WO2024032661A1 - Kif18a抑制剂及其用途 - Google Patents
Kif18a抑制剂及其用途 Download PDFInfo
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- WO2024032661A1 WO2024032661A1 PCT/CN2023/112020 CN2023112020W WO2024032661A1 WO 2024032661 A1 WO2024032661 A1 WO 2024032661A1 CN 2023112020 W CN2023112020 W CN 2023112020W WO 2024032661 A1 WO2024032661 A1 WO 2024032661A1
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- Prior art keywords
- alkyl
- membered
- group
- alkoxy
- amino
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- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 354
- 238000002360 preparation method Methods 0.000 claims abstract description 226
- 150000003839 salts Chemical class 0.000 claims abstract description 141
- 150000002148 esters Chemical class 0.000 claims abstract description 136
- 101001091231 Homo sapiens Kinesin-like protein KIF18A Proteins 0.000 claims abstract description 29
- 229940126262 KIF18A Drugs 0.000 claims abstract description 29
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- 201000010099 disease Diseases 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
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- 230000001404 mediated effect Effects 0.000 claims abstract description 11
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- 125000000217 alkyl group Chemical group 0.000 claims description 284
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 133
- 125000003545 alkoxy group Chemical group 0.000 claims description 123
- 125000000623 heterocyclic group Chemical group 0.000 claims description 115
- 229910052757 nitrogen Inorganic materials 0.000 claims description 79
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 77
- 125000005843 halogen group Chemical group 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 74
- 125000001424 substituent group Chemical group 0.000 claims description 70
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 67
- 229910052736 halogen Inorganic materials 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 26
- 125000004122 cyclic group Chemical group 0.000 claims description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 20
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
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- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 9
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 9
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 8
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
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- 201000011510 cancer Diseases 0.000 claims description 7
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- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 claims description 7
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 6
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
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- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
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- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 claims description 5
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 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 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
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- 206010018852 Haematoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
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- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- WURYWHAKEJHAOV-UHFFFAOYSA-N 2,5-dihydrothiophene Chemical compound C1SCC=C1 WURYWHAKEJHAOV-UHFFFAOYSA-N 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 567
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 296
- 238000006243 chemical reaction Methods 0.000 description 272
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 182
- 239000000243 solution Substances 0.000 description 129
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 117
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 103
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 101
- 239000000741 silica gel Substances 0.000 description 101
- 229910002027 silica gel Inorganic materials 0.000 description 101
- 239000003208 petroleum Substances 0.000 description 91
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 67
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 57
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 52
- 239000012043 crude product Substances 0.000 description 48
- 150000002431 hydrogen Chemical class 0.000 description 44
- 238000010791 quenching Methods 0.000 description 40
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 38
- 239000012141 concentrate Substances 0.000 description 34
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- 239000002585 base Substances 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000012360 testing method Methods 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- 229910000160 potassium phosphate Inorganic materials 0.000 description 26
- 235000011009 potassium phosphates Nutrition 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 24
- 229910000024 caesium carbonate Inorganic materials 0.000 description 24
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 24
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
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- JSWVROOEEJDBDC-UHFFFAOYSA-N OC(=O)c1ccc(I)cc1N1CCC2(CC2)CC1 Chemical compound OC(=O)c1ccc(I)cc1N1CCC2(CC2)CC1 JSWVROOEEJDBDC-UHFFFAOYSA-N 0.000 description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 17
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 16
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
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- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 6
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 6
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- 230000005764 inhibitory process Effects 0.000 description 6
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
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- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to the field of medical technology, specifically to KIF18A inhibitors, their pharmaceutically acceptable salts, their esters or their stereoisomers, containing the compounds, their pharmaceutically acceptable salts, their esters or their stereoisomers.
- Pharmaceutical compositions and preparations thereof, methods for preparing said compounds, their pharmaceutically acceptable salts, their esters or their stereoisomers, and said compounds, their pharmaceutically acceptable salts, their esters or their stereoisomers Use of isomers in the preparation of medicaments for the treatment and/or prevention of diseases mediated by KIF18A and related diseases.
- Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes.
- Various microtubule-associated proteins (MAPs) of the kinesin-8 family play a role in regulating the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules. It has been reported that the kinesin family is closely related to the invasion, metastasis and poor prognosis of various cancers. An increasing number of kinesin family members are considered to be involved in tumor occurrence and progression.
- KIF18A a member of the kinesin-8 family, is a multifunctional protein that uses adenosine triphosphate (ATP) hydrolysis to generate force and move along microtubules. It is involved in multiple cellular functions, including cell division, cell motility, microtubule dynamics, and organelle transport. KIF18A affects cell differentiation and cancer development. Studies have shown that KIF18A is related to tumor behavior and can be used as a potential biomarker for breast cancer, colorectal cancer, and hepatocellular carcinoma.
- ATP adenosine triphosphate
- CIN chromosomal instability
- KIF18A Altered microtubule dynamics in mitotic CIN cells render them specifically dependent on KIF18A to reduce kinetochore-microtubule turnover and limit microtubule growth.
- centrosome fragmentation occurs and mitotic progression is slowed or halted.
- KIF18A is largely dispensable for the proliferation of diploid somatic cells in vivo but is required for the proliferation of CIN tumor cells.
- CIN tumor cells Upon inhibition of KIF18A, CIN tumor cells exhibit delayed mitosis, multipolar spindles, and increased cell death. Therefore, KIF18A may be an effective target to specifically inhibit the growth of CIN tumor cells, while having relatively low toxicity in somatic cells and diploid cells.
- inhibitors targeting KIF18A will provide new ideas and strategies for the treatment of different types of tumors.
- the purpose of the present invention is to provide a KIF18A inhibitor and its application.
- the specific technical solutions are as follows:
- the present invention first provides compounds represented by general formula (I), pharmaceutically acceptable salts, esters or stereoisomers thereof:
- X 1 and X 4 are independently selected from N or CR a ;
- connection mode between X 2 and X 3 is single bond or double bond
- connection mode between X 2 and X 3 is a single bond
- X 2 and X 3 are independently selected from N or C
- connection mode between X 2 and X 3 is a double bond
- X 2 , X 3 are all C
- Ring A is selected from 5-12-membered cycloalkyl, 5-12-membered heterocyclyl, 6-10-membered aryl, 5-12-membered heteroaryl, 5-12-membered spirocyclyl, 5-12-membered spiroheterocycle base, 5-12-membered bridged cyclic group or 5-12-membered bridged heterocyclic group;
- R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5 optionally substituted by one or more substituents Q 2 -12-membered spirocyclyl, 5-12-membered spiroheterocyclyl, 5-12-membered bridged cyclyl, 5-12-membered bridged heterocyclyl;
- R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH 2 , -S(O) 2 -NH 2 , -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m - optionally substituted by one or more substituents Q 3 C 2-6 alkynyl, -(L) m -C 1-6 alkoxy, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy , hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, -(L) m -3-12-membered cycloalkyl, -(L) m -3-12-membered hetero Ring group,
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, halo C 1- 6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -C(O)-NH 2 , C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl , C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonylamino, 3-12 membered cycloalkyl optionally substituted by 1-4 substituents q, 3-12-membered heterocyclyl, 6-10-member
- Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O) 2 -, -NR c -, -S(O)(NR c )-, -CR a1 R b -;
- Each R a , each R a1 , and each R b are independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkyl Aminosulfonyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, -(L ) m -6-10-membered aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8-membered cycloalkyl or -(L) m -3-8-membered heterocycle base;
- Each R c is independently selected from hydrogen, C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl;
- Each m and n are independently an integer from 0 to 6.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- X 1 and X 4 are independently selected from N or CR a ;
- connection mode between X 2 and X 3 is single bond or double bond
- connection mode between X 2 and X 3 is a single bond
- X 2 and X 3 are independently selected from N or C
- connection mode between X 2 and X 3 is a double bond
- X 2 , X 3 are all C
- Ring A is selected from 5-12-membered cycloalkyl, 5-12-membered heterocyclyl, 6-10-membered aryl, 5-12-membered heteroaryl, 5-12-membered spirocyclyl, 5-12-membered spiroheterocycle base, 5-12-membered bridged cyclic group or 5-12-membered bridged heterocyclic group;
- R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5 optionally substituted by one or more substituents Q 2 -12-membered spirocyclyl, 5-12-membered spiroheterocyclyl, 5-12-membered bridged cyclyl, 5-12-membered bridged heterocyclyl;
- R 2 , R 3 , R 4 and R 6 are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH 2 , -S(O) 2 -NH 2 , -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m -C 2- optionally substituted by one or more substituents Q 3 6 alkynyl, -(L) m -C 1-6 alkoxy, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, -(L) m -3-12 membered cycloalkyl, -(L) m -3-12 membered heterocyclyl, -(L) m -6-10
- R 5 is selected from -(L) m -3-10-membered cycloalkyl optionally substituted by 1-4 substituents Q 3 , -(L) m -3-10-membered heterocyclyl, -(L) m -6-10-membered aryl group, -(L) m -5-10-membered heteroaryl group, -(L) m -5-11-membered spirocyclic group, -(L) m -5-11-membered spiroheterocyclic group ;
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, halo C 1- 6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -C(O)-NH 2 , C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl , C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonylamino, 3-12 membered cycloalkyl optionally substituted by 1-4 substituents q, 3-12 membered heterocycle base, 6-10 membered
- Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O) 2 -, -NR c -, -S(O)(NR c )-, -CR a1 R b -;
- Each R a , each R a1 , and each R b are independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkyl Aminosulfonyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, -(L ) m -6-10-membered aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8-membered cycloalkyl or -(L) m -3-8-membered heterocycle base;
- Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl;
- Each m and n are independently an integer from 0 to 6.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- X 1 and X 4 are independently selected from N or CR a ;
- connection mode between X 2 and X 3 is single bond or double bond
- connection mode between X 2 and X 3 is a single bond
- X 2 and X 3 are independently selected from N or C
- connection mode between X 2 and X 3 is a double bond
- X 2 , X 3 are all C
- Ring A is selected from 5-12-membered cycloalkyl, 5-12-membered heterocyclyl, 6-10-membered aryl, 5-12-membered heteroaryl, 5-12-membered spirocyclyl, 5-12-membered spiroheterocycle base, 5-12-membered bridged cyclic group or 5-12-membered bridged heterocyclic group;
- R 1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5 optionally substituted by one or more substituents Q 2 -12-membered spirocyclyl, 5-12-membered spiroheterocyclyl, 5-12-membered bridged cyclyl, 5-12-membered bridged heterocyclyl;
- R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH 2 , -S(O) 2 -NH 2 , optional -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m -C 2-6 alkynyl substituted by one or more substituents Q 3 , -(L) m -C 1-6 alkoxy, di(C 1-6 alkyl)amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl C 1-6 Alkyl group, amino C 1-6 alkyl group, carboxyl C 1-6 alkyl group, -(L) m -3-12-membered cycloalkyl group, -(L) m -3-12-membered heterocyclic group, -(L
- R 5 is selected from -(L) m -3-10-membered cycloalkyl optionally substituted by 1-4 substituents Q 3 , -(L) m -3-10-membered heterocyclyl, -(L) m -6-10-membered aryl group, -(L) m -5-10-membered heteroaryl group, -(L) m -5-11-membered spirocyclic group, -(L) m -5-11-membered spiroheterocyclic group ;
- R 6 is selected from -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N optionally substituted by 1-4 substituents Q 3 (R c )S(O) 2 -3-6-membered cycloalkyl group, -N(R c )S(O) 2 -3-6-membered heterocyclyl group, -S(O) 2 N(R c )- C 1-6 alkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -S(O) 2 N(R c )-3-6-membered heterocyclyl, -S( O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -S(O) 2 -3-6-membered heterocyclyl, -S(O)(NR c )
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, halo C 1- 6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -C(O)-NH 2 , C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl , C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonylamino, 3-12 membered cycloalkyl optionally substituted by 1-4 substituents q, 3-12-membered heterocyclyl, 6-10-member
- Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O) 2 -, -NR c -, -S(O)(NR c )-, -CR a1 R b -;
- Each R a , each R a1 , and each R b are independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkyl Aminosulfonyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, -(L ) m -6-10-membered aryl, -(L) m -5-12-membered heteroaryl, -(L) m -3-8-membered cycloalkyl or -(L) m -3-8-membered heterocycle base;
- Each R c is independently selected from hydrogen, C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl;
- Each m and n are independently an integer from 0 to 6.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein at least one of X 1 , X 2 , X 3 and X 4 is N.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein at least two of X 1 , X 2 , X 3 and X 4 are N .
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 1 is selected from CR a .
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 1 is selected from N.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 2 is selected from C.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 2 is selected from N.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 3 is selected from C.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 3 is selected from N.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 4 is selected from CR a .
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein X 4 is selected from N.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-10 membered cycloalkyl, 5-10 membered hetero Ring group, 6-10 membered aryl group or 5-10 membered heteroaryl group.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-8 membered cycloalkyl, 5-8 membered hetero Ring group, phenyl or 5-8 membered heteroaryl.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-6 membered cycloalkyl, 5-6 membered hetero Ring group, phenyl or 5-6 membered heteroaryl.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-6 membered cycloalkyl, 5-6 membered containing Nitrogen heterocyclyl or 5-6 membered nitrogen-containing heteroaryl.
- the compound shown in the preceding scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from cyclopentyl, cyclohexyl, dihydropyrrolyl ,pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidine base, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazole Base, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridony
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, Dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl , phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-tri Azolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyr
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein, Selected from the following structures,
- each R a , each R 1 , each Q 1 , and each n are as described in any one of the foregoing technical solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 4 substituents Q 2 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, 7-11 membered spirocyclyl, 7-11 membered spiroheterocyclyl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 7-10 membered spirocyclyl, 7-10 membered spiroheterocyclyl or 5-6 membered heteroaryl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 3-6 membered cycloalkyl group, 3-6 membered nitrogen-containing heterocyclyl group, phenyl group, 7-8 membered spiroheterocyclyl group or 5-6 membered nitrogen-containing heteroaryl group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from 3 optionally substituted by 1 to 3 substituents Q2 -6-membered cycloalkyl, 7-8-membered spiroheterocyclyl or 3-6-membered nitrogen-containing heterocyclyl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 5-6 membered cycloalkyl group, 5-6 membered heterocyclyl group, 7-8 membered spiroheterocyclyl group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 4-6 membered heterocyclic group, preferably 4-6 membered nitrogen-containing heterocyclic group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 5-6 membered cycloalkyl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 7-8 membered spiroheterocyclyl group, preferably 7-8 membered nitrogen-containing spiroheterocyclyl group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 Cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, azetidinyl, oxetanyl, 1,4-dioxanyl, 1,3-di Oxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, Imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 1 is selected from optionally substituted by 1 to 3 substituents Q 2 Dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl base, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 2-piperidone base,
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are independently selected from hydrogen, halogen, cyano, Carboxyl, hydroxyl, amino, nitro, -(L) m -C 1-6 alkyl optionally substituted by 1-4 substituents Q 3 , -(L) m -C 1-6 alkoxy, - (L) m -3-10 membered cycloalkyl group, -(L) m -3-10 membered heterocyclic group, -(L) m -6-10 membered aryl group, -(L) m -5-10 membered Heteroaryl, -(L) m -5-11-membered spirocyclic group, -(L) m -5-11-membered spiroheterocyclyl.
- R 2 and R 5 are independently selected from hydrogen, halogen, cyano, Carboxyl, hydroxy
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are each independently selected from hydrogen, optionally replaced by 1- 4 substituents Q 3 substituted -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -5-10 membered cycloalkyl, - (L) m -5-10 membered heterocyclyl group, -(L) m -7-11 membered spirocyclic group, -(L) m -7-11 membered spiroheterocyclyl group.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are each independently selected from hydrogen, optionally replaced by 1- 3 substituents Q 3- substituted 5-6 membered heterocyclyl, 7-10 membered spiroheterocyclyl.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are each independently selected from hydrogen, optionally replaced by 1- 3 substituents Q: 3 -substituted 5-6-membered nitrogen-containing heterocyclic group, 7-9-membered nitrogen-containing spiroheterocyclyl group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R5 is selected from optionally substituted by 1-3 substituents Q3 8-membered nitrogen-containing spiroheterocyclyl; R 2 is selected from hydrogen.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are each independently selected from hydrogen, optionally replaced by 1-
- R 2 and R 5 are each independently selected from hydrogen, optionally replaced by 1-
- the following structure is substituted by 3 substituents Q 3 :
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 5 is selected from optionally substituted by 1 to 4 substituents Q 3 -(L) m -3-10-membered cycloalkyl, -(L) m -3-10-membered heterocyclyl, -(L) m -6-10-membered aryl, -(L) m -5-10 1-membered heteroaryl, -(L) m -5-11-membered spirocyclic group, -(L) m -5-11-membered spiroheterocyclyl;
- R 2 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -(L) m -C 1-6 alkyl, -(L) optionally substituted by 1-4 substituents Q 3 m -C 1-6 alkoxy group, -(L) m -3-10 membered cycloalkyl group, -(L) m -3-10 membered heterocyclyl group, -(L) m -6-10 membered aryl group , -(L) m -5-10 membered heteroaryl group, -(L) m -5-11 membered spirocyclic group, -(L) m -5-11 membered spiroheterocyclic group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 5 is selected from optionally substituted by 1 to 4 substituents Q 3 -(L) m -5-10 membered cycloalkyl group, -(L) m -5-10 membered heterocyclyl group, -(L) m -7-11 membered spirocyclic group, -(L) m -7- 11-membered spiroheterocyclyl;
- R 2 is selected from hydrogen, -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -C 1-6 alkyl optionally substituted by 1-4 substituents Q 3 m -5-10-membered cycloalkyl, -(L) m -5-10-membered heterocyclyl, -(L) m -7-11-membered spirocyclic group, -(L) m -7-11-membered spirocyclic group ring base.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R5 is selected from optionally substituted by 1-3 substituents Q3 5-6 membered heterocyclyl, 7-10 membered spiroheterocyclyl; R 2 is selected from hydrogen.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R5 is selected from optionally substituted by 1-3 substituents Q3 5-6 membered nitrogen-containing heterocyclyl group, 7-9 membered nitrogen-containing spiroheterocyclyl group; R 2 is selected from hydrogen.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 and R 4 are independently selected from hydrogen, halogen, cyano, Carboxyl, hydroxyl, amino, nitro, cyano, -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy optionally substituted by 1-4 substituents Q 3 group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, and amino C 1-6 alkyl group.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkane Base, C 1-6 alkoxy group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 3 and R 4 are independently selected from hydrogen, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
- R 3 and R 4 are independently selected from hydrogen, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein each L is independently selected from -C(O)-, -S (O)-, -S(O) 2 -, -NR c -, -S(O)(NR c )-, -CR a1 R b -.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein each L is independently selected from -S(O) 2 -, - NR c -, -CR a1 R b -.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from optionally substituted by 1 to 4 substituents Q 3 -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )S(O) 2 -3-6-membered cycloalkyl , -N(R c )S(O) 2 -3-6 membered heterocyclyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -S(O) 2 N(R c )-3-6-membered heterocyclyl, -S(O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered heterocyclyl, -S
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from optionally substituted by 1 to 4 substituents Q 3 -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )S(O) 2 -3-6-membered cycloalkyl , -N(R c )S(O) 2 -3-6 membered heterocyclyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -S(O) 2 N(R c )-3-6-membered heterocyclyl, -S(O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered heterocyclyl, -S
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from optionally substituted by 1-3 substituents Q 3 -N(R c )S(O) 2 -C 1-6 alkyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 -C 1-6 alkyl base, -S(O) 2 -3-6-membered cycloalkyl, -N(R c )S(O) 2 -3-6-membered cycloalkyl, -S(O) 2 N(R c )-3 -6-membered cycloalkyl group, -N(R c )-C 1-6 alkyl group, -N(R c )-C 1-6 alkyl group.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from optionally substituted by 1-3 substituents Q 3 -N(H)S(O) 2 -C 1-4 alkyl, -S(O) 2 N(H)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -N(H)S(O) 2 -3-6-membered cycloalkyl, -S(O) 2 N(H)-3-6-membered ring Alkyl, -N(H)-C 1-4 alkyl, -N(H)-C 1-4 alkyl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from the following structure:
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R 6 is selected from the following structure:
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halogen C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino, di (C 1-6 alkyl)amino.
- each Q 1 , each Q 2 , and each Q 3 are independently Selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl Base, carboxyl C 1-6 alkyl.
- each Q 1 , each Q 2 , and each Q 3 are independently Selected from fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy , ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl , hydroxyethyl, methylamino, ethylamino, dimethylamino.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from halogen, hydroxyl, amino, C 1- 4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl , amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoro Methyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
- each R a , each R a1 , and each R b are independently Selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo Substituted C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl.
- each R a , each R a1 , and each R b are independently Selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo Substituted C 1-4 alkyl, halogenated C 1-4 alkoxy.
- each R a , each R a1 , and each R b are independently Selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methyl Oxy, ethoxy, propoxy, isopropoxy, methylamino, ethyl Amino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
- each R a , each R a1 , and each R b are independently Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy base, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
- the compound shown in the foregoing scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein each R a , each R a1 , and each R b are independently Selected from hydrogen.
- each R c is independently selected from hydrogen, C 1-4 alkyl , C 1-4 alkoxy group, halogenated C 1-4 alkyl group , halogenated C 1-4 alkoxy group, hydroxyl C 1-4 alkyl group, amino C 1-4 alkyl group, carboxyl C 1-4 alkyl group base.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c is independently selected from hydrogen, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl Fluoromethoxy.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently an integer from 0 to 4.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently 0, 1, 2, 3.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein each n is independently an integer from 0 to 4.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently 0, 1, 2, 3.
- the compound shown in the previous scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from 5-8 membered cycloalkyl, 5-8 membered hetero Cyclic group, phenyl or 5-8 membered heteroaryl;
- R 1 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, 7-11 membered spirocyclic optionally substituted by 1-4 substituents Q 2 Base, 7-11 membered spiroheterocyclyl;
- R 2 and R 5 are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted by 1-4 substituents Q 3 -(L) m -C 1-6 alkane base, -(L) m -C 1-6 alkoxy group, -(L) m -3-10 membered cycloalkyl group, -(L) m -3-10 membered heterocyclyl group, -(L) m - 6-10-membered aryl group, -(L) m -5-10-membered heteroaryl group, -(L) m -5-11-membered spirocyclic group, -(L) m -5-11-membered spiroheterocyclic group;
- R 3 and R 4 are each independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, optionally substituted by 1-4 substituents Q 3 -(L) m -C 1-6 alkane base, -(L) m -C 1-6 alkoxy group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, amino C 1-6 alkyl group ;
- R 6 is selected from -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N optionally substituted by 1-4 substituents Q 3 (R c )S(O) 2 -3-6-membered cycloalkyl group, -N(R c )S(O) 2 -3-6-membered heterocyclyl group, -S(O) 2 N(R c )- C 1-6 alkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -S(O) 2 N(R c )-3-6-membered heterocyclyl, -S( O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -S(O) 2 -3-6-membered heterocyclyl, -S(O)(NR c )
- Each R a , each R a1 , and each R b are independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl , Carboxy C 1-6 alkyl;
- Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halogen C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino, di (C 1-6 alkyl)amino;
- Each m and n are independently an integer from 0 to 4.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;
- R 1 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 7-10 membered spirocyclic optionally substituted by 1-3 substituents Q 2 Base, 7-10 membered spiroheterocyclyl;
- R 2 and R 5 are each independently selected from hydrogen, -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy optionally substituted by 1-3 substituents Q 3 base, -(L) m -3-10 membered cycloalkyl group, -(L) m -3-10 membered heterocyclyl group, -(L) m -5-11 membered spirocyclic group, -(L) m - 5-11 membered spiroheterocyclyl; R 2 and R 5 are not hydrogen at the same time;
- R 6 is selected from -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )S(O) 2 -3- optionally substituted by 1-3 substituents Q 3 6-membered cycloalkyl, -N(R c )S(O) 2 -3-6-membered heterocyclyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -S(O) 2 N(R c )-3-6-membered heterocyclyl, -S(O) 2 -C 1-6 alkyl, - S(O) 2 -3-6-membered cycloalkyl, -S(O) 2 -3-6-membered heterocyclyl, -N(R c )-C 1-6 alkyl.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- Ring A is selected from cyclopentyl, cyclohexyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothiophene base, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl Azolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, 2-pyridonyl, 4 -pyridonyl, pyrimidinyl, pyridaziny
- R 1 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocyclyl, phenyl, 7-10-membered spirocyclyl, 7-10-membered spiroheterogene optionally substituted by 1-3 substituents Q 2 Cyclic group or 5-6 membered heteroaryl group;
- R 2 and R 5 are independently selected from hydrogen, 5-6-membered heterocyclyl and 7-10-membered spiroheterocyclyl optionally substituted by 1-3 substituents Q 3 ;
- R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy;
- R 6 is selected from -N(R c )S(O) 2 -C 1-6 alkyl, -S(O) 2 N(R c )-C 1 optionally substituted by 1-3 substituents Q 3 -6 alkyl, -S(O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -N(R c )S(O) 2 -3-6-membered Cycloalkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -N(R c )-C 1-6 alkyl;
- Each R a is independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1 -6 alkoxy;
- Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkyl. , Halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, carboxyl C 1-6 alkyl group.
- the compound shown in the previous scheme has a structure represented by formula (I-1),
- Y 1 and Y 2 are independently selected from N or CH;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and each Q 1 and n are as described in any one of the aforementioned solutions.
- the compound shown in the previous scheme has a structure represented by formula (I-1'),
- Y 1 and Y 2 are independently selected from N or CH;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , each R a , each Q 1 , and n are as described in any of the foregoing solutions.
- the compound shown in the previous scheme has a structure represented by formula (I-2),
- Y 1 and Y 2 are independently selected from N or CH;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and each Q 1 and n are as described in any one of the aforementioned solutions.
- the compound shown in the previous scheme has a structure represented by formula (II),
- n 0, 1, 2;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and each Q 1 are as described in any one of the aforementioned solutions.
- the compound shown in the previous scheme has a structure represented by formula (II'),
- the compound shown in the foregoing scheme has a structure represented by formula (II'), wherein n is 0, 1 , 2 ; _ _ _ _ _ _ _ _ _ _ _
- the compound shown in the previous scheme has a structure represented by formula (II'), wherein X 1 is selected from N or CR a ;
- R 1 is selected from 3-6-membered cycloalkyl, 7-8-membered spiroheterocyclyl or 3-6-membered nitrogen-containing heterocyclyl optionally substituted by 1-3 substituents Q 2 ;
- R 2 and R 5 are each independently selected from hydrogen, a 5-6-membered nitrogen-containing heterocyclyl group and a 7-9-membered nitrogen-containing spiroheterocyclyl group optionally substituted by 1-3 substituents Q 3 ;
- R 3 and R 4 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, and halogenated C 1-4 alkoxy;
- R 6 is selected from -NHS(O) 2 -C 1-6 alkyl, -S(O) 2 NH-C 1-6 alkyl, -S(O) optionally substituted by 1-4 substituents Q 3 ) 2 -C 1-6 alkyl, -S(O) 2 -3-6 membered cycloalkyl, -NH-C 1-6 alkyl;
- Each R a is independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1- 4 alkyl) amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, and halogenated C 1-4 alkyl. , Halogenated C 1-4 alkoxy group, hydroxyl C 1-4 alkyl group, carboxyl C 1-4 alkyl group;
- n 0, 1, 2.
- the compound shown in the foregoing scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 2 and R 5 are not hydrogen at the same time.
- the compound shown in the preceding scheme has a structure represented by formula (II-1) or (II-1') ,
- each X 6 is selected from N or CH;
- Each R 1 , each R 2 , each R 3 , each R 4 , each R 6 , R a , each Q 1 , each Q 2 , each Q 3 , and each n are as defined above any of the plans.
- the compound shown in the preceding scheme has a formula (II-2) or a formula (II-2'). structure,
- each L 1 is independently selected from NR c , O, S or CR a1 R b ; each X 5 and each X 6 is independently selected from N or CH;
- p is selected from an integer from 0 to 2;
- R 2 , R 3 , R 4 , R 6 , R a , each R a1 , each R b , each Q 1 , each Q 2 , each Q 3 , and each n are as in any of the aforementioned solutions. mentioned in the item.
- the compound shown in the foregoing scheme has the formula (II-3) or formula (II-3') structure,
- each L 1 is independently selected from -NH-, -O-, -S- or -CH 2 -; each p is selected from an integer of 0-2;
- each R 6 , R a , each Q 1 , each Q 2 , each Q 3 , and each n are as described in any of the foregoing solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- the compound shown in the previous scheme has a structure represented by formula (III) or formula (III'),
- X 5 and X 6 are independently selected from N or CH;
- Each R 2 , each R 3 , each R 4 , each R 6 , R a , each Q 1 , each Q 2 , each Q 3 , each n is defined as in any of the foregoing solutions. narrate.
- the compound shown in the preceding scheme has a structure represented by formula (III) or formula (III'),
- each X 5 and each X 6 are independently N;
- Each R 2 , each R 3 , and each R 4 are independently hydrogen;
- R 6 is selected from the following structures:
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkyl. , Halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, carboxyl C 1-6 alkyl group;
- n 0, 1, 2.
- the compound shown in the preceding scheme has a formula (II-2) or a formula (II-2'). structure,
- X 5 and X 6 are independently selected from N or CH;
- Each L 1 is independently selected from NH, O or CH 2 ;
- R 2 , R 3 , and R 4 are each independently selected from hydrogen or C 1-6 alkyl
- R 6 is selected from the following structures:
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkyl. , Halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, carboxyl C 1-6 alkyl group;
- p and n are independently 0, 1, and 2 respectively.
- the compound shown in the preceding scheme has a structure represented by formula (IV) or formula (IV'),
- the definitions of Q 1 , each Q 2 , each Q 3 , and each n are as described in any of the foregoing solutions.
- the compound shown in the foregoing scheme has the formula (IV-1) or formula (IV-1') structure,
- Each R 1 , each R 6 , each R a , each X 2 , each X 3 , each X 4 , each Q 1 , each Q 2 , each Q 3 , n is as defined above any of the plans.
- the compound shown in the preceding scheme has a formula (IV-2) or a formula (IV-2') structure,
- each R 1 , R a , each X 2 , each X 3 , each X 4 , each Q 1 , each Q 2 , and each n are as described in any of the foregoing solutions.
- the compound shown in the foregoing scheme has the formula (IV-3) or formula (IV-3') structure,
- each X 2 , each X 3 , each X 4 , each Q 1 , each n, and each R a are as described in any of the foregoing solutions.
- the compound shown in the preceding scheme a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein,
- R 1 is selected from dihydropyrrolyl , pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5- Dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 2-piperidinonyl,
- R 2 is selected from hydrogen
- R5 is selected from the following structures optionally substituted by 1-3 substituents Q3 :
- Each R a , R 3 , and R 4 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy. ;
- R 6 is selected from the following structures:
- Each Q 1 , each Q 2 , and each Q 3 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkyl. , Halogenated C 1-6 alkoxy group, hydroxyl C 1-6 alkyl group, carboxyl C 1-6 alkyl group.
- the compounds shown in the present invention their pharmaceutically acceptable salts, esters or their stereoisomers have a structure represented by general formula (I'),
- the compound shown in the preceding scheme has a structure represented by general formula (I'-1),
- Y 1 and Y 2 are independently selected from N or CH;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and each Q 1 and n are as described in any one of the aforementioned solutions.
- the compound shown in the previous scheme has a structure represented by formula (I'-1),
- R 1 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocyclyl, phenyl, 7-10-membered spirocyclyl, 7-10-membered spiroheterogene optionally substituted by 1-3 substituents Q 2 Cyclic group or 5-6 membered heteroaryl group;
- R 2 and R 5 are independently selected from hydrogen, 5-6-membered heterocyclyl and 7-10-membered spiroheterocyclyl optionally substituted by 1-3 substituents Q 3 ; R 2 and R 5 are not simultaneously hydrogen;
- R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;
- R 6 is selected from -N(R c )S(O) 2 -C 1-6 alkyl, -S(O) 2 N(R c )-C 1 optionally substituted by 1-3 substituents Q 3 -6 alkyl, -S(O) 2 -C 1-6 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -N(R c )S(O) 2 -3-6-membered Cycloalkyl, -S(O) 2 N(R c )-3-6-membered cycloalkyl, -N(R c )-C 1-6 alkyl;
- Each R a is independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1 -6 alkoxy;
- Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;
- Each Q 1 is selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl C 1-6 alkyl, carboxyl C 1-6 alkyl;
- n 0, 1, 2.
- the compound shown in the previous scheme has a structure represented by general formula (I'-2),
- Y 2 is selected from N or CH;
- R 1 is selected from 5-6-membered cycloalkyl, 5-6-membered heterocyclyl, and 7-8-membered spiroheterocyclyl optionally substituted by 1-3 substituents Q 2 ;
- R 2 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy;
- R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy;
- R 6 is selected from -N(H)S(O) 2 -C 1-4 alkyl, -S(O) 2 N(H)-C 1-4 optionally substituted by 1-3 substituents Q 3 Alkyl group, -S(O) 2 -C 1-4 alkyl group, -S(O) 2 -3-6 membered cycloalkyl group, -N(H)S(O) 2 -3-6 membered cycloalkyl group , -S(O) 2 N(H)-3-6-membered cycloalkyl, -N(H)-C 1-4 alkyl, -N(H)-C 1-4 alkyl;
- R a is independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 Alkoxy;
- Each Q 1 is selected from halogen, carboxyl, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, hydroxyl C 1-4 alkyl, carboxyl C 1-4 alkyl;
- n 0, 1, 2.
- the structures of the provided compounds, their pharmaceutically acceptable salts, esters or their stereoisomers are as follows:
- the present invention also provides a pharmaceutical composition, which contains the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I' ), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), General formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula ( IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3 ), a compound represented by general formula (IV-3'), its pharmaceutically acceptable salt, ester or its stereoisomer, and one or more second therapeutically active agents, optionally, the drug
- the compositions also include one or more pharmaceutical carriers and/or diluents.
- the second therapeutic agent of the present invention includes, but is not limited to, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotic agents, angiogenesis inhibitors, biological response modifiers, and antihormones. agents, anticancer drugs.
- the present invention also provides a pharmaceutical preparation, which contains the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I') , General formula (I'-1), General formula (I'-2), General formula (II), General formula (II'), General formula (II-1), General formula (II-1'), General formula Formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV ), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3) , the compound represented by the general formula (IV-3'), its pharmaceutically acceptable salt, ester or its stereoisomer, and one or more pharmaceutical carriers and/or diluents; the pharmaceutical preparation is Any dosage form that is clinically or pharmaceutically acceptable.
- the above-mentioned pharmaceutical preparations can be administered to patients or subjects in need of such treatment by oral, parenteral, rectal or pulmonary administration.
- the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solutions, oral suspensions, syrups, etc.
- oral preparations appropriate fillers, binders, disintegrants, lubricants, etc. can be added.
- parenteral administration the above pharmaceutical preparations can also be made into injections, including injection liquids, sterile powders for injection and concentrated solutions for injection.
- the pharmaceutical composition When making injections, conventional methods in the existing pharmaceutical field can be used. When preparing injections, no additives may be added, or appropriate additives may be added according to the properties of the drug.
- the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for transpulmonary administration, the pharmaceutical composition can be made into inhalants or sprays.
- the pharmaceutical carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carrier and/or diluent in the field of pharmaceutical preparation.
- the selection of the specific carrier and/or diluent will depend on the use. Mode of administration or disease type and condition to treat a specific patient. Methods for the preparation of suitable pharmaceutical compositions for a particular mode of administration are well within the knowledge of those skilled in the pharmaceutical art.
- pharmaceutical carriers and/or diluents may include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, Stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc.
- flavoring agents, preservatives, sweeteners, etc. can also be added to the pharmaceutical composition.
- the present invention also provides the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'- 1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), General formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (IV' ), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), general formula (IV-3 '), pharmaceutically acceptable salts, esters or stereoisomers thereof, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions are prepared for the treatment and/or prevention of KIF18A-mediated diseases and related diseases. used in medicines Method; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.
- the present invention also provides the aforementioned general formula (I), general formula (I-1), general formula (I-1'), general formula (I-2), general formula (I'), general formula (I'- 1), general formula (I'-2), general formula (II), general formula (II'), general formula (II-1), general formula (II-1'), general formula (II-2), General formula (II-2'), general formula (II-3), general formula (II-3'), general formula (III), general formula (III'), general formula (IV), general formula (IV' ), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), general formula (IV-3), general formula (IV-3 ')
- the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.
- the present invention also provides a method for treating diseases, which method includes administering to a patient in need a therapeutically effective amount of the aforementioned general formula (I), general formula (I-1), general formula (I-1'), General formula (I-2), general formula (I'), general formula (I'-1), general formula (I'-2), general formula (II), general formula (II'), general formula (II -1), general formula (II-1'), general formula (II-2), general formula (II-2'), general formula (II-3), general formula (II-3'), general formula ( III), general formula (III'), general formula (IV), general formula (IV'), general formula (IV-1), general formula (IV-1'), general formula (IV-2), general formula (IV-2'), the compound represented by the general formula (IV-3), the general formula (IV-3'), its pharmaceutically acceptable salt, ester or its stereoisomer, the aforementioned pharmaceutical preparation or the aforementioned
- the pharmaceutical composition wherein the disease is a KIF18A-mediated disease and related diseases; the
- the cancer or benign tumor includes but is not limited to breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, stomach cancer, liver cancer, kidney cancer, pancreatic cancer Cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, menstrual cancer, skin cancer, bone cancer and hematoma;
- the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer;
- the hematoma includes but is not limited to Limited to leukemia, lymphoma, and myeloma;
- the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, and meningioma.
- the invention provides a preparation method of the above compound, but is not limited to the following method.
- the reaction equation of the preparation method is as follows:
- Step 1 Dissolve the compound of formula (II'-2) in an appropriate solvent (such as dichloromethane), add the compound of formula (II'-1) and a basic substance (such as N,N-diisopropylethylamine) In an organic solvent (such as dichloromethane), react for 1-5 hours, and then obtain the compound of formula II'-3 of the present invention through an appropriate method (such as silica gel column chromatography).
- an appropriate solvent such as dichloromethane
- a basic substance such as N,N-diisopropylethylamine
- Step 2 Dissolve the compound of formula (II'-3) in an appropriate solvent (such as N,N-dimethylformamide), add a catalyst (such as cuprous halide), and an alkaline substance (such as potassium phosphate, N,N- diisopropylethylamine, etc.), add R 6 -H, and react under nitrogen protection for 1-5 hours. After post-treatment, the compound of general formula II' of the present invention is obtained.
- an appropriate solvent such as N,N-dimethylformamide
- a catalyst such as cuprous halide
- an alkaline substance such as potassium phosphate, N,N- diisopropylethylamine, etc.
- Post-treatment includes, but is not limited to, one or a combination of several methods including water quenching, organic solvent (such as ethyl acetate) extraction, concentration, and column chromatography.
- organic solvent such as ethyl acetate
- X is halogen ; _ _ _ _
- the present invention also provides intermediates for preparing compounds represented by general formula (I) to general formula (IV-3'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof, which have the following Structural formula:
- Each X is independently a halogen; each X 1 , each R 1 , each R 2 , each R 3 , each R 4 , each R 5 , each R 6 , each R a , the definition of each n and each Q 1 is as described in any of the previous solutions.
- the present invention also provides intermediates for preparing compounds represented by general formula (I) to general formula (IV-3'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof, which have the following Structural formula:
- each X is independently a halogen; each X 1 , each R 1 , each R 2 , each R 3 , each R 4 , each R 6 , each R a , each n
- Each Q 1 is defined as described in any of the preceding schemes.
- Halogen in the present invention refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
- Halo in the present invention means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen” is as defined above.
- C 1-6 alkyl refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-5 alkyl” and “C 1-4 alkyl” , “C 1-3 alkyl", “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl “, “C 2-4 alkyl”, “C 2- 3 alkyl”, “C 3-6 alkyl”, “C 3-5 alkyl”, “C 3-4 alkyl”, “C 4-6 alkyl”, “C 4-5 alkyl", “C 5-6 alkyl”, etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, 2-methylbutyl, neopentyl, 1-ethyl
- C 1-6 alkylene group refers to the group formed by removing one hydrogen atom from the above-mentioned C 1-6 alkyl group, including, for example, "C 1-5 alkylene group”, “C 1-4 "Alkylene”, “C 1-3 alkylene”, “C 1-2 alkylene”, “C 2-6 alkylene”, “C 2-5 alkylene”, “C 2-4 "Alkylene”, “C 2-3 alkylene”, “C 3-6 alkylene", “C 3-5 alkylene", “C 3-4 alkylene”, “C 4-6 "Alkylene", “C 4-5 alkylene", “C 5-6 alkylene”, etc.
- C 1-4 alkylene group refers to specific examples of C 1-6 alkylene groups containing 1 to 4 carbon atoms.
- C 2-6 alkenyl refers to a linear, branched or cyclic alkenyl group with 2-6 carbon atoms containing at least one double bond, including, for example, “C 2-5 alkenyl group”",”C 2-4 alkenyl", “C 2-3 alkenyl”, etc.
- Specific examples include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl Alkenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butene base, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexyl Alkenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl Alkenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl
- C 2-6 alkynyl refers to a straight-chain or branched alkynyl group with a triple bond and a carbon number of 2-8, including, for example, “C 2-5 alkynyl”, “C 2-4 alkynyl”, “C 2-3 alkynyl”, etc.
- Specific examples include but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1- Ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3- Pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.
- C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylaminoacyl, C 1-6 alkylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylaminosulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl refers to C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C 1-6 alkyl) 2 -N-, C 1-6 alkyl-NH-C(O)-, C 1- 6alkyl -C(O)-NH-, C 1-6 alkyl-S(O) 2 -, C 1-6 alkyl-S(O) 2 -NH-, C 1-6 alkyl-NH -S(O) 2 -, C 1-6 alkyl-C(O)-, C 1-6 alkyl-C(O)-,
- C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoacyl, C 1-4 alkylamino, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonamido, C 1-4 alkylaminosulfonyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl refers to C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl) 2 -N-, C 1-4 alkyl-NH-C(O)-, C 1- 4Alkyl -C(O)-NH-, C 1-4 Alkyl-S(O) 2 -, C 1-4 Alkyl-S(O) 2 -NH-, C 1-4 Alkyl-NH -S(O) 2 -, C 1-4 alkyl-C(O)-, C 1-4 alkyl-, C 1-4 alky
- halogenated C 1-6 alkyl group, hydroxyl C 1-6 alkyl group, amino C 1-6 alkyl group, carboxyl C 1-6 alkyl group, and halogenated C 1-6 alkoxy group refers to One or more (for example, 1-4, 1-3, 1-2) halogen atoms, hydroxyl, amino, and carboxyl groups are respectively substituted for C 1-6 alkyl, C 1-6 alkylene, and C 1-6 alkyl.
- halogenated C 1-4 alkyl group, hydroxyl C 1-4 alkyl group, amino C 1-4 alkyl group, carboxyl C 1-4 alkyl group, and halogenated C 1-4 alkoxy group refers to A group formed by one or more (such as 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, and amino groups respectively replacing the hydrogen atoms in the C 1-4 alkyl group and the C 1-4 alkoxy group. group.
- the "3-12-membered cycloalkyl group” mentioned in the present invention refers to a saturated or partially saturated cyclic alkyl group containing 3-12 carbon atoms and not aromatic, including "monocyclic alkyl group” and “condensed cycloalkyl group”. Cycloalkyl”.
- the "monocyclic alkyl group” mentioned in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group without aromaticity, including "3-8 membered saturated cycloalkyl group” and "3-8 membered partially saturated cycloalkyl group”.
- Cycloalkyl ; preferably “3-4-membered cycloalkyl”, “3-5-membered cycloalkyl”, “3-6-membered cycloalkyl”, “3-7-membered cycloalkyl”, “4-5 “Member cycloalkyl”, “4-6 member cycloalkyl”, “4-7 member cycloalkyl”, “4-8 member cycloalkyl”, “5-6 member cycloalkyl”, “5-7 “Member cycloalkyl”, “5-8 member cycloalkyl”, “6-7 member cycloalkyl”, “6-8 member cycloalkyl”, “7-8 member cycloalkyl”, “3-6 “Member saturated cycloalkyl”, “4-7 member saturated cycloalkyl”, “4-8 member saturated cycloalkyl”, “5-8 member saturated cycloalkyl”, “5-7 member saturated cycloalkyl” , “5-6 membered saturated cycloalkyl”, “3-6 membered partially saturated
- the "3-8 membered saturated cycloalkyl” include but are not limited to: cyclopropyl (cyclopropyl), cyclobutyl (cyclobutyl), cyclopentyl (cyclopentyl), Cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated cycloalkyl” include but are not Limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl , cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trieny
- Condensed cycloalkyl refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms.
- One of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic; its fusion method can be: 5-6 membered cycloalkyl, 5-6 membered cycloalkyl, benzo 5- 6-membered cycloalkyl, benzo 5-6-membered saturated cycloalkyl, etc.
- Examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , Bicyclo[4.2.0]octyl, octahydropentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthyl, bicyclo[3.1.0]hexan-2- Alkenyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydropentadienyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,
- the "3-12-membered heterocyclic group" mentioned in the present invention refers to one containing at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and with a number of ring atoms of 3-12 A saturated or partially saturated and non-aromatic monocyclic or condensed ring cyclic group, the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the cyclic structure ( For example, a carbon atom, a nitrogen atom or a sulfur atom) can be oxo-substituted.
- the "3-12-membered heterocyclic group” described in the present invention includes “3-12-membered saturated heterocyclic group” and "3-12-membered partially saturated heterocyclic group”.
- the "3-12-membered heterocyclic group” described in the present invention contains 1-3 heteroatoms;
- the "3-12-membered heterocyclic group” described in the present invention contains 1-2 heteroatoms,
- the heteroatoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-12-membered heterocyclic group” described in the present invention contains 1-2 nitrogen atoms.
- the "3-12-membered heterocyclyl” is preferably "3-10-membered heterocyclyl", “3-8-membered heterocyclyl", “4-8-membered heterocyclyl", "3-6-membered heterocyclyl”",”3-6 membered saturated heterocyclic group", "3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “4-6 membered heterocyclic group”, “4 -6-membered nitrogen-containing heterocyclyl”, "5-6-membered heterocyclyl”, “5-6-membered saturated "Heterocyclyl” etc.
- 3-12-membered heterocyclyl include but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazacyclyl Allyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolyl, 1,4-dioxanyl Dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-bis Hydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, 2-piperidinonyl, piperazinyl, morpholinyl, 4,5
- the "6-10-membered aryl group” mentioned in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8-membered monocyclic aryl group” and "8-10-membered aryl group”. Fused ring aryl”.
- the "6-8 membered monocyclic aryl group" described in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms. Examples thereof include but are not limited to: phenyl, cyclooctatetraenyl, etc.; benzene is preferred base.
- the "8-10 membered fused ring aryl group” mentioned in the present invention refers to an aryl group formed by two or more cyclic structures sharing two adjacent atoms and containing 8-10 ring carbon atoms.
- Saturated, aromatic cyclic groups are preferably "9-10 membered fused ring aryl groups", specific examples include naphthyl, etc.
- the "5-12-membered heteroaryl” used in the present invention refers to an aromatic ring containing 5-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
- the group may be, for example, a 5- to 12-membered nitrogen-containing heteroaryl group, a 5- to 12-membered oxygen-containing heteroaryl group, a 5- to 12-membered sulfur-containing heteroaryl group, and the like. Including "5-8-membered monoheteroaryl" and "8-10-membered condensed heteroaryl".
- the "5-8 membered monoheteroaryl group" used in the present invention refers to an aromatic monoheteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Ring cyclic group.
- ring atoms eg carbon atoms, nitrogen atoms or sulfur atoms
- in the cyclic structure can be oxo-substituted.
- 5-8-membered monoheteroaryl includes, for example, “5-7-membered monoheteroaryl", “5-6-membered monoheteroaryl”, “5-6-membered nitrogen-containing monoheteroaryl”, “5-membered Nitrogen-containing monoheteroaryl” etc.
- 5-8 membered monocyclic heteroaryl include but are not limited to furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadizoyl Azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepantrienyl, 1,3-diazepantrienyl Alken
- the "8-10-membered fused heteroaryl" mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms and containing 8-10 ring atoms (at least one of which is The ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom) and is an unsaturated aromatic ring structure.
- ring atoms eg carbon atoms, nitrogen atoms or sulfur atoms
- in the cyclic structure can be oxo-substituted.
- the condensation method can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl 5- 6-membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazothiophene, furanothiophene, pyrazooxazole, benzofuranyl, benzoiso Furyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4 -Quinolinonyl, 1-isoquinolinonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl,
- the "5-12-membered bridged ring group” mentioned in the present invention refers to a structure containing 5-12 carbon atoms formed by any two rings sharing two atoms that are not directly connected.
- the "5-12-membered bridged ring” includes 5-12-membered bridged ring group. 12-membered saturated bridged ring group, 5-12 membered partially saturated bridged ring group. Preferred are 5-10-membered bridged ring groups, 5-8-membered bridged ring groups, 5-10-membered saturated bridged ring groups, 5-8-membered saturated bridged ring groups, 6-10-membered saturated bridged ring groups, and 7-12-membered partially saturated ones.
- Bridged ring group specific examples include but not limited to
- the "5-12-membered bridged heterocyclyl group" described in the present invention means that at least one ring carbon atom in the above-mentioned 5-12-membered bridged cyclic group is replaced by a heteroatom selected from O, S, and N, preferably 1-3.
- Heteroatoms, including carbon atoms, nitrogen atoms and sulfur atoms that can be oxygenated, are preferably 5-10-membered bridged heterocyclyl groups and 5-8-membered bridged heterocyclyl groups. Specific examples include but are not limited to:
- the "5-12 membered spirocyclic group” mentioned in the present invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing one atom. Contains 5-12-membered saturated spirocyclic groups and 5-12-membered partially saturated spirocyclic groups, including, for example, “5-10-membered saturated spirocyclic groups”, “5-10-membered unsaturated spirocyclic groups”, “5-8-membered spirocyclic groups”"Spirocyclyl”,”5-8 membered saturated spirocyclyl", “5-8 membered unsaturated spirocyclyl”, “6-8 membered spirocyclyl", "7-11 membered spirocyclyl", “7 -10-membered spirocyclic group”, “7-9-membered spirocyclic group”, “8-10-membered spirocyclic group”, "8-11-membered spirocycl
- a 5-12-membered partially saturated spirocyclic group refers to a cyclic group in which at least one ring of the spirocyclic group is unsaturated. Specific examples include but are not limited to: A group formed by replacing any substitutable hydrogen atom with a cyclic structure.
- the "5-12-membered spiroheterocyclyl" mentioned in the present invention means that at least one ring carbon atom in the 5-12-membered spirocyclic group is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms. , including the case where carbon atoms, nitrogen atoms and sulfur atoms can be oxygenated.
- spiroheterocyclyl Including, for example, 5-10 membered spiroheterocyclyl, 5-8 membered spiroheterocyclyl, 5-6 membered spiroheterocyclyl, 7-12 membered spiroheterocyclyl, 7-11 membered spiroheterocyclyl, 7-11 7-10-membered nitrogen-containing spiroheterocyclyl, 7-10-membered nitrogen-containing spiroheterocyclyl, 7-10-membered nitrogen-containing spiroheterocyclyl, 7-9-membered nitrogen-containing spiroheterocyclyl, 7- 8-membered spiroheterocyclyl, 7-8 membered nitrogen-containing Spiroheterocyclyl, 8-membered nitrogen-containing spiroheterocyclyl.
- Specific examples include but are not limited to:
- the “pharmaceutically acceptable salt” mentioned in the present invention refers to the addition salt of pharmaceutically acceptable acids and bases, such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, and salts with inorganic salts. Salts formed with acids, salts formed with acidic amino acids or basic amino acids, etc.
- esters refers to a pharmaceutically acceptable ester, especially the following ester, which is hydrolyzed in vivo and is easily decomposed in the human body to leave the parent compound (the compound described in the general formula (I)) or Esters of its salts.
- esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl part of the carboxylic acid compound is selected from, for example, C 1 -20 linear or branched alkyl, C 1-12 linear or branched alkyl, C 1-8 linear or branched alkyl, C 1-6 linear or branched alkyl (such as methyl, Ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (such as methoxymethyl), C 6-10 aryl C 1-6 alkyl (e.g.
- benzyl C 6-10 aryloxy C 1-6 alkyl (e.g. phenoxymethyl), C 6-10 aryl (e.g. phenyl), optionally replaced by e.g. halogen, C 1-4 alkyl group or C 1-4 alkoxy or amino substituted); (2) sulfonate ester, such as alkylsulfonyl or aralkylsulfonyl (such as methylsulfonyl); (3) amino acid ester (such as L-valer Aminoacyl or L-isoleucyl); and (4) mono-, di- or triphosphate, etc.; (4) esters obtained by esterification with alcoholic compounds, wherein non-hydroxyl groups of alcoholic compounds
- the moiety is selected from, for example, C 1-20 linear or branched alkyl, C 1-12 linear or branched alkyl, C 1-8 linear or branched alkyl, C 1-6 linear or branched alkyl group (such as methyl,
- benzyl C 6-10 aryloxy C 1-6 alkyl (e.g. phenoxymethyl), C 6-10 aryl (e.g. phenyl), optionally replaced by, for example, halogen , C 1-4 alkyl or C 1-4 alkoxy or amino substituted).
- Stepoisomers refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomers. Conformational mixtures and single diastereomers.
- the compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers.
- the scope of the invention includes all possible optical isomers and mixtures thereof. If the compounds described in the present invention contain olefin double bonds, unless otherwise specified, they include cis isomers and trans isomers.
- the compounds of the present invention may exist as tautomers (a type of functional group isomer) having different points of attachment of hydrogens through the displacement of one or more double bonds, for example, a ketone and its alkene
- tautomers a type of functional group isomer
- the alcohol form is the keto-enol tautomer.
- Each tautomer and mixtures thereof are included within the scope of the invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures, etc. are included in the scope of the present invention.
- the “therapeutically effective amount” used in the present invention refers to the amount of the aforementioned compounds, pharmaceutical preparations, and pharmaceutical compositions that can at least alleviate the symptoms of the patient's disease when administered to a patient.
- the actual amount encompassed by a “therapeutically effective amount” will vary depending on a variety of circumstances, including, but not limited to, the specific condition being treated, the severity of the condition, the physical and health condition of the patient, and the route of administration. The appropriate amount can be readily determined by a skilled medical practitioner using methods known in the medical art.
- the compounds of the present invention have excellent KIF18A inhibitory activity and can treat and/or prevent KIF18A-mediated diseases and related diseases;
- the compound of the present invention has good inhibitory effect on tumor cells
- the compound of the present invention has a simple preparation process, high pharmaceutical purity, stable quality, and is easy to carry out large-scale industrial production.
- Test products some compounds of the present invention, their chemical names and structures are shown in the preparation examples.
- test compounds are 10000nM, 3333.3nM, 1111.1nM, 370.4nM, 123.5nM, 41.2nM, 13.7nM, 4.57nM, 1.52nM, 0.51nM.
- ave High control means the luminescence signal intensity of the positive control well without compound
- ave Low control means the luminescence signal intensity of the negative control well without enzyme
- cpd well Indicates the luminescence signal intensity of the test compound
- the IC 50 value of compound 10 for KIF18A inhibitory activity is between 50 nM and 500 nM. From the above experimental results, it can be seen that the compound of the present invention can effectively inhibit the activity of KIF18A and is an effective KIF18A inhibitor.
- Test products some compounds of the present invention, their chemical names and structures are shown in the preparation examples.
- OVCAR3 TP53 mutant human ovarian cancer cells
- OVCAR3 cell culture medium is RPMI Medium 1640+20% FBS+1% PS. The cells were tested in the logarithmic growth phase.
- Cells in logarithmic growth phase were harvested and counted using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust to the appropriate concentration and add 90 ⁇ L of cell suspension to the 96-well plate.
- test compound stock solution 10mM was first diluted with DMSO to 0.123mM, and then serially diluted 1.5 times to a total of 9 concentrations. Then add 2 ⁇ L of DMSO gradient diluted compounds to 198 ⁇ L of culture medium to form a working stock solution of the test compound (the compound concentration is 10 times the final concentration, and the highest concentration is 123 nM).
- test compounds were: 123nM, 82.3nM, 54.8nM, 36.6nM, 24.4nM, 16.3nM, 10.9nM, 7.2nM, 4.5nM.
- Inhibition rate (%) 1-(reading of test wells – readings of blank control wells)/(readings of DMSO solvent control wells – readings of blank control wells) ⁇ 100%;
- the IC 50 value of the inhibitory activity of the compound of the present invention on OVCAR3 is represented by A from 1 nM to 100 nM, B from 100 nM to 500 nM, and C from 500 nM to 1000 nM.
- the compounds of the present invention can effectively inhibit the proliferation of OVCAR3 cells, indicating that the compounds of the present invention have clinical application potential in treating cancerous diseases with TP53 mutations.
- Test products some compounds of the present invention, their chemical names and structures are shown in the preparation examples.
- OVCAR3 TP53 mutant human ovarian cancer cells
- MDA-MB-157 TP53 mutant human breast cancer cells
- the OVCAR3 cell culture medium is RPMI Medium 1640+20% FBS+1% PS.
- the MDA-MB-157 cell culture medium is DMEM Medium+10% FBS+1% PS. The cells are growing logarithmically. period of testing.
- Cells in logarithmic growth phase were harvested and counted using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust to the appropriate concentration and add 90 ⁇ L of cell suspension to the 96-well plate.
- test compound stock solution is 10mM, 3-fold serial dilution, a total of 9 concentrations. Then add 2 ⁇ L of DMSO gradient diluted compounds to 198 ⁇ L of culture medium to form a working stock solution of the test compound (the compound concentration is 10 times the final concentration, and the highest concentration is 100 ⁇ M).
- test compounds were: 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.57 nM, 1.52 nM.
- Inhibition rate (%) 1-(reading of test wells – readings of blank control wells)/(readings of DMSO solvent control wells – readings of blank control wells) ⁇ 100%;
- the IC 50 value of the inhibitory activity of the compound of the present invention against OVCAR3 is represented by A, 1nM to 100nM is represented by A, 100nM to 500nM is represented by B, and 500nM to 1000nM is represented by C; the IC 50 value of the inhibitory activity of the compound of the present invention against MDA-MB-157 , 1nM ⁇ 100nM is represented by A, 100nM ⁇ 500nM is represented by B, and 500nM ⁇ 1000nM is represented by C.
- Test product The compound of the present invention is self-made. Please refer to the preparation examples of each compound for its chemical name and preparation method.
- Test animals mice, female, 6/administration route/compound.
- Preparation method of blank solvent (1) Weigh 28g HP- ⁇ -CD (hydroxypropyl- ⁇ -cyclodextrin), add appropriate amount of water for injection to dissolve, then adjust the volume to 100mL with water for injection, vortex and mix, that is Obtain 28% HP- ⁇ -CD.
- HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
- Preparation method of blank solvent (2) Weigh 20g HPC (hydroxypropyl cellulose), slowly add 500mL stirring purified water, then add 1mL Tween 80, stir until clear and transparent, adjust the volume to 1000mL, stir evenly. Get 2% HPC + 0.1% Tween 80.
- IV (intravenous push) administration
- DMA N,N-dimethylacetamide
- Kolliphor HS15 polyethylene glycol-15-hydroxystearate
- DPBS Dulbecco's Phosphate Buffered Saline
- the IV administration dose is 5 mg/kg, the administration concentration is 1 mg/mL, and the administration volume is 5 mL/kg.
- the PO dosage is 30 mg/kg, the dosage concentration is 3 mg/mL, and the dosage volume is 10 mL/kg. Or the PO dosage is 10 mg/kg, the dosage concentration is 1 mg/mL, and the dosage volume is 10 mL/kg.
- Blood collection time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration. Specifically, blood collection is as shown in the table:
- the compound of the present invention has good pharmacokinetic properties, a low clearance rate, and high exposure and bioavailability.
- Xphos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1' - biphenyl)]palladium(II); '-bis(diphenylphosphine)ferrocene]palladium; RuphosPdG3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-Amino-1,1'-biphenyl-2-yl)palladium(II); DIPEA: N,N-diisopropylethylamine; PPTS: pyridine-p-toluenesulfonate
- ethyl acetate hydrochloride solution (20 mL) was added to the solution containing (8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)carbamic acid.
- Tert-butyl ester 850 mg, 2.4 mmol was reacted in ethyl acetate (10 mL) for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure and directly put into the next step of reaction.
- N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[ 2.5] Oct-6-yl) benzamide (220 mg, 0.37 mmol) was dissolved in N, N-dimethylformamide (10 mL), copper iodide (70 mg, 0.37 mmol), N-methylglycine ( 33mg, 0.37mmol) and potassium phosphate (383mg, 1.8mmol), react at 50°C for 5 minutes, add 2-hydroxyethane-1-sulfonamide (94mg, 0.75mmol) and react at 100°C under nitrogen protection 2 hours.
- N-(8-(4,4-difluoropiperidin-1-yl)-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6 -Azaspiro[2.5]octane-6-yl)benzamide 200 mg, 0.33 mmol was dissolved in N,N-dimethylformamide (10 mL), and copper iodide (63 mg, 0.33 mmol) was added , N-methylglycine (59mg, 0.66mmol) and potassium phosphate (280mg, 1.32mmol), react at 50°C for 5 minutes, add 2-hydroxyethane-1-sulfonamide (124mg, 0.99mmol), and incubate under nitrogen protection The reaction mixture was placed at 100°C for 2 hours. After the reaction was completed, water was added to quench, and the reaction was suction filtered. The filter cake was slurried with ethyl acetate to obtain the target compound (19 mg, yield:
- N-(5-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-4-iodo-2 -(6-Azaspiro[2.5]octane-6-yl)benzamide (190 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (5 mL), and copper iodide (61 mg, 0.32mmol), N-methylglycine (57mg, 0.64mmol) and potassium phosphate (271mg, 1.28mmol), react at 50°C for 5 minutes, add 2-hydroxyethane-1-sulfonamide (120mg, 0.96mmol), Place the mixture at 100°C for 2 hours under nitrogen protection.
- N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo- 2-(6-Azaspiro[2.5]octane-6-methyl)benzamide 130 mg, 0.22 mmol was dissolved in N,N-dimethylformamide (5 mL), and copper iodide ( 42mg, 0.22mmol), N-methylglycine (39mg, 0.44mmol) and potassium phosphate (187mg, 0.88mmol), react at 50°C for 5 minutes, add 2-hydroxyethane-1-sulfonamide (82mg, 0.66mmol) ), place it at 100°C for 2 hours under nitrogen protection.
- Lithium borohydride (2 mg, 0.092 mmol) was added to a solution containing 2-((4-((8-(4,4-difluoropiperidin-1-yl))imidazo[1,2-a]pyra) at 0°C.
- a solution of ethyl azine-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)sulfonyl)acetate (40 mg, 0.065 mmol) in tetrahydrofuran (10 mL) , react for 3 hours.
- N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6-azaspiro[ 2.5]oct-6-yl)benzamide 100mg, 0.17mmol
- sodium cyclopropanesulfinate 44mg, 0.34mmol
- potassium carbonate 5mg, 0.034mmol
- copper iodide 3mg, 0.016mmol
- L-proline 4 mg, 0.034 mmol
- lithium borohydride (7 mg, 0.3 mmol) was added to a solution containing (R)-2-((4-((8-(2-methylmorpholine))imidazo[1,2-a]pyrazine- A solution of ethyl 6-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)sulfonyl)acetate (90 mg, 0.15 mmol) in tetrahydrofuran (20 mL), react 30 minutes.
- N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6- Azaspiro[2.5]octane-6-yl)benzamide (30 mg, 0.049 mmol) was dissolved in N,N-dimethylformamide (10 mL), and copper iodide (10 mg, 0.052 mmol) was added.
- N-Methylglycine (5mg, 0.056mmol) and potassium phosphate (51mg, 0.24mmol) were reacted at 50°C for 5 minutes.
- N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-4-iodo- 2-(6-Azaspiro[2.5]octane-6-yl)benzamide 140mg, 0.24mmol was dissolved in N,N-dimethylformamide (5mL), and D-aminopropanol (43mg ,0.58mmol), N,N-diisopropylethylamine (112mg, 0.87mmol), react at 80°C for 3h.
- N-(8-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylimidazo[1,2-a]pyrazin-6-yl)-4-iodo- 2-(6-Azaspiro[2.5]octane-6-yl)benzamide (170 mg, 0.27 mmol) in N,N-dimethylformamide (10 mL), add copper iodide (51 mg, 0.27 mmol), N-methylglycine (48mg, 0.54mmol) and potassium phosphate (287mg, 1.4mmol) and 2-hydroxyethane-1-sulfonamide (101mg, 0.81mmol), placed at 100°C under nitrogen protection Reaction takes 3 hours.
- lithium borohydride (2 mg, 0.086 mmol) was added to 2-((4-((8-(4,4-difluoropiperidin-1-yl))-3-fluoro-2-methylimidazo [1,2-a]pyrazin-6-yl)carbamoyl)-3-(6-azaspiro[2.5]octane-6-ylphenyl)sulfonyl)ethyl acetate (18 mg, 0.028 mmol ) in tetrahydrofuran (1mL), react for 1 hour.
- N-(3-fluoro-8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6 -Azaspiro[2.5]oct-6-yl)benzyl Amide (150mg, 0.26mmol) was dissolved in N,N-dimethylformamide (5mL), copper iodide (49mg, 0.26mmol), N-methylglycine (23mg, 0.26mmol) and potassium phosphate (276mg) were added ,1.30mmol) and 2-hydroxyethane-1-sulfonamide (65mg, 0.52mmol), reacted at 100°C for 2 hours under nitrogen protection, and the reaction was completed.
- tert-butyl (8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl) carbamate (98 mg, 2.31 mmol) in dichloro Methane (6 mL), add trifluoroacetic acid (3 mL), and react for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound (85 mg, yield: 13.7%).
- N-(8-(4,4-difluorocyclohexyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5 ]oct-6-yl)benzamide 100 mg, 0.16 mmol was dissolved in N, N-dimethylformamide (15 mL), copper iodide (15 mg, 0.08 mmol) and N-methylglycine (14 mg were added , 0.16mmol), potassium phosphate trihydrate (213mg, 0.8mmol) and 2-hydroxyethane-1-sulfonamide (41mg, 0.33mmol), reacted under nitrogen protection at 100°C for 3 hours, and the reaction was completed.
- N-(8-(4-(difluoromethyl)piperidin-1-yl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6 -Azaspiro[2.5]oct-6-yl)benzamide 120mg, 0.19mmol was dissolved in N,N-dimethylformamide (5mL), copper iodide (37mg, 0.19mmol) was added, N -Methylglycine (17mg, 0.19mmol), potassium phosphate (201mg, 0.95mmol) and 2-hydroxyethane-1-sulfonamide (48mg, 0.38mmol) were reacted under nitrogen protection at 100°C for 3 hours.
- N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-iodo-2 -(6-Azaspiro[2.5]oct-6-yl)benzamide 400mg, 0.67mmol was dissolved in N,N-dimethylformamide (15mL), and copper iodide (64mg, 0.33mmol) was added ), N-methylglycine (60mg, 0.67mmol), potassium phosphate (892mg, 4.2mmol) and 2-hydroxyethane-1-sulfonamide (169mg, 1.3mmol), react under nitrogen protection at 100°C for 3 hours , the reaction is completed.
- N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5 ]oct-6-yl)benzamide (420 mg, 0.71 mmol) was dissolved in N, N-dimethylformamide (10 mL), copper iodide (135 mg, 0.71 mmol) and N-methylglycine (64 mg were added ,0.71mmol), potassium phosphate (753mg, 3.55mmol) and 2-hydroxyethane-1-sulfonamide (178mg, 1.42mmol), reacted at 100°C for 3 hours under nitrogen protection, and the reaction was completed.
- N-(5-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-4-iodo-2-(6-azaspiro[2.5 ]oct-6-yl)benzamide 200 mg, 0.34 mmol was dissolved in N, N-dimethylformamide (5 mL), copper iodide (65 mg, 0.34 mmol) and N-methylglycine (30 mg were added ,0.34mmol), potassium phosphate (360mg, 1.7mmol) and 2-hydroxyethane-1-sulfonamide (85mg, 0.68mmol), reacted at 100°C for 3 hours under nitrogen protection, and the reaction was completed.
- N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5 ]oct-6-yl)benzamide (200mg, 0.34mmol) was dissolved in DMSO (10mL), potassium metabisulfite (113mg, 0.51mmol), sodium formate (46mg, 0.68mmol), triphenylphosphorus (13mg, 0.05mmol), 1,10-phenanthroline (9mg, 0.051mmol), tetrabutylammonium bromide (164mg, 0.51mmol) and palladium acetate (6mg, 0.027mmol), under nitrogen protection, react at 70°C for 45 minutes, cool down, add ethyl bromoacetate (85 mg, 0.51 mmol), and react at 25°C for 10 minutes.
- N-(8-(4,4-difluoropiperidin-1-yl)-5-fluoroimidazo[1,2-a]pyrazin-6-yl)-4-iodo-2-(6- Azaspiro[2.5]oct-6-yl)benzamide (20mg, 0.033mmol) was dissolved in N,N-dimethylformamide (10mL), copper iodide (6mg, 0.032mmol) was added, N- Methylglycine (6mg, 0.067mmol), potassium phosphate (35mg, 0.16mmol) and 2-hydroxyethane-1-sulfonamide (12mg, 0.096mmol) were reacted under nitrogen protection at 100°C for 10 hours, and the reaction was completed.
Abstract
本发明涉及医药技术领域,具体涉及KIF18A抑制剂化合物、其药学上可接受的盐、其酯或其立体异构体,含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂,制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法,以及所述化合物、其药学上可接受的盐、其酯或其立体异构体在制备治疗和/或预防由KIF18A介导的疾病及相关疾病的药物中的用途。
Description
本发明涉及医药技术领域,具体涉及KIF18A抑制剂、其药学上可接受的盐、其酯或其立体异构体,含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂,制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法,以及所述化合物、其药学上可接受的盐、其酯或其立体异构体在制备治疗和/或预防由KIF18A介导的疾病及相关疾病的药物中的用途。
驱动蛋白分子是以微管为轨道的马达蛋白,在细胞器迁移、组织器官发育、信号传导、有丝分裂、减数分裂等过程中发挥重要作用。驱动蛋白kinesin-8家族的多种微管结合蛋白(microtubule–associated protein,MAP)通过影响微管的聚合和解聚行使着调控微管动态不稳定性的功能。据报道,驱动蛋白家族与多种癌症的侵袭、转移和预后不良密切相关。越来越多的驱动蛋白家族成员被认为与肿瘤的发生和进展有关。KIF18A是kinesin-8家族的一员,是一种多功能蛋白,它利用三磷酸腺苷(ATP)水解产生力并沿着微管移动。它参与多种细胞功能,包括细胞分裂、细胞运动、微管动力学和细胞器运输。KIF18A会影响细胞分化以及癌症发展。已有研究表明,KIF18A与肿瘤行为有关,可用作乳腺癌、结直肠癌和肝细胞癌的潜在生物标志物。
遗传不稳定性是肿瘤细胞的共同特征,大量肿瘤细胞表现出染色体的频繁丢失或增加。这种染色体不稳定性(Chromosomal instability,CIN)主要是由于缺陷导致染色体和有丝分裂纺锤体微管之间的异常相互作用,进而增加染色体分离错误。与染色体稳定的细胞相比,CIN细胞显示纺锤体微管聚合增加,纺锤体微管和动粒之间的附着物周转减少,动粒是在有丝分裂染色体的着丝粒区域组装的特殊蛋白质结构。因此,CIN细胞可能特别容易受到针对微管细胞骨架的抗有丝分裂疗法的影响。
有丝分裂CIN细胞中改变的微管动力学使它们特别依赖KIF18A来减少动粒-微管周转并限制微管生长。在缺失KIF18A活性的情况下,会发生中心体断裂,并且有丝分裂进程会减慢或停止。KIF18A对于体内二倍体体细胞的增殖在很大程度上是可有可无的,但对于CIN肿瘤细胞的增殖是必需的。在抑制KIF18A后,CIN肿瘤细胞表现出有丝分裂延迟、多极纺锤体和细胞死亡增加。因此,KIF18A可能是特异性抑制CIN肿瘤细胞生长的有效靶点,同时在体细胞、二倍体细胞中具有相对较低的毒性。
综上所述,以KIF18A为靶点开发抑制剂将为不同类型肿瘤的治疗提供新的思路和策略。
发明内容
本发明的目的在于提供一种KIF18A抑制剂及其应用。具体技术方案如下:
在某些实施方案中,本发明首先提供了通式(I)所示的化合物、其药学上可接受的盐、酯或其立体异构体:
其中,
X1、X4分别独立地选自N或CRa;
X2与X3之间的连接方式为单键或双键;
当X2与X3之间的连接方式为单键时,X2、X3分别独立地选自N或C;当X2与X3之间的连接方式为双键时,X2、X3均为C;
环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基;
R1选自任选被1个或多个取代基Q2取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基、5-12元桥杂环基;
R2、R3、R4、R5、R6分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,-C(O)-NH2,-S(O)2-NH2,任选被1个或多个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、-(L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,卤代C1-6烷基,卤代C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,-C(O)-NH2,C1-6烷基羰基,C1-6烷基氧基羰基,C1-6烷基磺酰基,C1-6烷基氨基磺酰基,C1-6烷基磺酰氨基,任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基,所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;
每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-;
每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,C1-6烷基氨酰基,C1-6烷基酰氨基,C1-6烷基磺酰氨基,C1-6烷基氨基磺酰基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基,-(L)m-6-10元芳基,-(L)m-5-12元杂芳基,-(L)m-3-8元环烷基或-(L)m-3-8元杂环基;
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基;
每一m、n分别独立地为0-6的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
X1、X4分别独立地选自N或CRa;
X2与X3之间的连接方式为单键或双键;
当X2与X3之间的连接方式为单键时,X2、X3分别独立地选自N或C;当X2与X3之间的连接方式为双键时,X2、X3均为C;
环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基;
R1选自任选被1个或多个取代基Q2取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基、5-12元桥杂环基;
R2、R3、R4、R6分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,-C(O)-NH2,-S(O)2-NH2,任选被1个或多个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、-(L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基;且R2、R3、R4、R6至少有一个不为氢;
R5选自任选被1-4个取代基Q3取代的-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,卤代C1-6烷基,卤代C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,-C(O)-NH2,C1-6烷基羰基,C1-6烷基氧基羰基,C1-6烷基磺酰基,C1-6烷基氨基磺酰基,C1-6烷基磺酰氨基,任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环
基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基,所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;
每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-;
每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,C1-6烷基氨酰基,C1-6烷基酰氨基,C1-6烷基磺酰氨基,C1-6烷基氨基磺酰基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基,-(L)m-6-10元芳基,-(L)m-5-12元杂芳基,-(L)m-3-8元环烷基或-(L)m-3-8元杂环基;
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基;
每一m、n分别独立地为0-6的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
X1、X4分别独立地选自N或CRa;
X2与X3之间的连接方式为单键或双键;
当X2与X3之间的连接方式为单键时,X2、X3分别独立地选自N或C;当X2与X3之间的连接方式为双键时,X2、X3均为C;
环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基;
R1选自任选被1个或多个取代基Q2取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基、5-12元桥杂环基;
R2、R3、R4分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,-C(O)-NH2,-S(O)2-NH2,任选被1个或多个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、-(L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基;
R5选自任选被1-4个取代基Q3取代的-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;
R6选自任选被1-4个取代基Q3取代的-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基、-N(Rc)-C1-6烷基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,卤代C1-6烷基,卤代C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,-C(O)-NH2,C1-6烷基羰基,C1-6烷基氧基羰基,C1-6烷基磺酰基,C1-6烷基氨基磺酰基,C1-6烷基磺酰氨基,任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基,所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;
每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-;
每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,C1-6烷基氨酰基,C1-6烷基酰氨基,C1-6烷基磺酰氨基,C1-6烷基氨基磺酰基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基,-(L)m-6-10元芳基,-(L)m-5-12元杂芳基,-(L)m-3-8元环烷基或-(L)m-3-8元杂环基;
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基;
每一m、n分别独立地为0-6的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X1、X2、X3、X4至少有一个为N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X1、X2、X3、X4至少有两个为N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X1选自CRa。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X1选自N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X2选自C。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X2选自N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X3选自C。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X3选自N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X4选自CRa。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,X4选自N。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自5-8元环烷基、5-8元杂环基、苯基或5-8元杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自5-6元环烷基、5-6元杂环基、苯基或5-6元杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自5-6元环烷基、5-6元含氮杂环基或5-6元含氮杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-4个取代基Q2取代的3-8元环烷基、3-8元杂环基、苯基、5-8元杂芳基、7-11元螺环基、7-11元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元杂环基、苯基、7-10元螺环基、7-10元螺杂环基或5-6元杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元含氮杂环基、苯基、7-8元螺杂环基或5-6元含氮杂芳基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的3-6元环烷基、7-8元螺杂环基或3-6元含氮杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的5-6元环烷基、5-6元杂环基、7-8元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的4-6元杂环基,优选4-6元含氮杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的5-6元环烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的7-8元螺杂环基,优选7-8元含氮螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的环丙烷基、环丁烷基、环戊烷基、环己烷基、氮杂环丁烷基、氧杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、四氢吡喃基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、呋喃基、吡喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、2-哌啶酮基、
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R1选自任选被1-3个取代基Q2取代的二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、氮杂环丁烷基、2-哌啶酮
基、
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5分别独立地选自氢,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元杂环基、7-10元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元含氮杂环基、7-9元含氮螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R5选自任选被1-3个取代基Q3取代的8元含氮螺杂环基;R2选自氢。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的如下结构:
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R5选自任选被1-4个取代基Q3取代的-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;
R2选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R5选自任选被1-4个取代基Q3取代的-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基;
R2选自氢,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R5选自任选被1-3个取代基Q3取代的5-6元杂环基、7-10元螺杂环基;R2选自氢。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R5选自任选被1-3个取代基Q3取代的5-6元含氮杂环基、7-9元含氮螺杂环基;R2选自氢。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R3、R4分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,氰基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R3、R4分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R3、R4分别独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一L分别独立地选自-C(O)-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一L分别独立地选自-S(O)2-、-NRc-、-CRa1Rb-。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自任选被1-4个取代基Q3取代的-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基、-N(Rc)-C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自任选被1-4个取代基Q3取代的-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)-C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自任选被1-3个取代基Q3取代的-N(Rc)S(O)2-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元环烷基、-S(O)2N(Rc)-3-6元环烷基、-N(Rc)-C1-6烷基、-N(Rc)-C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自任选被1-3个取代基Q3取代的-N(H)S(O)2-C1-4烷基、-S(O)2N(H)-C1-4烷基、-S(O)2-C1-4烷基、-S(O)2-3-6元环烷基、-N(H)S(O)2-3-6元环烷基、-S(O)2N(H)-3-6元环烷基、-N(H)-C1-4烷基、-N(H)-C1-4烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自以下结构:
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R6选自以下结构:
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,C1-6烷基氨基,二(C1-6烷基)氨基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Q1、每一Q2、每一Q3分别独立地选自氟,氯,溴,碘,羧基,羟基,氰基,氨基,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,一氟甲基,二氟甲基,三氟甲基,一氟甲氧基,二氟甲氧基,三氟甲氧基,羟基甲基,羟基乙基,甲基氨基,乙基氨基,二甲氨基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一q分别独立地选自卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一q分别独立地选自氟,氯,溴,碘,羟基,氨基,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,一氟甲基,二氟甲基,三氟甲基,一氟甲氧基,二氟甲氧基,三氟甲氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-4烷基,C1-4烷氧基,C1-4烷基氨基,二(C1-4烷基)氨基,卤代C1-4烷基,卤代C1-4烷氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Ra、每一Ra1、每一Rb分别独立地选自氢,氟,氯,溴,碘,羧基,羟基,氰基,氨基,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,甲基氨基,乙基
氨基,二甲氨基,一氟甲基,二氟甲基,三氟甲基,一氟甲氧基,二氟甲氧基,三氟甲氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Ra、每一Ra1、每一Rb分别独立地选自氢,氟,氯,溴,碘,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,一氟甲基,二氟甲基,三氟甲基,一氟甲氧基,二氟甲氧基,三氟甲氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Ra、每一Ra1、每一Rb分别独立地选自氢。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Rc分别独立地选自氢,C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、羟基C1-4烷基、氨基C1-4烷基、羧基C1-4烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一Rc分别独立地选自氢,甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,一氟甲基,二氟甲基,三氟甲基,一氟甲氧基,二氟甲氧基,三氟甲氧基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一m分别独立地为0-4的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一m分别独立地为0、1、2、3。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一n分别独立地为0-4的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,每一n分别独立地为0、1、2、3。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,环A选自5-8元环烷基、5-8元杂环基、苯基或5-8元杂芳基;
R1选自任选被1-4个取代基Q2取代的3-8元环烷基、3-8元杂环基、苯基、5-8元杂芳基、7-11元螺环基、7-11元螺杂环基;
R2、R5分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;
R3、R4分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基;
R6选自任选被1-4个取代基Q3取代的-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基、-N(Rc)-C1-6烷基;
每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基;
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,C1-6烷基氨基,二(C1-6烷基)氨基;
每一m、n分别独立地为0-4的整数。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
环A选自5-6元环烷基、5-6元杂环基或5-6元杂芳基;
R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基、7-10元螺环基、7-10元螺杂环基;
R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;R2、R5不同时为氢;
R6选自任选被1-3个取代基Q3取代的-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-N(Rc)-C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基;
R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元杂环基、苯基、7-10元螺环基、7-10元螺杂环基或5-6元杂芳基;
R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元杂环基、7-10元螺杂环基;
R3、R4分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
R6选自任选被1-3个取代基Q3取代的-N(Rc)S(O)2-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元环烷基、-S(O)2N(Rc)-3-6元环烷基、-N(Rc)-C1-6烷基;
每一Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
每一Rc分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(I-1)所示的结构,
其中,Y1、Y2分别独立地选自N或CH;
R1、R2、R3、R4、R5、R6、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(I-1’)所示的结构,
其中,Y1、Y2分别独立地选自N或CH;
R1、R2、R3、R4、R5、R6、X1、每一Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(I-2)所示的结构,
其中,Y1、Y2分别独立地选自N或CH;
R1、R2、R3、R4、R5、R6、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II)所示的结构,
其中,n为0、1、2;
R1、R2、R3、R4、R5、R6、每一Q1的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II’)所示的结构,
其中,X1、R1、R2、R3、R4、R5、R6、每一Ra、n、每一Q1的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II’)所示的结构,其中,n为0、1、2;X1、R1、R2、R3、R4、R5、R6、每一Ra、n、每一Q1的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II’)所示的结构,其中,X1选自N或CRa;
R1选自任选被1-3个取代基Q2取代的3-6元环烷基、7-8元螺杂环基或3-6元含氮杂环基;
R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元含氮杂环基、7-9元含氮螺杂环基;
R3、R4分别独立地选自氢,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基;
R6选自任选被1-4个取代基Q3取代的-NHS(O)2-C1-6烷基、-S(O)2NH-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-NH-C1-6烷基;
每一Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-4烷基,C1-4烷氧基,C1-4烷基氨基,二(C1-4烷基)氨基,卤代C1-4烷基,卤代C1-4烷氧基;
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基,羟基C1-4烷基,羧基C1-4烷基;
n为0、1、2。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,R2、R5不同时为氢。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II-1)或(II-1’)所示的结构,
其中,每一X6选自N或CH;
每一R1、每一R2、每一R3、每一R4、每一R6、Ra、每一Q1、每一Q2、每一Q3、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II-2)或式(II-2’)所示的结构,
其中,每一L1分别独立地选自NRc、O、S或CRa1Rb;每一X5、每一X6分别独立地选自N或CH;
p选自0-2的整数;
R2、R3、R4、R6、Ra、每一Ra1、每一Rb、每一Q1、每一Q2、每一Q3、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II-3)或式(II-3’)所示的结构,
其中,每一L1分别独立地选自-NH-、-O-、-S-或-CH2-;每一p选自0-2的整数;
每一R6、Ra、每一Q1、每一Q2、每一Q3、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
选自以下结构:
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(III)或式(III’)所示的结构,
其中,X5、X6分别独立地选自N或CH;
每一R2、每一R3、每一R4、每一R6、Ra、每一Q1、每一Q2、每一Q3、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(III)或式(III’)所示的结构,
其中,每一X5、每一X6分别独立地为N;
每一R2、每一R3、每一R4分别独立地为氢;
R6选自以下结构:
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基;
每一n为0、1、2。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(II-2)或式(II-2’)所示的结构,
其中,X5、X6分别独立地选自N或CH;
每一L1分别独立地选自NH、O或CH2;
R2、R3、R4分别独立地选自氢或C1-6烷基;
R6选自以下结构:
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基;
p、n分别独立地为0、1、2。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(IV)或式(IV’)所示的结构,
每一R1、每一R2、每一R3、每一R4、每一R5、每一R6、Ra、每一X2、每一X3、每一X4、每一Q1、每一Q2、每一Q3、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(IV-1)或式(IV-1’)所示的结构,
每一R1、每一R6、每一Ra、每一X2、每一X3、每一X4、每一Q1、每一Q2、每一Q3、n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(IV-2)或式(IV-2’)所示的结构,
每一R1、Ra、每一X2、每一X3、每一X4、每一Q1、每一Q2、每一n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(IV-3)或式(IV-3’)所示的结构,
每一X2、每一X3、每一X4、每一Q1、每一n、每一Ra的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其中,
选自如下结构,
R1选自任选被1-3个取代基Q2取代的二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、氮杂环丁烷基、2-哌啶酮基、
R2选自氢;
R5选自任选被1-3个取代基Q3取代的如下结构:
每一Ra、R3、R4分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
R6选自以下结构:
每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基。
在某些实施方案中,本发明所示的化合物、其药学上可接受的盐、酯或其立体异构体,其具有通式(I’)所示的结构,
其中,X1、X2、X3、X4、R1、R2、R3、R5、R6、每一Ra、每一Q1的定义如前述技术方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有通式(I’-1)所示的结构,
其中,Y1、Y2分别独立地选自N或CH;
R1、R2、R3、R4、R5、R6、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有式(I’-1)所示的结构,
R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元杂环基、苯基、7-10元螺环基、7-10元螺杂环基或5-6元杂芳基;
R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元杂环基、7-10元螺杂环基;R2、R5不同时为氢;
R3选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
R6选自任选被1-3个取代基Q3取代的-N(Rc)S(O)2-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元环烷基、-S(O)2N(Rc)-3-6元环烷基、-N(Rc)-C1-6烷基;
每一Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
每一Rc分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
每一Q1选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基;
n为0、1、2。
在某些实施方案中,前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体,其具有通式(I’-2)所示的结构,
其中,Y2选自N或CH;
R1选自任选被1-3个取代基Q2取代的5-6元环烷基、5-6元杂环基、7-8元螺杂环基;
R2选自氢,卤素,氰基,羧基,羟基,氨基,硝基,C1-6烷基,C1-6烷氧基;
R3选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;
R6选自任选被1-3个取代基Q3取代的-N(H)S(O)2-C1-4烷基、-S(O)2N(H)-C1-4烷基、-S(O)2-C1-4烷基、-S(O)2-3-6元环烷基、-N(H)S(O)2-3-6元环烷基、-S(O)2N(H)-3-6元环烷基、-N(H)-C1-4烷基、-N(H)-C1-4烷基;
Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基;
每一Q1选自卤素,羧基,羟基,氨基,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基,羟基C1-4烷基,羧基C1-4烷基;
n为0、1、2。
本发明的一些实施方式中,所提供的化合物、其药学上可接受的盐、酯或其立体异构体的结构如下所示:
本发明还提供了一种药物组合物,其含有前述通式(I)、通式(I-1)、通式(I-1’)、通式(I-2)、通式(I’)、通式(I’-1)、通式(I’-2)、通式(II)、通式(II’)、通式(II-1)、通式(II-1’)、通式(II-2)、通式(II-2’)、通式(II-3)、通式(II-3’)、通式(III)、通式(III’)、通式(IV)、通式(IV’)、通式(IV-1)、通式(IV-1’)、通式(IV-2)、通式(IV-2’)、通式(IV-3)、通式(IV-3’)所示的化合物、其药学上可接受的盐、酯或其立体异构体,及一种或多种第二治疗活性剂,任选地,所述药物组合物还包含一种或多种药用载体和/或稀释剂。
本发明所述的第二治疗剂包括但不限于生长因子抑制剂、细胞周期抑制剂、拓扑异构酶抑制剂、抗代谢药、抗有丝分裂剂、血管发生抑制剂、生物反应修饰剂、抗激素剂、抗癌药物。
本发明还提供了一种药物制剂,其含有前述通式(I)、通式(I-1)、通式(I-1’)、通式(I-2)、通式(I’)、通式(I’-1)、通式(I’-2)、通式(II)、通式(II’)、通式(II-1)、通式(II-1’)、通式(II-2)、通式(II-2’)、通式(II-3)、通式(II-3’)、通式(III)、通式(III’)、通式(IV)、通式(IV’)、通式(IV-1)、通式(IV-1’)、通式(IV-2)、通式(IV-2’)、通式(IV-3)、通式(IV-3’)所示的化合物、其药学上可接受的盐、酯或其立体异构体,及一种或多种药用载体和/或稀释剂;所述药物制剂为临床上或药学上可接受的任一剂型。
在本发明的一些实施方式中,上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,所述药物组合物可制成口服制剂,例如可以制成常规的口服固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,上述药物制剂也可制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中的常规方法生产,配置注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。用于直肠给药时,所述药物组合物可制成栓剂等。用于经肺给药时,所述药物组合物可制成吸入剂或喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂,特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。例如,药用载体和/或稀释剂可以包括药学领域常规的溶剂、稀释剂、分散剂、助悬剂、表面活性剂、等渗剂、增稠剂、乳化剂、粘合剂、润滑剂、稳定剂、水合剂、乳化加速剂、缓冲剂、吸收剂、着色剂、离子交换剂、脱模剂、涂布剂、矫味剂、和抗氧化剂等。必要时,还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
本发明还提供了前述通式(I)、通式(I-1)、通式(I-1’)、通式(I-2)、通式(I’)、通式(I’-1)、通式(I’-2)、通式(II)、通式(II’)、通式(II-1)、通式(II-1’)、通式(II-2)、通式(II-2’)、通式(II-3)、通式(II-3’)、通式(III)、通式(III’)、通式(IV)、通式(IV’)、通式(IV-1)、通式(IV-1’)、通式(IV-2)、通式(IV-2’)、通式(IV-3)、通式(IV-3’)所示的化合物、其药学上可接受的盐、酯或其立体异构体、前述的药物制剂或前述的药物组合物在制备用于治疗和/或预防KIF18A介导的疾病及相关疾病的药物中的用
途;所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了前述通式(I)、通式(I-1)、通式(I-1’)、通式(I-2)、通式(I’)、通式(I’-1)、通式(I’-2)、通式(II)、通式(II’)、通式(II-1)、通式(II-1’)、通式(II-2)、通式(II-2’)、通式(II-3)、通式(II-3’)、通式(III)、通式(III’)、通式(IV)、通式(IV’)、通式(IV-1)、通式(IV-1’)、通式(IV-2)、通式(IV-2’)、通式(IV-3)、通式(IV-3’)所示的化合物、其药学上可接受的盐、酯或其立体异构体、前述的药物制剂或前述的药物组合物在治疗/或预防KIF18A介导的疾病及相关疾病中的应用;所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了一种治疗疾病的方法,该方法包括向有需要的患者给药治疗有效量的前述通式(I)、通式(I-1)、通式(I-1’)、通式(I-2)、通式(I’)、通式(I’-1)、通式(I’-2)、通式(II)、通式(II’)、通式(II-1)、通式(II-1’)、通式(II-2)、通式(II-2’)、通式(II-3)、通式(II-3’)、通式(III)、通式(III’)、通式(IV)、通式(IV’)、通式(IV-1)、通式(IV-1’)、通式(IV-2)、通式(IV-2’)、通式(IV-3)、通式(IV-3’)所示的化合物、其药学上可接受的盐、酯或其立体异构体、前述的药物制剂或前述的药物组合物,其中,所述疾病为KIF18A介导的疾病及相关疾病;所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
所述癌症或良性肿瘤包括但不限于乳腺癌、卵巢癌、子宫内膜癌、子宫颈癌、脑癌、头颈癌、甲状腺癌、肺癌、支气管癌、食管癌、胃癌、肝癌、肾癌、胰腺癌、胆囊癌、结肠癌、膀胱癌、前列腺癌、罩丸癌、皮肤癌、骨癌及血液瘤;所述肺癌包括但不限于小细胞肺癌及非小细胞肺癌;所述血液瘤包括但不限于白血病、淋巴瘤、骨髓瘤;所述脑癌包括但不限于神经胶质瘤、神经母细胞瘤、星形细胞瘤、脑膜瘤。
本发明提供了上述化合物的制备方法,但不仅限于以下方法,制备方法的反应方程式如下:
步骤1:将式(II’-2)化合物溶于适当溶剂(例如二氯甲烷),加入式(II’-1)化合物和碱性物质(例如N,N-二异丙基乙胺)的有机溶剂(例如二氯甲烷)中,反应1-5小时,经适当方法(例如硅胶柱层析)得本发明式II’-3化合物。
步骤2:将式(II’-3)化合物溶于适当溶剂(例如N,N-二甲基甲酰胺),加入催化剂(例如卤化亚铜)、碱性物质(例如磷酸钾、N,N-二异丙基乙胺等)反应,加入R6-H,氮气保护下反应1-5小时。经后处理得本发明通式II’化合物。
后处理包括但不限于加水淬灭、有机溶剂(例如乙酸乙酯)萃取、浓缩、柱层析中的一种或几种方法的组合。
上述制备方法可以简单概括为:将式(II’-1)化合物与式(II’-2)所示的化合物反应,得到式(II’-3)化合物;式(II’-3)化合物与R6-H反应,得到通式II’化合物。
其中,X为卤素;X1、R1、R2、R3、R4、R5、R6、每一Ra、n、每一Q1的定义如前述方案任一项所述。
本发明还提供了用于制备通式(I)至通式(IV-3’)所示化合物、其药学上可接受的盐、其酯、或其立体异构体的中间体,其具有以下结构式:
其中,每一X分别独立地为卤素;每一X1、每一R1、每一R2、每一R3、每一R4、每一R5、每一R6、每一Ra、每一n、每一Q1的定义如前述方案任一项所述。
本发明还提供了用于制备通式(I)至通式(IV-3’)所示化合物、其药学上可接受的盐、其酯、或其立体异构体的中间体,其具有以下结构式:
其中,每一X分别独立地为卤素;每一X1、每一R1、每一R2、每一R3、每一R4、每一R6、每一Ra、每一n、每一Q1的定义如前述方案任一项所述。
在本申请的说明书和权利要求书中,化合物都是依据化学结构式而命名,如果表示同一化合物时化合物的命名和化学结构式不符,以化学结构式为准。
在本申请中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义,然而为了更好地理解本发明,下面提供了部分术语的定义。当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候,以本申请所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟、氯、溴和碘,优选氟和氯。
本发明所述的“卤代”是指取代基中的任一氢可被一个或多个相同或不同的卤素取代。“卤素”如前文所定义。
本发明所述的“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基,包括例如“C1-5烷基”、“C1-4烷基”、“C1-3烷基”、“C1-2烷基”、“C2-6烷基”、“C2-5烷基”、“C2-4烷基”、“C2-3烷基”、“C3-6烷基”、“C3-5烷基”、“C3-4烷基”、“C4-6烷基”、“C4-5烷基”、“C5-6烷基”等,具体实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C1-4烷基”指C1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C1-6亚烷基”指上述所述C1-6烷基去除一个氢原子形成的基团,包括例如“C1-5亚烷基”、“C1-4亚烷基”、“C1-3亚烷基”、“C1-2亚烷基”、“C2-6亚烷基”、“C2-5亚烷基”、“C2-4亚烷基”、“C2-3亚烷基”、“C3-6亚烷基”、“C3-5亚烷基”、“C3-4亚烷基”、“C4-6亚烷基”、“C4-5亚烷基”、“C5-6亚烷基”等,具体实例包括但不限于:亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基等。本发明所述的“C1-4亚烷基”指C1-6亚烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C2-6烯基”是指含有至少一个双键的碳原子数为2-6的直链或支链或环状的烯基,包括例如“C2-5烯基”、“C2-4烯基”、“C2-3烯基”等,具体实例包括但不限于:乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、2-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1-乙基-2-丙烯基、2-己烯基、3-己烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、1-甲基-2-戊烯基、3-甲基-2-戊烯基、2-甲基-3-戊烯基、1-甲基-4-戊烯基、3-甲基-4-戊烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-1-丁烯基、2-乙基-1-丁烯基、2-乙基-3-丁烯基等。
本发明所述的“C2-6炔基”是指含有三键的碳原子数为2-8的直链或支链的炔基,其中包括例如“C2-5炔基”、“C2-4炔基”、“C2-3炔基”等,具体实例包括但不限于:乙炔基、1-丙炔基、2-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1,1-二甲基-3-丁炔基、2-乙基-3-丁炔基等。
本文所述的“C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基氨酰基、C1-6烷基酰氨基、C1-6烷基磺酰基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、C1-6烷基羰基、C1-6烷氧基羰基”是指以C1-6烷基-O-、C1-6烷基-NH-、(C1-6烷基)2-N-、C1-6烷基-NH-C(O)-、C1-6烷基-C(O)-NH-、C1-6烷基-S(O)2-、C1-6烷基-S(O)2-NH-、C1-6烷基-NH-S(O)2-、C1-6烷基-C(O)-、C1-6烷基-O-C(O)-方式形成的基团,其中“C1-6烷基”的定义如前文所述。
本文所述的“C1-4烷氧基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-4烷基氨酰基、C1-4烷基酰氨基、C1-4烷基磺酰基、C1-4烷基磺酰氨基、C1-4烷基氨基磺酰基、C1-4烷基羰基、C1-4烷氧基羰基”是指以C1-4烷基-O-、C1-4烷基-NH-、(C1-4烷基)2-N-、C1-4烷基-NH-C(O)-、C1-4烷基-C(O)-NH-、C1-4烷基-S(O)2-、C1-4烷基-S(O)2-NH-、C1-4烷基-NH-S(O)2-、C1-4烷基-C(O)-、C1-4烷基-O-C(O)-方式形成的基团,其中“C1-4烷基”的定义如前文所述。
本文所述的“卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、卤代C1-6烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基、羧基分别取代C1-6烷基、C1-6亚烷基、C1-6烷氧基中的氢原子所形成的基团。
本文所述的“卤代C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、羧基C1-4烷基、卤代C1-4烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基分别取代C1-4烷基、C1-4烷氧基中的氢原子所形成的基团。
本发明所述的“3-12元环烷基”是指含有3-12个碳原子的饱和或部分饱和的且不具有芳香性的环状烷基,包括“单环烷基”和“稠环烷基”。
本发明所述的“单环烷基”是指饱和或部分饱和的且不具有芳香性的单环环状烷基,包括“3-8元饱和环烷基”和“3-8元部分饱和环烷基”;优选“3-4元环烷基”、“3-5元环烷基”、“3-6元环烷基”、“3-7元环烷基”、“4-5元环烷基”、“4-6元环烷基”、“4-7元环烷基”、“4-8元环烷基”、“5-6元环烷基”、“5-7元环烷基”、“5-8元环烷基”、“6-7元环烷基”、“6-8元环烷基”、“7-8元环烷基”、“3-6元饱和环烷基”、“4-7元饱和环烷基”、“4-8元饱和环烷基”、“5-8元饱和环烷基”、“5-7元饱和环烷基”、“5-6元饱和环烷基”、“3-6元部分饱和环烷基”、“4-7元部分饱和环烷基”、“4-8元部分饱和环烷基”、“5-8元部分饱和环烷基”、“5-7元部分饱和环烷基”、“5-6元部分饱和环烷基”等。所述的“3-8元饱和环烷基”的具体实例包括但不限于:环丙烷基(环丙基)、环丁烷基(环丁基)、环戊烷基(环戊基)、环己烷基(环己基)、环庚烷基(环庚基)、环辛烷基(环辛基)等;所述的“3-8元部分饱和环烷基”的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己-1,3-二烯、环己-1,4-二烯、环庚烯基、环庚-1,3-二烯基、环庚-1,4-二烯基、环庚-1,3,5-三烯基,环辛烯基、环辛-1,3-二烯基、环辛-1,4-二烯基、环辛-1,5-二烯基、环辛-1,3,5-三烯基、环辛四烯基等。
本发明所述的“稠环烷基”是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的饱和或部分饱和的、非芳香性环状基团,所述的稠环中的一个环可以为芳香性环,但稠环整体不具备芳香性;其稠和方式可以为:5-6元环烷基并5-6元环烷基、苯并5-6元环烷基、苯并5-6元饱和环烷基等。其实例包括但不限于:二环[3.1.0]己烷基、二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基、双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1,2,3,3a-四氢并环戊二烯基、2,3,3a,4,7,7a-六氢-1H-茚基、1,2,3,4,4a,5,6,8a-八氢化萘基、1,2,4a,5,6,8a-六氢化萘基、1,2,3,4,5,6,7,8,9,10-十氢菲基、苯并环戊基、苯并环己基、苯并环己烯基、苯并环戊烯基等。
本发明所述的“3-12元杂环基”是指至少含有一个杂原子(例如,含有1个、2个、3个、4个或5个)的且环原子数为3-12个的饱和或部分饱和的且不具有芳香性的单环或稠环环状基团,所述杂原子为氮原子、氧原子和/或硫原子,任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-12元杂环基”包括“3-12元饱和杂环基”和“3-12元部分饱和杂环基”。优选地,本发明所述的“3-12元杂环基”含有1-3个杂原子;优选地,本发明所述的“3-12元杂环基”含有1-2个杂原子,且所述的杂原子选自氮原子和/或氧原子;优选地,本发明所述的“3-12元杂环基”含有1-2个氮原子。所述“3-12元杂环基”优选“3-10元杂环基”、“3-8元杂环基”、“4-8元杂环基”、“3-6元杂环基”、“3-6元饱和杂环基”、“3-6元含氮杂环基”、“3-6元饱和含氮杂环基”、“4-6元杂环基”、“4-6元含氮杂环基”、“5-6元杂环基”、“5-6元饱和
杂环基”等。“3-12元杂环基”的具体实例包括但不仅限于:氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、四氢吡喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、2-哌啶酮基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基、吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基;四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。
本发明所述的“6-10元芳基”是指含有6-10个环碳原子的具有芳香性的环状基团,包括“6-8元单环芳基”和“8-10元稠环芳基”。
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基,其实例包括但不限于:苯基、环辛四烯基等;优选苯基。
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团,优选“9-10元稠环芳基”,具体实例如萘基等。
本发明所述的“5-12元杂芳基”是指含有5-12个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的具有芳香性的环状基团,例如可以是5-12元含氮杂芳基、5-12元含氧杂芳基、5-12元含硫杂芳基等。包括“5-8元单杂芳基”和“8-10元稠杂芳基”。
本发明所述的“5-8元单杂芳基”是指含有5-8个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的具有芳香性的单环环状基团。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单杂芳基”包括例如“5-7元单杂芳基”、“5-6元单杂芳基”、“5-6元含氮单杂芳基”、“5元含氮单杂芳基”等。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。
本发明所述的“8-10元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环原子(其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地,环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“9-10元稠杂芳基”,“8-9元稠杂芳基”等,其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等;具体实例包括但不限于:吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。
本发明所述的“5-12元桥环基”是指任意两个环共用两不直接相连的原子形成的含有5-12个碳原子的结构,“5-12元桥环”包括5-12元饱和桥环基、5-12元部分饱和桥环基。优选5-10元桥环基、5-8元桥环基、5-10元饱和桥环基、5-8元饱和桥环基、6-10元饱和桥环基、7-12元部分饱和桥环基,具体实例包括但不
仅限于
本发明所述的“5-12元桥杂环基”是指上述5-12元桥环基中的至少一个环碳原子被选自O、S、N的杂原子替代,优选1-3个杂原子,同时包括碳原子、氮原子和硫原子可以被氧代的情况,优选5-10元桥杂环基,5-8元桥杂环基。具体实例包括但不仅限于:
本发明所述“5-12元螺环基”是指一类至少有两个环共享一个原子形成的含有5-12个碳原子的结构。包含5-12元饱和螺环基和5-12元部分饱和螺环基,包括例如“5-10元饱和螺环基”、“5-10元不饱和螺环基”、“5-8元螺环基”、“5-8元饱和螺环基”、“5-8元不饱和螺环基”、“6-8元螺环基”、“7-11元螺环基”、“7-10元螺环基”、“7-9元螺环基”、“8-10元螺环基”、“8-11元螺环基”,5-12元饱和螺环基具体实例包括但不仅限于:
等环状结构取代任意可取代的氢原子所形成的基团。5-12元部分饱和螺环基,是指该螺环基中至少有一个环为不饱和的环状基团,具体实例包括但不仅限于:
等环状结构取代任意可取代的氢原子所形成的基团。
本发明所述的“5-12元螺杂环基”是指5-12元螺环基中至少一个环碳原子被选自O、S、N的杂原子替代,优选1-3个杂原子,同时包括碳原子、氮原子和硫原子可以被氧代的情况。包括例如5-10元螺杂环基、5-8元螺杂环基、5-6元螺杂环基、7-12元螺杂环基、7-11元螺杂环基、7-11元含氮螺杂环基、7-10元螺杂环基、7-10元含氮螺杂环基、7-9元螺杂环基、7-9元含氮螺杂环基、7-8元螺杂环基、7-8元含氮
螺杂环基、8元含氮螺杂环基。具体实例包括但不仅限于:
本发明所述的“任选被…取代”包括“被取代”和“未被取代”两种情形。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐,例如金属盐、铵盐、与有机酸形成的盐、与有机碱形成的盐、与无机酸形成的盐、与酸性氨基酸或碱性氨基酸形成的盐等。
本发明所述的“酯”是指药学上可接受的酯,尤其指如下酯,其在活体内水解且包括容易在人体内分解留下母体化合物(通式(I)所述的化合物)或其盐的酯。本发明所述的“酯”例如可以选自下列各组:(1)通过与羧酸类化合物的酯化作用所获得的羧酸酯,其中羧酸类化合物的非羰基部分选自例如C1-20直链或支链烷基、C1-12直链或支链烷基、C1-8直链或支链烷基、C1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C1-6烷氧基C1-6烷基(例如甲氧基甲基)、C6-10芳基C1-6烷基(例如苄基)、C6-10芳氧基C1-6烷基(例如苯氧基甲基)、C6-10芳基(例如苯基,任选被例如卤素、C1-4烷基或C1-4烷氧基或氨基取代);(2)磺酸酯,例如烷基磺酰基或芳烷基磺酰基(例如甲基磺酰基);(3)氨基酸酯(例如L-缬氨酰基或L-异亮氨酰基);和(4)单-、二-或三磷酸酯等;(4)通过与醇类化合物的酯化作用所获得的酯,其中醇类化合物的非羟基部分选自例如C1-20直链或支链烷基、C1-12直链或支链烷基、C1-8直链或支链烷基、C1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C1-6烷氧基C1-6烷基(例如甲氧基甲基)、C6-10芳基C1-6烷基(例如苄基)、C6-10芳氧基C1-6烷基(例如苯氧基甲基)、C6-10芳基(例如苯基,任选被例如卤素、C1-4烷基或C1-4烷氧基或氨基取代)。
本发明所述的“立体异构体”是指当本发明化合物含有一个或多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心,这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。本发明所述的化合物若含有烯烃双键,除非特别说明,包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在,其通过一个或多个双键位移而具有不同的氢的连接点,例如,酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物、药物制剂、药物组合物的量。包含“治疗有效量”的实际量会根据多种情况而变化,多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
发明的有益效果
(1)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有优异的KIF18A抑制活性,能够治疗和/或预防KIF18A介导的疾病及相关疾病;
(2)本发明化合物对肿瘤细胞具有良好的抑制作用;
(3)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有良好的药代动力学性质,作用更持久,生物利用度高;
(4)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有良好的安全性;
(5)本发明化合物制备工艺简单,药品纯度高,质量稳定,易于进行大规模工业生产。
以下通过实验进一步阐述本发明实施例提供的化合物的有益效果,但不应将此理解为本发明实施例提供的化合物仅具有下列有益效果。
实验例1本发明化合物的体外酶学活性
供试品:本发明部分化合物,其化学名称和结构见制备实施例。
实验试剂:
实验方法:
1、化合物稀释
1)使用DMSO配制本发明化合物至10mM,作为试验储备液。
2)将试验储备液3倍梯度稀释至10个浓度,最高浓度为10mM。
3)测试化合物终浓度为10000nM、3333.3nM、1111.1nM、370.4nM、123.5nM、41.2nM、13.7nM、4.57nM、1.52nM、0.51nM。
2、酶反应实验
1)使用Echo 650将0.025μL化合物稀释液转移到384孔测定板的每个孔中,每列包含2个重复。
2)向384孔检测板中加入2.5μL酶工作液,1000rpm离心1分钟。25℃孵育10分钟。
3)添加2.5μL ATP工作溶液。25℃孵育60分钟。
4)添加4μL ADP-Glo工作溶液。25℃孵育40分钟。
5)加入8μL检测工作溶液。25℃孵育40分钟。
3、结果检测
1)在BMG HTS高通量药筛多功能酶标仪上读取化学发光信号。
2)收集数据。
4、数据分析
使用如下公式计算抑制率inhibition(%inh):
供试品化合物抑制率(%inh)=100*(ave High control-cpd well)/(ave High control-ave Low control)
其中,ave High control表示:不加化合物的阳性对照孔的发光信号强度;
ave Low control表示:不加酶的阴性对照孔的发光信号强度;
cpd well表示:表示供试品化合物的发光信号强度;
采用XLfit计算IC50,
实验结果:
表1本发明化合物对KIF18A抑制活性
除了表1中的化合物,化合物10对KIF18A抑制活性的IC50值在50nM~500nM之间,从上述实验结果可以看出,本发明化合物能够有效抑制KIF18A的活性,是有效的KIF18A抑制剂。
实验例2本发明化合物的体外细胞学活性
供试品:本发明部分化合物,其化学名称和结构见制备实施例。
下述实验中所用细胞株如下:
OVCAR3:TP53突变人卵巢癌细胞
实验方法(CelltiterGlo assay)
1.准备细胞
1.1细胞培养:
所有细胞均为贴壁细胞,OVCAR3细胞培养基为RPMI Medium 1640+20%FBS+1%PS,细胞在对数生长期进行试验。
1.2细胞悬液制备:
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力,确保细胞活力在90%以上。调整到合适浓度,分别添加90μL细胞悬液至96孔板中。
表2细胞接种数目
2.配制测试化合物
2.1配制测试化合物DMSO储备液,测试化合物的储备液浓度为10mM。
2.2配制测试化合物工作储备液
测试化合物储备液10mM先用DMSO稀释至0.123mM,再1.5倍连续梯度稀释,共9个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中,为测试化合物工作储备液(化合物浓度为终浓度的10倍,最高浓度为123nM)。
2.3化合物处理
在接种有细胞的96孔板中每孔加入10μL化合物工作储备液(10倍稀释,DMSO终浓度为0.1%)。
测试化合物的终浓度为:123nM,82.3nM,54.8nM,36.6nM,24.4nM,16.3nM,10.9nM,7.2nM,4.5nM。
2.4对照孔设置
溶剂对照:0.1%DMSO。
空白对照:培养液
2.5将96孔板置于37℃、5%CO2细胞培养箱中培养4天。
3.检测
融化CTG试剂并平衡96孔板至室温30分钟,每孔加入60μL试剂(Celltiter Glo assay kit),振荡器震摇2min混匀(避光),室温孵育20分钟(避光)。多功能酶标仪读取光信号值。
4.数据处理
1)抑制率(%)=1-(测试物孔读数–空白对照孔读数)/(DMSO溶剂对照孔读数–空白对照孔读数)×100%;
2)输入GraphPad Prism作图,得到曲线及IC50。
实验结果及结论
本发明化合物对OVCAR3的抑制活性的IC50值,1nM~100nM用A表示,100nM~500nM用B表示,500nM~1000nM用C表示。
表3本发明化合物的体外细胞学活性(IC50,nM)
由表3可知,本发明化合物可以有效地抑制OVCAR3细胞的增殖,表明本发明化合物具有治疗TP53突变的癌性疾病的临床应用潜力。
实验例3本发明化合物的体外细胞学活性
供试品:本发明部分化合物,其化学名称和结构见制备实施例。
下述实验中所用细胞株如下:
OVCAR3:TP53突变人卵巢癌细胞;MDA-MB-157:TP53突变人乳腺癌细胞
实验方法(CelltiterGlo assay)
1.准备细胞
1.1细胞培养:
所有细胞均为贴壁细胞,OVCAR3细胞培养基为RPMI Medium 1640+20%FBS+1%PS,MDA-MB-157细胞培养基为DMEM Medium+10%FBS+1%PS,细胞在对数生长期进行试验。
1.2细胞悬液制备:
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力,确保细胞活力在90%以上。调整到合适浓度,分别添加90μL细胞悬液至96孔板中。
表4.细胞接种数目
2.配制测试化合物
2.1配制测试化合物DMSO储备液,测试化合物的储备液浓度为10mM。
2.2配制测试化合物工作储备液
测试化合物储备液10mM,3倍连续梯度稀释,共9个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中,为测试化合物工作储备液(化合物浓度为终浓度的10倍,最高浓度为100μM)。
2.3化合物处理
在接种有细胞的96孔板中每孔加入10μL化合物工作储备液(10倍稀释,DMSO终浓度为0.1%)。
测试化合物的终浓度为:10μM,3.33μM,1.11μM,370nM,123nM,41.1nM,13.7nM,4.57nM,1.52nM。
2.4对照孔设置
溶剂对照:0.1%DMSO。
空白对照:培养液
2.5将96孔板置于37℃、5%CO2细胞培养箱中培养4天。
3.检测
融化CTG试剂并平衡96孔板至室温30分钟,每孔加入60μL试剂(Celltiter Glo assay kit),振荡器震摇2min混匀(避光),室温孵育20分钟(避光)。多功能酶标仪读取光信号值。
4.数据处理
1)抑制率(%)=1-(测试物孔读数–空白对照孔读数)/(DMSO溶剂对照孔读数–空白对照孔读数)×100%;
2)输入GraphPad Prism作图,得到曲线及IC50。
实验结果及结论
本发明化合物对OVCAR3的抑制活性的IC50值,1nM~100nM用A表示,100nM~500nM用B表示,500nM~1000nM用C表示;本发明化合物对MDA-MB-157的抑制活性的IC50值,1nM~100nM用A表示,100nM~500nM用B表示,500nM~1000nM用C表示。
表5.本发明化合物的体外细胞学活性(IC50,nM)
说明了本发明化合物可以有效地抑制OVCAR3、MDA-MB-157细胞的增殖,表明本发明化合物具有治疗TP53突变的癌性疾病的临床应用潜力。
实验例4本发明化合物的小鼠体内药代动力学实验
供试品:本发明化合物,自制,其化学名称和制备方法见各化合物的制备实施例。
受试动物:小鼠,雌性,6只/给药途径/化合物。
1、供试品溶液制备:
空白溶媒(1)的配制方法:称取28g HP-β-CD(羟丙基-β-环糊精),加入适量注射用水溶解,再用注射用水定容到100mL,涡旋混匀,即得28%HP-β-CD。
空白溶媒(2)的配制方法:称取20g HPC(羟丙基纤维素),缓慢加入500mL搅拌着的纯化水中,再加入1mL吐温80,搅拌至澄清透明,定容到1000mL,搅拌均匀即得2%HPC+0.1%吐温80。
IV(静脉推注)给药:
称取本发明化合物适量,加入DMA(N,N-二甲基乙酰胺),超声涡旋溶解,然后加入Kolliphor HS15(聚乙二醇-15-羟基硬脂酸酯),涡旋混匀,最后加入DPBS(杜氏磷酸盐缓冲液),涡旋混匀,制备得1mg/mL的澄清溶液,作为测试化合物的IV给药溶液。
PO(灌胃)给药:
称取本发明实施例化合物适量,置于组织研磨器中,加入空白溶媒(2),以1000转/分钟的转速研磨均匀,制备得1mg/mL或3mg/mL的混悬药液,作为测试化合物的PO给药药液。
2、实验方法
IV给药剂量为5mg/kg,给药浓度为1mg/mL,给药体积为5mL/kg。
PO给药剂量为30mg/kg,给药浓度为3mg/mL,给药体积为10mL/kg。或者PO给药剂量为10mg/kg,给药浓度为1mg/mL,给药体积为10mL/kg。
采血时间点:给药后0.083、0.25、0.5、1、2、4、6、8、24h,具体按下表所示方式采血:
每个时间点通过眼内眦采集全血约50μL,放置到含有EDTA-K2抗凝剂的抗凝管中,在4℃条件下8000转/分钟离心6min得到血浆样品,血浆于-80℃冰箱冻存,待分析。
3、血浆样品分析
采用蛋白沉淀法:取血浆样品20μL,加入内标(含甲苯磺丁脲200ng/mL的乙腈溶液)200μL,涡旋10min后,然后4000转/分钟离心20分钟,取上清液100μL,再加入100μL水,涡旋混匀3min后,LC-MS/MS分析血浆中的药物浓度。
4、实验结果及结论
通过测试结果可知,本发明化合物具有良好的药代动力学性质,且具有较低的清除率,以及较高的暴露量和生物利用度。
下面将结合具体实施例对本发明的技术方案进行描述,所描述的实施例仅仅是本发明一部分实施例,
而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
下述实验中所用缩写代表的含义如下:
Xphos-Pd-G2:氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II);Xphos:2-二环己基磷-2',4',6'-三异丙基联苯;Pd(dppf)Cl2:二氯[1,1'-二(二苯基膦)二茂铁]钯;RuphosPdG3:甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II);DIPEA:N,N-二异丙基乙胺;PPTS:吡啶对甲苯磺酸盐
实施例1 N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺胺)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备(化合物1)
(1)6,8-二氯咪唑并[1,2-a]吡嗪的制备
氯乙醛(7.2g,36.7mmol,40%水溶液)加入至含有3,5-二氯吡嗪-2-胺(3.0g,18.3mmol)的DMF(40mL)中,100℃反应3小时。反应完毕,降至室温,将反应液倒入水中,乙酸乙酯萃取三次,合并乙酸乙酯层,水洗,饱和氯化钠溶液洗涤,减压除去乙酸乙酯。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(2.8g,收率:81.4%)。
(2)6-氯-8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪的制备
微波管中加入6,8-二氯咪唑并[1,2-a]吡嗪(2.8g,14.9mmol),4,4-二氟哌啶(2.0g,16.5mmol),DIPEA(5.8g,44.9mmol)和NMP(8mL),微波100℃下反应50分钟。反应完毕,降至室温,将反应液倒入水中,乙酸乙酯萃取三次,合并乙酸乙酯层,水洗,饱和氯化钠溶液洗涤,减压除去乙酸乙酯。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:2),得目标化合物(3.4g,收率:83.7%)。
(3)(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
含有6-氯-8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪(1.2g,4.4mmol),BocNH2(1.0g,8.8mmol)RuphosPdG3(368mg,0.44mmol)和碳酸铯(2.9g,8.8mmol)的1,4-dioxane(20mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(1.5g,收率:96.4%)。
(4)8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-胺的制备
30℃下,盐酸乙酸乙酯溶液(20mL)加入至含有(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(850mg,2.4mmol)的乙酸乙酯(10mL)中,反应3小时。反应完毕,减压除去溶剂,直接投入下一步反应。
(5)2-氟-4-碘苯甲酰氯的制备
0℃下,DMF(0.1mL)加入至含有2-氟-4碘苯甲酸(1.3g,4.9mmol)和草酰氯(1.2g,9.4mmol)的二氯甲烷(40mL)中,继续反应1小时。反应完毕,反应液浓缩旋干直接用于下一步。
(6)N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-2-氟-4-碘苯甲酰胺的制备
0℃下,2-氟-4-碘苯甲酰氯(上步反应粗品)的二氯甲烷(100mL)溶液滴加入含有8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-胺(第四步粗品)和DIPEA(3.0g,23.2mmol)的二氯甲烷(20mL)中,继续反应3小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:5),得目标化合物(400mg,三步收率:33.2%)。
(7)N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
于N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-2-氟-4-碘苯甲酰胺(380mg,0.76mmol)的二甲基亚砜(15mL)中,加入碳酸钾(318mg,2.3mmol)和6-氮杂螺环[2.5]辛烷盐酸盐(221mg,1.5mmol),100℃反应12小时。加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:5),得目标化合物(220mg,收率:49.0%)。
(8)N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺胺)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(220mg,0.37mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(70mg,0.37mmol),N-甲基甘氨酸(33mg,0.37mmol)和磷酸钾(383mg,1.8mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(94mg,0.75mmol)后在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:1)以及反相柱纯化(80%CH3OH/H2O)得目标化合物(45mg,收率:20.5%)。
分子式:C27H33F2N7O4S 分子量:589.7 LC-MS(M/e):590.3(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.88(s,1H),8.83(s,1H),8.08(m,2H),7.55(m,1H),7.27(m,1H),7.12(m,1H),4.42(m,4H),3.84(m,2H),3.33(m,2H),3.14(m,4H),2.11(m,4H),1.98-1.67(m,5H),0.57(m,4H).
实施例2 N-(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-(2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物3)
(1)6,8-二溴-2-甲基咪唑并[1,2-a]吡嗪的制备
将3,5-二溴吡嗪-2-胺(5g,20mmol),1-溴-2,2-二甲氧基丙烷(5.5g,30mmol)和PPTS(503mg,2mmol)溶于异丙醇(50mL)中,70℃反应16小时。反应完毕,降至室温,用三乙胺调节pH至8-9,旋干。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(2.6g,收率:44.5%)。
(2)6-溴-8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪的制备
将6,8-二溴-2-甲基咪唑并[1,2-a]吡嗪(1.2g,4.1mmol),4,4-二氟哌啶(977mg,6.2mmol),DIPEA(1.6g,12.3mmol)溶于NMP(10mL),100℃下反应1h。反应完毕,降至室温,将反应液倒入水中,乙酸乙酯萃取三次,合并乙酸乙酯层,水洗,饱和氯化钠溶液洗涤,减压除去乙酸乙酯。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(1.3g,收率:95.7%)。
(3)(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪(1.2g,3.6mmol),BocNH2(1.3g,11.1mmol)、RuphosPdG3(301mg,0.36mmol)和碳酸铯(4.7g,14.4mmol)溶于1,4-dioxane(50mL),氮气保护下100℃下反应3小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(1.2g,收率:90.7%)。
(4)8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-胺的制备
将(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(1.2g,3.3mmol)溶于DCM(10mL)中,加入TFA(3mL),25℃下反应3小时。反应完毕,减压除去溶剂,饱和碳酸氢钠水溶液调节pH至8-9,DCM萃取,有机相旋干得产品800mg,收率90.5%。
(5)N-(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,向4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(粗品,2.0mmol)的二氯甲烷(10mL)溶液滴加入磷酸钾(425mg,2.0mmol),后滴加含有8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-胺(536mg,2mmol)和DIPEA(774mg,6.0mmol)的二氯甲烷(20mL),25℃继续反应1小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(800mg,收率:66.0%)。
(6)N-(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-(2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺(200mg,0.33mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(63mg,0.33mmol),N-甲基甘氨酸(59mg,0.66mmol)和磷酸钾(280mg,1.32mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(124mg,0.99mmol),在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,抽滤,滤饼用乙酸乙酯打浆得目标化合物(19mg,收率:9.5%)。
分子式:C28H35F2N7O4S 分子量:603.7 LC-MS(M/e):604.2(M+H+)
1H-NMR(400MHz,DMSO-d6+D2O)δ:12.89(s,1H),8.72(s,1H),8.02-8.10(m,1H),7.78(s,1H),7.26(s,1H),7.09-7.12(m,1H),4.28-4.40(m,4H),3.70-3.80(m,2H),3.30-3.40(m,2H),2.97(s,4H),2.32(s,3H),2.00-2.20(m,4H),1.60-1.90(m,4H),0.39(s,4H).
实施例3 N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物5)
1、(3,5-二氯吡嗪-2-基)甲酰胺的制备
将3,5-二氯吡嗪-2-氰基(9.6g,55.2mmol)加入醋酸(120mL)中,加入雷尼镍(1.90g),氢气置换3次,氢气保护下,50℃反应18小时。降至室温过滤,滤液浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=99:1),得目标化合物(3.5g,收率:35.6%)。
2、6,8-二氯咪唑[1,5-a]吡嗪的制备
将无水甲酸(20ml)加入反应瓶,0℃下,滴加乙酸酐(10ml),反应1.5h,同时将(3,5-二氯吡嗪-2-基)甲酰胺(2.5g,14.0mmol)和DIEA(4.5g,34.8mmol)溶于DCM(20ml)中,缓慢滴加入反应体系中,反应1h;先浓缩,粗品加入乙酸乙酯,用饱和碳酸氢钠洗涤,分液,有机相浓缩,加入氧氯化磷(20ml),升温100℃反应1h,降温浓缩,用MTBE打浆得到产物2.10g,收率79.5%。
3、6-氯-8-(4,4-二氟哌啶-1-基)咪唑[1,5-a]吡嗪的制备
单口瓶中加入6,8-二氯咪唑[1,5-a]吡嗪(2.1g,11.2mmol),4,4-二氟哌啶(2.1g,13.4mmol),DIPEA(7.2g,56.0mmol)和NMP(25mL),100℃下反应1.5h,反应完毕,降至室温,将反应液倒入水中,打浆,过滤,滤饼晾干得到产物(1.7g,收率:55.6%)。
4、(8-(4,4-二氟哌啶-1-基)咪唑[1,5-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将6-氯-8-(4,4-二氟哌啶-1-基)咪唑[1,5-a]吡嗪(1.4g,5.13mmol),BocNH2(1.2g,10.26mmol),
RuphosPdG3(427mg,0.51mmol)和碳酸铯(5.0g,15.39mmol)的1,4-dioxane(60mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(1.3g,收率:71.7%)。
5、8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-胺的制备
30℃下,将(8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-基)氨基甲酸叔丁酯(1.1g,3.1mmol)的溶于DCM(10mL)中,滴加三氟乙酸(10ml),反应3小时。反应完毕,减压除去溶剂,直接投入下一步反应。
6、4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰氯的制备
0℃下,DMF(0.1mL)加入至含有4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酸(667mg,1.87mmol)和草酰氯(475mg,3.74mmol)的二氯甲烷(20mL)中,继续反应1小时。反应完毕,反应液浓缩旋干直接用于下一步。
7、N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基]苯甲酰胺的制备
0℃下,4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰氯(上步反应粗品)的二氯甲烷(10mL)溶液滴加入含有8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-胺(第四步粗品)和DIPEA(2.0g,15.6mmol)的二氯甲烷(10mL)中,继续反应3小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:2),得目标化合物(50mg,三步收率:2.7%)。
8、N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,5-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基]苯甲酰胺(50mg,0.08mol)溶于DMAC(5mL),加入碘化亚铜(15mg,0.08mmol),N-甲基甘氨酸(7mg,0.08mmol)和磷酸钾(85mg,0.40mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(20mg,0.16mmol)后在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:2)以及反相柱纯化(100%CH3OH/H2O)得目标化合物(3mg,收率:6.3%)。
分子式:C27H33F2N7O4S 分子量:589.66 LC-MS(M/e):590.3(M+H+)
1H-NMR(400MHz,CDCl3-d6)δ:12.83(s,1H),8.75(s,1H),8.27-8.25(m,1H),8.10(m,1H),7.65(m,1H),7.35-7.29(m,1H),7.11-7.08(m,1H),4.17(m,2H),4.03(m,4H),3.51(m,2H),3.37(m,2H),3.08(m,4H),2.21(m,4H),1.25(m,4H),0.42(m,4H).
实施例4 N-(5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-基)-4-(2-羟乙基)磺胺基)-2-(6-氮杂螺并[2.5]辛烷-6-基)苯甲酰胺的制备(化合物7)
(1)1,4,6-三氨基嘧啶-2(1H)-硫酮的制备
将丙二腈(10.0g,0.15mol)溶于乙醇钠(20%wt76.5g,0.23mol)的乙醇溶液中,加入肼硫代酰胺(13.8g,0.15mol),25℃反应16小时。反应完毕,析出大量固体,过滤,旋干得目标化合物(9.6g,收率:40.3%)。
(2)7-氨基-[1,2,4]三唑并[1,5-c]嘧啶-5-硫醇的制备
将1,4,6-三氨基嘧啶-2(1H)-硫酮(9.6g,61.1mmol)溶于甲酸(160mL)中,100℃反应16小时。反
应完毕,浓缩,加入纯化水析出大量固体,过滤,旋干得目标化合物(5.5g,收率:53.9%)。
(3)5-(甲硫基)-[1,2,4]三唑[1,5-c]嘧啶-7-胺的制备
将7-氨基-[1,2,4]三唑并[1,5-c]嘧啶-5-硫醇(2.2g,131mmol)溶于N,N-二甲基甲酰胺(25mL)中,加入碘甲烷(1.7g,1.2mmol),加入碳酸钾(5.4g,39mmol),25℃反应2小时。反应完毕,加入纯化水,加入乙酸乙酯萃取两次,水洗一次,浓缩得目标化合物(2.0g,收率:84.2%)。
(4)5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-胺的制备
将5-(甲硫基)-[1,2,4]三唑[1,5-c]嘧啶-7-胺(2.0g,10mmol)溶于二氯甲烷(50mL)中,0℃加入间氯过氧苯甲酸(85%)(4.1g,20mmol)。25℃反应1小时,加入N,N-二异丙基乙胺(3.9g,30mmol),加入4,4-二氟哌啶盐酸盐(1.7g,11mmol),25℃反应16小时,加入纯化水,加入二氯甲烷萃取,浓缩柱纯化(乙酸乙酯/正庚烷:90%)得目标化合物325mg,收率:12.8%。
(5)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(840mg,2.4mmol)溶于二氯甲烷(10mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃加入二甲基亚砜(428mg,5.5mmol),25℃反应0.5小时。反应完毕,直接浓缩干用于下一步(1.1g粗品)。
(6)N-(5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-基)-4-碘-2-(6-氮杂螺并[2.5]辛烷-6-基)苯甲酰胺的制备
将5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-胺(300mg,1.2mmol)溶于二氯甲烷(10mL),加入N,N-异丙基乙胺(464mg,3.6mmol),滴加至4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(1.1g,粗品)溶于二氯甲烷(10mL)和磷酸钾(254mg,1.2mmol)体系中,25℃下反应1小时。反应完毕,加水淬灭,二氯甲烷萃取,浓缩硅胶柱纯化(乙酸乙酯:正庚烷=32%)得目标化合物190mg,两步收率:13.3%。
(7)N-(5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-基)-4-(2-羟乙基)磺胺基)-2-(6-氮杂螺并[2.5]辛烷-6-基)苯甲酰胺的制备
将N-(5-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-c]嘧啶-7-基)-4-碘-2-(6-氮杂螺并[2.5]辛烷-6-基)苯甲酰胺(190mg,0.32mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(61mg,0.32mmol),N-甲基甘氨酸(57mg,0.64mmol)和磷酸钾(271mg,1.28mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(120mg,0.96mmol),在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:正庚烷=80%)得20mg粗品,高压柱层析(乙腈/水:35%)纯化目标化合物(2mg,收率:1.1%)。
分子式:C26H32F2N8O4S 分子量:590.65 LC-MS(M/e):591.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.38(s,1H),10.32(s,1H),8.42(s,1H),8.0(d,1H),7.92(s,1H),7.19(s,1H),7.14(d,1H),4.01-4.24(m,4H),3.60-3.78(m,2H),3.25-3.42(m,2H),3.00(m,4H),2.50-2.67(m,4H),2.21-2.33(m,2H),1.46-1.73(m,2H),0.422(m,4H).
实施例5 N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺并[2.5]辛烷-6-甲基)苯甲酰胺的制备(化合物8)
(1)N’-(3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼的制备
将2-氯-3-肼基吡嗪(5.0g,35mmol)溶于THF(100mL)中,-5℃下加入三氟乙酸酐(6.5mL)的100mL THF溶液,-5℃反应1小时。反应完毕,浓缩反应液,加入纯化水,加入乙酸乙酯萃取,浓缩得目标化合物(7.0g,收率:84.3%)。
(2)N’-(5-溴-3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼的制备
将N’-(3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼(7.0g,0.03mol)溶于二氯甲烷(70mL),0℃下加入N-溴代琥珀酰亚胺(7.6g,0.045mol),0℃反应1小时。反应完毕,浓缩硅胶柱纯化(乙酸乙酯/正庚烷=12%),得目标化合物(3.5g,收率:38.0%)。
(3)5-溴-3-氯-2-肼基吡嗪的制备
将N’-(5-溴-3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼(3.5g,11mmol)溶于无水乙醇(60mL)中,加入浓盐酸(9mL),100℃下反应2小时。反应完毕,降温,用饱和碳酸氢钠溶液调节pH至8,加入乙酸乙酯萃取,水洗一次,浓缩得目标化合物(2.5g,粗品)。
(4)6-溴-8-氯-[1,2,4]三唑[4,3-a]吡嗪的制备
将5-溴-3-氯-2-肼基吡嗪(2.5g,粗品)溶于原甲酸三乙酯(40mL)中,100℃反应2小时。反应完毕,加入纯化水,加入乙酸乙酯萃取,浓缩柱纯化(乙酸乙酯/正庚烷:60%)得目标化合物2.5g,两步收率:97.4%。
(5)6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪的制备
将6-溴-8-氯-[1,2,4]三唑[4,3-a]吡嗪(2.0g,8.6mmol)溶于N-甲基吡咯烷酮(20mL),加入4,4-二氟哌啶盐酸盐(1.5g,9.4mmol),加入N,N-二异丙基乙胺(4.4g,34.4mmol),微波100℃反应50分钟。反应完毕,降温,将反应液滴至纯化水中,析出大量固体,过滤,旋干得目标产物2.5g,收率:91.1%。
(6)(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪(2.5g,8mmol)溶于二氧六环(30mL)中,加入氨基甲酸叔丁酯(3.7g,32mmol),加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(1.3g,1.6mmol),加入碳酸铯(10.4g,32mmol),氮气保护下,100℃下反应2小时。反应完毕,加入乙酸乙酯萃取,直接硅胶柱纯化(乙酸乙酯:正庚烷=65%),得目标化合物1.0g,收率:35.9%。
(7)8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-胺的制备
将(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)氨基甲酸叔丁酯(1.2g,3.4mmol)溶于乙酸乙酯(5mL),加入4N.HCl乙酸乙酯溶液(6mL),25℃反应16小时。反应完毕,直接浓缩干用于下一步(1.2g粗品)。
(8)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(1.1g,3.1mmol)溶于二氯甲烷(10mL)中,加入N,N-
二甲基甲酰胺(0.1mL),0℃加入二甲基亚砜(740mg,9.5mmol),25℃反应0.5小时。反应完毕,直接浓缩干用于下一步(1.1g粗品)。
(9)N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺并[2.5]辛烷-6-甲基)苯甲酰胺的制备
将8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-胺(1.0g,粗品)溶于二氯甲烷(10mL),加入N,N-异丙基乙胺(1.7g,13.2mmol),滴加至4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(1.1g,粗品)溶于二氯甲烷(10mL)和磷酸钾(934mg,4.4mmol)的体系中,25℃下反应1小时。反应完毕,加水淬灭,二氯甲烷萃取,浓缩硅胶柱纯化(乙酸乙酯:正庚烷=40%)得目标化合物300mg,两步收率:15.0%。
(10)N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺并[2.5]辛烷-6-甲基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺并[2.5]辛烷-6-甲基)苯甲酰胺(130mg,0.22mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(42mg,0.22mmol),N-甲基甘氨酸(39mg,0.44mmol)和磷酸钾(187mg,0.88mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(82mg,0.66mmol),在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:正庚烷=1:4)以及乙酸乙酯打浆得目标化合物(30mg,收率:23.0%。
分子式:C26H32F2N8O4S 分子量:590.65 LC-MS(M/e):591.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.07(s,1H),12.32(s,1H),9.37(s,1H),8.79(s,1H),8.09(d,1H),7.30(s,1H),7.15(d,1H),4.96(s,1H),4.45(m,4H),3.75-3.78(m,2H),3.29-3.38(m,2H),2.99(m,4H),2.51(m,4H),1.73-1.99(m,3H),0.422(m,4H).
实施例6 N-(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-基)-4-(2-羟乙基)磺酰胺)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物10)
(1)2-氯-4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶的制备
于2,4-二氯-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶(2.2g,9.8mmol)的乙腈(100mL)溶液中,加入4,4-二氟吡啶盐酸盐(1.5g,9.5mmol),N,N-二异丙基乙胺(4.9g,37.9mmol),25℃下反应3h。反应完毕,体系加水淬灭,乙酸乙酯萃取有机相,干燥浓缩,旋干后正相纯化(乙酸乙酯:石油醚=1:3),得目标化合物2.8g,收率:92.1%。
(2)(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-基)氨基甲酸叔丁酯的制备
于2-氯-4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶(2.0g,6.5mmol)的1,4-二氧六环(60mL)溶液中,加入BocNH2(1.5g,12.8mmol),RuphosPdG3(544mg,0.65mmol)和碳酸铯(6.4g,19.6mmol),氮气保护下100℃下反应16小时。反应完毕,体系加水淬灭,乙酸乙酯萃取有机相,干燥浓缩,旋干后正相纯化(乙酸乙酯:石油醚=1:6),得目标化合物1.2g,收率:47.6%。
(3)4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-胺的制备
于(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-基)氨基甲酸叔丁酯(1.2g,3.1
mmol)的DCM(10mL)溶液中,加入TFA(5mL),25℃下反应1小时。反应完毕,减压除去溶剂,饱和碳酸氢钠水溶液调节pH至碱性,二氯甲烷萃取有机相,干燥浓缩,旋干后正相纯化(乙酸乙酯=100%),得目标化合物800mg,收率:89.7%。
(4)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
0℃下,于4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(900mg,2.5mmol)溶的二氯甲烷(20mL)溶液中,加入N,N-二甲基甲酰胺(0.2mL)和氯化亚砜(908mg,7.5mmol),继续反应30分钟。反应完毕,将反应液浓缩旋干直接用于下一步。
(5)N-(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊[d]嘧啶-2-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,向4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(N/A,2.5mmol)的二氯甲烷(15mL)溶液中,加入磷酸钾(531mg,2.5mmol),后加入4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-胺(363mg,1.3mmol)和N,N-二异丙基乙胺(1.9g,14.7mmol)的二氯甲烷(10mL),25℃继续反应16小时。反应完毕,体系加水,二氯甲烷萃取有机相,干燥浓缩,旋干后正相纯化(乙酸乙酯:石油醚=3:7),得目标化合物100mg,两步收率:6.3%。
(6)N-(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊基[d]嘧啶-2-基)-4-(2-羟乙基)磺酰胺)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将N-(4-(4,4-二氟哌啶-1-基)-7,7-二氟-6,7-双氢-5H-环戊[d]嘧啶-2-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(80mg,0.13mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(25mg,0.13mmol),N-甲基甘氨酸(23mg,0.26mmol),磷酸钾(138mg,0.65mmol)和2-羟基乙烷-1-磺酰胺(49mg,0.391mmol)后,氮气保护下,将混合物置于100℃下反应16小时。加水淬灭,乙酸乙酯萃取,浓缩TLC板纯化(二氯甲烷:甲醇=10:1),得目标化合物6mg,收率:7.5%。
分子式:C28H34F4N6O4S 分子量:626.7 LC-MS(M/e):627.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.80-12.70(m,1H),10.30-10.05(m,1H),7.94(d,J=8.4Hz,1H),7.21(s,1H),7.09(d,J=8.4Hz,1H),5.10-4.90(m,1H),3.95-3.75(m,6H),3.25-3.15(m,2H),3.05-2.90(m,4H),2.60-2.50(m,2H),2.20-2.00(m,4H),1.80-1.50(m,6H),0.90-0.70(m,4H).
实施例7 N-(8-(3,3-二氟氮杂环丁烷-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-甲基)苯甲酰胺的制备(化合物11)
(1)6-氯-8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪的制备
将6,8-二氯咪唑并[1,2-a]吡嗪(3g,16mmol),3,3-二氟氮杂环丁烷盐酸盐(2.2g,17mmol),DIPEA(6.2g,48mmol)溶于NMP(30mL)中,100℃下反应1h。反应完毕,降至室温,将反应液倒入水中,抽滤,滤饼干燥得目标化合物(3g,收率:76.7%)。
(2)(8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将6-氯-8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪(1.3g,5.3mmol),BocNH2(1.9g,15.9mmol),RuphosPdG3(444mg,0.53mmol)和碳酸铯(6.9g,21.2mmol)溶于1,4-dioxane(50mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(1.1g,收率:63.8%)。
(3)8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪-6-胺的制备
将(8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(1.1g,3.4mmol)溶于DCM(10mL)中,加入TFA(4mL),30℃下反应3小时。反应完毕,减压除去溶剂,饱和碳酸氢钠水溶液调节pH至8-9,DCM萃取,有机相旋干得产品680mg,收率88.5%。
(4)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸的制备
将2-氟-4-碘苯甲酸(6g,22.6mmol)溶于DMSO(50mL)中,加入TFA、6-氮杂螺[2.5]辛烷盐酸盐(4.3g,29.4mmol)和碳酸钾(9.4g,67.8mmol),140℃下反应16h。反应完毕,反应液倒入水中,正己烷萃取,水相2M稀盐酸调节pH至5-6,抽滤,滤饼干燥得产品5g,收率62.0%。
(5)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
0℃下,DMF(0.1mL)加入至含有4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(1.1g,3mmol)和氯化亚砜(1.1g,9mmol)的二氯甲烷(10mL)中,继续反应1小时。反应完毕,反应液浓缩旋干,直接用于下一步。
(6)N-(8-(3,3-二氟氮杂环丁烷-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-甲基)苯甲酰胺的制备
0℃下,向4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(上步反应粗品)的二氯甲烷(10mL)溶液滴加入磷酸钾(510mg,2.4mmol),滴加含有8-(3,3-二氟氮杂丁-1-基)咪唑并[1,2-a]吡嗪-6-胺(550mg,2.4mmol)和DIPEA(929mg,7.2mmol)的二氯甲烷(10mL),25℃继续反应1小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(650mg,收率:47.9%)。
(7)N-(8-(3,3-二氟氮杂环丁烷-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺胺基)-2-(6-氮杂螺[2.5]辛烷-6-甲基)苯甲酰胺的制备
将N-(8-(3,3-二氟氮杂环丁烷-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-甲基)苯甲酰胺(150mg,0.27mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(51mg,0.27mmol),N-甲基甘氨酸(48mg,0.54mmol)和磷酸钾(229mg,1.08mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(101mg,0.81mmol),在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=4:1)得目标化合物(75mg,收率:49.4%)。
分子式:C25H29F2N7O4S 分子量:561.6 LC-MS(M/e):562.1(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.18(s,1H),10.19(s,1H),8.82(s,1H),8.07-8.10(m,2H),7.58(s,1H),7.30(s,1H),7.14-7.17(m,1H),4.93(s,1H),4.76-4.82(m,4H),3.72-3.80(m,2H),3.36-3.38(m,4H),2.99(s,4H),1.70-1.90(m,2H),0.42(s,4H).
实施例8 N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备(化合物12)
(1)2-((4-((8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(100mg,0.17mmol)溶于DMSO(8mL),加入焦亚硫酸钾(57mg,0.26mmol),甲酸钠(25mg,0.37mmol),三苯基磷(7mg,0.026mmol),1,10-二氮杂菲(5mg,0.026mmol),四丁基溴化铵(84mg,0.26mmol)和醋酸钯(1mg,0.0044mmol),氮气保护下,在70℃反应45分钟,降温,加入溴乙酸乙酯(43mg,0.26mmol)反应30min,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:石油醚=1:4)得到目标化合物(40mg,收率:38.4%)。
(2)N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,将硼氢化锂(2mg,0.092mmol)加入含有2-((4-((8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯(40mg,0.065mmol)的四氢呋喃(10mL)溶液,反应3小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(5mg,收率:13.4%)。
分子式:C27H32F2N6O4S 分子量:574.65 LC-MS(M/e):575.0(M+H+)
1H-NMR(400MHz,CDCl3-d6)δ:12.71(s,1H),8.84(s,1H),8.50(m,1H),7.92(m,1H),7.86(m,1H),7.52(m,2H),4.50(m,4H),4.10(m,2H),3.41(m,2H),3.18(m,4H),2.64(m,1H),2.23(m,4H),1.85(m,2H),1.28(m,2H),0.52(m,4H).
实施例9 4-(环丙基磺酰基)-N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备(化合物13)
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(100mg,0.17mmol),环丙烷亚磺酸钠(44mg,0.34mmol),碳酸钾(5mg,0.034mmol),碘化亚铜(3mg,0.016mmol)和L-脯氨酸(4mg,0.034mmol)加入到DMSO(4ml)溶液,置换氮气后,微波140℃,反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(45mg,收率:46.4%)。
分子式:C28H32F2N6O3S 分子量:570.66 LC-MS(M/e):571.0(M+H+)
1H-NMR(400MHz,CDCl3-d6)δ:12.76(s,1H),8.87(s,1H),8.32-8.30(m,1H),8.12(s,1H),7.91(m,1H),7.84-7.82(m,1H),7.58(s,1H),4.44(m,4H),3.10(m,4H),3.01(m,1H),2.16-2.09(m,4H),1.74(m,4H),1.12(m,4H),1.08(m,4H).
实施例10 4-(2-羟乙基)磺胺基)-N-(8-吗啉代咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物15)
(1)4-(6-氯咪唑并[1,2-a]吡嗪-8-基)吗啉的制备
将6,8-二氯咪唑并[1,2-a]吡嗪(3g,16mmol)和吗啉(1.4g,16mmol)溶于NMP(20mL)中,100℃下反应3h。反应完毕,降至室温,将反应液倒入水中,抽滤,滤饼干燥得目标化合物(3g,收率:78.5%)。
(2)(8-吗啉酰咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将4-(6-氯咪唑并[1,2-a]吡嗪-8-基)吗啉(1.2g,5mmol),BocNH2(1.8g,15mmol),RuphosPdG3(419mg,0.5mmol)和碳酸铯(6.5g,20mmol)溶于1,4-dioxane(50mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(1.2g,收率:75.0%)。
(3)8-吗啉代咪唑并[1,2-a]吡嗪-6-胺的制备
将(8-吗啉代咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(1.2g,3.75mmol)溶于DCM(8mL)中,加入TFA(4mL),30℃下反应3小时。反应完毕,减压除去溶剂,饱和碳酸氢钠水溶液调节pH至8-9,DCM萃取,有机相旋干得产品800mg,收率97.0%。
(4)4-碘代-N-(8-吗啉代咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基苯甲酰胺的制备
0℃下,向4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(706mg,1.88mmol)的二氯甲烷(10mL)溶液滴加入磷酸钾(399mg,1.88mmol),后滴加含有8-吗啉代咪唑并[1,2-a]吡嗪-6-胺(414mg,1.88mmol)和DIPEA(728mg,5.64mmol)的二氯甲烷(10mL),25℃继续反应1小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(500mg,收率:47.6%)。
(5)4-(2-羟乙基)磺胺基)-N-(8-吗啉代咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将4-碘代-N-(8-吗啉酰咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(200mg,0.36mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(68mg,0.36mmol),N-甲基甘氨酸(64mg,0.72mmol)和磷酸钾(306mg,1.44mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(135mg,1.08mmol)后在氮气保护下置于100℃下反应2小时。反应完毕,加入饱和氯化铵水溶液淬灭,抽滤,滤饼经甲醇打浆得得目标化合物(9.7mg,收率:4.8%)。
分子式:C26H33N7O5S 分子量:555.7 LC-MS(M/e):556.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.97(s,1H),10.19(s,1H),8.80(s,1H),8.05-8.10(m,2H),7.54(s,1H),7.28(s,1H),7.06-7.12(m,1H),4.28(s,4H),3.72-3.80(m,6H),3.35-3.45(m,4H),2.99(s,4H),1.70-1.90(m,2H),0.42(s,4H).
实施例11(R)-4-((2-羟乙基)磺酰胺)-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物16)
1、6,8-二氯咪唑并[1,2-a]吡嗪的制备
氯乙醛(40%水溶液)(23.2g,0.118mol)加入至含有3,5-二氯吡嗪-2-胺(9.64g,0.059mol)的乙腈(150mL)中,75℃反应3小时。反应完毕,降至20℃,析出固体,过滤得目标化合物(9.5g,收率:85.6%)。
2、(R)-4-(6-氯咪唑并[1,2-a]吡嗪-8-基)-2-甲基吗啉的制备
将6,8-二氯咪唑并[1,2-a]吡嗪(5.8g,31mmol),(R)-2-甲基吗啉盐酸盐(4.7g,34mmol),DIPEA(12.0g,93mmol)和NMP(50mL),加入到反应瓶中,100℃下反应1小时。反应完毕,降至室温,将反应液倒入水500ml中,析出固体,过滤得产品8.0g。
3、(R)-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将(R)-4-(6-氯咪唑并[1,2-a]吡嗪-8-基)-2-甲基吗啉(7.7g,30mmol),BocNH2(7.0g,60mmol),RuphosPdG3(2.5g,3mmol)和碳酸铯(19.5g,60mmol)依次加入到1,4-dioxane(100mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(3.6g,收率:36%)。
4、(R)-8-(2-甲基吗啉)咪唑[1,2-a]吡嗪-6-胺的制备
25℃下,三氟乙酸(10mL)加入至含有(R)-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(1.6g,4.8mmol)的DCM(20mL)中,反应1小时。反应完毕,减压除去溶剂,得产品1.5g。
5、4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰氯的制备
0℃下,DMF(0.1mL)加入至含有4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酸(2.0g,5.6mmol)和草酰氯(1.1g,8.4mmol)的二氯甲烷(40mL)中,继续反应1小时。反应完毕,反应液直接用于下一步反应。
6、(R)-4-碘-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,将4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰氯的二氯甲烷(40mL)溶液滴加入到含有(R)-8-(2-甲基吗啉)咪唑[1,2-a]吡嗪-6-胺(1.4g,6mmol)和DIPEA(2.0g,15.5mmol)的二氯甲烷(20mL)中,继续反应1小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:5),得目标化合物(1.5g,两步收率:46.8%)。
7、(R)-4-((2-羟乙基)磺酰胺)-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将(R)-4-碘-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺(200mg,0.35mmol)溶于N,N-二甲基乙酰胺(5mL),加入碘化亚铜(67mg,0.35mmol),N-甲基甘氨酸(31mg,0.35mmol)和磷酸钾(372mg,1.75mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(88mg,0.70mmol)后在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物(90mg,收率:45.1%)。
分子式:C27H35N7O5S 分子量:569.7 LC-MS(M/e):570.7(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.75(s,1H),10.18(s,1H),8.81(s,1H),8.08(m,2H),7.55(m,1H),
7.28(m,1H),7.13(m,1H),5.32(m,2H),4.95(m,1H),3.97(m,1H),3.76(m,3H),3.68(m,2H),3.33(m,2H),2.99(m,4H),2.87(m,1H),1.99(m,1H),1.75(m,3H),1.18-1.24(m,3H),0.41(m,4H).
实施例12(R)-4-碘-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备(化合物17)
将(R)-4-碘-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基(150mg,0.26mmol),环丙烷亚磺酸钠(67mg,0.52mmol),碳酸钾(7mg,0.052mmol),碘化亚铜(10mg,0.052mmol)和L-脯氨酸(6mg,0.052mmol)加入到DMSO(4ml)溶液,置换氮气后,微波140℃,反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物58mg,收率:40.5%。
分子式:C28H34N6O4S 分子量:550.68 LC-MS(M/e):551.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.64(s,1H),8.84(s,1H),8.32-8.30(m,1H),8.11(s,1H),7.90(m,1H),7.83-7.81(m,1H),7.57(s,1H),5.32-5.35(m,2H),3.97(m,1H),3.65(m,2H),3.20(m,1H),3.12(m,4H),3.02(m,1H),2.98(m,1H),1.74(m,4H),1.23(m,5H),1.10(m,2H),0.42(m,4H).
实施例13(R)-4-((2-羟乙基)磺酰基)-N-(8-(2-甲基吗啉)咪唑[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物18)
1、(R)-2-((4-((8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)氨甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯的制备
依次将(R)-4-碘-N-(8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺(200mg,0.35mmol)溶于DMSO(10mL),加入焦亚硫酸钾(118mg,0.53mmol),甲酸钠(53mg,0.77mmol),三苯基磷(14mg,0.053mmol),1,10-二氮杂菲(10mg,0.053mmol),四丁基溴化铵(171mg,0.53mmol)和醋酸钯(2.6mg,0.02mmol),氮气保护下,在70℃反应45分钟,降温,加入溴乙酸乙酯(89mg,0.53mmol)反应10min,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:4)得到目标化合物(100mg,收率:47.9%)。
2、(R)-4-((2-羟乙基)磺酰基)-N-(8-(2-甲基吗啉)咪唑[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
25℃下,将硼氢化锂(7mg,0.3mmol)加入含有(R)-2-((4-((8-(2-甲基吗啉)咪唑并[1,2-a]吡嗪-6-基)氨甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯(90mg,0.15mmol)的四氢呋喃(20mL)溶液,反应30分钟。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(35mg,收率:42.1%)。
分子式:C27H34N6O5S 分子量:554.7 LC-MS(M/e):555.7(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.70(s,1H),8.83(s,1H),8.30(s,1H),8.11(m,1H),7.93(m,1H),7.83(m,1H),7.81(m,1H),7.56(m,1H),5.76(m,2H),4.95(m,1H),3.98(m,1H),3.75(m,2H),3.71(m,2H)3.68(m,2H),3.10(m,4H),2.87(m,1H),1.99-1.75(m,4H),1.18-1.34(m,3H)0.40(m,4H).
实施例14(R)-N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-6-((1-羟基丙-2-基)氨基)-2-(6-氮杂螺环[2.5]辛-6-基)烟酰胺的制备(化合物19)
(1)6-氟-2-(6-氮杂螺环[2.5]辛烷-6-基)烟酸的制备
含有2,6-二氟烟酸(5.0g,31.4mmol),6-氮杂螺[2.5]辛烷盐酸盐(5.1g,34.6mmol)和DIPEA(12.2g,94.5mmol)的1,4-dioxane(50mL),30℃反应15小时。反应完毕,将反应液倒入水中,析出固体,干燥得到目标产物(6.0g,收率:76.4%)。
(2)6-氟-2-(6-氮杂螺[2.5]辛烷-6-基)烟酰氯的制备
30℃下,DMF(0.1mL)加入至含有6-氟-2-(6-氮杂螺环[2.5]辛烷-6-基)烟酸(800mg,3.2mmol)和草酰氯(812mg,6.4mmol)的二氯甲烷(10mL)中,继续反应1小时。反应完毕,反应液浓缩旋干,直接用于下一步反应。
(3)N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-6-氟-2-(6-氮杂螺环[2.5]辛烷-6-基)烟酰胺的制备
0℃下,6-氟-2-(6-氮杂螺[2.5]辛烷-6-基)烟酰氯(上步反应粗品)的二氯甲烷(5mL)溶液滴加入含有8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-胺(500mg,2.0mmol)和DIPEA(775mg,6.0mmol)的二氯甲烷(15mL)中,继续反应1小时。反应完毕,直接硅胶拌样,经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(140mg,收率:14.6%)。
(4)(R)-N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-6-((1-羟基丙-2-基)氨基)-2-(6-氮杂螺环[2.5]辛-6-基)烟酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡嗪-6-基)-6-氟-2-(6-氮杂螺环[2.5]辛烷-6-基)烟酰胺(140mg,0.29mmol)溶于DMSO(10mL),加入DIPEA(112mg,0.87mmol)和D-氨基丙醇(44mg,0.58mmol),25℃下反应15h。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,残留物经硅胶大板纯化(乙酸乙酯:石油醚=1:1)得目标化合物(60mg,收率:38.5%)。
分子式:C27H34F2N8O2 分子量:540.6 LC-MS(M/e):541.1(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.30(s,1H),8.77(s,1H),8.07(s,1H),7.99(m,1H),7.54(s,1H),7.04(m,1H),6.39(m,1H),4.74(m,1H),4.43(m,4H),4.03(m,1H),3.50(m,2H),3.09(m,4H),2.15(m,4H),1.71(m,4H),1.27(m,3H),0.48(m,4H).
实施例15 N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺环[2.5]辛-6-基)苯甲酰胺的制备(化合物20)
(1)6,8-二氯咪唑并[1,2-a]吡嗪的制备
氯乙醛(14.4g,73.4mmol,40%水溶液)加入至含有3,5-二氯吡嗪-2-胺(6.0g,36.6mmol)的DMF(50mL)中,100℃反应2小时。反应完毕,降至室温,将反应液倒入水中,乙酸乙酯萃取三次,合并乙酸乙酯层,水洗,饱和氯化钠溶液洗涤,减压除去乙酸乙酯。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(5.5g,收率:80.0%)。
(2)6,8-二氯-3-氟咪唑并[1,2-a]吡嗪的制备
Select F(10.0g,28.2mmol)加入至含有6,8-二氯咪唑并[1,2-a]吡嗪(5.5g,29.3mmol)的乙腈(50mL)中,30℃反应2小时。反应完毕,反应液直接旋干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(2.1g,收率:34.8%)。
(3)6-氯-8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪的制备
微波管中加入6,8-二氯-3-氟咪唑并[1,2-a]吡嗪(2.1g,10.2mmol),4,4-二氟哌啶盐酸盐(1.4g,8.9mmol),DIPEA(4.0g,31.0mmol)和NMP(8mL),微波100℃下反应50分钟。反应完毕,降至室温,将反应液倒入水中,乙酸乙酯萃取三次,合并乙酸乙酯层,水洗,饱和氯化钠溶液洗涤,减压除去乙酸乙酯。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:2),得目标化合物(2.7g,收率:91.1%)。
(4)(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
含有6-氯-8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪(2.7g,9.3mmol),BocNH2(2.2g,18.8mmol)、RuphosPdG3(1.6g,1.9mmol)和碳酸铯(6.0g,18.4mmol)的1,4-dioxane(40mL),氮气保护下100℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(2.4g,收率:69.6%)。
(5)8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-胺的制备
30℃下,三氟乙酸(4mL)加入至含有(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)氨基甲酸叔丁酯(200mg,0.54mmol)的二氯甲烷(2mL)中,反应3小时。反应完毕,减压除去溶剂,残留物经甲基叔丁基醚打浆得到目标产物(80g,收率:54.8%)。
(6)4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
30℃下,DMF(0.1mL)加入至含有4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(200mg,0.56mmol)和草酰氯(140mg,1.1mmol)的二氯甲烷(40mL)中,继续反应1小时。反应完毕,反应液浓缩旋干直接用于下一步。
(7)N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(上步反应粗品)的二氯甲烷(5mL)溶液滴加入含有8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-胺(80mg,0.29mmol)和DIPEA(112mg,0.87mmol)的二氯甲烷(10mL)中,继续反应3小时。反应完毕,直接硅胶大板纯化(乙酸乙酯:石油醚=1:3),得目标化合物(30mg,收率:16.7%)。
(8)N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺环[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺(30mg,0.049mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(10mg,0.052mmol),N-甲基甘氨酸(5mg,0.056mmol)和磷酸钾(51mg,0.24mmol),50℃下反应5分钟,加入2-羟基乙烷-1-磺酰胺(12mg,0.096mmol),在氮气保护下置于100℃下反应2小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,硅胶大板纯化(乙酸乙酯:石油醚=1:1)得目标化合物(11mg,收率:36.8%)。
分子式:C27H32F3N7O4S 分子量:607.7 LC-MS(M/e):608.1(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),10.15(brs,1H),8.44(s,1H),8.08(m,1H),7.40(m,1H),7.30(m,1H),7.16(m,1H),4.98(brs,1H),4.42(m,4H),3.77(m,2H),3.33(m,2H),3.04(m,4H),2.11(m,4H),1.98-1.67(m,4H),0.42(m,4H).
实施例16(R)-N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-6-((1-羟基丙基-2-基)氨基)-2-(6-氮杂螺[2.5]辛烷-6-基)烟酰胺的制备(化合物21)
1、N’-(3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼的制备
将2-氯-3-肼基吡嗪(10.0g,69mmol)溶于THF(100mL)中,-5℃下加入三氟乙酸酐(12ml)的100mLTHF溶液,-5℃反应1小时。反应完毕,浓缩反应液,加入纯化水,加入乙酸乙酯萃取,浓缩得目标化合物(12.0g,收率:71.9%)。
2、N’-(5-溴-3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼的制备
将N’-(3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼(12.0g,0.05mol)溶于二氯甲烷(150mL),0℃下加入N-溴代琥珀酰亚胺(13.3g,0.07mol),0℃反应1小时。反应完毕,浓缩硅胶柱纯化(乙酸乙酯/正庚烷=15%),得目标化合物(12.0g,收率:75.5%)。
3、5-溴-3-氯-2-肼基吡嗪的制备
将N’-(5-溴-3-氯吡嗪-2-基)-2,2,2-三氟乙酰肼(12.0g,0.04mol)溶于无水乙醇(150mL)中,加入浓盐酸(12mL),100℃下反应2小时。反应完毕,降温,用饱和碳酸氢钠溶液调节pH至8,加入乙酸乙酯萃取,水洗一次,浓缩得目标化合物(8.0g,收率:95.2%)。
4、6-溴-8-氯-[1,2,4]三唑[4,3-a]吡嗪的制备
将5-溴-3-氯-2-肼基吡嗪(8.0g,35.9mmol)溶于原甲酸三乙酯(120mL)中,100℃反应2小时。反应完毕,加入纯化水,加入乙酸乙酯萃取,浓缩,剩余物经柱纯化(乙酸乙酯/正庚烷:60%)得目标化合物6.5g,收率:77.8%。
5、6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪的制备
将6-溴-8-氯-[1,2,4]三唑[4,3-a]吡嗪(6.5g,27.8mmol)溶于N-甲基吡咯烷酮(30mL),加入4,4-二氟哌啶盐酸盐(4.8g,30.7mmol),加入N,N-二异丙基乙胺(14.4g,111.6mmol),微波100℃反应50分钟。反应完毕,降温,将反应液滴至纯化水中,析出大量固体,过滤,旋干得目标产物8.0g,收率:90.4%。
6、(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)氨基甲酸叔丁酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪(8.0g,25mol)溶于二氧六环(80mL)中,加入氨基甲氧叔丁酯(11.8g,100mmol),加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(2.1g,2.5mmol),加入碳酸铯(32.6g,100mmol)氮气保护下,100℃下反应2小时。反应完毕,加入乙酸乙酯萃取,直接硅胶柱纯化(乙酸乙酯:正庚烷=55%),得目标化合物8.0g,收率:89.4%。
7、8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-胺的制备
将(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)氨基甲酸叔丁酯(4.0g,11.3mmol)溶于
乙酸乙酯(10mL),加入4N.HCl乙酸乙酯溶液(20mL),25℃反应16小时。反应完毕,直接浓缩用于下一步(3.0g粗品)。
8、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(2.5g,7mmol)溶于二氯甲烷(20mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃加入二甲基亚砜(1.8g,23mmol),25℃反应0.5小时。反应完毕,直接浓缩用于下一步(3.0g粗品)。
9、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-胺(3.0g,粗品)溶于二氯甲烷(15mL),加入N,N-异丙基乙胺(4.5g,35.1mmol),滴加至4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(3.0g,粗品)溶于二氯甲烷(15mL)和磷酸钾(2.5g,11.7mmol)体系中,25℃下反应1小时。反应完毕,加水淬灭,二氯甲烷萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:正庚烷=60%)得目标化合物400mg,两步收率:9.6%。
10、(R)-N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-6-((1-羟基丙基-2-基)氨基)-2-(6-氮杂螺[2.5]辛烷-6-基)烟酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(140mg,0.24mmol)溶于N,N-二甲基甲酰胺(5mL),加入D-氨基丙醇(43mg,0.58mmol),N,N-二异丙基乙胺(112mg,0.87mmol),80℃下反应3h。反应完毕,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:正庚烷=80%)以及乙酸乙酯打浆得目标化合物(28mg,收率:21.9%)。
分子式:C26H33F2N9O2 分子量:541.6 LC-MS(M/e):541.3(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.50(s,1H),9.35(s,1H),8.72(s,1H),8.00-8.98(m,1H),7.12-7.10(m,1H),6.40-6.39(m,1H),4.75-4.72(m,1H),4.44(m,4H),4.06-4.02(m,1H),3.52-3.48(m,1H),3.41-3.33(m,1H),3.08-3.06(m,4H),2.51-2.12(m,4H),1.69(m,4H),1.24(m,3H),0.422(m,4H).
实施例17 4-(环丙基磺酰基)-N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物23)
将N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基苯甲酰胺(80mg,0.13mmol),环丙烷亚磺酸钠(33mg,0.26mmol),碳酸钾(4mg,0.029mmol),碘化亚铜(5mg,0.026mmol)和L-脯氨酸(3mg,0.026mmol)加入到DMSO(4ml)溶液,置换氮气后,微波140℃,反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,硅胶柱纯化(乙酸乙酯:石油醚=1:4),得目标化合物(20mg)。
分子式:C28H31F3N6O3S 分子量:588.65 LC-MS(M/e):589.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.93(s,1H),8.45(s,1H),8.32-8.30(m,1H),7.93(s,1H),7.84-7.82(m,1H),7.43-7.41(m,1H),4.42(m,4H),3.12(m,4H),3.03(m,1H),2.13(m,4H),1.72(m,4H),1.20(m,4H),0.44(m,4H).
实施例18 N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物24)
1、6,8-二溴-2-甲基咪唑并[1,2-a]吡嗪的制备
于3,5-二溴吡嗪-2-胺(5.0g,19.8mmol)的异丙醇(50mL)中,加入1-溴-2,2-二甲氧基丙烷(5.4g,29.5mmol)和吡啶对甲苯磺酸盐(498mg,2.0mmol),70℃反应16小时。反应完毕,降至室温,用三乙胺调节pH至碱性,旋干。残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:2),得目标化合物(2.1g,收率:36.5%)。
2、6,8-二溴-3-氟-2-甲基咪唑并[1,2-a]吡嗪的制备
于6,8-二溴-2-甲基咪唑并[1,2-a]吡嗪(2.1g,7.2mmol)的乙腈(30mL)中,加入N-氟-N'-(氯甲基)三乙二胺双(四氟硼酸盐)(3.8g,10.7mmol),25℃下反应16h。反应完毕,体系加水淬灭,乙酸乙酯萃取有机相,浓缩,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:9),得目标化合物(560mg,收率:25.1%)。
3、6-溴-8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪的制备
于6,8-二溴-3-氟-2-甲基咪唑并[1,2-a]吡嗪(560mg,1.8mmol)的N-甲基吡咯烷酮(10mL),加入4,4-二氟哌啶(369mg,2.3mmol),N,N-二异丙基乙胺(698mg,5.4mmol),100℃下反应1h。反应完毕,体系加水淬灭,乙酸乙酯萃取有机相浓缩,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:10),得目标化合物(530mg,收率:83.7%)。
4、叔丁基(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑[1,2-a]吡嗪-6-基)氨基甲酸酯的制备
于6-溴-8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪(530mg,1.5mmol)的1,4-二氧六环(20mL),氨基甲酸叔丁酯(352mg,3.0mmol),甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(126mg,0.15mmol)和碳酸铯(1.5g,4.6mmol),氮气保护下100℃下反应3小时。体系加水淬灭,乙酸乙酯萃取有机相,干燥,浓缩,残留物经硅胶柱纯化(二氯甲烷:石油醚=1:9),得目标化合物(300mg,收率:51.3%)。
5、8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-胺三氟乙酸盐的制备
于叔丁基(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑[1,2-a]吡嗪-6-基)氨基甲酸酯(250mg,0.65mmol)的二氯甲烷(6mL)中,加入三氟乙酸(2mL),25℃下反应1小时。反应完毕,减压除去溶剂,得粗品直接用于下一步。
6、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
25℃下,于4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(232mg,0.65mmol)的二氯甲烷溶液(10mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃下再加入二氯亚砜(236mg,2.0mmol),继续反应30分钟。反应完毕,反应液浓缩旋干直接用于下一步。
7、N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
-10℃下,于8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-胺三氟乙酸盐(粗品,0.65mmol)的二氯甲烷(10mL)溶液中,加入N,N-二异丙基乙胺(840mg,6.5mmol)和4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(粗品,0.65mmol),继续反应10分钟。反应完毕,体系加水淬灭,二氯甲烷萃取有机相,浓缩,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:8),得目标化合物(250mg,两步收率:61.7%)。
8、N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
于N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(170mg,0.27mmol)的N,N-二甲基甲酰胺(10mL),加入碘化亚铜(51mg,0.27mmol),N-甲基甘氨酸(48mg,0.54mmol)和磷酸钾(287mg,1.4mmol)和2-羟基乙烷-1-磺酰胺(101mg,0.81mmol),在氮气保护下置于100℃下反应3小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=2:1),得目标化合物(35mg,收率:20.7%)。
分子式:C28H34F3N7O4S 分子量:621.7 LC-MS(M/e):622.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.03(s,1H),10.22(s,1H),8.40(s,1H),8.09-8.07(m,1H),7.29-7.28(m,1H),7.16-7.13(m,1H),4.95(s,1H),4.45-4.35(m,4H),3.80-3.70(m,2H),3.40-3.30(m,2H),3.10-2.92(m,4H),2.32(s,3H),2.22-2.10(m,4H),1.90-1.60(m,4H),0.42-0.40(m,4H).
实施例19 N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备(化合物25)
1、2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)氨甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯的制备
将N-(8-(4,4-二氟哌啶-1-基)-3-咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(150mg,0.24mmol)溶于DMSO(6mL),加入焦亚硫酸钾(80mg,0.36mmol),甲酸钠(36mg,0.53mmol),三苯基磷(9mg,0.036mmol),1,10-二氮杂菲(6mg,0.036mmol),四丁基溴化铵(116mg,0.36mmol)和醋酸钯(3mg,0.012mmol),氮气保护下,在70℃反应45分钟,降温,加入溴乙酸乙酯(60mg,0.36mmol)反应30min,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,硅胶柱纯化(乙酸乙酯:石油醚=1:1)得到目标化合物(50mg,收率32.8%)。
2、N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺环[2.5]辛烷-6-基)苯甲酰胺的制备
0℃下,将硼氢化锂(4mg,0.19mmol)加入含有2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡嗪-6-基)氨甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯(50mg,0.08mmol)的四氢呋喃(5ml)溶液,反应3小时。反应完毕,加甲醇淬灭,浓缩硅胶柱纯化(乙酸乙酯:石油醚=3:2),得目标化合物(2.0mg,收率:12.7%)。
分子式:C27H31F3N6O4S 分子量:592.64 LC-MS(M/e):593.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:12.98(s,1H),8.45(s,1H),8.31~8.29(m,1H),7.95(m,1H),7.84~7.82(m,1H),7.63~7.60(m,1H),4.95(m,1H),4.26(m,4H),3.76~3.72(m,2H),3.59~3.57(m,2H),3.11(m,4H),2.13(m,4H),1.72(m,4H),0.42(m,4H).
实施例20 4-(环丙基磺酰基)-N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物26)
于N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺(40mg,0.064mmol)的二甲基亚砜(2mL)溶液中,加入碘化亚铜(12mg,0.063mmol),L-脯氨酸(15mg,0.13mmol)和碳酸钾(18mg,0.13mmol)和环丙基亚磺酸钠(25mg,0.20mmol),在氮气保护下置于微波140℃下反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(35mg,收率:90.7%)。
分子式:C29H33F3N6O3S 分子量:602.7 LC-MS(M/e):603.2(M+H+)
1H-NMR(400MHz,CDCl3)δ:12.80(s,1H),8.57(s,1H),8.49(d,J=8.4Hz,1H),7.89(s,1H),7.82-7.80(m,1H),4.47-4.44(m,4H),3.20-3.15(m,4H),2.55-2.49(m,1H),2.39(s,3H),2.20-2.12(m,4H),2.10-1.75(m,4H),1.45-1.35(m,2H),1.20-1.10(m,2H),0.51-0.49(m,4H).
实施例21 N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物27)
1、2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)氨基甲酰基)-3-3-(6-氮杂螺[2.5]辛烷-6-基苯基)磺酰基)乙酸乙酯的制备
依次将N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺(40mg,0.064mmol)溶于二甲基亚砜(5mL),加入焦亚硫酸钾(21mg,0.094mmol),甲酸钠(10mg,0.15mmol),三苯基磷(3mg,0.011mmol)),1,10-二氮杂菲(2mg,0.011mmol)),四丁基溴化铵(31mg,0.096mmol))和醋酸钯(1mg,0.0045mmol),氮气保护下,在70℃反应45分钟,降温,加入溴乙酸乙酯(16mg,0.096mmol))反应10min,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,硅胶柱纯化(乙酸乙酯:石油醚=1:2)得到目标化合物(20mg,收率:48.1%)。
2、N-(8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备
25℃下,将硼氢化锂(2mg,0.086mmol)加入2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟-2-甲基咪唑并[1,2-a]吡嗪-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基苯基)磺酰基)乙酸乙酯(18mg,0.028mmol)的四氢呋喃(1mL)溶液,反应1小时。反应完毕,加水淬灭,二氯甲烷萃取,浓缩,硅胶柱纯化(乙酸乙酯:石油醚=3:2),及乙酸乙酯打浆得目标化合物(15mg,收率:89.1%)。
分子式:C28H33F3N6O4S 分子量:606.7 LC-MS(M/e):607.2(M+H+)
1H-NMR(400MHz,CDCl3)δ:12.70(s,1H),8.56(s,1H),8.51(d,J=8.4Hz,1H),7.92(s,1H),7.86-7.85(m,1H),4.46-4.45(m,4H),4.10-4.09(m,2H),3.44-3.42(m,2H),3.18-3.16(m,4H),2.39(s,4H),2.18-2.16(m,4H),1.90-1.60(m,4H),0.45-0.44(m,4H).
实施例22 N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物28)
1、6-溴-8-碘代咪唑[1,2-a]吡啶的制备
48%HBr水溶液(20mL)加入至含有5-溴-3-碘吡啶-2-胺(10.0g,33.5mmol)和2-溴-1,1-二甲氧基乙烷(5.7g,33.7mmol)的无水乙醇(80mL)中,85℃反应6小时。反应完毕,降至室温,析出固体,过滤,滤饼用二氯甲烷溶解后,用饱和碳酸氢钠溶液调节pH至碱性,二氯甲烷层用无水硫酸钠干燥,过滤,滤液减压旋干得到目标化合物(9.0g,收率:83.3%)。
2、6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶的制备
Select F(9.9g,27.9mmol)加入至含有6-溴-8-碘代咪唑[1,2-a]吡啶(9.0g,27.9mmol)的乙腈(40mL)中,20℃反应0.5小时。反应液直接旋干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3)得到目标化合物(1.8g,收率:18.9%)。
3、6-溴-8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶的制备
含有6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶(1.8g,5.3mmol),4,4-二氟哌啶盐酸盐(1.7g,10.9mmol),Xantphos(636mg,1.1mmol),Pd2dba3(485mg,0.53mmol)和碳酸铯(3.4g,10.4mmol)的1,4-dioxane(50mL),氮气保护下105℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:3),得目标化合物(1.7g,收率:96.4%)。
4、叔丁基(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶(1.6g,4.8mmol)溶于1,4-二氧六环(20mL),加入氨基甲酸叔丁酯(1.1g,9.4mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(800mg,0.96mmol)和碳酸铯(3.1g,9.5mmol),氮气保护下105℃下反应3小时,反应完毕。浓缩干,浓缩残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物(550mg,收率:31.0%)。
5、8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-胺的制备
将叔丁基(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(550mg,1.5mmol)溶于二氯甲烷(3mL),加入三氟乙酸(10mL),25℃反应2小时。反应完毕,减压除去溶剂,饱和碳酸氢钠调节pH至8,乙酸乙酯萃取,干燥,浓缩得目标化合物(300mg,收率:74.7%)。
6、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(1.0g,2.9mmol)溶于二氯甲烷(20mL)中,20℃下再加入二氯亚砜(1.2g,10.4mmol),继续反应1小时。反应完毕,反应液浓缩旋干得1.5g粗品直接用于下一步。
7、N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
-20℃下,2-氟-4-碘苯甲酰氯(600mg粗品)加入至含有8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-胺(220mg,0.81mmol)和TEA(324mg,3.2mmol)的二氯甲烷(20mL)中,转至45℃继续反应15小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物(75mg,收率:15.1%)。
8、N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(75mg,0.12mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(23mg,0.12mmol),N-甲基甘氨酸
(11mg,0.12mmol)和磷酸钾(127mg,0.60mmol)和2-羟基乙烷-1-磺酰胺(30mg,0.24mmol),氮气保护下,100℃下反应3小时,反应完毕。加饱和碳酸氢钠水溶液淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=3:1)得目标化合物(40mg,收率:53.6%)。
分子式:C28H33F3N6O4S 分子量:606.7 LC-MS(M/e):607.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.72(s,1H),10.17(s,1H),8.81(s,1H),7.78(s,1H),7.62(m,1H),7.18(m,1H),7.05(m,1H),6.88(m,1H),4.95(m,1H),3.84(m,4H),3.34(m,2H),3.13(m,2H),2.97(m,4H),2.11(m,4H),1.55(m,4H),0.34(m,4H).
实施例23 N-(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物32)
1、6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶的制备
Select F(9.9g,27.9mmol)加入至含有6-溴-8-碘代咪唑[1,2-a]吡啶(9.0g,27.9mmol)的乙腈(40mL)中,20℃反应0.5小时。反应液直接旋干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:3)得到目标化合物(1.8g,收率:18.9%)
2、6-溴-3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶的制备
含有6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶(1.2g,3.52mmol),2-氮杂螺[3.3]庚烷盐酸盐(940mg,7.04mmol),Xantphos(407mg,0.70mmol),Pd2dba3(322mg,0.35mmol)和碳酸铯(2.3g,7.04mmol)的1,4-dioxane(20mL),氮气保护下105℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1),得目标化合物(0.7g,收率:64.2%)。
3、叔丁基(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶(0.7g,2.26mmol)溶于1,4-二氧六环(30mL),加入氨基甲酸叔丁酯(529mg,4.52mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(189mg,0.23mmol)和碳酸铯(2.2g,6.78mmol),氮气保护下100℃下反应,反应完毕。浓缩干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:4)得目标化合物(800mg粗品)。
4、3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-胺的三氟乙酸盐的制备
将叔丁基(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(800mg,2.31mmol)溶于二氯甲烷(6mL),加入三氟乙酸(3mL),反应3小时。反应完毕,减压除去溶剂,加入MTBE打浆,过滤,晾干得到产物(600mg,收率:75.4%)。
5、N-(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(356mg,1.00mmol)加入二氯甲烷(10ml),加入HATU(471mg,1.24mmol)和TEA(420mg,4.15mmol),搅拌5min后,加入3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-胺的三氟乙酸盐(300mg,0.87mmol),50℃搅拌2h,加水淬灭反应,二氯甲烷萃取后,浓缩、经硅胶柱纯化(乙酸乙酯:石油醚=1:9)得目标化合物(150mg,收率:29.4%)。
6、N-(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(3-氟-8-(2-氮杂螺[3.3]庚烷-2-基)咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲
酰胺(150mg,0.26mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(49mg,0.26mmol),N-甲基甘氨酸(23mg,0.26mmol)和磷酸钾(276mg,1.30mmol)和2-羟基乙烷-1-磺酰胺(65mg,0.52mmol),氮气保护下,100℃下反应2小时,反应完毕。加饱和碳酸氢钠水溶液淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=3:1)得产物,浓缩后使用MTBE打浆,过滤、抽干得到目标产物(36mg,收率:23.1%)。
分子式:C29H35FN6O4S 分子量:582.7 LC-MS(M/e):583.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.67(s,1H),10.13(s,1H),8.48(m,1H),7.80~7.78(m,1H),7.20~7.18(m,1H),7.15(m,1H),7.04~7.01(m,1H),5.89(m,1H),4.97(m,1H),4.12(m,4H),3.75(m,2H),3.29(m,2H),2.97(m,4H),2.20(m,4H),1.85(m,2H),1.26(m,4H),0.35(m,4H).
实施例24 N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物33)
1、6-溴-8-(4,4-二氟环己-1-烯-1-基)-3-氟咪唑并[1,2-a]吡啶的制备
将含有6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶(1.4g,4.11mmol),4,4-二氟环己烯-1-硼酸频哪醇酯(1.3g,5.34mmol),Pd(dppf)Cl2(300mg,0.41mmol),K2CO3(1.7g,12.33mmol)溶于二氧六环(30ml)和水(3ml),升温到60℃反应,加水淬灭,用乙酸乙酯萃取,浓缩干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=14:86)得目标化合物(900mg,收率:66.1%)。
2、叔丁基(8-(4,4-二氟环己-1-烯-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-8-(4,4-二氟环己-1-烯-1-基)-3-氟咪唑并[1,2-a]吡啶(0.8g,2.42mmol)溶于1,4-二氧六环(20mL),加入氨基甲酸叔丁酯(567mg,4.84mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(203mg,0.24mmol)和碳酸铯(2.4g,7.26mmol),氮气保护下100℃下反应,反应完毕。浓缩干,残留物经硅胶柱纯化(乙酸乙酯:石油醚=1:4)得目标化合物(500mg,收率:56.2%)。
3、叔丁基(8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将叔丁基(8-(4,4-二氟环己-1-烯-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(420mg,1.14mmol)溶于四氢呋喃(10ml),加入Pd/C(230mg),使用氢气置换3次,氢气保护下,反应4天,过滤、滤液浓缩,残留物经硅胶柱纯化(乙酸乙酯:石油醚=15:85)得目标化合物(98mg,收率:23.3%)。
4、8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-胺的制备
将叔丁基(8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(98mg,2.31mmol)溶于二氯甲烷(6mL),加入三氟乙酸(3mL),反应3小时。反应完毕,减压除去溶剂,二氯甲烷萃取,饱和碳酸氢钠溶液洗,无水硫酸钠干燥,过滤浓缩得到目标化合物(85mg,收率:13.7%)。
5、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(1.0g,2.9mmol)溶于二氯甲烷(20mL)中,20℃下再加入二氯亚砜(1.2g,10.4mmol),继续反应1小时。反应完毕,反应液浓缩旋干得1.5g粗品直接用于下一步。
6、N-(8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
-20℃下,2-氟-4-碘苯甲酰氯(600mg粗品)加入至含有8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶
-6-胺(85mg,0.32mmol)和TEA(648mg,6.4mmol)的二氯甲烷(20mL)中,转至45℃继续反应15小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物(110mg,收率:56%)。
7、N-(8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟环己基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(100mg,0.16mmol)溶于N,N-二甲基甲酰胺(15mL),加入碘化亚铜(15mg,0.08mmol),N-甲基甘氨酸(14mg,0.16mmol)和磷酸钾三水合物(213mg,0.8mmol)和2-羟基乙烷-1-磺酰胺(41mg,0.33mmol),氮气保护下,100℃下反应3小时,反应完毕。加饱和氯化铵水溶液淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=50-100%)得目标化合物(60mg,收率:62%)。
分子式:C29H34F3N5O4S 分子量:605.7 LC-MS(M/e):606.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.95(s,1H),8.00(s,1H),7.62(m,1H),7.28(s,1H),7.08(s,1H),6.85(m,1H),6.65(m,1H),3.74(m,2H),3.34(m,3H),3.03(m,4H),2.11(m,6H),1.75(m,2H),1.55(m,4H),0.34(m,4H).
实施例25 N-(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物34)
1、6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶的制备
Select F(4.8g,13.6mmol)加入至含有6-溴-8-碘代咪唑[1,2-a]吡啶(4.0g,12.4mmol)的乙腈(40mL)中,20℃反应0.5小时。反应液直接旋干,残留物经硅胶柱纯化(乙酸乙酯/石油醚=40%)得到目标化合物(1.0g,收率:23.8%)。
2、6-溴-8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶的制备
含有6-溴-3-氟-8-碘代咪唑[1,2-a]吡啶(700mg,2.0mmol),4-(二氟甲基)哌啶盐酸盐(686mg,4.0mmol),Xantphos(231mg,0.4mmol),Pd2dba3(183mg,0.2mmol)和碳酸铯(1.9g,6.0mmol)的1,4-dioxane(10mL),氮气保护下105℃下反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=20%),得目标化合物(700mg,收率:98.0%)。
3、叔丁基(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶(700mg,2.0mmol)溶于1,4-二氧六环(10mL),加入氨基甲酸叔丁酯(469g,4.0mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(335mg,0.4mmol)和碳酸铯(1.95g,6.0mmol),氮气保护下105℃下反应5小时,反应完毕。浓缩干,浓缩残留物经硅胶柱纯化(乙酸乙酯/石油醚=30%)得目标化合物(280mg,收率:36.4%)。
4、8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-胺的制备
将叔丁基(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(400mg,1.0mmol)溶于二氯甲烷(5mL),加入三氟乙酸(2mL),25℃反应3小时。浓缩得目标化合物(460mg粗品)。
5、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(410mg,1.1mmol)溶于二氯甲烷(8mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃下再加入二氯亚砜(410mg,3.3mmol),继续反应1小时。反应完毕,反应液浓缩旋干得520mg粗品直接用于下一步。
6、N-(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺
的制备
-20℃下,4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(520mg粗品)加入至含有8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-胺(420mg粗品)和TEA(507mg,5.0mmol)的二氯甲烷(10mL)中,转至45℃继续反应18小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=35%)得目标化合物(120mg,两步收率:18.5%)。
7、N-(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4-(二氟甲基)哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(120mg,0.19mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(37mg,0.19mmol),N-甲基甘氨酸(17mg,0.19mmol)和磷酸钾(201mg,0.95mmol)和2-羟基乙烷-1-磺酰胺(48mg,0.38mmol),氮气保护下,100℃下反应3小时,反应完毕。加饱和碳酸氢钠水溶液淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯/石油醚=95%)得目标化合物(80mg,收率:67.0%)。
分子式:C29H35F3N6O4S 分子量:620.7 LC-MS(M/e):621.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.83(s,1H),10.18(s,1H),8.78(s,1H),7.81-7.79(m,1H),7.33-7.26(m,1H),7.17(s,1H),7.06-7.03(m,1H),6.51-6.46(m,1H),6.11-5.76(m,1H),4.34-4.19(m,2H),3.77-3.74(m,2H),3.35-3.32(m,2H),3.05-2.98(m,4H),2.91-2.87(m,2H),2.15-2.03(m,1H),1.81-1.78(m,2H),1.72-1.58(m,6H),0.36(m,4H).
实施例26 N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物36)
1、N'-(5-溴-3-碘吡啶-2-基)-N,N-二甲基甲酰胺的制备
5-溴-3-碘吡啶-2-胺(10.0g,33.5mmol)溶于DMF(50mL)中,加入DMF·DMA(20g,167.3mmol)的,130℃反应3小时。反应完毕,降至室温,浓缩,乙酸乙酯萃取,水洗,无水硫酸钠干燥,过滤,滤液减压旋干得到目标化合物(11g,收率:93%)。
2、6-溴-8-碘-[1,2,4]三唑并[1,5-a]吡啶的制备
N'-(5-溴-3-碘吡啶-2-基)-N,N-二甲基甲酰胺(11g,33mmol)溶于甲醇(100mL)中,加入吡啶(13g,165mmol),磺酸羟胺(7.5g,66mmol)。25℃反应16小时。反应完毕,降至室温,浓缩,二氯甲烷萃取,用饱和碳酸氢钠溶液洗,二氯甲烷层用无水硫酸钠干燥,过滤,滤液减压旋干柱层析(乙酸乙酯/石油醚=0-40%)得到目标化合物(2.8g,收率:26%)。
3、6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶的制备
含有6-溴-8-碘-[1,2,4]三唑并[1,5-a]吡啶(2.8g,8.6mmol),4,4-二氟哌啶盐酸盐(21.7g,13.7mmol),Xantphos(995mg,1.7mmol),Pd2(dba)3(787mg,0.86mmol)和碳酸铯(8.4g,25.8mmol)的1,4-dioxane(50mL),氮气保护下105℃下反应8小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=0-30%),得目标化合物(2.4g,收率:88%)。
4、叔丁基(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶(2.3g,7.3mmol)溶于1,4-二氧六环(40mL),加入氨基甲酸叔丁酯(1.7g,14.5mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(1.2g,1.5mmol)和碳酸铯(7.1g,21.9mmol),氮气保护下105℃下反应3小时,反应完毕。浓缩干,浓缩残留物经硅胶柱纯化(乙酸乙酯:石油醚=0-40%)得目标化合物(1.5g,收率:58%)。
5、8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-胺的制备
将叔丁基(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基甲酸酯(1.4g,4mmol)溶于二氯甲烷(10mL),加入三氟乙酸(5mL),25℃反应2小时。反应完毕,减压除去溶剂,饱和碳酸氢钠调节pH至8,乙酸乙酯萃取,干燥,浓缩得目标化合物(640mg,收率:63%)。
6、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(1.0g,2.9mmol)溶于二氯甲烷(20mL)中,20℃下再加入二氯亚砜(1.2g,10.4mmol),继续反应1小时。反应完毕,反应液浓缩旋干得1.5g粗品直接用于下一步。
7、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
-20℃下,2-氟-4-碘苯甲酰氯(600mg粗品)加入至含有8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-胺(530mg,2.1mmol)和TEA(648mg,6.4mmol)的二氯甲烷(20mL)中,转至45℃继续反应15小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=1:1)得目标化合物(600mg,收率:48%)。
8、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(400mg,0.67mmol)溶于N,N-二甲基甲酰胺(15mL),加入碘化亚铜(64mg,0.33mmol),N-甲基甘氨酸(60mg,0.67mmol)和磷酸钾(892mg,4.2mmol)和2-羟基乙烷-1-磺酰胺(169mg,1.3mmol),氮气保护下,100℃下反应3小时,反应完毕。加饱和氯化铵水溶液淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(乙酸乙酯:石油醚=50-100%)得目标化合物(300mg,收率:76%)。
分子式:C27H33F2N7O4S 分子量:589.7 LC-MS(M/e):590.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.67(s,1H),10.17(s,1H),9.20(s,1H),8.40(s,1H),7.82(m,1H),7.18(s,1H),7.05(m,1H),6.95(s,1H),4.95(m,1H),3.84(m,6H),3.34(m,2H),3.03(m,4H),2.11(m,4H),1.55(m,4H),0.34(m,4H).
实施例27 N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物37)
1、6-溴-8-碘代咪唑[1,2-a]吡啶的制备
48%HBr水溶液(40mL)加入至含有5-溴-3-碘吡啶-2-胺(26.7g,89.3mmol)和2-溴-1,1-二甲氧基乙烷(15.0g,88.7mmol)的无水乙醇(80mL)中,85℃反应6小时。反应完毕,降至室温,析出固体,过滤,滤饼用二氯甲烷溶解后,用饱和碳酸氢钠溶液调节pH至碱性,二氯甲烷层用无水硫酸钠干燥,过滤,滤液减压旋干得到目标化合物(22.0g,收率:76.7%)。
2、6-溴-8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶的制备
含有6-溴-8-碘代咪唑[1,2-a]吡啶(8.0g,24.8mmol),4,4-二氟哌啶盐酸盐(7.8g,49.6mmol),Xantphos(2.9g,4.96mmol),Pd2dba3(2.3g,2.48mmol)和碳酸铯(40.3g,124mmol)的1,4-dioxane(80mL),氮气保护下105℃下反应18小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=18%),得目标化合物(1.9g,收率:24.4%)。
3、叔丁基(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯的制备
将6-溴-8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶(1.9g,6.0mmol)溶于1,4-二氧六环(20mL),加入氨基甲酸叔丁酯(1.4g,12.0mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(1.0g,1.2mmol)和碳酸铯(9.8g,30.0mmol),氮气保护下105℃下反应16小时,反应完毕。浓缩干,浓缩残留物经硅胶柱纯化(乙酸乙酯/石油醚=45%)得目标化合物(650mg,收率:
31.0%)。
4、8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-胺的制备
将叔丁基(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酸酯(650mg,1.8mmol)溶于二氯甲烷(10mL),加入三氟乙酸(6mL),25℃反应6小时。反应完毕,直接浓缩得目标化合物(730mg粗品)。
5、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(723g,2.0mmol)溶于二氯甲烷(10mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃下再加入二氯亚砜(714g,6.0mmol),反应0.5小时。反应完毕,反应液浓缩旋干得850mg粗品直接用于下一步。
6、N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(850mg粗品)加入至含有8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-胺(730mg粗品)和TEA(914mg,9.0mmol)的二氯甲烷(15mL)中,转至45℃继续反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=30%)得目标化合物(520mg,两步收率:49%)。
7、N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(420mg,0.71mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(135mg,0.71mmol),N-甲基甘氨酸(64mg,0.71mmol)和磷酸钾(753mg,3.55mmol)和2-羟基乙烷-1-磺酰胺(178mg,1.42mmol),氮气保护下,100℃下反应3小时,反应完毕。加水淬灭,乙酸乙酯萃取,浓缩残留物经硅胶柱纯化(乙酸乙酯/石油醚=93%)得目标化合物(210mg,收率:50.2%)。
分子式:C28H34F2N6O4S 分子量:588.7 LC-MS(M/e):589.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.59(s,1H),10.09(s,1H),9.05(s,1H),7.98-7.95(m,1H),7.81-7.79(m,1H),7.45(m,1H),7.15(m,1H),7.04-7.02(m,1H),6.56(m,1H),4.95(m,1H),3.77-3.76(m,6H),3.34-3.32(m,2H),2.97-2.89(m,4H),2.18-2.11(m,4H),1.56(m,4H),0.34(m,4H).
实施例28 N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑[4,3-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物38)
1、5-溴-2-氟-3-碘吡啶的制备
将5-溴-3-碘吡啶-2-胺(15g,50mmol)溶于四氟硼酸(150mL)中,-30℃下分批加入亚硝酸钠(9g,130mmol),缓慢升温至0℃,反应1h。加入水淬灭,抽滤,滤饼干燥得目标化合物(15g,收率:99.4%)。2、5-溴-2-肼基-3-碘吡啶的制备
将5-溴-2-氟-3-碘吡啶(15g,49.7mmol)溶于乙醇(150mL)中,加入水合肼(13g,259mmol),70℃反应4h。冷却至25℃,抽滤,滤饼旋干得目标化合物(6.5g,收率:41.7%)。
3、6-溴-8-碘-[1,2,4]三唑并[4,3-a]吡啶的制备
将5-溴-2-肼基-3-碘吡啶(6.5g,21mmol)溶于乙酸(60mL)中,加入原甲酸三乙酯(31g,210mmol),110℃反应1h。反应液旋干,加入饱和碳酸氢钠水溶液调pH至7-8,抽滤,滤饼干燥,得目标化合物(3.7g,收率:54.4%)。
4、6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶的制备
含有6-溴-8-碘-[1,2,4]三唑并[4,3-a]吡啶(3.7g,11mmol),4,4-二氟哌啶盐酸盐(3.4g,22mmol),Xantphos(1.3g,2.2mmol),Pd2dba3(1.0g,1.1mmol)和碳酸铯(18g,55mmol)的1,4-dioxane(80mL),氮气保护下105℃下反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=2:1),得目标化合物(1.2g,收率:34.4%)。
5、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-基)-1,1-二苯基甲烷亚胺的制备
含有6-溴-8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶(600mg,1.9mmol),二苯基甲烷亚胺(525g,2.9mmol),Xantphos(220mg,0.38mmol),Pd2dba3(174g,0.19mmol)和叔丁醇钠(548g,5.7mmol)的1,4-dioxane(30mL),氮气保护下105℃下反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯:石油醚=0-100%),得目标化合物(210mg,收率:26.5%)。
6、8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-基)-1,1-二苯基甲烷亚胺(200mg,0.48mmol)溶于四氢呋喃(3mL)中,加入2M稀盐酸(3mL),25℃反应0.5h。加入饱和碳酸氢钠水溶液调节pH至7-8,乙酸乙酯萃取,硅胶柱纯化(甲醇:二氯甲烷=1:10),得目标化合物(80mg,收率:65.8%)。
7、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
25℃下,于4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(110mg,0.31mmol)二氯甲烷(10mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃下再加入二氯亚砜(190mg,1.6mmol),继续反应30分钟。反应完毕,反应液浓缩旋干直接用于下一步。
8、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,于8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-胺(80mg,0.31mmol)的二氯甲烷(10mL)中,加入TEA(162mg,1.6mmol)和4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯(上步反应粗品),40℃下继续反应4小时。反应完毕,浓缩,残留物经硅胶柱纯化(甲醇:二氯甲烷=1:10),得目标化合物(60mg,收率:32.6%)。
9、N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑[4,3-a]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
于N-(8-(4,4-二氟哌啶-1-基)-[1,2,4]三唑并[4,3-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(60mg,0.10mmol)的N,N-二甲基甲酰胺(5mL),加入碘化亚铜(19mg,0.10mmol),N-甲基甘氨酸(18mg,0.20mmol)和磷酸钾(64mg,0.30mmol)和2-羟基乙烷-1-磺酰胺(38mg,0.30mmol),后在氮气保护下置于100℃下反应3小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,经硅胶柱纯化(甲醇:二氯甲烷=1:10),得目标化合物(19mg,收率:32.2%)。
分子式:C27H33F2N7O4S 分子量:589.7 LC-MS(M/e):589.9(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.60(s,1H),10.10(s,1H),9.30(s,1H),9.06(s,1H),7.75-7.80(m,1H),7.14(s,1H),6.95-7.00(m,1H),6.59(s,1H),4.90-5.00(m,1H),3.85(s,4H),3.70-3.80(m,2H),3.35-3.40(m,1H),3.10-3.15(m,4H),2.05-2.20(m,4H),1.23(s,4H),0.34(s,4H).
实施例29 N-(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物39)
1、5,7-二氯咪唑并[1,2-a]吡啶的制备
将4,6-二氯吡啶-2-胺(4.5g,27.6mmol)溶于无水乙醇(50mL)中,加入碳酸氢钠(3.5g,41.4mmol),加入氯乙醛(17.3g,221mmol),85℃反应3小时。直接浓缩,剩余物经硅胶柱纯化(乙酸乙酯/石油醚=25%),
得目标化合物(2.1g,收率:40.3%)。
2、7-氯-5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶的制备
含有5,7-二氯咪唑并[1,2-a]吡啶(2.0g,10.7mmol),4,4-二氟哌啶盐酸盐(3.4g,21.4mmol),Xantphos(1.2g,2.1mmol),Pd2dba3(1.0g,1.1mmol)和碳酸铯(17.4g,53.5mmol)的1,4-dioxane(20mL),氮气保护下105℃下反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=35%),得目标化合物(960mg,收率:33.3%)。
3、叔丁基(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)氨基甲酸酯的制备
将7-氯-5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶(700mg,2.6mmol)溶于1,4-二氧六环(10mL),加入氨基甲酸叔丁酯(609mg,5.2mmol),加入甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(435mg,0.52mmol)和碳酸铯(4.2g,13.0mmol),氮气保护下105℃下反应16小时,反应完毕。浓缩干,浓缩残留物经硅胶柱纯化(乙酸乙酯/石油醚=80%)得目标化合物(520mg,收率:57.3%)。
4、5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-胺的制备
将叔丁基(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)氨基甲酸酯(520mg,1.5mmol)溶于二氯甲烷(10mL),加入三氟乙酸(5mL),25℃反应1小时。反应完毕,直接浓缩得目标化合物(650mg粗品)。
5、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(631mg,1.77mmol)溶于二氯甲烷(10mL)中,加入N,N-二甲基甲酰胺(0.1mL),0℃下再加入二氯亚砜(631g,5.31mmol),反应0.5小时。反应完毕,反应液浓缩旋干得735mg,粗品直接用于下一步。
6、N-(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,2-氟-4-碘苯甲酰氯(735mg粗品)加入至含有5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-胺(650mg粗品)和TEA(746mg,7.35mmol)的二氯甲烷(20mL)中,转至45℃继续反应16小时。反应完毕,直接硅胶柱纯化(乙酸乙酯/石油醚=15%)得目标化合物(200mg,两步收率:22.9%)。
7、N-(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(5-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-7-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(200mg,0.34mmol)溶于N,N-二甲基甲酰胺(5mL),加入碘化亚铜(65mg,0.34mmol),N-甲基甘氨酸(30mg,0.34mmol)和磷酸钾(360mg,1.7mmol)和2-羟基乙烷-1-磺酰胺(85mg,0.68mmol),氮气保护下,100℃下反应3小时,反应完毕。加水淬灭,乙酸乙酯萃取,浓缩残留物经硅胶柱纯化(甲醇/二氯甲烷=10%)得目标化合物(60mg,收率:30.2%)。
分子式:C28H34F2N6O4S 分子量:588.67 LC-MS(M/e):589.2(M+H+)
实施例30 N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物41)
1、2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛-6-基)苯基)磺酰基)乙酸乙酯的制备
于N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(450mg,0.74mmol)的二甲基亚砜(20mL)溶液中,加入焦亚硫酸钾(247mg,1.1mmol),甲酸钠(111mg,1.6mmol),三苯基磷(29mg,0.11mmol),1,10-二氮杂菲(20mg,0.11mmol),四丁基溴化铵(358mg,1.1mmol)和醋酸钯(13mg,0.058mmol),氮气保护下,在70℃反应45分钟,降温至25℃,加入溴乙酸
乙酯(185mg,1.1mmol)反应10分钟,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:石油醚=1:2)得到目标化合物210mg,收率:44.9%。
2、N-(8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,于2-((4-((8-(4,4-二氟哌啶-1-基)-3-氟咪唑并[1,2-a]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛-6-基)苯基)磺酰基)乙酸乙酯(180mg,0.28mmol)的四氢呋喃(10mL)溶液,加入硼氢化锂(31mg,1.4mmol),25℃反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:石油醚=2:1)得到目标化合物140mg,收率:83.6%。
分子式:C28H32F3N5O4S 分子量:591.7 LC-MS(M/e):592.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.0(s,1H),8.66(s,1H),7.83-7.81(m,1H),7.65-7.60(m,2H),7.29-7.27(m,1H),6.66(s,1H),4.95-4.93(m,1H),3.77-3.70(m,6H),3.55-3.51(m,2H),3.09-3.07(m,4H),2.25-2.05(m,4H),0.60-0.40(m,4H),0.30(s,4H).
实施例31 N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物42)
1、2-((4-((8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛-6-基)苯基)磺酰基)乙酸乙酯的制备
将N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(200mg,0.34mmol)溶于DMSO(10mL),加入焦亚硫酸钾(113mg,0.51mmol),甲酸钠(46mg,0.68mmol),三苯基磷(13mg,0.05mmol),1,10-二氮杂菲(9mg,0.051mmol),四丁基溴化铵(164mg,0.51mmol)和醋酸钯(6mg,0.027mmol),氮气保护下,在70℃反应45分钟,降温,加入溴乙酸乙酯(85mg,0.51mmol),25℃反应10min,反应完毕,加水淬灭,乙酸乙酯萃取,浓缩,剩余物经硅胶柱纯化(乙酸乙酯:石油醚=1:1)得到目标化合物(30mg,收率:14.3%)。
2、N-(8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,将硼氢化锂(5.7mg,0.025mmol)加入含有2-((4-((8-(4,4-二氟哌啶-1-基)咪唑并[1,2-a]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛-6-基)苯基)磺酰基)乙酸乙酯(30mg,0.049mmol)的四氢呋喃(10mL)溶液,25℃反应1小时。反应完毕,加水淬灭,乙酸乙酯萃取,制备板纯化(100%乙酸乙酯),得目标化合物(17mg,收率:60.4%)。
分子式:C28H33F2N5O4S 分子量:573.66 LC-MS(M/e):574.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.01(s,1H),9.17(s,1H),8.10-8.20(s,1H),7.70-7.80(m,1H),7.55-7.65(m,2H),3.70-3.75(m,2H),3.45-3.50(m,6H),3.00-3.10(m,4H),2.10-2.30(m,4H),1.90-2.05(m,2H),1.46(s,4H),0.30(s,4H).
实施例32 N-(8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备(化合物43)
1、8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-胺的制备
将叔丁基(8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-基)氨基甲酸酯(200mg,0.54mmol)溶
于二氯甲烷(5mL),加入三氟乙酸(1mL),20℃反应1小时。反应完毕,减压除去溶剂,二氯甲烷萃取,饱和碳酸氢钠溶液洗,无水硫酸钠干燥,过滤浓缩得到目标化合物粗品,直接用于下一步。
2、4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备
将4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(193mg,0.54mmol)溶于二氯甲烷(5mL)和N,N-二甲基甲酰胺(0.1mL)中,0℃下再加入二氯亚砜(196mg,1.6mmol),继续反应30分钟。反应完毕,反应液浓缩旋干得粗品,直接用于下一步。
3、N-(8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
0℃下,2-氟-4-碘苯甲酰氯(粗品)加入至含有8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-胺(粗品)和TEA(328mg,3.2mmol)的二氯甲烷(10mL)中,继续反应30分钟。反应完毕,体系加水,二氯甲烷萃取有机相,干燥浓缩硅胶柱纯化(乙酸乙酯:石油醚=1:4)得目标化合物20mg,两步收率:6.1%。
4、N-(8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺的制备
将N-(8-(4,4-二氟哌啶-1-基)-5-氟咪唑并[1,2-a]吡嗪-6-基)-4-碘-2-(6-氮杂螺[2.5]辛-6-基)苯甲酰胺(20mg,0.033mmol)溶于N,N-二甲基甲酰胺(10mL),加入碘化亚铜(6mg,0.032mmol),N-甲基甘氨酸(6mg,0.067mmol)和磷酸钾(35mg,0.16mmol)和2-羟基乙烷-1-磺酰胺(12mg,0.096mmol),氮气保护下,100℃下反应10小时,反应完毕。加饱和氯化铵水溶液淬灭,乙酸乙酯萃取,浓缩,经TLC板纯化(乙酸乙酯:石油醚=4:1)得目标化合物5mg,收率:25.1%。
分子式:C27H32F3N7O4S 分子量:607.7 LC-MS(M/e):608.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.85(s,1H),10.14(s,1H),8.14-8.13(m,1H),7.94-7.89(m,1H),7.73-7.72(m,1H),7.23-7.22(m,1H),7.09-7.06(m,1H),4.95-4.92(m,1H),4.40-4.30(m,4H),3.76-3.73(m,2H),3.35-3.31(m,2H),3.05-2.95(m,4H),2.09-2.05(m,4H),1.80-1.70(m,4H),0.40-0.37(m,4H).
使用与上述实施例相同或相似的方法制备了以下表格所示的化合物:
以上对本发明所提供的KIF18A抑制剂及其应用进行了详细介绍。本文中应用了具体实施例对本发明的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护。
Claims (14)
- 通式(I)所示的化合物、其药学上可接受的盐、酯或其立体异构体,
其中,X1、X4分别独立地选自N或CRa;X2与X3之间的连接方式为单键或双键;当X2与X3之间的连接方式为单键时,X2、X3分别独立地选自N或C;当X2与X3之间的连接方式为双键时,X2、X3均为C;环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基;R1选自任选被1个或多个取代基Q2取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基、5-12元桥杂环基;R2、R3、R4、R5、R6分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,-C(O)-NH2,-S(O)2-NH2,任选被1个或多个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、-(L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基;每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,卤代C1-6烷基,卤代C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,-C(O)-NH2,C1-6烷基羰基,C1-6烷基氧基羰基,C1-6烷基磺酰基,C1-6烷基氨基磺酰基,C1-6烷基磺酰氨基,任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基,所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-;每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,C1-6烷基氨酰基,C1-6烷基酰氨基,C1-6烷基磺酰氨基,C1-6烷基氨基磺酰基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基,-(L)m-6-10元芳基,-(L)m-5-12元杂芳基,-(L)m-3-8元环烷基或-(L)m-3-8元杂环基;每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基;每一m、n分别独立地为0-6的整数。 - 如权利要求1所述的化合物、其药学上可接受的盐、酯或其立体异构体,其中,环A选自5-8元环烷基、5-8元杂环基、苯基或5-8元杂芳基;R1选自任选被1-4个取代基Q2取代的3-8元环烷基、3-8元杂环基、苯基、5-8元杂芳基、7-11元螺 环基、7-11元螺杂环基;R2、R5分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基;R3、R4分别独立地选自氢,卤素,氰基,羧基,羟基,氨基,硝基,任选被1-4个取代基Q3取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基;R6选自任选被1-4个取代基Q3取代的-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基、-N(Rc)-C1-6烷基;每一L分别独立地选自-C(O)-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-;每一Ra、每一Ra1、每一Rb分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基,二(C1-6烷基)氨基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,氨基C1-6烷基,羧基C1-6烷基;每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基;每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氰基,硝基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基,氨基C1-6烷基,C1-6烷基氨基,二(C1-6烷基)氨基;每一m、n分别独立地为0-4的整数。
- 如权利要求1或2所述的化合物、其药学上可接受的盐、酯或其立体异构体,其中,环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基;R1选自任选被1-3个取代基Q2取代的3-6元环烷基、3-6元杂环基、苯基、7-10元螺环基、7-10元螺杂环基或5-6元杂芳基;R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元杂环基、7-10元螺杂环基;R3、R4分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;R6选自任选被1-3个取代基Q3取代的-N(Rc)S(O)2-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元环烷基、-S(O)2N(Rc)-3-6元环烷基、-N(Rc)-C1-6烷基;每一Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;每一Rc分别独立地选自氢,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基;每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-6烷基,C1-6烷氧基,卤代C1-6烷基,卤代C1-6烷氧基,羟基C1-6烷基,羧基C1-6烷基。
- 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体,其中,选自如下结构,
每一Ra、每一R1、每一Q1、每一n的定义如权利要求1-3任一项所述。 - 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体,其具有式(II’)所示的结构,
其中,n为0、1、2;X1、R1、R2、R3、R4、R5、R6、每一Ra、每一Q1的定义如权利要求1-4任一项所述。 - 如权利要求5所述的化合物、其药学上可接受的盐、酯或其立体异构体,其中,X1选自N或CRa;R1选自任选被1-3个取代基Q2取代的3-6元环烷基、7-8元螺杂环基或3-6元含氮杂环基;R2、R5分别独立地选自氢,任选被1-3个取代基Q3取代的5-6元含氮杂环基、7-9元含氮螺杂环基;R3、R4分别独立地选自氢,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基;R6选自任选被1-4个取代基Q3取代的-NHS(O)2-C1-6烷基、-S(O)2NH-C1-6烷基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-NH-C1-6烷基;每一Ra分别独立地选自氢,卤素,氨基,羟基,羧基,氰基,C1-4烷基,C1-4烷氧基,C1-4烷基氨基,二(C1-4烷基)氨基,卤代C1-4烷基,卤代C1-4烷氧基;每一Q1、每一Q2、每一Q3分别独立地选自卤素,羧基,羟基,氨基,C1-4烷基,C1-4烷氧基,卤代C1-4烷基,卤代C1-4烷氧基,羟基C1-4烷基,羧基C1-4烷基;n为0、1、2。
- 通式(I’)所示的化合物、其药学上可接受的盐、酯或其立体异构体,
其中,X1、X2、X3、X4、R1、R2、R3、R5、R6、每一Ra、每一Q1的定义如权利要求1-6任一项所述。 - 一种化合物、其药学上可接受的盐、酯或其立体异构体,具有以下结构:
- 一种药物制剂,其含有权利要求1-8中任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体,及一种或多种药用载体和/或稀释剂;所述药物制剂为临床上或药学上可接受的任一剂型。
- 一种药物组合物,其含有权利要求1-8中任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体,及一种或多种第二治疗活性剂;任选地,所述药物组合物还包含一种或多种药用载体和/或稀释剂。
- 权利要求1-8任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体、或权利要求9所述的药物制剂、或权利要求10所述的药物组合物在制备用于治疗和/或预防KIF18A介导的疾病及相关疾病的药物中的用途。
- 如权利要求11所述的用途,其中,KIF18A介导的疾病及相关疾病选自乳腺癌、卵巢癌、子宫内膜癌、子宫颈癌、脑癌、头颈癌、甲状腺癌、肺癌、支气管癌、食管癌、胃癌、肝癌、肾癌、胰腺癌、胆囊癌、结肠癌、膀胱癌、前列腺癌、罩丸癌、皮肤癌、骨癌及血液瘤。
- 权利要求1-8任一项所述的化合物、其药学上可接受的盐、酯或其立体异构体的制备方法,其包括以下步骤:
将式(II’-1)化合物与式(II’-2)化合物反应,得到式(II’-3)化合物;式(II’-3)化合物与R6-H反应,得到通式(II’)化合物;其中,X为卤素;X1、R1、R2、R3、R4、R5、R6、每一Ra、n、每一Q1的定义如权利要求1-8任一项所述。 - 具有如下结构的化合物:
其中,每一X分别独立地为卤素;每一X1、每一R1、每一R2、每一R3、每一R4、每一R5、每一R6、每一Ra、每一n、每一Q1的定义如权利要求1-8任一项所述。
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