CN114014842B - Heterocyclic ketone compound and composition thereof, and preparation method and application thereof - Google Patents
Heterocyclic ketone compound and composition thereof, and preparation method and application thereof Download PDFInfo
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- CN114014842B CN114014842B CN202111298424.7A CN202111298424A CN114014842B CN 114014842 B CN114014842 B CN 114014842B CN 202111298424 A CN202111298424 A CN 202111298424A CN 114014842 B CN114014842 B CN 114014842B
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- Prior art keywords
- indazol
- benzyl
- methyl
- reaction
- trans
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- -1 Heterocyclic ketone compound Chemical class 0.000 title claims abstract description 176
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 239000000203 mixture Substances 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 108091005625 BRD4 Proteins 0.000 claims abstract description 11
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- GWTFQNZDRCSCTL-UHFFFAOYSA-N 5-(1-benzylindazol-6-yl)-4-ethoxy-1-methylpyridin-2-one Chemical compound CCOC(C(C1=CC=C(C=NN2CC3=CC=CC=C3)C2=C1)=CN1C)=CC1=O GWTFQNZDRCSCTL-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 125000004431 deuterium atom Chemical group 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 208000006454 hepatitis Diseases 0.000 claims 1
- 231100000283 hepatitis Toxicity 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract description 4
- 239000000651 prodrug Substances 0.000 abstract description 4
- 229940002612 prodrug Drugs 0.000 abstract description 4
- 239000012453 solvate Substances 0.000 abstract description 4
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- 238000006243 chemical reaction Methods 0.000 description 108
- 239000007787 solid Substances 0.000 description 69
- 238000004440 column chromatography Methods 0.000 description 54
- 230000015572 biosynthetic process Effects 0.000 description 53
- 238000003786 synthesis reaction Methods 0.000 description 53
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
- 239000012074 organic phase Substances 0.000 description 50
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
- 238000000746 purification Methods 0.000 description 50
- 238000000967 suction filtration Methods 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 32
- 239000002904 solvent Substances 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 description 25
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 23
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 238000005086 pumping Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 8
- WMKDUJVLNZANRN-UHFFFAOYSA-N 6-bromo-1h-indazole Chemical compound BrC1=CC=C2C=NNC2=C1 WMKDUJVLNZANRN-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- OCFPVZWXLARJEV-UHFFFAOYSA-N 5-bromo-4-ethoxy-1-methylpyridin-2-one Chemical compound CCOC1=CC(=O)N(C)C=C1Br OCFPVZWXLARJEV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000004438 haloalkoxy group Chemical group 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229940057995 liquid paraffin Drugs 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
- 102000001805 Bromodomains Human genes 0.000 description 4
- 108050009021 Bromodomains Proteins 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
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- PSRARXVEBZQEML-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1CBr PSRARXVEBZQEML-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000009739 binding Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 150000001924 cycloalkanes Chemical class 0.000 description 3
- 238000011161 development Methods 0.000 description 3
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- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- KVQRSOCDPMASRB-UHFFFAOYSA-N 1-benzyl-6-bromoindazole Chemical compound C12=CC(Br)=CC=C2C=NN1CC1=CC=CC=C1 KVQRSOCDPMASRB-UHFFFAOYSA-N 0.000 description 2
- UQGNSLYYFIRZOM-UHFFFAOYSA-N 1-benzyl-6-bromoindole Chemical compound C12=CC(Br)=CC=C2C=CN1CC1=CC=CC=C1 UQGNSLYYFIRZOM-UHFFFAOYSA-N 0.000 description 2
- UTNQRBGIIRUPOO-UHFFFAOYSA-N 5-bromo-4-fluoro-1-methylpyridin-2-one Chemical compound BrC=1C(=CC(N(C=1)C)=O)F UTNQRBGIIRUPOO-UHFFFAOYSA-N 0.000 description 2
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 2
- DXVPKKRFBPLRRN-UHFFFAOYSA-N 6-bromo-2,3-dihydro-1h-inden-1-ol Chemical compound C1=C(Br)C=C2C(O)CCC2=C1 DXVPKKRFBPLRRN-UHFFFAOYSA-N 0.000 description 2
- SEQHEDQNODAFIU-UHFFFAOYSA-N 6-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2CCC(=O)C2=C1 SEQHEDQNODAFIU-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
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- 150000001447 alkali salts Chemical class 0.000 description 2
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- 235000019270 ammonium chloride Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
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- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
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- YPWAJLGHACDYQS-UHFFFAOYSA-N (2-methoxypyrimidin-5-yl)boronic acid Chemical compound COC1=NC=C(B(O)O)C=N1 YPWAJLGHACDYQS-UHFFFAOYSA-N 0.000 description 1
- IBLMYGXJKQIGSN-UHFFFAOYSA-N 1-(bromomethyl)-2,4-difluorobenzene Chemical compound FC1=CC=C(CBr)C(F)=C1 IBLMYGXJKQIGSN-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention relates to a heterocyclic ketone compound, a pharmaceutical composition, a preparation method and application thereof. The invention specifically discloses pyridones shown in a general formula I, or pharmaceutically acceptable salts, prodrugs, isomers, racemates, precursors or solvates thereof. The heterocyclic ketone compound is a high-efficiency and high-selectivity BRD4 inhibitor, and has good treatment effects on inflammation, autoimmune diseases and various cancers, such as prostate cancer and the like. The invention also discloses the preparation of the compound shown in the general formula I.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a heterocyclic ketone compound and a composition thereof, and a preparation method and application thereof.
Background
The bromodomain and the super terminal domain (BET) belong to bromodomain protein families, play an important role in regulating the cell cycle and mediating gene transcription, and further participate in regulating the process of tumorigenesis and development. Is a potential drug target.
The human BET family consists of BRD2, BRD3, BRD4, BRDT. The BET protein family consists of two conserved bromodomains (BD 1, BD 2) and one super terminal domain (ET). BRD2 is expressed mainly in spermatocytes and round sperm cells, regulating the development of neurons; BRD3 is highly expressed in the ovary, uterus, placenta and brain, transcriptionally regulating the hematopoietic process; BRDT is specifically present in testes and affects gene expression in sperm. BRD4 studies are most widespread compared to the other three members. BRD4 is overexpressed in various tumors, such as ovarian cancer, melanoma, etc., recognizes and binds to histone acetylated lysines, recruits chromatin regulatory factors, promotes gene transcription, and promotes tumor development. Studies have shown that many human diseases have a close relationship with BRD4 proteins, such as tumors, autoimmune or inflammatory diseases, viral infections, and the like. Among them, the BRD4 protein-associated tumors include breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, and hematopoietic system tumors.
Therefore, the development of drugs that inhibit the binding of bromodomains to acetylated lysine residues on histones can be effectively used to treat the above-mentioned diseases.
Disclosure of Invention
Object of the Invention
The invention provides a BRD4 inhibitor which is different from the prior art, and one of the technical problems to be solved by the invention is to provide a novel pyridone compound which provides possibility for subsequent drug development.
Technical proposal
A compound shown in a general formula I, pharmaceutically acceptable salts, prodrugs, isomers, racemates, precursors or solvates thereof, is characterized in that the structural formula is shown in the formula I,
wherein,
R 1 is hydrogen, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl; wherein saidC of (2) 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl groups may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano, and the like;
z is CR 5 Or NR (NR) 6 ；
Y is CR 7 Or NR (NR) 8 ；
R 5 -R 7 Independently selected from hydrogen, deuterium atom, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C 1 -C 3 Alkyl, C 1 -C 3 An alkoxy group;
R 8 independently selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl; wherein said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl groups may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano, and the like;
each of which isIndependently a single bond or a double bond, provided that:
(1) When (when) When it is a single bond, Z is CR 5 Y is NR 8 ；R 5 And R is 8 The substitutions are as described above;
(2) When (when)In the case of a double bond, Z and Y can be any combination of C, N;
R 2 independently selected from hydrogen, deuterium atoms, halogens, amino groups, -OR 9 、C 6- C 12 Aromatic ring, C 6 -C 12 A heteroaromatic ring; wherein said C 6- C 12 Aromatic ring, C 6 -C 12 Heteroaryl ring is independentIs substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, C 1 -C 3 Alkyl, -N (R) 10-1 )C(O)R 10-2 、-N(R 10-3 )S(O) 2 R 10-4 、-CON(R 10-5 ) 2 Substitution with an isosubstituted substituent;
R 9 is C 1 -C 4 Alkyl, C 3 -C 12 Cycloalkane, C 3 -C 12 A heterocyclic alkane; wherein said C 3 -C 12 Cycloalkane, C 3 -C 12 The heterocycloalkane may be a single ring, a parallel ring, a spiro ring, or a bridged ring; the C is 3 -C 6 The heterocyclic alkane is 3-6 membered heterocyclic alkyl with 1-3 hetero atoms, wherein the hetero atoms are one or more selected from N, O or S; the C is 1 -C 6 Alkyl, C 3 -C 6 Cycloalkane, C 3 -C 6 The heterocycloalkyl(s) can optionally be substituted with one or more groups independently selected from halogen, amino, oxo, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, -N (R) 9-1 )C(O)R 9-2 Or, -N (R) 9-3 )S(O) 2 R 9-4 Substitution with an isosubstituted substituent;
R 9-1 ～R 9-4 independently selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkanes, C 3 -C 6 Cycloalkyl or "heteroatom is selected from one or more of N, O or S, 3-6 membered" heterocycloalkyl with 1-3 heteroatoms; wherein said C 3 -C 6 Cycloalkyl or "heteroatom selected from one or more of N, O or S, 3-6 membered" heterocycloalkyl having 1-3 heteroatoms optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, and the like;
R 10-1 ～R 10-5 independently selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkanes, or C 3 -C 6 Is a cycloalkane of (2);
R 3 is hydrogen, unsubstituted or R 11 Substituted C 1 -C 6 Alkyl, -C (O) N (R) 11-1 )(R 11-2 )、-N(R 11-3 )COR 11-4 、-N( 11-5 )SO 2 R 11-6 Or (b),
R 11-1 ～R 11-8 Independently selected from hydrogen, C 1 -C 3 Alkyl, C 1- C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl or C 3 -C 6 Cycloalkyl;
ring A is selected from saturated C 3 -C 6 Carbocyclic, saturated C 3 -C 6 Heterocyclic, unsaturated C 5 -C 10 Carbocycles, aromatic rings; wherein the saturated C 3 -C 6 Heterocyclic, unsaturated C 5 -C 10 The carbocycle is a heterocyclic ring of which hetero atoms are 1-3 and are selected from one or more of N, O or S; said saturated C 3 -C 6 Carbocyclic, saturated C 3 -C 6 Heterocyclic, unsaturated C 5 -C 10 Carbocycles, aromatic rings are independently substituted with one or more substituents independently selected from halogen, amino, nitro, cyano, hydroxy, oxo, alkoxy, haloalkoxy, hydroxyalkyl, and the like;
w is independently selected from C (R) 12 ) n N, O, S; wherein n represents 0, 1, 2; r is R 12 Is hydrogen or C 1 -C 3 Alkane, C 1- C 3 Deuterated alkyl, C 1 -C 3 Haloalkyl or C 3 -C 6 Cycloalkyl;
R 4 independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, haloalkoxy, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkanes, C 1 -C 3 An alkoxy group;
p represents 0, 1,2 or 3;
the halogen is selected from fluorine, chlorine, bromine and iodine;
the compound shown in the general formula I, pharmaceutically acceptable salts, prodrugs, isomers, racemates, precursors or solvates thereof according to any one of the present invention is characterized in that the compound shown in the general formula I is any one of the following compounds:
5- (1-benzyl-1H-indazol-6-yl) -1-methylpyrimidin-2 (1H) -one (I-1)
5- (1-benzyl-1H-indazol-6-yl) -1-methyltetrahydropyrimidin-2 (1H) -one (I-2)
5- (1-benzyl-1H-indazol-6-yl) -1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (I-3)
6- (1-benzyl-1H-indazol-6-yl) -5-ethoxy-2-methylpyridazin-3 (2H) -one (I-4)
5- (1-benzyl-1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-5)
N- (4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) methanesulfonimide (I-6)
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide (I-7)
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) -N-methylacetamide (I-8)
trans-N- ((4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) methylsulfonamide (I-9)
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) cyclopropanecarboxamide (I-10)
Trans-4- (8-acetyl-8-azabicyclo [3.2.1] oct-3-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-11)
Trans-5- (1-benzyl-1H-indazol-6-yl) -1-methyl-4- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) pyridin-2 (1H) -one (I-12)
4- ((1-Acetylpiperidin-4-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-13)
(R) -4-ethoxy-1-methyl-5- (1- (1-phenethyl) -1H-indazol-6-yl) pyridin-2 (1H) -one (I-14)
5- (1- (2, 4-difluorobenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-15)
5- (1- (2, 6-dimethylbenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-16)
5- (1-benzyl-1H-indol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-17)
4-ethoxy-1-methyl-5- (3-phenoxy-2, 3-dihydro-1H-inden-5-yl) pyridin-2 (1H) -one (I-18)
Trans-6- (4- ((4-acetaminocyclohexyl) oxo) -1-methyl-6-carbonyl-1, 6-dihydropyridin-3-yl) -1-benzyl-N-methyl-1H-indazole-4-carboxamide (I-19)
trans-N- (4- ((5- (1-benzyl-4- (hydroxymethyl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-20)
trans-N- (4- ((5- (1-benzyl-4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-21)
trans-N- (4- ((5- (1- (2, 6-dimethylbenzyl) -4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-22)
The structure of the compounds is shown in the following table:
the invention also provides a preparation method of the compound shown in the formula I, which is characterized by comprising the following steps:
therein, Z, Y, R 1 、R 2 、R 3 、R 4 The definition of A, W is as described above.
Intermediate 1 and intermediate 2 are coupled by Suzuki in an anaerobic solvent to give I, preferably at a reaction time of 8-12 hours, preferably at a reaction temperature of 100-110deg.C, and preferably in a reaction solvent of 1, 4-dioxane and water. The preparation of I adopts a conventional preparation method.
In the present invention, after the substitution reaction is completed, it may further comprise a post-treatment step. The conditions and operations of the post-treatment may be those conventional in the art, including the steps of: cooling the reaction liquid, adding a solvent, extracting to obtain an organic layer, drying, filtering, removing the solvent in the filtrate to obtain a residue, and separating and purifying the residue. The cooling is preferably to room temperature. The solvent is preferably saline, for example, saturated saline. The conditions and operations of the extraction may be those conventional in the art, and the solvent of the extraction is preferably an ester solvent such as ethyl acetate. The drying conditions and operations may be those conventional in the art, and the drying agent may be those conventional in the art, such as anhydrous sodium sulfate. The conditions and operations of the filtration may be those conventional in the art. The conditions and operations for removing the solvent may be those conventional in the art, such as evaporating the solvent. The separation and purification are preferably column chromatography separation.
The term "room temperature" as used herein means 20-30℃unless otherwise specified.
The invention also provides a pharmaceutical composition, which comprises a compound shown in a general formula I, or pharmaceutically acceptable salt, ester prodrug, isomer, racemate, precursor or solvate thereof, and pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound shown in the general formula I or pharmaceutically acceptable salt, ester or pharmaceutical composition thereof in preparing a BET inhibitor, in particular to application in preparing a BRD4 protein inhibitor.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt and ester thereof in preparing medicines. The invention also provides a compound shown in the formula I, or pharmaceutically acceptable salt and ester thereof, and the medicament can be used for tumors.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating tumors.
In the present invention, the tumors include, but are not limited to, breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, and hematopoietic system tumors. The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
In the compounds of the invention, when any variable occurs more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds of interest that are chemically stable and readily synthesized from readily available starting materials by one of ordinary skill in the art and the methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with mammalian, especially human, tissues without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and are well known in the art.
The term "pharmaceutically acceptable ester" refers to a compound that is composed of a compound and an acid, such as a phosphate, carboxylate, sulfonate, and the like.
The compounds of the present invention may form salts. The term "salt" as used herein refers to acid salts with inorganic or organic acids, as well as basic salts with inorganic or organic bases. In addition, when the compounds have a basic moiety (e.g., pyridine, imidazole, etc.) and an acidic moiety (e.g., carboxylic acid), a zwitterionic ("inner salt") may be formed and is also included in the term "salt" as used herein. Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of the compounds are formed by reaction with suitable inorganic or organic bases. Pharmaceutically acceptable, non-toxic, physiologically acceptable salts are preferred, although other salts are also useful. Exemplary non-toxic acid salts include salts prepared from inorganic acids, such as hydrochloric, sulfuric, hydrobromic, sulfamic, phosphoric, nitric, and the like, and also from organic acids, such as acetic, propionic, succinic, glycolic, acetic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, glycerophosphoric, salicylic, sulfanilic, fumaric, 2-acetoxy-benzoic, fumaric, p-toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, hydroxyethanesulfonic, trifluoroacetic, and the like. Exemplary non-toxic basic salts include salts from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like, as well as salts from organic bases including salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, beet, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, methylglucamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine, and the like.
The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Alkyl groups having 1 to 3 carbon atoms are preferred, with methyl and ethyl groups being most preferred. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, as well as various branched isomers thereof and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained. The reagents and materials used in the present invention are commercially available.
Detailed Description
For a better understanding of the present invention, the present invention is further illustrated by the following examples, but the content of the present invention is not limited to the following examples only.
Example 1:5- (1-benzyl-1H-indazol-6-yl) -1-methylpyrimidin-2 (1H) -one (I-1)
Step one: synthesis of intermediate 1-benzyl-6-bromo-1H-indazole (A-002)
6-bromo-1H-indazole (A-001) (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. Benzyl bromide (1.2 eq) was slowly added dropwise at 0deg.C, the flask was brought to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-002 with 67 percent of yield. 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝1.0Hz,1H),7.60(dd,J＝8.5,0.7Hz,1H),7.53(m,1H),7.35–7.26(m,3H),7.24(dd,J＝8.5,1.5Hz 1H),7.21-7.16(m,2H),5.55(s,2H).
ESI-MS(m/z):287.0[M+H]+
Step two: synthesis of intermediate 1-benzyl-6- (2-methoxypyrimidin-5-yl) -1H-indazole (A-003)
A-002 (2.0 g,6.96mmol,1 eq), 2-methoxy-5-pyrimidine-boronic acid (1.28 g,1.2 eq), potassium carbonate (1.92 g,2 eq) and Pd (dppf) Cl 2 (50.9 mg,1% mmol) was added to a 100mL eggplant-type bottle. 27mL dioxane, 3mL water was added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 8 hours. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-003 with the yield of 79 percent. 1 H NMR(300MHz,Chloroform-d)δ8.71(s,2H),8.10(d,J＝0.8Hz,1H),7.85(dd,J＝8.28,0.68Hz,1H),7.41-7.38(m,1H),7.36–7.27(m,4H),7.25–7.19(m,2H),5.66(s,2H),4.07(s,3H).ESI-MS(m/z):317.1[M+H]+
Step three: synthesis of intermediate 5- (1-benzyl-1H-indazol-6-yl) pyrimidin-2 (1H) -one (A-004)
A-003 (1.70 g,5.37mmol,1 eq) was added to the tomatoIn the flask, 9mL hydrobromic acid and 11mL glacial acetic acid were added and heated at reflux for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid A-004, and the yield is 90%. 1 H NMR(300MHz,DMSO-d 6 )δ9.05(s,2H),8.16(s,1H),8.15(s,1H),7.87(d,J＝8.4Hz,1H),7.46(dd,J＝8.5,1.4Hz,1H),7.34–7.20(m,5H),5.69(s,2H).
ESI-MS(m/z):303.1[M+H]+
Step four: synthesis of 5- (1-benzyl-1H-indazol-6-yl) -1-methylpyrimidin-2 (1H) -one (I-1)
A-004 (2.50 g,8.81mmol,1 eq) and cesium carbonate (1.2 eq) were placed in a 100mL single-necked flask, 15mL DMF was added and stirred at room temperature, methyl iodide (1.2 eq) was added dropwise, the reaction was stopped at room temperature for 10min, 100mL ethyl acetate was added, then washed with saturated sodium chloride solution (15 mL X5), concentrated and purified by column chromatography to give white solid I-1 in 73% yield. m.p.182.6-184.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.86(d,1H,J＝3.3Hz),8.08(s,1H),7.85(d,1H,J＝3.3Hz),7.83(d,1H,J＝8.6Hz),7.36-7.27(m,4H),7.23-7.13(m,3H),5.99(s,1H),5.65(s.2H),3.66(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ165.0,156.0,146.1,139.8,136.4,133.3,131.3,128.6,127.7,126.9,123.6,122.1,119.0,118.3,106.1,52.7,39.3；HRMS(ESI)calcd for C 19 H 17 N 4 O + [M+H] + 317.1397,found 317.1390.
Example 2:5- (1-benzyl-1H-indazol-6-yl) -1-methyltetrahydropyrimidin-2 (1H) -one (I-2)
Step one: synthesis of 5- (1-benzyl-1H-indazol-6-yl) -1-methyltetrahydropyrimidin-2 (1H) -one (I-2)
I-1 (500 mg,1.58mmol,1 eq) and 10% palladium hydroxide were placed in a single-necked flask, 10mL of methanol was added to replace hydrogen, and the mixture was reacted overnight at room temperature in a hydrogen atmosphere. After the reaction is monitored by the spot plate, the white solid is obtained by suction filtration and concentrationI-1, yield 86%. m.p.94.3-95.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.01(d,1H,J＝0.7Hz),7.70(d,1H,J＝8.4Hz),7.34-7.23(m,3H),7.22-7.15(m,3H),7.00(dd,1H,J＝8.4,1.1Hz),5.77(s,1H),5.58(s,2H),3.50-3.40(m,3H),3.40-3.30(m,2H),2.95(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ156.6,139.8,138.2,136.7,133.3,128.8,127.9,127.2,123.8,121.6,120.5,107.6,53.7,53.0,46.5,39.1,35.2；HRMS(ESI)calcd for C 19 H 21 N 4 O + [M+H] + 321.1710,found 321.1709.
example 3:5- (1-benzyl-1H-indazol-6-yl) -1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (I-3)
Step one: synthesis of 5- (1-benzyl-1H-indazol-6-yl) -1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (I-3)
I-2 (100 mg,0.31mmol,1 eq) was dissolved in 2mL DMF and methyl iodide (29 uL,1.5 eq) was added dropwise and stirred for 1.5h. The reaction was stopped, extracted with 20mL of ethyl acetate, washed with saturated sodium chloride solution (5 mL of X5), concentrated, and purified by column chromatography to give white solid I-3 in 72% yield. m.p.108.0-109.6 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.03(d,1H,J＝0.7Hz),7.71(d,1H,J＝8.4Hz),7.35-7.23(m,3H),7.22-7.14(m,3H),7.02(dd,1H,J＝8.4,1.2Hz),5.59(s,2H),3.56-3.30(m,5H),2.96(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ156.3,139.7,138.2,136.6,133.2,128.7,127.8,127.1,123.7,121.6,120.4,107.5,54.0,52.9,38.9,35.8；HRMS(ESI)calcd for C 20 H 23 N 4 O + [M+H] + 335.1866,found 335.1861.
example 4:6- (1-benzyl-1H-indazol-6-yl) -5-ethoxy-2-methylpyridazin-3 (2H) -one (I-4)
Step one: synthesis of intermediate 1-benzyl-6- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indazole (A-005)
A-002 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-005 with the yield of 74 percent. ESI-MS (m/z): 335.2[ M+H ] +
Step two: synthesis of 6- (1-benzyl-1H-indazol-6-yl) -5-ethoxy-2-methylpyridazin-3 (2H) -one (I-4)
A-005 (1 eq), 6-bromo-5-ethoxy-2-methylpyridazin-3 (2H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-4, and the yield is 71%. m.p.151.0-152.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.08(s,1H),7.79(d,1H,J＝8.4Hz),7.75(s,1H),7.50(dd,1H.J＝8.4,1.0Hz),7.35-7.27(m,3H),7.23-7.16(m,2H),6.25(s,1H),5.64(s,2H),4.03(q,2H,J＝7.0Hz),3.81(s,3H),1.32(t,3H,J＝7.0Hz)； 13 C NMR(75Hz,CDCl 3 )165.1,156.0,146.0,139.8,136.4,133.3,131.4,128.6,127.7,126.9,123.7,122.1,119.0,118.4,106.1,52.8,39.4；HRMS(ESI)calcd for C 21 H 21 N 4 O 2 + [M+H] + 361.1659,found 361.1658.
example 5:5- (1-benzyl-1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-5)
Step one: synthesis of 5- (1-benzyl-1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-5)
A-005 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-5, and the yield is 84%. m.p.49.1-50.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.06(s,1H),7.73(d,1H,J＝8.4Hz),7.37(s,1H),7.35-7.27(m,3H),7.23-7.14(m,4H),5.99(s,1H),5.61(s.2H),4.00(q,2H,J＝7.0Hz),3.54(s,3H),1.26(t,3H,J＝7.0Hz)； 13 C NMR(101MHz,CDCl 3 )δ164.8,163.7,139.6,137.7,136.8,133.1,132.1,128.6,127.6,126.9,123.3,122.4,120.5,115.1,109.4,97.2,64.1,52.7,36.6,13.9；HRMS(ESI)calcd for C 22 H 22 N 3 O 2 + [M+H] + 360.1707,found 360.1705.
example 6: n- (4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) methanesulfonimide (I-6)
Step one: synthesis of intermediate 5- (1-benzyl-1H-indazol-6-yl) -4-chloro-1-methylpyridin-2 (1H) -one (A-006)
A-005 (1 eq), 5-bromo-4-chloro-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-006 with 67% yield. 1 H NMR(300MHz,Chloroform-d)δ8.08(d,J＝1.0Hz,1H),7.77(dd,J＝8.3,0.8Hz,1H),7.35–7.27(m,4H),7.24-7.19(m,2H),7.11(dd,J＝8.3,1.4Hz,1H),6.77(s,1H),5.63(s,2H),3.57(s,3H).
ESI-MS(m/z):350.1[M+H]+
Step two: synthesis of N- (4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) methanesulfonimide (I-6)
A-006 (100 mg,0.28mmol,1 eq), 4-methanesulfonylaminophenyl boronic acid pinacol ester (99.8 mg,0.34mmol,1.2 eq), pd 2 (dba) 3 (2mol％)，P(Cy) 3 (6%) and potassium carbonate (3 eq) were added to a single flask, dioxane and t-butanol (4:1, 0.2M) were added and reacted at 120℃for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-6, and the yield is 87%. m.p.216.9-219.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ9.94(s,1H),8.09(s,1H),7.90(s,1H),7.63(d,1H,J＝8.1Hz),7.58(s,1H),7.41-7.27(m,3H),7.20(d,2H),7.11(s,4H),6.78(d,1H,J＝8.1Hz),6.47(s,1H),5.58(s,2H),3.58(s,3H),3.02(s,3H)
13 C NMR(101MHz,CDCl 3 )δ161.1,151.4,140.1,139.5,138.4,137.4,135.0,133.2,132.9,129.6,128.5,127.50,127.47,122.9,122.2,120.3,118.8,118.5,118.3,110.0,51.7,36.5；HRMS(ESI)calcd for C 27 H 25 N 4 O 3 S + [M+H] + 485.1642,found 485.1636.
example 7: n- ((1 r,4 r) -4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide (I-7)
Step one: synthesis of intermediate 5- (1-benzyl-1H-indazol-6-yl) -4-fluoro-1-methylpyridin-2 (1H) -one (A-007) A-005 (1 eq), 5-bromo-4-fluoro-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single vial. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the spot-plate monitoring reaction, the solvent was dried by spinning, extracted with 100mL of ethyl acetate, washed with saturated brine for 5 times, and dried The organic phase was dried over sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-007 with the yield of 45 percent. 1 H NMR(300MHz,Chloroform-d)δ8.09(d,J＝1.0Hz,1H),7.81(dd,J＝8.4,0.8Hz,1H),7.43(d,J＝9.3Hz,1H),7.38–7.29(m,4H),7.25-7.20(m,2H),7.17(dt,J＝8.4,1.6Hz,1H),6.37(d,J＝12.1Hz,1H),5.65(s,2H),3.62(s,3H).
ESI-MS(m/z):334.1[M+H]+
Step two: synthesis of intermediate trans-tert-butyl-4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) carbamate (A-008)
Trans-tert-butyl- (4-hydroxycyclohexyl) carbamate (2.0 g,9.3mmol,1.2 eq) was dissolved in 40mL THF, placed in a low temperature reaction bath at 0deg.C, sodium hydride (744 mg,60%, dispersed in liquid paraffin) was slowly added, and stirred at 0deg.C for 30min. A-007 (2.58 g,7.75mmol,1 eq) was then dissolved in 10mL THF and added dropwise to the reaction system and the flask was moved to 60℃for overnight reaction. After the completion of the reaction, the reaction mixture was spotted on a plate, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain an organic phase. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-008 with the yield of 75 percent. Delta 8.08 (d, j=1.0 hz, 1H), 7.36-7.30 (m, 5H), 7.21 (s, 1H), 7.19 (dd, j=7.4, 2.1hz, 1H), 7.16-7.12 (m, 2H), 6.00 (s, 1H), 5.63 (s, 2H), 4.50-4.36 (m, 1H), 4.25-4.09 (m, 2H), 3.55 (s, 3H), 2.19-2.05 (m, 4H), 1.62-1.50 (m, 2H), 1.27 (s, 9H), 1.28-1.16 (m, 2H) ESI-MS (m/z): 529.3[ m+h ] +
Step three: synthesis of trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide (I-7)
A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and acetyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-7, and the yield of the two steps is 60 percent. m.p.206.0-208.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.06(s,1H),7.73(d,1H,J＝8.4Hz),7.35-7.28(m,4H),7.22(s,1H),7.18-7.14(m,2H),7.12(d,1H,J＝8.4Hz),6.12-6.04(m,1H),5.96(s,1H),5.61(s,2H),4.22-4.13(m,1H),3.81-3.69(m,1H),3.53(s,3H),2.09-1.98(m,4H),1.97(s,3H),1.40-1.17(m,4H).； 13 C NMR(101MHz,CDCl 3 )δ169.5,163.7,139.5,138.1,136.8,133.1,132.0,128.7,127.7,126.7,123.4,122.4,120.7,115.7,109.5,97.6,75.5,52.8,46.9,36.7,30.0,29.2,23.3；HRMS(ESI)calcd for C 28 H 31 N 4 O 3 + [M+H] + 471.2391,found 471.2388.
example 8: n- ((1 r,4 r) -4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) -N-methylacetamide (I-8)
Step one: synthesis of trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) -N-methylacetamide (I-8)
I-7 (80 mg,0.17mmol,1 eq) was dissolved in 5mL DMF and placed in a low temperature reaction bath at 0deg.C, sodium hydride (27.2 mg,60% dispersed in liquid paraffin) was slowly added and stirred for 30min. Methyl iodide (32 uL,3 eq) was added dropwise at 0deg.C, and the mixture was allowed to react overnight at 50deg.C. The reaction was stopped, extracted with 15mL of ethyl acetate, washed with saturated sodium chloride solution (5 mL of X5), concentrated, and purified by column chromatography to give white solid I-8 in 78% yield. m.p.79.4-81.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.06(s,1H),7.73(d,1H,J＝8.5Hz),7.39-7.28(M,3H),7.24-7.09(m,4H),5.99(s,1H),5.62(s,2H),4.57-4.39(m,1H),4.22-4.04(m,1H),3.53(s,3H),2.84(s,1H),2.80(s,1H),2.24-2.05(m,2H),2.09(s,3H),1.73-1.61(m,2H),1.55-1.23(m,4H)； 13 C NMR(101Hz CDCl 3 )170.4,163.74,163.65,139.4,138.0,136.8,133.1,132.0,128.7,127.8,126.7,123.4,122.3,120.6,115.6,109.5,97.6,75.7,56.1,52.8,50.5,36.7,30.1,29.9,27.9,26.9,22.4；HRMS(ESI)calcd for C 29 H 33 N 4 O 3 + [M+H] + 485.2547,found 485.2541.
Example 9: trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) methylsulfonamide (I-9)
Step one: synthesis of trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) methylsulfonamide (I-9)
A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and methylsulfonyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-7, and the yield of the two steps is 69 percent. m.p.218.0-220.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.17(s,1H),7.85-7.76(m,2H),7.71(s,1H),7.42-7.28(m,3H),7.27-7.19(m,3H),7.14(d,1H,J＝7.1Hz),6.06(s,1H),5.72(s,2H),4.48-4.32(m,1H),3.46(s,3H),3.25-3.08(m,1H),2.96(s,3H),2.07-1.93(m,2H),1.92-1.79(m,2H),1.52-1.34(m,2H),1.33-1.16(m,2H)； 13 C NMR(75MHz,DMSO)δ162.9,162.6,139.6,139.4,137.8,133.0,132.3,128.6,127.4,127.0,122.6,122.4,120.3,113.4,109.7,96.8,74.2,51.7,50.7,40.8,35.9,30.4,28.8；HRMS(ESI)calcd for C 27 H 31 N 4 O 4 S + [M+H] + 507.2061,found 507.2060.
example 10: trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) cyclopropanecarboxamide (I-10)
Step one: synthesis of trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) cyclopropanecarboxamide (I-10)
A-008 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at room temperature for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and cyclopropylcarbonyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-10, and the yield of the two steps is 75%. m.p.119.4-121.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.07(s,1H),7.73(d,1H,J＝8.1Hz),7.36-7.28(m,4H),7.23-7.08(m,4H),6.00(s,1H),5.62(s,2H),5.48(d,1H,J＝7.1Hz),4.25-4.12(m,1H),3.84-3.71(m,1H),3.54(s,3H),2.11-1.94(m,5H),1.35-1.194H),1.01-0.92(m,2H),0.79-0.69(m,2H)； 13 C NMR(75MHz,CDCl 3 )δ172.9,163.8,163.8,139.5,138.1,136.8,133.2,132.0,128.7,127.8,126.7,123.4,122.4,120.7,115.8,109.5,97.6,75.6,52.8,47.0,36.8,30.2,29.2,14.6,7.1；HRMS(ESI)calcd for C 30 H 33 N 4 O 3 + [M+H] + 497.2547,found 497.2542.
Example 11: trans-4- (8-acetyl-8-azabicyclo [3.2.1] oct-3-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-11)
Step one: synthesis of intermediate trans-tert-butyl (3- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (A-009)
Trans-3-hydroxy-8-azabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (2.0 g,9.3mmol,1.2 eq) was dissolved in 40mL THF, placed in a low temperature reaction bath at 0deg.C, sodium hydride (744 mg,60% dispersed in liquid paraffin) was slowly added, and stirred at 0deg.C for 30min. A-007 (2.58 g,7.75mmol,1 eq) was then dissolved in 10mL of HF and added dropwise to the reaction system, and the flask was moved to 60℃for overnight reaction. After the spot plate monitoring reaction is completed, ethyl acetate extraction and saturated salt water washing are carried out,the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-009 with a yield of 78%. 1 H NMR(300MHz,Chloroform-d)δ8.08(d,J＝0.9Hz,1H),7.74(dd,J＝8.3,0.8Hz,1H),7.35–7.25(m,5H),7.17–7.09(m,3H),5.88(s,1H),5.62(s,2H),4.55(t,J＝4.5Hz,1H),4.07–3.87(m,2H),3.53(s,3H),2.05-1.92(m,2H),1.81-1.69(m,2H),1.44(s,9H),1.24–1.18(m,2H).
ESI-MS(m/z):541.3[M+H]+
Step two: synthesis of trans-4- (8-acetyl-8-azabicyclo [3.2.1] oct-3-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-11)
A-009 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at RT for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and acetyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-11, and the yield of the two steps is 46%. m.p.120.0-121.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.09(d,1H,J＝0.8Hz),7.75(d,1H,J＝8.4Hz),7.35-7.27(m,4H),7.22-7.08(m,4H),5.85(s,1H),5.62(s,2H),4.60-4.52(m,1H),4.48-4.41(m,1H),3.92-3.85(m,1H),3.53(s,3H),2.15-2.06(m,1H),2.00(s,3H),1.96-1.90(m,2H),1.86-1.77(m,1H),1.39-1.22(m,4H)； 13 C NMR(101MHz,CDCl 3 )δ165.3,162.9,162.6,139.43,139.39,137.8,133.1,132.39,128.5,127.4,127.0,122.74,122.65,120.3,113.9,110.0,96.6,70.5,53.1,51.5,49.3,35.8,35.3,33.7,27.8,26.2,21.3；HRMS(ESI)calcd for C 29 H 31 N 4 O 3 + [M+H] + 483.2391,found 483.2389.
Example 12: trans-5- (1-benzyl-1H-indazol-6-yl) -1-methyl-4- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) pyridin-2 (1H) -one (I-12)
Step one: trans-5- (1-benzyl-1H-indazol-6-yl) -1-methyl-4- (8- (methylsulfonyl) -8-azabicyclo [ 3.2.1)]Synthesis of octan-3-yloxy) pyridin-2 (1H) -one (I-12) A-009 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at RT for 2H and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and methylsulfonyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-12, and the yield of the two steps is 55%. m.p.189.0-190.6 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.08(s,1H),7.74(d,1H,J＝8.3Hz),7.34-7.27(m,4H),7.21-7.06(m,4H),5.85(s,1H),5.62(s,2H),4.53(t,1H,J＝4.8Hz),4.00(s,2H),3.53(s,3H),2.79(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ163.7,163.1,139.4,138.0,136.9,133.3,132.2,128.7,127.7,126.7,123.5,122.8,120.8,115.8,109.7,97.7,70.3,60.3,55.1,52.8,40.2,36.8,36.4,28.1,21.0,14.1；HRMS(ESI)calcd for C 28 H 31 N 4 O 4 S + [M+H] + 519.2061,found 519.2060.
example 13:4- ((1-Acetylpiperidin-4-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-13)
Step one: synthesis of intermediate 4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxypiperidine-1-carboxylic acid tert-butyl ester (A-010)
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g,9.3mmol,1.2 eq) was dissolved in 40ml of THF, placed in a low temperature reaction bath at 0deg.C, sodium hydride (744 mg,60% dispersed in liquid paraffin) was slowly added, and stirred at 0deg.C for 30min. A-007 (2.58 g,7.75mmol,1 eq) was then dissolved in 10mL THF and added dropwise to the reaction system and the flask was moved to 60℃for overnight reaction. After the completion of the reaction, the reaction mixture was spotted on a plate, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain an organic phase. Suction filtration, concentration and column chromatography purification And (3) obtaining white solid A-010 with a yield of 72%. 1 H NMR(300MHz,Chloroform-d)δ8.07(d,J＝1.0Hz,1H),7.73(dd,J＝8.4,0.8Hz,1H),7.35-7.28(m,4H),7.21(s,1H),7.20–7.11(m,3H),5.99(s,1H),5.61(s,2H),4.53-4.43(m,1H),3.53(s,3H),3.45–3.23(m,4H),1.99-1.81(m,2H),1.68-1.53(m,2H),1.45(s,9H).ESI-MS(m/z):515.3[M+H]+
Step two: synthesis of 4- ((1-acetylpiperidin-4-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one (I-13)
A-010 (1 eq) was dissolved in 2M EA/HCl (0.1M), stirred at RT for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (4 eq) was dissolved in 0.2M THF and acetyl chloride (1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-11, and the yield of the two steps is 72 percent. m.p.162.4-163.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.07(d,1H,J＝0.8Hz),7.74(d,1H,J＝8.5Hz),7.34-7.28(m,4H),7.21(s,1H),7.20-7.11(m,3H),6.00(s,1H),5.61(s.2H),4.60-4.50(m,1H),3.54(s,3H),3.46-3.35(m,1H),3.33-3.23(m,2H),2.04(s,3H),1.91-1.77(m,2H),1.75-1.63(m,2H)； 13 C NMR(101MHz,CDCl 3 )δ168.7,163.7,163.1,139.5,138.2,136.78,133.3,132.1,128.7,127.7,126.8,123.4,122.5,120.7,115.6,109.4,98.0,72.0,52.8,42.6,37.7,36.8,30.2,29.2,21.3；HRMS(ESI)calcd for C 27 H 29 N 4 O 3 + [M+H] + 457.2234,found 457.2234.
example 14: (R) -4-ethoxy-1-methyl-5- (1- (1-phenethyl) -1H-indazol-6-yl) pyridin-2 (1H) -one (I-14)
Step one: synthesis of intermediate (R) -6-bromo-1- (1-phenethyl) -1H-indazole (A-011)
6-bromo-1H-indazole (A-001) (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Small additions of tertiary in portionsPotassium butoxide (1.2 eq) was stirred for 30min. (R) - (1-bromoethyl) benzene (1.2 eq) was slowly added dropwise at 0deg.C, the reaction flask was allowed to warm to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-011 with the yield of 48 percent. 1 H NMR(300MHz,Chloroform-d)δ8.03(d,J＝1.0Hz,1H),7.58(dd,J＝8.5,0.7Hz,1H),7.49–7.45(m,1H),7.34–7.19(m,6H),5.74(q,J＝7.1Hz,1H),2.03(d,J＝7.1Hz,3H)，ESI-MS(m/z):301.0[M+H]+
Step two: synthesis of intermediate (R) -1- (1-phenethyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indazole (A-013)
A-011 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-013 with the yield of 79 percent. ESI-MS (m/z): 349.2[ M+H ] +
Step three: synthesis of (R) -4-ethoxy-1-methyl-5- (1- (1-phenethyl) -1H-indazol-6-yl) pyridin-2 (1H) -one (I-14)
A-013 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-14 with the yield of 80 percent. m.p.151.3-152.5 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.06(s,1H),7.70(d,1H,J＝8.4Hz),7.32(s,1H),7.31-7.19(m,5H),7.17-7.11(m,2H),5.97(s,1H),5.83(q,1H,J＝7.0Hz),3.97(q,2H,J＝7.0Hz),3.50(s,3H),2.05(d,3H,J＝7.0Hz),1.25(t,3H,J＝7.0Hz)； 13 C NMR(101MHz,CDCl 3 )δ164.8,163.7,142.1,139.2,137.7,132.7,131.8,128.5,127.4,126.0,123.4,122.5,120.4,115.2,109.6,97.2,64.1,57.9,36.6,21.3,13.9；HRMS(ESI)calcd for C 23 H 24 N 3 O 2 + [M+H] + 374.1863,found 374.1859.
Example 15:5- (1- (2, 4-difluorobenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-15)
Step one: synthesis of intermediate 6-bromo-1- (2, 4-difluorobenzyl) -1H indazole (A-014)
6-bromo-1H-indazole (A-001) (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. 1- (bromomethyl) -2, 4-difluorobenzene (1.2 eq) was slowly added dropwise at 0deg.C, the reaction flask was brought to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-014 with a yield of 64%. 1 H NMR(300MHz,Chloroform-d)δ8.00(d,J＝1.0Hz,1H),7.62–7.60(m,1H),7.58(d,J＝8.6Hz,1H),7.25(dd,J＝8.6,1.5Hz,1H),7.06(td,J＝8.5,6.2Hz,1H),6.88–6.76(m,2H),5.53(s,2H).
ESI-MS(m/z):323.0[M+H]+
Step two: synthesis of intermediate 1- (2, 4-difluorobenzyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H indazole (A-015)
A-014 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-015 with the yield of 79 percent. ESI-MS (m/z): 371.2[ M+H ] +
Step three: synthesis of 5- (1- (2, 4-difluorobenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-15)
A-015 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single vial. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-15 with the yield of 61 percent. m.p.135.2-137.0 ℃. 1 H NMR(300MHz,CDCl 3 )δ8.05(s,1H),7.73(d,1H,J＝8.4Hz),7.45(s,1H),7.19(d,1H,J＝8.4Hz),7.12-7.02(m,1H),6.89-6.73(m,2H),6.00(s,1H),5.60(s,2H),4.03(q,2H,J＝7.0Hz),3.57(s,3H),2.32(s,6H),1.31(t,3H,J＝7.0Hz).； 13 C NMR(101MHz,CDCl 3 )δ164.9,163.8(dd,J＝11.9,11.9Hz),161.4(dd,J＝7.7,7.7Hz),158.9(d,J＝11.6Hz),139.6,137.8,133.7,132.6,130.5(dd,J＝5.4,5.4Hz),123.3,122.7,120.7,119.9(dd,J＝3.9,3.9Hz),115.1,111.7(dd,J＝3.8,3.8Hz),109.2,103.9(t,J＝25.4Hz),97.4,64.3,45.5(d,J＝4.3Hz),36.8,14.0；HRMS(ESI)calcd for C 22 H 20 F 2 N 3 O 2 +[M+H] + 396.1518,found 396.1516.
Example 16:5- (1- (2, 6-dimethylbenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-16)
Step one: synthesis of intermediate 6-bromo-1- (2, 6-dimethylbenzyl) -1H indazole (A-016)
6-bromo-1H-indazole (A-001) (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. 2- (bromomethyl) -1, 3-dimethylbenzene (1.2 eq) was slowly added dropwise at 0 ℃, the reaction flask was moved to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-016 with the yield of 54 percent. 1 H NMR(300MHz,Chloroform-d)δ7.94(d,J＝1.0Hz,1H),7.56(dd,J＝8.5,0.7Hz,1H),7.39(m,1H),7.22(dd,J＝8.5,1.6Hz,1H),7.22-7.16(m,1H),7.11(s,1H),7.10(d,J＝7.45Hz,1H)5.49(s,2H),2.31(s,6H).ESI-MS(m/z):315.0[M+H]+
Step two: synthesis of intermediate 1- (2, 6-dimethylbenzyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H indazole (A-017)
A-016 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-017 with the yield of 84 percent. ESI-MS (m/z): 363.2[ M+H ] +
Step three: synthesis of 5- (1- (2, 6-dimethylbenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-16)
A-017 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single vial. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-16 with the yield of 72 percent. m.p.180.5-182.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ7.97(s,1H),7.68(d,1H,J＝8.3Hz),7.26-7.14(m,3H),7.14-7.04(m,3H),6.00(s,1H),5.54(s,2H),4.03(q,2H,J＝7.0Hz),3.52(s,3H),2.32(s,6H),1.35(t,3H,J＝7.0Hz)； 13 C NMR(101MHz,CDCl 3 )δ164.8,163.7,139.6,137.9,137.7,132.9,132.0,131.9,128.4,128.2,123.0,122.3,120.4,115.2,109.2,97.2,64.1,47.5,36.6,20.1,14.0；HRMS(ESI)calcd for C 24 H 26 N 3 O 2 + [M+H] + 388.2020,found 388.2015.
Example 17:5- (1-benzyl-1H-indol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-17)
Step one: synthesis of intermediate 1-benzyl-6-bromo-1H-indole (A-019)
6-bromo-1H-indole (A-018) (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. 2- (bromomethyl) -1, 3-dimethylbenzene (1.2 eq) was slowly added dropwise at 0 ℃, the reaction flask was moved to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-019 with the yield of 88 percent. 1 H NMR(300MHz,Chloroform-d)δ7.50(dd,J＝8.4,0.5Hz,1H),7.43(m,1H),7.35–7.26(m,3H),7.20(dd,J＝8.4,1.7Hz,1H),7.12–7.06(m,3H),6.52(dd,J＝3.2,0.9Hz,1H),5.28(s,2H).ESI-MS(m/z):286.0[M+H]+
Step two: synthesis of intermediate 1-benzyl-6- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H indole (A-020)
A-019 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-017 with the yield of 76%. ESI-MS (m/z): 334.2[ M+H ] +
Step three: synthesis of 5- (1-benzyl-1H-indol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one (I-17)
A-020 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-17 with the yield of 57 percent. m.p.69.0-71.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ7.64(d,1H,J＝8.2Hz),7.35-7.27(m,4H),7.19-7.15(m,2H),7.15-7.08(m,3H),6.57(d,1H,J＝3.1Hz),5.98(s,1H),5.34(s.2H),3.97(q,2H,J＝7.0Hz),3.52(s,3H),1.22(t,3H,J＝7.0Hz)； 13 C NMR(75MHz,CDCl 3 )δ165.2,163.9,137.4,137.3,136.2,128.9,128.7,127.8,127.5,127.2,126.5,121.0,120.5,116.2,110.3,101.6,97.1,64.0,49.9,36.7,13.9；HRMS(ESI)calcd for C 23 H 23 N 2 O 2 + [M+H] + 359.1754,found 359.1754.
example 18: 4-ethoxy-1-methyl-5- (3-phenoxy-2, 3-dihydro-1H-inden-5-yl) pyridin-2 (1H) -one (I-18)
Step one: synthesis of intermediate 6-bromo-2, 3-dihydro-1H-inden-1-ol (A-022)
6-bromo-2, 3-dihydro-1H-inden-1-one (A-021) (2.0 g,9.48mmol,1 eq) was dissolved in 20mL of methanol and placed in a low temperature reaction bath at 0deg.C. Sodium borohydride (360.2 mg,1 eq) was added in small portions and stirred for 1h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-022 with the yield of 92 percent. 1 H NMR(300MHz,Chloroform-d)δ7.54(d,J＝1.9Hz,1H),7.37(dd,J＝8.0,1.9Hz,1H),7.12(d,J＝8.0Hz,1H),5.22(q,J＝6.4Hz,1H),2.99(ddd,J＝16.2,8.6,4.5Hz,1H),2.76(dt,J＝16.0,7.6Hz,1H),2.51(dddd,J＝12.9,8.3,6.9,4.5Hz,1H),1.95(dddd,J＝13.5,8.7,6.9,5.6Hz,1H),1.79(d,J＝6.9Hz,1H).
ESI-MS(m/z)213.0[M+H]+
Step two: synthesis of intermediate 6-bromo-1-phenoxy-2, 3-dihydro-1H-indene (A-023)
A-022 (1.0 g,4.7mmol,1 eq), phenol (1 eq), triphenylphosphine (1.1 eq) were dissolved in 20mL DCM and placed in a low temperature reaction bath at 0deg.C, DEAD (1.1 eq) was added dropwise and reacted for 12h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-023 with the yield of 61 percent. ESI-MS (m/z): 289.0[ M+H ] +
Step three: synthesis of intermediate 4, 5-tetramethyl-2- (3-phenoxy-2, 3-dihydro-1H-inden-5-yl) -1,3, 2-dioxabenzaldehyde (A-024)
A-023 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-024 with the yield of 76 percent. ESI-MS (m/z): 337.2[ M+H ] +
Step four: synthesis of 4-ethoxy-1-methyl-5- (3-phenoxy-2, 3-dihydro-1H-inden-5-yl) pyridin-2 (1H) -one (I-18)
A-024 (1 eq), 5-bromo-4-ethoxy-1-methylpyridin-2 (1H) -one (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single vial. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid I-18 with the yield of 82 percent. m.p.51.0-51.6 ℃; 1 H NMR(300MHz,CDCl 3 )δ7.45(s,1H),7.40-7.28(m,4H),7.17(s,1H),7.10-6.94(m,3H),5.98(s,1H),5.79(d,1H),4.01(q,2H,J＝7.0Hz),3.52(s,3H),3.23-3.10(m,1H),3.02-2.89(m,1H),2.69-2.55(m,1H),2.32-2.18(m,1H),1.34(t,3H,J＝7.0Hz)； 13 C NMR(101MHz,CDCl 3 )δ164.8,163.6,158.1,142.8,141.8,137.2,132.3,129.6,129.3,125.6,124.4,120.6,115.5,114.9,97.0,81.1,63.9,36.4,32.3,29.8,13.8；HRMS(ESI)calcd for C 23 H 24 NO 3 + [M+H] + 362.1751,found 362.1748.
example 19: trans-6- (4- ((4-acetaminocyclohexyl) oxo) -1-methyl-6-carbonyl-1, 6-dihydropyridin-3-yl) -1-benzyl-N-methyl-1H-indazole-4-carboxamide (I-19)
Step one: synthesis of intermediate trans-tert-butyl (4- ((5-bromo-1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) carbamate (A-025)
Trans-tert-butyl 4-hydroxycyclohexyl) carbamate (1.5 g,6.97mmol,1.2 eq) was dissolved in 40mL THF, placed in a low temperature reaction bath at 0deg.C, sodium hydride (557.6 mg,60%, dispersed in liquid paraffin, 2.4 eq) was slowly added and stirred at 0deg.C for 30min. Then, 5-bromo-4-fluoro-1-methylpyridin-2 (1H) -one (1.19 g,5.81mmol,1 eq) was dissolved in 8mL THF and added dropwise to the reaction system for 2H at room temperature. After completion of the reaction, the reaction mixture was spotted on a plate, extracted with ethyl acetate (3X 50 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-025 with the yield of 83 percent. 1 H NMR(300MHz,Chloroform-d)δ7.44(s,1H),5.92(s,1H),4.57(d,J＝7.9Hz,1H),4.26-4.16(m,1H),3.66–3.51(m,1H),3.47(s,3H),2.19-2.06(m,4H),1.72-1.57(m,2H),1.45(s,9H),1.38–1.20(m,2H).ESI-MS(m/z):401.1[M+H]+
Step two: synthesis of intermediate trans-N- (4- ((5-bromo-1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (A-026)
A-025 (1.9 g,4.74 mmol) was dissolved in 2M EA/HCl (40 mL), stirred at room temperature for 2h and filtered under vacuum to give a white solid. The solid (1 eq), triethylamine (1.91 g,4 eq) was dissolved in 20ml of hf, acetyl chloride (578 mg,1.5 eq) was added dropwise and stirred overnight at room temperature. After the completion of the reaction, the reaction was monitored by spotting, the solvent was dried, extracted with ethyl acetate (3X 30 mL), washed 3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-026, and the yield of the two steps is 84 percent. 1 H NMR(300MHz,Chloroform-d)δ7.44(s,1H),5.93(s,1H),5.60(d,J＝7.9Hz,1H),4.28-4.14(m,1H),3.94–3.80(m,1H),3.48(s,3H),2.21-2.01(m,4H),1.97(d,J＝5.6Hz,3H),1.75–1.58(m,2H),1.38–1.21(m,2H).ESI-MS(m/z):343.1[M+H]+
Step three: synthesis of intermediate methyl 1-benzyl-6-bromo-1H-indazole-4-carboxylate (A-028)
Methyl 6-bromo-1H-indazole-4-carboxylate (A-027) (1 eq) was dissolved in anhydrous DMSO (0.7M),is placed in a low-temperature reaction bath at 0 ℃. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. Benzyl bromide (1.2 eq) was slowly added dropwise at 0deg.C, the flask was brought to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-028 with the yield of 44%. 1 H NMR(300MHz,Chloroform-d)δ8.51(d,J＝1.0Hz,1H),8.00(d,J＝1.6Hz,1H),7.72–7.70(m,1H),7.37–7.27(m,3H),7.20-7.14(m,2H),5.59(s,2H),4.02(s,3H).ESI-MS(m/z):345.0[M+H]+
Step four: synthesis of intermediate 1-benzyl-6-bromo-N-methyl-1H-indazole-4-carboxamide (A-029)
A-028 (500 mg,1.45mmol,1 eq) and sodium hydroxide (116 mg,2 eq) were dissolved in 10mL of HF and 2mL of water and stirred at room temperature for 1h. After completion of the reaction, the reaction was monitored by spotting, neutralized with 2M HCl, extracted with ethyl acetate (3X 50 mL), and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating. Methylamine hydrochloride (97.8 mg,3 eq) and EDCI (306 mg,1.1 eq) were added, dissolved in 15mL THF and stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-029, and the yield of the two steps is 73 percent. 1 H NMR(300MHz,Chloroform-d)δ8.12(s,1H),7.45(s,1H),7.36–7.23(m,4H),7.20–7.14(m,2H),5.54(s,2H),4.98(d,J＝5.6Hz,3H),2.22(t,J＝5.8Hz,1H).
ESI-MS(m/z):344.0[M+H]+
Step five: synthesis of intermediate 1-benzyl-N-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole-4-carboxamide (A-030)
A-029 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-030 with the yield of 74 percent. ESI-MS (m/z): 392.2[ M+H ] +
Step six: synthesis of trans-6- (4- (4-acetaminocyclohexyl) oxo) -1-methyl-6-carbonyl-1, 6-dihydropyridin-3-yl) -1-benzyl-N-methyl-1H-indazole-4-carboxamide (I-19)
A-030 (1 eq), A-026 (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-19, and the yield is 26%.
m.p.142.0-143.5℃； 1 H NMR(300MHz,DMSO)δ8.49(d,1H,J＝4.4Hz),8.38(s,1H),7.86(s,1H),7.81(s,1H),7.76(d,1H,J＝7.3Hz),7.58(s,1H),7.37-7.21(m,3H),7.16(d,2H,J＝7.0Hz),6.03(s,1H),5.71(s,2H),4.46-4.27(m,1H),3.59-3.47(m,1H),3.43(s,3H),2.85(d,3H,J＝4.4Hz),2.00-1.85(m,2H),1.78(s,3H),1.75-1.64(m,2H),1.57-1.19(m,4H)； 13 C NMR(151MHz,CDCl3)δ171.6,168.9,165.1,164.7,140.5,139.6,137.1,133.93,133.86,132.2,129.4,128.5,127.0,126.9,122.4,121.7,116.1,113.6,97.7,76.4,53.3,47.4,37.2,29.9,29.7,26.8,22.8；HRMS(ESI)calcd for C 30 H 34 N 5 O 4 + [M+H] + 528.2605,found 528.2607.
Example 20: trans-N- (4- ((5- (1-benzyl-4- (hydroxymethyl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-20)
Step one: intermediate (1-benzyl-6-bromo-1H-indazol-4-yl) methanol (A-031)
A-028 (500 mg,1.45 mmol) was dissolved in 20mL THF, lithium aluminum hydride (55 mg,1 eq) was added at 0deg.C and stirred overnight at room temperature. After the completion of the point half monitoring reaction, saturated ammonium chloride is added dropwise at 0 ℃ for quenching, ethyl acetate is added for dilution, magnesium sulfate is added, and stirring is carried out for 30min. Suction filtering, washing filtrate with saturated sodium chloride water solution, anhydrous sulfuric acidSodium drying, suction filtering and concentrating. Purifying by column chromatography to obtain colorless liquid A-031 with a yield of 76%. 1 H NMR(300MHz,Chloroform-d)δ8.12(s,1H),7.45(s,1H),7.36–7.23(m,4H),7.20–7.14(m,2H),5.54(s,2H),4.98(d,J＝5.6Hz,3H),2.22(t,J＝5.8Hz,1H)。ESI-MS(m/z):317.0[M+H]+
Step two: synthesis of intermediate (1-benzyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazol-4-yl) methanol (A-032)
A-031 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-032 with the yield of 74 percent. ESI-MS (m/z): 365.2[ M+H ] +
Step three: synthesis of trans-N- (4- ((5- (1-benzyl-4- (hydroxymethyl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-20)
A-032 (1 eq), A-026 (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-20 with the yield of 16 percent. m.p.139.0-140.4 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.07(s,1H),7.57(s,1H),7.41-7.29(m,5H),7.25(s,1H),7.06(s,1H),5.99(s,1H),5.59(s,2H),5.42(d,1H,J＝7.7Hz),4.91(s,2H),4.32-4.16(m,1H),3.87-3.69(m,1H),3.52(s,3H),2.21-1.97(m,4H),1.96(s,3H),1.60-1.44(m,2H),1.31-1.05(m,2H)； 13 C NMR(75MHz,CDCl 3 )δ169.6,164.0,149.4,137.9,135.6,133.1,131.8,128.9,128.4,128.0,122.5,121.3,119.9,116.3,116.2,97.7,76.4,64.0,57.6,47.0,36.8,29.9,29.2,23.4；HRMS(ESI)calcd for C 29 H 33 N 4 O 4 +[M+H] + 501.2496,found 501.2494.
Example 21: trans-N- (4- ((5- (1-benzyl-4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-21)
Step one: synthesis of intermediate 2- (1-benzyl-6-bromo-1H-indazol-4-yl) propan-2-ol (A-033)
A-028 (1.0 g,2.9 mmol) was dissolved in 10mL of THF, 1M methyl magnesium bromide (8.7 mL,3 eq) was added dropwise at 0deg.C and stirred for 4h. After the completion of the reaction, the plate was monitored, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3X 50 mL), washed 3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-033 with the yield of 92 percent. 1 H NMR(300MHz,Chloroform-d)δ8.30(t,J＝0.8Hz,1H),7.43(t,J＝1.2Hz,1H),7.38–7.27(m,3H),7.24(d,J＝1.5Hz,1H),7.22–7.17(m,2H),5.53(s,2H),1.72(s,6H).
ESI-MS(m/z):345.1[M+H]+
Step two: synthesis of intermediate 2- (1-benzyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazol-4-yl) propan-2-ol (A-034)
A-033 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-034 with the yield of 74 percent. ESI-MS (m/z): 393.2[ M+H ] +
Step three: synthesis of trans-N- (4- ((5- (1-benzyl-4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide (I-21)
A-034 (1 eq), A-026 (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the reaction is completely monitored by the spot plate, the spot plate is rotatedThe organic phase was dried over anhydrous sodium sulfate, extracted with 100mL of ethyl acetate, washed 5 times with saturated brine. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-21 with the yield of 30 percent. m.p.139.4-140.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ8.35(s,1H),7.36-7.28(m,3H),7.25-7.12(m,5H),5.98(s,1H),5.60(s,2H),5.58-5.12(m,1H),4.25-4.10(m,1H),3.83-3.66(m,1H),3.52(s,3H),2.30(s,1H),2.11-1.92(m,4H),1.97(s,3H),1.77(s,6H),1.43-1.14(m,4H)； 13 C NMR(101MHz,CDCl 3 )δ169.6,163.8,142.6,140.3,138.1,136.8,134.1,131.8,128.7,127.7,126.8,120.6,118.0,115.9,108.1,97.6,75.5,73.01,72.97,52.8,46.9,36.7,31.5,30.0,29.2,23.3；HRMS(ESI)calcd for C 31 H 37 N 4 O 4 + [M+H] + 529.2809,found529.2803.
example 22: n- ((1 r,4 r) -4- ((5- (1- (2, 6-dimethylbenzyl) -4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-22)
Step one: synthesis of intermediate methyl 6-bromo-1- (2, 6-dimethylbenzyl) -1H-indazole-4-carboxylate (A-035)
A-027 (1 eq) was dissolved in anhydrous DMSO (0.7M) and placed in a low temperature reaction bath at 0deg.C. Potassium tert-butoxide (1.2 eq) was added in small portions and stirred for 30min. 2- (bromomethyl) -1, 3-dimethylbenzene (1.2 eq) was slowly added dropwise at 0 ℃, the reaction flask was moved to room temperature and stirred for 4h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-035 with the yield of 38%. ESI-MS (m/z): 373.0[ M+H ] +
Step two: synthesis of intermediate 2- (6-bromo-1- (2, 6-dimethylbenzyl) -1H-indazol-4-yl) propan-2-ol (A-036)
A-035 (1.0 g,2.9 mmol) was dissolved in 10mL of HF, and 1M methyl magnesium bromide (8.7 mL,3 eq) was added dropwise at 0deg.C and stirred for 4h. After the completion of the reaction, the plate was monitored, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3X 50 mL), washed 3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-036 with the yield of 87 percent. ESI-MS (m/z): 373.1[ M+H ] +
Step three: synthesis of intermediate 2- (1- (2, 6-dimethylbenzyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazol-4-yl) propan-2-ol (A-037)
A-036 (1 eq), pinacol diboronate (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a 100mL eggplant-type bottle. 0.2M dioxane was added, heated to 95℃and reacted for 12h. After the completion of the reaction, 100mL of ethyl acetate was extracted, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain white solid A-037 with the yield of 74 percent. ESI-MS (m/z): 421.3[ M+H ] +
Step four: synthesis of trans-N- (4- ((5- (1- (2, 6-dimethylbenzyl) -4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide (I-22)
A-037 (1 eq), A-026 (1.2 eq), potassium carbonate (2 eq) and Pd (dppf) Cl2 (2% mmol) were added to a single-necked flask. Dioxane and water (9:1) were added. Vacuum-pumping, replacing nitrogen, and reacting at 100 ℃ for 12h. After the completion of the reaction, the reaction was monitored by spotting on a plate, the solvent was dried, extracted with 100mL of ethyl acetate, washed with saturated brine 5 times, and the organic phase was dried over anhydrous sodium sulfate. Suction filtration, concentration and column chromatography purification are carried out to obtain yellow solid I-22, and the yield is 32%.
m.p.164.6-166.0℃； 1 H NMR(300MHz,CDCl 3 )δ8.27(s,1H),7.25-7.07(m,5H),7.04(s,1H),5.99(s,1H),5.70(d,1H,J＝7.9Hz),5.52(s,2H),4.30-4.18(m,1H),3.85-3.70(m,1H),3.53(s,3H),2.32(s,1H),2.19-1.98(m,4H),1.96(s,3H),1.73(s,6H),1.57-1.19(m,4H)； 13 C NMR(151MHz,DMSO)δ168.6,163.2,162.7,143.1,140.5,139.5,137.9,133.8,133.3,131.8,128.2,127.8,119.5,118.1,114.1,107.7,96.9,74.6,71.5,55.0,48.7,46.5,46.1,36.0,31.5,29.1,29.0,22.8,20.0；HRMS(ESI)calcd for C 33 H 41 N 4 O 4 + [M+H] + 557.3122,found 557.3122.
Example 23: in vitro test for BRD4 (BD 1) enzyme Activity
The BRD4 (BD 1) enzyme level activity of each of the compounds of the above examples was tested as follows:
the experimental method comprises the following steps:
binding reaction procedure
(1) 1 XAssay buffer was prepared.
(2) Preparing a compound concentration gradient: the final concentrations of the test compounds were all 10 μm initial, 3-fold diluted, 10 concentrations, each concentration set up as a single well test. The solution was diluted in a 384 well Source plate in a gradient to a corresponding 1000-fold final concentration, and then transferred with Echo550 to a 384 well reaction plate for assay. The Max wells transferred 20nL of 100% dmso and the min wells transferred the highest concentration of positive compounds of 20 nL.
(3) A4X protein solution was prepared from the 1X reaction solution.
(4) mu.L of a 4 Xprotein solution was added to each well, and the mixture was centrifuged at 1000rpm for 1min and incubated at room temperature for 15 min.
(5) A4X polypeptide solution was prepared from the 1X reaction solution.
(6) mu.L of 4 Xpolypeptide solution was added to each well of the reaction plate, and the mixture was centrifuged at 1000rpm for 1min.
(7) 10. Mu.L of the test solution was added, centrifuged at 1000rpm for 60 seconds, and after gentle shaking and mixing, incubated at room temperature for 60 minutes.
(8) Read with EnVision.
And (3) data processing:
％Inhibition＝(Signal_max-Signal_sample)/(Signal_max-Signal_min)X 100
the log value of concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and an analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope fit effect curve is adopted, so that the IC50 value of the compound on protein binding inhibition is obtained.
Note that: JQ-1 is a BET inhibitor, purchased from jiangsu mugwort Kang Shengwu pharmaceutical development limited, as a positive control.
The specific results are shown in the table:
example 24 in vitro antiproliferative Activity of Compounds
1. Experimental procedure
(1) The PBS solution was autoclaved and stored in a refrigerator at 4 ℃.
(2) Weighing trypsin and pancreatin digestion solution, adding ultrapure water for dissolving, and filtering with microporous filter to obtain solution
The body is preserved in a refrigerator at-20deg.C.
(3) Respectively weighing culture medium powder and NaHCO 3 Adding ultrapure water for full dissolution, adding 10% diabody, filtering with microporous membrane to obtain culture solution, storing at 4deg.C in refrigerator, and adding 10% foetus calf serum before use.
(4) The 22RV1 cells or LNcap cells are taken out from a liquid nitrogen tank, immediately placed in a constant temperature water bath kettle at 37 ℃ and shaken to melt, then the cells are poured into a culture bottle, and the culture solution (containing 10% of fetal calf serum) is added for dilution. Transferring the diluted culture medium into a centrifuge tube, centrifuging at 1000r/min for 5 min, discarding supernatant, adding fresh culture medium, blowing, mixing, transferring into a culture bottle, and culturing in 5% CO 2 Culturing in an incubator at 37 ℃. When the cell is adhered to the wall and is fully paved at the bottom of the bottle, a small amount of fresh culture medium (containing 10% of fetal calf serum) is added to stop digestion, liquid in the culture bottle is poured out, PBS is used for washing twice, fresh culture medium is added to blow and uniformly mix, and the culture is continued in the two culture bottles.
(5) Taking cells in the logarithmic phase, pouring out the old culture medium, adding a trypsin solution for digestion for 3 minutes, adding a fresh culture medium containing 10% of fetal bovine serum for stopping digestion, transferring the solution into a centrifuge tube, centrifuging at 1000r/min for 5 minutes, and discarding the supernatant. The cells were counted by adding a medium to prepare a cell suspension. After counting, the cells were planted at a concentration of 5000-10000 cells per wellIn 96-well plates. The 96-well plate with the cells spread was placed in a 5% CO2 incubator at 37℃for continuous culture for 24 hours. The drugs were diluted in gradient to 160. Mu. Mol/L, 80. Mu. Mol/L, 40. Mu. Mol/L, 20. Mu. Mol/L, 10. Mu. Mol/L, 5. Mu. Mol/L with medium and then added to 96-well plates at 100. Mu.L per well, three multiplex wells were set for each concentration. Adding medium containing solvent in corresponding concentration into control group, adding blank medium with the same volume into zeroing hole, and placing in 5% CO 2 Incubate at 37℃for 3 days with medium changed every two days. mu.L MTT (5 mg/mL) was added to each well, and after mixing well, the mixture was treated with 5% CO 2 Culturing in a 37 ℃ incubator for 4 hours in dark. The liquid in the 96-well plate was removed, 200 μl DMSO was added to each well, and the mixture was placed on a micro-shaker and shaken to completely dissolve the crystals at the bottom. The 96-well plate was then placed in an microplate reader and absorbance was measured at 490 nm.
2. Data processing
Drawing curve and calculating inhibition rate of drug to cell and IC 50 。
Inhibition ratio = [ (control mean OD value-experimental mean OD value)/(control mean OD value-blank mean OD value) ]x100%.
3. Experimental results
The inhibitory activity of the compounds on human prostate cancer cell line 22RV1 and LNcap cells was as follows:
| numbering of compounds | 22RV1IC 50 (μM) | LNcapIC 50 (μM) |
| I-5 | 8.27±0.28 | 7.33±0.49 |
| I-6 | 16.99±1.36 | 9.22±0.65 |
| I-7 | 14.38±3.2 | 15.74±2.50 |
| I-8 | 10.66±0.16 | 13.55±1.66 |
| I-13 | 49.6±1.05 | 26.32±1.62 |
| I-14 | 11.32±0.73 | 12.59±1.38 |
| I-15 | 19.23±1.38 | 18.53±2.22 |
| I-22 | 16.35±0.82 | 20.32±1.62 |
| JQ-1 | 28.29±2.66 | 18.38±2.23 |
Claims (5)
1. A compound shown in a general formula I or pharmaceutically acceptable salt thereof is characterized in that the structural formula is shown in the formula I,
wherein,
R 1 is hydrogen, C 1 -C 3 An alkyl group; wherein said C 1 -C 3 The alkyl group may be optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, amino, cyano;
z is CR 5 Or NR (NR) 6 ；
Y is CR 7 ；
R 5 -R 7 Independently selected from hydrogen, deuterium atoms, C 1 -C 3 An alkyl group;
each of which isIndependently a double bond;
R 2 independently selected from hydrogen, deuterium atoms, -OR 9 、C 6 An aromatic ring;
R 9 is C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkane, C 3 -C 12 A heterocyclic alkane wherein the heteroatom in the C3-C12 heterocyclic alkane is selected from N, the number of heteroatoms being 1; wherein said C 3 -C 6 Cycloalkane, C 3 -C 12 The heterocycloalkane is a single ring, a parallel ring, a spiro ring or a bridged ring;
R 3 is hydrogen, -C (O) N (R) 11 -1)(R 11 -2) or,R 11-1 、R 11-2 、R 11-7 、R 11-8 Independently selected from hydrogen, C 1 -C 3 Alkyl, C 1- C 3 Deuterated alkyl;
ring a is selected from pyrazole rings;
w is independently selected from C (R) 12 ) n The method comprises the steps of carrying out a first treatment on the surface of the Wherein the method comprises the steps ofn represents 1, 2; r is R 12 Is hydrogen or C 1 -C 3 Is an alkane of (a);
R 4 independently selected from hydrogen, halogen, C 1 -C 3 An alkyl group;
p represents 0, 1, 2.
2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is any one of the following:
6- (1-benzyl-1H-indazol-6-yl) -5-ethoxy-2-methylpyridazin-3 (2H) -one, i.e. I-4;
5- (1-benzyl-1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one, i.e., I-5;
n- (4- (5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) methanesulfonimide, i.e., I-6;
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) acetamide; i.e. I-7;
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) -N-methylacetamide, i.e., I-8;
trans-N- ((4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) methanesulfonamide, i.e., I-9;
trans-N- (4- ((5- (1-benzyl-1H-indazol-6-yl) -1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) oxy) cyclohexyl) cyclopropanecarboxamide, i.e., I-10;
trans-4- (8-acetyl-8-azabicyclo [3.2.1] oct-3-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one, i.e., I-11;
trans-5- (1-benzyl-1H-indazol-6-yl) -1-methyl-4- (8- (methylsulfonyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) pyridin-2 (1H) -one, i.e., I-12;
4- ((1-acetylpiperidin-4-yl) oxy) -5- (1-benzyl-1H-indazol-6-yl) -1-methylpyridin-2 (1H) -one, i.e., I-13;
(R) -4-ethoxy-1-methyl-5- (1- (1-phenethyl) -1H-indazol-6-yl) pyridin-2 (1H) -one, i.e., I-14;
5- (1- (2, 4-difluorobenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one, i.e., I-15;
5- (1- (2, 6-dimethylbenzyl) -1H-indazol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one, i.e., I-16;
5- (1-benzyl-1H-indol-6-yl) -4-ethoxy-1-methylpyridin-2 (1H) -one, i.e., I-17;
trans-6- (4- ((4-acetaminocyclohexyl) oxo) -1-methyl-6-carbonyl-1, 6-dihydropyridin-3-yl) -1-benzyl-N-methyl-1H-indazole-4-carboxamide, i.e., I-19;
trans-N- (4- ((5- (1-benzyl-4- (hydroxymethyl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide, i.e., I-20;
trans-N- (4- ((5- (1-benzyl-4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide, i.e., I-21;
trans-N- (4- ((5- (1- (2, 6-dimethylbenzyl) -4- (2-hydroxypropan-2-yl) -1H-indazol-6-yl) -1-methyl-2-carbonyl-1, 2-dihydropyridin-4-yl) oxo) cyclohexyl) acetamide, i.e., I-22.
3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition according to claim 3, in the manufacture of a medicament for the treatment of a disease associated with BRD4 inhibition.
5. The use according to claim 4, wherein the BRD 4-associated disease is breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, arthritis, hepatitis.
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