63的合成
在25mL单口瓶中,将中间体3-63(200mg,0.41mmol)用THF(5mL)溶解,溶清后分批加入NBS(72mg,0.41mmol),在室温下反应2h。反应液倒入饱和亚硫酸钠溶液,用DCM萃取,有机相浓缩,粗品经硅胶Flash柱纯化(DCM/MeOH=96/4),得中间体4-63(100mg,收率:43.10%),黄色固体。LCMS(ESI)m/z=571.00[M+H]+.
第四步:中间体5-63的合成
将中间体4-63(100mg,0.18mmol)、4-氯苯硼酸频哪醇酯(83mg,0.35mmol)、Pd(dppf)Cl2(14mg,0.02mmol)、碳酸钾(48mg,0.35mmol)、1,4-二氧六环(3ml)、水(0.6ml)依次投入25mL单口瓶中,N2保护下110℃反应16h。将反应液过滤,收集滤液,浓缩得粗品,经硅胶Flash柱纯化(0-3%甲醇/DCM),得黄色固体5-63(40mg,收率:37.74%)。LCMS(ESI)m/z=603.15[M+H]+.
第五步:化合物63的合成
在25mL单口瓶中,将中间体5-63(40mg,0.07mmol)溶于TBAF四氢呋喃溶液(6mL),60℃回流反应2h。反应液浓缩,加入EA,用水洗除去TBAF,有机相浓缩,粗品经prep-TLC纯化(DCM/MeOH=12/1),冷冻干燥后得到终产物化合物63(7.25mg,收率:23.39%),白色固体。1H NMR(400MHz,DMSO)δ13.18(s,1H),8.52(s,1H),8.37(s,1H),7.66(s,1H),7.61(d,J=8.9Hz,1H),7.47(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H),7.09(dd,J=9.1,1.7Hz,1H),
5.98(t,J=7.5Hz,1H),4.20(s,3H),4.17-4.05(m,2H).LCMS(ESI)m/z=473.05[M+H]+.
采用实施例11的合成方法,制备化合物105-108、123、129.
实施例12:化合物64的合成
第一步:中间体2-64的合成
在50mL反应釜中,将4-2(1.0g,3.55mmol)用乙胺的四氢呋喃溶液(12mL)溶解,110℃反应16h。反应液中加水,用EA萃取,有机相浓缩后,粗品经硅胶Flash柱纯化(DCM/MeOH=40/1)得到中间体2-64(550mg,收率:50.0%),白色固体。1H NMR(400MHz,DMSO)δ10.64(s,1H),8.21(s,1H),6.90(t,J=5.0Hz,1H),5.44(s,2H),4.89(s,1H),3.64-3.50(m,2H),3.16(dd,J=7.1,5.2Hz,2H),1.24(t,J=7.2Hz,3H),0.94-0.83(m,2H),-0.00(s,9H).
第二步:中间体3-64的合成
将中间体2-64(550mg,1.78mmol)、5-溴-2-甲基吲唑(753mg,3.57mmol)、反式N,N’-二甲基环己二胺(254mg,1.78mmol)、碘化亚铜(340mg,1.78mmol)、磷酸钾(757mg,3.57mmol)、DMSO(4ml)依次投入25mL单口瓶中,N2保护下110℃反应16h。将反应液浓缩,粗品经硅胶Flash柱纯化(DCM/MeOH=97/3),得中间体3-64(800mg,收率:100%),黑色固体。LCMS(ESI)m/z=439.10[M+H]+.
第三步:中间体4-64的合成
在50mL单口瓶中,将中间体3-64(800mg,1.82mmol)用THF(10mL)溶解,溶清后分批加入NBS(292mg,1.64mmol),在室温下反应2h。反应液倒入饱和亚硫酸钠溶液,用DCM萃取,有机相浓缩,粗品经硅胶Flash柱纯化(DCM/MeOH=96/4),得中间体4-64(700mg,收率:74.23%),黄色固体。LCMS(ESI)m/z=518.05[M+H]+.
第四步:中间体5-64的合成
将中间体4-64(350mg,0.68mmol)、4-氯苯硼酸频哪醇酯(323mg,1.35mmol)、Pd(dppf)Cl2(56mg,0.07mmol)、碳酸钾(189mg,1.35mmol)、1,4-二氧六环(5ml)、水(1ml)依次投入25mL单口瓶中,N2保护下100℃反应16h。将反应液过滤,滤液浓缩得粗品,经硅胶Flash柱纯化(DCM/MeOH=97/3),得中间体5-64(260mg,收率:70.08%),黄色固体。1H NMR(400MHz,DMSO)δ8.68(s,1H),8.41(s,1H),7.76-7.56(m,2H),7.49(dd,J=8.8,2.1Hz,2H),7.40-7.24(m,2H),7.11(dd,J=9.0,2.0Hz,1H),5.80(t,J=6.2Hz,1H),5.43(s,2H),4.25(s,3H),3.76-3.52(m,2H),1.17(t,J=7.0Hz,3H),0.93-0.84(m,2H),0.06(s,2H),0.01(s,9H).
第五步:中间体6-64的合成
将中间体5-64(109mg,0.20mmol)和溶剂DMF(5mL)加入在25mL三口瓶中,N2保护下降温至0℃,加入NaH(24mg,0.60mmol),搅拌10min左右,加入CH3I(56mg,0.40mmol)继续搅拌20min。反应液加水淬灭,用EA萃取,有机相浓缩,得中间体6-64粗品(109mg,纯度:83%,收率:80.78%),灰色固体。LCMS(ESI)m/z=562.95[M+H]+.
第六步:化合物64的合成
在25mL单口瓶中,将中间体9(109mg,0.19mmol)溶于HCl/1,4-二氧六环溶液(10mL)中,室温反应2h。将反应液倒入冰水中,用氨水溶液将pH调至9~10。用DCM/甲醇(10/1)萃取,有机相用水、饱和食盐水各洗涤一次,无水硫酸钠干燥、过滤,滤液减压浓缩,粗品经硅胶Flash纯化(DCM/MeOH=97/3),冷冻干燥后得到化合物64(14.95mg,收率:16.65%),白色固体。1H NMR(400MHz,DMSO)δ13.11(s,1H),8.36(s,1H),8.32(s,1H),7.68-7.56(m,2H),7.41-7.34(m,2H),7.33-7.27(m,2H),7.07(dd,J=9.1,1.5Hz,1H),4.19(s,3H),3.16(q,J=6.6Hz,2H),2.71(s,3H),1.00(t,J=7.0Hz,3H).LCMS(ESI)m/z=433.10[M+H]+.
实施例13:化合物112的合成
第一步:中间体2-112的合成
在100mL单口瓶中,将4-2(9.0g,32.0mmol),N-苯基双(三氟甲磺酰亚胺)(13.7g,38.4mmol),TEA(9.7g,96mmol)用DMF(50mL)溶解。氮气保护下室温反应16h。加冰水(50mL)淬灭反应,EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash纯化(PE/EA=2/1),得中间体2-112(2.6g,收率19.66%),白色固体。LCMS(ESI)m/z=414.0[M+H]+.
第二步:中间体3-112的合成
在100mL单口瓶中,依次加入中间体2-112(500mg,1.2mmol),正丙基三氟硼酸钾(259mg,2.4mmol),Pd(dppf)Cl2(101mg,0.12mmol),磷酸钾(770mg,3.6mmol),加入甲苯/水混合溶剂(10mL,10/1),氮气保护下90℃反应16h。加水(20mL)淬灭反应,DCM萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得粗品,经硅胶Flash纯化(DCM/甲醇=98/2),得到产物中间体3-112(180mg,收率:48.45%),白色固体。LCMS(ESI)m/z=308.0[M+H]+.
第三步:中间体4-112的合成
在100mL单口瓶中,依次加入中间体3-112(160mg,0.52mmol),5-溴-2-甲基吲唑(163mg,0.78mmol),(1R,2R)-二甲基环己烷-1,2-二胺(73.8mg,0.52mmol),碘化亚铜(99mg,0.52mmol)和磷酸钾(220mg,1.04mmol),加入二甲基亚砜(4mL),氮气保护下于110℃反应16h。加水(20mL)淬灭反应,EA(30mL/次)萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得粗品,经硅胶Flash分离纯化(甲醇/DCM=3/97),得中间体4-112(160mg,收率:70.41%),黑色固体。LCMS(ESI)m/z=438.1[M+H]+.
第四步:中间体5-112的合成
在100mL三口瓶中,将中间体4-112(140mg,0.32mmol)溶于THF(4mL),氮气保护下向其中分批加入NBS(62.7mmol,0.35mmol),室温反应2h。加饱和硫代硫酸钠溶液淬灭反应(10mL),EA萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经硅胶Flash纯化(PE/EA=65/35),得产物中间体5-112(120mg,收率:72.81%),无色粘稠固体。LCMS(ESI)m/z=516.1[M+H]+.
第五步:中间体6-112的合成
将中间体5-112(100mg,0.19mmol),2-(4-氯苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(92mg,0.39mmol),Pd(dppf)Cl2(16mg,0.019mmol),碳酸钾(53mg,0.39mmol)和1,4-二氧六环/水=5/1(2mL)依次加入25mL单口瓶,氮气保护下100℃反应16h。加水淬灭反应,DCM萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩,粗品经硅胶Flash纯化(甲醇/DCM=3/97)得中间体6-112(120mg,收率:94.15%),白色固体。LCMS(ESI)m/z=548.1[M+H]+.
第六步:化合物112的合成
中间体6-112(110mg,0.20mmol)加入25mL单口瓶中,氮气保护下加入盐酸-1,4-二氧六
环溶液(4M,4mL),室温反应4h。加冰水(10mL)淬灭反应,用氨水调节反应液pH=8~9,DCM/甲醇=10/1萃取,饱和食盐水洗涤,无水硫酸钠干燥。浓缩得到粗品,经prep-HPLC分离纯化(水/乙腈,0.1%NH3H2O),得到终产物112(41.73mg,收率:50.03%),白色固体。1H NMR(400MHz,DMSO)δ13.14(s,1H),8.38(d,J=5.6Hz,2H),7.73(s,1H),7.65(d,J=9.2Hz,1H),7.46(d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),7.14(dd,J=9.2,2.0Hz,1H),4.20(s,3H),2.53(m,2H),1.64-1.51(m,2H),0.84(t,J=7.2Hz,3H).LCMS(ESI)m/z=418.1[M+H]+.
实施例14:化合物122的合成
50mL单口瓶,将化合物13(110mg,0.26mmol)、碳酸铯(169mg,0.52mmol)和2-溴-1-醇(40mg,0.31mmol)溶于DMF(3mL),80℃反应3h。反应液过滤后经Prep-HPLC纯化(H2O/ACN,0.1%FA),冷冻干燥后得到化合物122(21mg,收率:17.4%),白色固体。1H NMR(400MHz,DMSO)δ8.54(s,1H),8.39(s,1H),7.69(d,J=1.3Hz,1H),7.66(d,J=9.1Hz,1H),7.38(s,4H),7.10(dd,J=9.1,1.9Hz,1H),4.92(s,1H),4.43(q,J=6.9Hz,2H),4.20(s,3H),4.12(t,J=5.3Hz,2H),3.67(t,J=5.1Hz,2H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m/z=464.05[M+H]+.
采用实施例14的合成方法,制备化合物134、136、138、140.
实施例15:化合物109和121的合成
在25mL单口瓶中,将化合物84(120mg,0.28mmol)溶于5mL DMF,冰浴下加入NaH(18mg,0.42mmol),搅拌10min后,再加入碘甲烷(48mg,0.34mmol),继续搅拌1h。反应液倒入水中,EA萃取,有机相水洗,饱和食盐水洗,浓缩得粗品,经prep-HPLC纯化(水/乙腈,0.1%FA),冷冻干燥后得到化合物109(34.96mg,收率:36.9%),白色固体,和化合物121(16.86mg,收率:17.8%),白色固体。
化合物109:1H NMR(400MHz,DMSO)δ8.68(s,1H),8.60(s,1H),8.23(dd,J=8.8,0.8Hz,1H),7.41-7.35(m,4H),7.25(d,J=8.9Hz,1H),4.45(q,J=7.2Hz,2H),4.26(s,3H),3.83(s,3H),1.26(t,J=7.2Hz,3H).LCMS(ESI)m/z=435.1[M+H]+.
化合物121:1H NMR(400MHz,DMSO)δ8.79(s,1H),8.33(d,J=8.8Hz,1H),8.19(s,1H),7.51(d,J=8.8Hz,1H),7.41-7.35(m,4H),4.51(q,J=6.8Hz,2H),4.28(s,3H),2.97(s,3H),1.26(t,J=6.8Hz,3H).LCMS(ESI)m/z=435.1[M+H]+.
实施例16:化合物130的合成
第一步:中间体2-130的合成
将化合物3-61(3.0g,5.8mmol)、4-氯苯硼酸频哪醇酯(2.8g,11.6mmol)、Pd(dppf)Cl2(0.47g,0.58mmol)、碳酸钾(1.6g,11.6mmol)、1,4-二氧六环(45mL)、水(9ml)依次投入100mL单口瓶中,N2保护下110℃反应过夜。将反应液过滤,滤饼用DCM冲洗,合并滤液,浓缩得粗品,经硅胶Flash柱纯化(0-2%甲醇/DCM),得中间体2-130(3.0g,收率:94.1%),淡黄色固体。LCMS(ESI)m/z=550.1[M+H]+.
第二步:中间体3-130的合成
将中间体2-130(550mg,1.0mmol)、乙硫醇钠(84mg,10mmol)、1,4-二氧六环(25mL)依次投入50mL三口瓶中,N2保护下70℃反应16h。将反应液倒入水中(50mL),用EA萃取,合并有机层,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经硅胶柱层析纯化(0-2%甲醇/DCM),得中间体3-130(350mg,收率:61.8%),淡黄色固体。LCMS(ESI)m/z=566.2[M+H]+.
第三步:化合物130的合成
在50mL三口瓶中,将中间体3-130(350mg,0.62mmol)溶于4M的HCl/1,4-二氧六环(16mL),室温反应4h。将反应液倒入冰水中(50mL),用氨水调pH至9-10,继续室温搅拌1h,用EA萃取,合并有机层,无水硫酸钠干燥、过滤,滤液浓缩得粗品,经prep-HPLC纯化(水/乙腈,0.1%NH3H2O),得到产物130(33.90mg,收率:12.7%),白色固体。1HNMR(400MHz,DMSO)δ13.25(s,1H),8.40(s,2H),7.75(s,1H),7.66(d,J=9.2Hz,1H),7.47-7.41(m,2H),7.34-7.26(m,2H),7.15(dd,J1=9.2Hz,J2=2.0Hz,1H),4.20(s,3H),2.99(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H).LCMS(ESI)m/z=436.1[M+H]+.
实施例17:化合物55的合成
第一步:中间体2-55的合成
在250mL单口瓶中,将4-硝基吡唑-5-羧酸乙酯1-55(10g,54.05mmol)用乙醇(100mL)溶解,加入湿钯碳1g,氢气气氛,室温搅拌过夜。将反应液过滤,滤液浓缩干得中间体2-55(8.7g,收率>100%,包含溶剂),紫色固体。1H NMR(400MHz,DMSO)δ12.80(s,1H),7.09(s,1H),4.78(s,2H),4.25(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H).
第二步:中间体3-55的合成
在500mL单口瓶中,将中间体2-55(8.66g,55.9mmol)用THF(200mL)溶解,冰浴冷至0℃,加入DIPEA(14.42g,111.8mmol),再滴加SEMCl(10.27g,61.49mmol),滴完室温搅拌过夜,补加SEMCl(5g,30mmol),加完继续室温搅拌16h。将反应液倒入水中,用EA萃取,无水硫酸钠干燥,过滤,滤液浓缩得16.3g中间体3-55粗品,淡黄色油状,无需纯化,直接下一步。LCMS(ESI)m/z=285.9[M+H]+.
第三步:中间体4-55的合成
在500mL单口瓶中,将中间体3-55(16.16g,56.7mmol)用乙醇(250mL)溶解,加入丙二酸二乙酯(54.4g,340mmol)和20%乙醇钠的乙醇溶液(115.7g,340mmol),加完85℃回流18h。将反应液减压浓缩,加水,用EA萃取,无水硫酸钠干燥,过滤,滤液浓缩得8g中间体4-55粗品,黄色油状,无需纯化,直接下一步。LCMS(ESI)m/z=354.1[M+H]+.
第四步:中间体5-55的合成
在250mL单口瓶中,将中间体4-55(7.5g,21.22mmol)加入到15%NaOH溶液中,升温至105℃,回流反应6h。反应液用2M盐酸调pH至4左右,析出固体,过滤,得中间体5-55(6.1g,收率:95.31%),黄色固体。LCMS(ESI)m/z=282.10[M+H]+.
第五步:中间体6-55的合成
在100mL单口瓶中,将中间体5-55(3.3g,11.73mmol)用DMF(60mL)溶解,加入Na2CO3(2.49g,23.45mmol),滴加碘乙烷(3.66g,23.45mmol),滴完升温至40℃搅拌3h。反应液倒入水中,用EA萃取,有机相水洗,饱和食盐水洗,干燥,过滤,滤液浓缩得粗品,经硅胶Flash纯化(DCM/MeOH=96/4),得中间体6-55(1g,收率:27.55%),白色固体。LCMS(ESI)m/z=310.15[M+H]+.
第六步:中间体7-55的合成
100mL单口瓶,加入6-55(1.05g,3.39mmol)、5-溴-2-甲基吲唑(1.43g,6.79mmol)、反式N,N’-二甲基环己二胺(483mg,3.39mmol)、碘化亚铜(646mg,6.79mmol)、磷酸钾(1.44
g,3.39mmol)、DMSO(12ml),N2保护下110℃反应16h。将反应液浓缩,粗品经硅胶Flash柱纯化(DCM/MeOH=96/4),得中间体7-55(1.2g,收率:80.54%),黑色油状。LCMS(ESI)m/z=440.15[M+H]+.
第七步:中间体8-55的合成
在25mL单口瓶中,将中间体7-55(1.2g,2.72mmol)用THF溶解,溶清后分批加入NBS(437mg,2.46mmol),室温反应10h。反应液倒入亚硫酸钠水溶液,用DCM萃取,有机相浓缩,经硅胶Flash柱纯化(DCM/MeOH=97/3),得中间体8-55(400mg,收率:28.5%),黄色固体。LCMS(ESI)m/z=518.05[M+H]+.
第八步:中间体9-55的合成
将中间体8-55(250mg,0.48mmol)、4-氯苯硼酸频哪醇酯(230mg,0.96mmol)、Pd(dppf)Cl2(39mg,0.05mmol)、碳酸钾(133mg,0.96mmol)、1,4-二氧六环(5ml)、水(1ml)依次投入50mL单口瓶中,N2保护下100℃反应16h。过滤,滤液浓缩,经硅胶Flash柱纯化(0-3%甲醇/DCM),得中间体9-55(150mg,收率:56.60%),黄色固体。LCMS(ESI)m/z=550.10[M+H]+.
第九步:化合物55的合成
在25mL单口瓶中,将中间体9-55(150mg,0.27mmol)溶于TBAF(10mL)中,升温至60℃回流反应1h。反应液浓缩,用水洗去TBAF,EA萃取,有机相浓缩,经Prep-HPLC(水/乙腈,0.1%FA)纯化,冷冻干燥后得到化合物55(77.75mg,收率:68.2%),白色固体。1H NMR(400MHz,DMSO)δ13.71(s,1H),8.43(s,1H),7.79(d,J=1.3Hz,1H),7.70(d,J=9.1Hz,1H),7.47-7.34(m,5H),7.18(dd,J=9.1,2.0Hz,1H),4.81(s,2H),4.21(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m/z=420.05[M+H]+.
实施例18:化合物56的合成
在25mL单口瓶中,将化合物55(50mg,0.12mmol)用丙酮(3mL)溶解,加入Cs2CO3(78mg,0.24mmol),再加入CH3I(34mg,0.24mmol),室温下搅拌1h。反应液过滤,浓缩,经Prep-HPLC(水/乙腈,0.1%TFA)纯化,冷冻干燥后得到化合物56(13.40mg,收率:25.8%),白色固体。1H NMR(400MHz,DMSO)δ8.43(s,1H),7.79(d,J=1.2Hz,1H),7.71(d,J=9.1Hz,1H),7.46(s,1H),7.43-7.36(m,4H),7.17(dd,J=9.1,2.0Hz,1H),4.78(q,J=7.0Hz,2H),4.21(s,3H),3.94(s,3H),1.25(t,J=7.0Hz,3H).LCMS(ESI)m/z=434.05[M+H]+.
实施例19:化合物100的合成
第一步:中间体2-100的合成
将4-硝基吡唑-5-羧酸乙酯1-55(5.0g,27.0mmol)溶于50mL DCM于100mL单口瓶中,缓慢加入Me3OBF4(6.0g,40.5mmol),室温反应3h。反应液浓缩,粗品经硅胶Flash柱纯化(0-1%甲醇/DCM)得中间体2-100(2.5g,收率:47%),淡黄色液体。LCMS(ESI)m/z=200.1[M+H]+.
第二步:中间体3-100的合成
在50mL单口瓶中,将中间体2-100(2.5g,12.56mmol)溶于30mL乙醇,加入Pd/C(0.5g),氢气气氛下室温反应过夜。用硅藻土过滤掉Pd/C,滤液浓缩得到中间体3-100(2.2g,收率:103%),黄色液体。LCMS(ESI)m/z=170.1[M+H]+.
第三步:中间体4-100的合成
在250mL单口瓶中,将中间体3-100(2.2g,13.0mmol)溶于100mL乙醇,依次加入丙二酸二乙酯(6.25g,39.0mmol)和NaOEt(20%的EtOH,4.42g,39.0mmol),升温至80℃反应过夜。反应液浓缩后,溶于EA(20mL),加入50mL HCl(二氧六环)搅拌1h,过滤收集固体得到中间体4-100(3.0g,收率:97%),黄色固体。LCMS(ESI)m/z=238.2[M+H]+.
第四步:中间体5-100的合成
在100mL单口瓶中,将中间体4-100溶于30mL 15%NaOH水溶液,升温至100℃反应过夜。加水稀释,用稀盐酸调pH至3-4,析出白色固体,过滤收集白色固体得到中间体5-100(1.2g,收率:57%),白色固体。LCMS(ESI)m/z=166.2[M+H]+.
第五步:中间体6-100的合成
在100mL单口瓶中,将中间体5-100(1.0g,6.1mmol)溶于20mL DMF,加入Na2CO3(1.9g,18.2mmol),EtI(0.94g,9.1mmol),室温搅拌过夜。将反应液倒入水中,EA萃取,有机相水洗,饱和食盐水洗、浓缩,粗品经硅胶Flash柱纯化(0-2%甲醇/DCM),得中间体6-100(300mg,收率:26%),白色固体。LCMS(ESI)m/z=194.2[M+H]+.
第六步:中间体7-100的合成
将中间体6-100(300mg,1.55mmol)、5-溴-2-甲基-2H-吲唑(492mg,2.33mmol)、反式N,N’-二甲基环己二胺(220mg,1.55mmol)、碘化亚铜(295mg,1.55mmol)、磷酸钾(660mg,3.10mmol)、DMSO(10ml)依次投入50mL单口瓶中,N2保护下110℃反应过夜。将反应液浓缩干,粗品经硅胶Flash柱纯化(0-3%甲醇/DCM),得到中间体7-100(300mg,收率:60%),淡黄色固体。LCMS(ESI)m/z=324.0[M+H]+.
第七步:中间体8-100的合成
反应在25mL单口瓶中进行。将中间体7-100(300mg,0.99mmol)溶于10mLDCM,加入NBS(211mg,1.19mmol),室温下搅拌2h。将反应液浓缩至干,经硅胶Flash柱纯化(0-3%甲醇/DCM),得到中间体8-100(300mg,收率:73%),黄色固体。LCMS(ESI)m/z=402.0[M+H]+.
第八步:化合物100的合成
将中间体8-100(80mg,0.2mmol)、4-氯苯硼酸频哪醇酯(95mg,0.4mmol)、Pd(dppf)Cl2(29mg,0.02mmol)、碳酸钾(55mg,0.4mmol)、1,4-二氧六环(5mL)、水(1ml)依次投入25mL
单口瓶中,N2保护下100℃反应16h。将反应液浓缩,粗品经硅胶Flash柱纯化(0-2%甲醇/DCM),得到粗产品,再经prep-HPLC纯化(水/乙腈,0.1%FA),冷冻干燥后得化合物100(16.26mg,收率:19%),白色固体。1H NMR(400MHz,DMSO)δ8.44(s,1H),7.79(d,J=1.6Hz,1H),7.72(d,J=9.2Hz,1H),7.53-7.44(m,4H),7.17(dd,J=9.2,2.0Hz,1H),7.06(s,1H),4.21(s,3H),4.14(s,3H),3.69(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H).LCMS(ESI)m/z=434.2[M+H]+.
测试例1、生物化学测试
试验原理:MAT2A可以催化L-甲硫氨酸和ATP转化为SAM、无机磷酸盐和无机二磷酸盐。通过向酶促反应体系中加入显色剂,可以定量检测样品中无机磷酸盐的含量,进而表征MAT2A的酶活性。
试验材料:Tris(Life science#0497);BSA(Sigma#);MAT2A his-tag(BPS#71401-1);384孔板(Corning#3765);L-methionine(Admas#1100469);ATP(Sigma#A7699);MgCl2(Sigma#M8266);KCl(Sigma#7447-40-7);Brij35(Sigma#B4184);EDTA(Sigma#E1644)
试验方法:
1.配制1xAssaybuffer(缓冲液组成:Tris,KCl,MgCl2,BSA,Brij35和EDTA;溶剂为超纯水)。用1xAssaybuffer分别配制MAT2A his-tag酶溶液(每1000μL含有1.3μL MAT2A酶和998.7μL 1xAssaybuffer)和底物混合溶液(每1000μL含有5μL ATP,1.3μL L-methionine和993.7μL 1xAssaybuffer)。
2.化合物浓度梯度的配制:受试化合物测试以10μM为起始浓度,按照3倍稀释设置10个等比浓度。具体而言,首先在384孔板中梯度稀释成10个不同浓度的系列溶液(使化合物的检测终浓度为10、3.33、1.11、0.37、0.123、0.041、0.0137、0.0046、0.0015和0.0005μM),然后用声波移液系统Echo550分别转移250nL上述系列溶液到384孔反应板中备用。阴性对照孔和阳性对照孔中分别加入250nL的100%DMSO。复孔测试。
3.在化合物孔和阳性对照孔中分别加入15μL的MAT2A his-tag酶溶液;在阴性对照孔中加入15μL的1xAssaybuffer。
4.将上述384孔板反应板1000rpm离心60秒,振荡混匀后孵育15分钟。向384孔反应板所有实验孔中分别加入10μL的底物混合溶液,起始反应。
5.将上述384孔反应板1000rpm离心60秒,振荡混匀后孵育150分钟。
6.向384孔反应板所有实验孔加入50μL酶反应终止液Biomol终止反应,1000rpm离心60秒后孵育15分钟。读取OD620,处理数据。
数据分析:计算化合物抑制率(%),拟合得到受试化合物的IC50。化合物抑制率计算方法:化合物抑制率(%)=(OD620_max-OD620_sample)/(OD620_max-OD620_min)X100,其中:OD620_sample是样品孔吸光值;OD620_min是阳性对照孔吸光值,表示没有酶活孔的读数;OD620_max是阴性对照孔吸光值,表示没有化合物抑制孔的读数。
试验结果:在本试验条件下,待测化合物对MAT2A酶活的抑制作用可以用对酶促反应过程中磷酸产生水平抑制的IC50值表示。待测化合物的MAT2A抑制活性具体见表1。结果显示,以结构相近化合物1作为对照,本发明化合物具有显著的MAT2A酶抑制效果。
表1.对MAT2A酶活性的抑制作用
测试例2、人胰腺癌KP-4细胞活性抑制试验
试验原理:将待测MAT2A抑制剂与KP-4细胞共孵育一段时间后,采用基于ATP含量的细胞活性测量方法来表征待测化合物对细胞活性的影响。
试验材料:KP-4细胞(JCRB#JCRB0182);IMDM(Gibco#12440061);胎牛血清(Fetal bovine serum)(EXCELL#FND500);青霉-链霉素(Penicillin-Streptomycin)(Gibco#15140-122);0.25%Typsin-EDTA(Gibco#25200-072);DMSO(Sigma#D2650);96孔板(Corning#3610);CellTiter-Glo(Promega#G7571)
试验方法:
1.KP-4细胞用含有10%胎牛血清和1%青霉素-链霉素的IMDM培养基于37℃、5%CO2条件下置于细胞培养箱中培养,处于对数生长期细胞方可用于后续试验。
2.将处于对数生长期的细胞接种在96孔板,接种数量为每孔500个细胞,于37℃、5%CO2条件下置于细胞培养箱中培养过夜。
3.使用DMSO溶解化合物,并用培养基稀释成10个不同的浓度(约10000、3333.3、1111.1、370、123、41.2、13.7、4.6、1.5和0.5nM)后加入细胞板中,于37℃、5%CO2条件下继续培养5天。
4.加入CellTiter-Glo试剂,使用酶标仪检测细胞活性。
数据分析:计算化合物抑制率(%),拟合得到受试化合物的IC50。化合物抑制率计算方法:化合物抑制率(%)=(Signal_max-Signal_sample)/(Signal_max-Signal_min)×100,其中:Signal_sample是样品孔读数,表示化合物抑制孔的细胞活性;Signal_min是阳性对照孔读数,表示没有细胞的本底活性;Signal_max是阴性对照孔读数,表示没有化合物抑制孔的细胞活性。
试验结果:在本试验条件下,待测化合物对KP-4细胞活性抑制的IC50值见表2。结果显示,相较于化合物1,本发明典型的化合物具有显著的抗肿瘤活性。
表2.人胰腺癌KP-4细胞活性抑制试验
测试例3、化合物13的体内抗肿瘤药效研究
使用人B细胞淋巴瘤DOHH-2细胞皮下异种移植肿瘤模型评价化合物13和AG-270(MAT2A抑制剂,)的体内抗肿瘤药效。
所用雌性CB-17SCID小鼠购自北京维通利华实验动物有限公司。肿瘤细胞培养及皮下接种:人B细胞淋巴瘤DOHH-2细胞(DSMZ)体外培养于含10%胎牛血清和1%双抗的RPMI-1640培养基中,37℃ 5%CO2孵箱培养。当细胞数量到达要求时,收取细胞,计数,将0.2mL(10×106个)DOHH-2细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到100~150mm3时开始随机分组,每组5只小鼠。给药组(化合物13或化合物AG-270)每天灌胃给药2次(给药剂量见表3),阴性对照组每天灌胃给以相同体积的空白溶媒。
实验指标及数据分析
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(%)或相对肿瘤增殖率T/C(%)评价。
TGI(%),反映肿瘤生长抑制率。TGI(%)的计算:TGI(%)=[(1-(给药组给药结束时平均瘤体积-该给药组开始给药时平均瘤体积))/(阴性对照组治疗结束时平均瘤体积-阴性对照组开始治疗时平均瘤体积)]×100%。
相对肿瘤增殖率T/C(%):计算公式如下:T/C%=TRTV/CRTV×100%(TRTV:给药组RTV;CRTV:阴性对照组RTV)。相对肿瘤体积(relative tumor volume,RTV),计算公式为RTV=Vt/V0,其中V0是分组给药时(即d0)测量所得平均肿瘤体积,Vt为某一次测量时的平均肿瘤体积,TRTV与CRTV取同一天数据。
实验结果:各组根据肿瘤体积增长曲线计算得到的TGI和T/C如表3所示,结果表明本发明化合物13展现了剂量相关性的体内药效。
表3.化合物13对人B细胞淋巴瘤DOHH-2异种移植肿瘤模型的抑瘤药效评价
Claims (10)
- 一种如式(I)所示的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,
其中,R1选自卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基磺酰基、C3-C7环烷基、3-6元杂环烷基、氰基、硝基、羧基、-NRaRa2、-NHCORa、-ORa、-SRa,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、3-6元杂环烷基为无取代或任选地被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C1-C10烷基、C3-C10环烷基、C6-C10芳基、5-10元杂芳基、3-6元杂环烷基、被一个或多个选自A组的取代基取代的C1-C10烷基、被一个或多个选自A组的取代基取代的C3-C10环烷基;A组取代基包括:D、卤素、C1-C3烷氧基、羟基、C6-C10芳基、5-10元杂芳基、无取代或被一个或多个选自A2组的取代基取代的C3-C10环烷基;所述A2组取代基包括:D、卤素、羟基、C1-C6烷基、C1-C10烷氧基;R2、R3各自独立地选自无取代或取代的C3-C10环烷基、无取代或取代的C6-C10芳基、无取代或取代的4-6元杂环烷基、无取代或取代的5-10元杂芳基;其中,所述取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基(-CN)、羟基(-OH)、氧代(=O)、巯基(-SH)、氨基(-NH2)、硝基(-NO2)、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基、-COOH、-CONHRb、-NHCORb、-NHSO2Rb;C组取代基包括:D、卤素、羟基、C3-C6环烷基、4-6元杂环烷基,C1-C4烷氧基;Rb选自H、C1-C4烷基、C3-C10环烷基、C1-C10烷氧基、C6-C10芳基,其中所述Rb中的C1-C4烷基、C3-C10环烷基、C1-C10烷氧基、C6-C10芳基为无取代或被选自卤素、羟基、氰基中的一个或多个取代;环A为五元杂芳环,其中,X、Y、Z中至多一个为CR4,其余各自独立地选自N、NR5、O、S;R4、R5各自独立地选自H、D、卤素、氨基、C1-C6烷基、C3-C6环烷基,所述C1-C6烷基、C3-C6环烷基为无取代或被羟基取代。 - 根据权利要求1所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,R1选自C1-C6烷基、C3-C7环烷基、3-6元杂环烷基、-ORa、-SRa、NRaRa2;所述C1-C6烷基、C3-C7环烷基、3-6元杂环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C7环烷基、无取代或被一个或多个选自A组的取代基取代的C1-C6 烷基,所述A组取代基包括:D、卤素、C1-C3烷氧基、羟基、C6-C10芳基、5-10元杂芳基、无取代或被一个或多个选自A2组的取代基取代的C3-C10环烷基;所述A2组取代基包括:D、卤素、羟基、C1-C6烷基、C1-C6烷氧基;R2、R3各自独立地选自无取代或取代的C3-C10环烷基、无取代或取代的C6-C10芳基、无取代或取代的5-10元杂芳基,所述取代是指被一个或多个选自B组的取代基所取代;所述B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、氧代基、无取代或取代的4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、羟基、C3-C6环烷基、4-6元杂环烷基、C1-C4烷氧基;特别地,所述5-10元杂芳基选自苯并5元杂芳基、苯并6元杂芳基、6元杂芳基并5元杂芳基、6元杂芳基并6元杂芳基、
- 根据权利要求1或2所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,R1选自C2-C6烷基、C3-C6环烷基、-ORa、-SRa、NRaRa2;所述C2-C6烷基、C3-C6环烷基为无取代或被一个或多个选自D、卤素的取代基所取代;Ra、Ra2各自独立地选自H、C3-C6环烷基、无取代或被一个或多个选自A组的取代基取代的C2-C6烷基,A组取代基包括:D、卤素、甲氧基、羟基、C3-C6环烷基;R2和R3各自独立地选自无取代或取代的环己基、无取代或取代的苯基、无取代或取代的5-10元杂芳基,所述5-10元杂芳基选自如下结构:
所述无取代或取代的苯基、无取代或取代的5-10元杂芳基中取代是指被一个或多个选自B组的取代基所取代,B组取代基包括:卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基;R5在每次出现时独立地为H、D、C1-C3烷基或C3-C6环烷基,所述C1-C3烷基、C3-C6环烷基为无取代或被羟基取代。 - 根据权利要求1-3任一项所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,R1选自C2-C6烷基、-ORa、NHRa;Ra选自C3-C6环烷基、无取代或被一个或多个选自A组的取代基所取代的C2-C6烷基;A组取代基包括:D、卤素、甲氧基、羟基、C3-C6环烷基;R2和R3各自独立地选自:其中,(R7)m表示在所在环上有m个相同或不同的R7取代基;m为1、2或3;R6和每个R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基,C1-C4烷氧基;优选地,m为1或2;R6和每个R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C2烷基、无取代或卤素取代的环丙基、无取代或卤素取代的C1-C2烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基,C1-C4烷氧基;R5在每次出现时独立地为H、甲基或羟乙基。
- 根据权利要求1-4任一项所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,R1选自C2-C6烷基、-ORa、-SRa、NHRa;Ra选自C3-C6环烷基、无取代的C2-C4烷基、卤素取代的C2-C4烷基、环丙基取代的C2-C4烷基、甲氧基取代的C2-C4烷基、羟基取代的C2-C4烷基;R2和R3各自独立地选自:其中,m为1、2或3;R6和R7各自独立地选自;H、卤素、氰基、羟基、巯基、硝基、氨基、4-6元杂环烷基、无取代或被一个或多个选自C组的取代基取代的C1-C4烷基、无取代或卤素取代的C3-C7环烷基、无取代或卤素取代的C1-C4烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、4-6元杂环烷基、C1-C4烷氧基;优选地,R6和R7各自独立地选自:H、卤素、氰基、羟基、巯基、硝基、氨基、 无取代或被一个或多个选自C组的取代基取代的C1-C3烷基、无取代或卤素 取代的环丙基、无取代或卤素取代的C1-C2烷氧基;C组取代基包括:D、卤素、C3-C6环烷基、羟基、甲氧基、优选地,R1选自丙基、-OC2H5、-SC2H5、-OCH2CF3、-NHCH3、-NHC2H5、R2选自其中,m为1、2或3;R8和R9各自独立地选自H、卤素、CN、甲氧基、被一个或多个卤素取代的甲基、被一个或多个卤素取代的甲氧基、环丙基;优选地,R2选自 其中,R8和R9各自独立地选自H、卤素、氰基、甲氧基、被一个或多个卤素取代的甲基、被一个或多个卤素取代的甲氧基、环丙基;R3选自 其中,m为1、2或3;R10和R11各自独立地选自氢、甲基、乙基、异丙基、氰基、甲氧基、羟基取代的乙基、甲氧基取代的乙基、环丙基、
- 根据权利要求1-5任一项所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,所述二并环类化合物选自如下结构:
优选地,所述二并环类化合物选自如下结构:
其中,R1、R2、R3、R5的定义同相应权利要求。 - 根据权利要求1所述的二并环类化合物,或其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物,其特征在于,所述二并环类化合物选自如下结构:
- 一种药物组合物,包含治疗有效剂量的选自权利要求1-7任一项所述的二并环类化合物、其可药用的盐、对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物、经同位素标记的化合物中的一种或多种,至少一种药学上可接受的载体,以及任选地,一种或多种其它治疗剂。
- 权利要求1-7任一项所述的二并环类化合物或其可药用的盐、其对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物或权利要求8所述药物组合物在制备用于抑制MAT2A活性的药物中的用途。
- 权利要求1-7任一项所述的二并环类化合物或其可药用的盐、其对映异构体、非对映异构体、外消旋体、阻转异构体、多晶型物、溶剂合物或经同位素标记的化合物或权利要求8所述药物组合物在制备治疗和/或预防MTAP相关疾病,特别是肿瘤的药物中的用途;优选地,所述肿瘤包括:MTAP缺失的肿瘤;MTAP低表达的肿瘤;MAT2A异常表达的肿瘤;其他MAT2A依赖的肿瘤;更优选地,所述肿瘤包括:乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
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