WO2024051819A1 - 一种丙酸衍生物及其在医药上的应用 - Google Patents
一种丙酸衍生物及其在医药上的应用 Download PDFInfo
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- WO2024051819A1 WO2024051819A1 PCT/CN2023/117732 CN2023117732W WO2024051819A1 WO 2024051819 A1 WO2024051819 A1 WO 2024051819A1 CN 2023117732 W CN2023117732 W CN 2023117732W WO 2024051819 A1 WO2024051819 A1 WO 2024051819A1
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- Prior art keywords
- alkyl
- substituted
- halogen
- alkoxy
- ring
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 13
- 150000005599 propionic acid derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 343
- 238000002360 preparation method Methods 0.000 claims abstract description 122
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000002207 metabolite Substances 0.000 claims abstract description 41
- 239000000651 prodrug Substances 0.000 claims abstract description 41
- 229940002612 prodrug Drugs 0.000 claims abstract description 41
- 239000012453 solvate Substances 0.000 claims abstract description 39
- 239000000047 product Substances 0.000 claims abstract description 38
- 239000013078 crystal Substances 0.000 claims abstract description 31
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 580
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- 125000003545 alkoxy group Chemical group 0.000 claims description 220
- 229910052736 halogen Inorganic materials 0.000 claims description 162
- 150000002367 halogens Chemical class 0.000 claims description 153
- 125000000623 heterocyclic group Chemical group 0.000 claims description 152
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 151
- 229910052805 deuterium Inorganic materials 0.000 claims description 151
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 132
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 124
- 125000001424 substituent group Chemical group 0.000 claims description 113
- 229910052757 nitrogen Inorganic materials 0.000 claims description 110
- 125000000304 alkynyl group Chemical group 0.000 claims description 106
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 93
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 88
- 229910052760 oxygen Inorganic materials 0.000 claims description 87
- 125000005842 heteroatom Chemical group 0.000 claims description 75
- 229910052717 sulfur Inorganic materials 0.000 claims description 73
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 69
- 125000002837 carbocyclic group Chemical group 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 62
- 229910052731 fluorine Inorganic materials 0.000 claims description 61
- 125000003342 alkenyl group Chemical group 0.000 claims description 57
- 229910052794 bromium Inorganic materials 0.000 claims description 56
- 229910052801 chlorine Inorganic materials 0.000 claims description 56
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 56
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 55
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000002393 azetidinyl group Chemical group 0.000 claims description 44
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 42
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 31
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 229910052740 iodine Inorganic materials 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 26
- 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 24
- 125000003566 oxetanyl group Chemical group 0.000 claims description 24
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 23
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 17
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 16
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 15
- 125000002757 morpholinyl group Chemical group 0.000 claims description 15
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 14
- 125000005605 benzo group Chemical group 0.000 claims description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 13
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- 229920002554 vinyl polymer Polymers 0.000 claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 230000000968 intestinal effect Effects 0.000 claims description 8
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000005494 pyridonyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 3
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 3
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 9
- 108010043603 integrin alpha4beta7 Proteins 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 239000012043 crude product Substances 0.000 description 117
- 238000003786 synthesis reaction Methods 0.000 description 107
- 230000015572 biosynthetic process Effects 0.000 description 106
- 230000002829 reductive effect Effects 0.000 description 97
- 238000005481 NMR spectroscopy Methods 0.000 description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- 239000012141 concentrate Substances 0.000 description 55
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 44
- 238000003756 stirring Methods 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 42
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 33
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
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- 238000003818 flash chromatography Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 20
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 20
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 20
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 13
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- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
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- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 11
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 5
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 5
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
Definitions
- the present invention relates to a compound described in general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and intermediates thereof
- the body and preparation method, and the application in preparing drugs for treating diseases related to integrin ⁇ 4 ⁇ 7 activity or expression level are particularly useful.
- the integrin family is a dimer formed by two subunit units, ⁇ (120-185KD) and ⁇ (90-110KD). There are 18 kinds of ⁇ subunits and 8 kinds of ⁇ subunits in mammalian species. More than 20 kinds of integrins can be formed according to different combinations.
- ⁇ 4 ⁇ 7 is a member of the integrin/integrin family. Intestinal inflammatory diseases related to ⁇ 4 ⁇ 7 have been identified, including Crohn's disease, ulcerative colitis, etc.
- the main ligand of ⁇ 4 ⁇ 7 is mucosal addressin cell adhesion molecule-1 (MADCAM-1).
- MAdCAM-1 is a transmembrane glycoprotein molecule selectively expressed in the high endothelial veins of mucosal lymphoid organs and intestinal lamina intestinal veins. Under inflammatory conditions, a variety of cytokines can promote the high expression of MAdCAM-1 in endothelial cells, and then MAdCAM-1 mediates the migration of ⁇ 4 ⁇ 7-expressing leukocytes to the inflammatory site. Either targeting integrin ⁇ 4 ⁇ 7 or MAdCAM-1 can reduce intestinal inflammation. There are currently no specific small molecule compounds on the market that target inflammation mediated by ⁇ 4 ⁇ 7.
- Natalizumab used clinically, is a humanized monoclonal antibody that targets the ⁇ 4 subunit and is mainly used to treat multiple sclerosis and Crohn's disease, but PML (progressive multifocal leukoencephalopathy) side effects have occurred during clinical use. Therefore, it is necessary to develop a small molecule compound that can inhibit integrin ⁇ 4 ⁇ 7 protein for the treatment of diseases related to integrin ⁇ 4 ⁇ 7 activity or expression.
- the present invention has developed an integrin ⁇ 4 ⁇ 7 inhibitor with novel structure, good efficacy, better ⁇ 4 ⁇ 1/ ⁇ 4 ⁇ 7 selectivity, better liver microsome stability, safer, and no obvious hERG or CYP inhibitory activity. These compounds It has good pharmacokinetic properties and good safety, and is used to treat diseases related to integrin ⁇ 4 ⁇ 7 such as intestinal inflammatory diseases.
- the object of the present invention is to provide a compound capable of inhibiting integrin ⁇ 4 ⁇ 7 or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and wherein Intermediates and preparation methods, and applications in preparing drugs for treating diseases related to integrin ⁇ 4 ⁇ 7 activity or expression.
- the present invention provides a compound described in general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- R 1 is selected from -CHR 1a R 1b or -NR 1a R 1b ;
- R1 is selected from b is selected from 0, 1, 2, 3;
- R1 is selected from In some embodiments, R1 is selected from
- R1 is selected from
- R1 is selected from In some embodiments, R1 is selected from In some embodiments, R1 is selected from In some embodiments, R1 is selected from In some embodiments, R1 is selected from In some embodiments, R1 is selected from or In some embodiments, R1 is selected from or
- R1 is selected from In some embodiments, R1 is selected from
- R b1 is selected from H, F, CH 2 F, CHF 2 , CF 3 , methyl, -CH 2 CH 2 N(CH 3 ) 2 ;
- R b2 , R b are each independently selected from R ba , Or one of the optionally substituted following groups: ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl base, oxanyl, oxanyl, morpholinyl, phenyl, pyridyl, -CH 2 NH(CH 2 CH 3 ), -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2
- R b2 , R b are each independently selected from R ba ,
- Rba is selected from
- R b1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 0 to 4 selected from deuterium, halogen, OH , CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy substituents substituted;
- R 1a is selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl;
- R 1a is selected from
- R 1b is selected from C 4-10 carbocyclic ring, 5 to 10 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally substituted by 0 to 4 R b , and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
- R b is selected from R ba ;
- each R b is independently selected from deuterium, F, Cl, Br, OH, cyano, R ba , or each R b is independently selected from one of the following groups, substituted or unsubstituted: methyl , ethyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepanyl, azepanyl, oxahetyl Butyl, oxanyl, oxanyl, morpholinyl, phenyl, pyridine, -CH 2 NH(CH 2 CH 3 ), -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 N(CH 2 CH
- R b is selected from R b2 ;
- Rba is selected from -C 0-4 alkyl - 7 to 12 membered heterocycle, -C 0-4 alkyl - 4 to 6 membered heterocycle attached through a carbon atom
- R ba is selected from -C 0-2 alkyl-7 to 8 membered monocyclic heterocycloalkyl, -C 0-2 alkyl-7 to 11 membered spirocyclic heterocycloalkyl, -C 0-2 alkyl-7 to 11-membered bridged ring heterocycloalkyl, -C 0-2 alkyl-4 to 6-membered monocyclic heterocycloalkyl connected through carbon atoms,
- Rba is selected from the group consisting of 7- to 8-membered monocyclic heterocycloalkyl, 7- to 11-membered spirocyclic heterocycloalkyl, 7- to 11-membered bridged cyclic heterocycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, -CH 2 -7 to 8-membered monocyclic heterocycloalkyl, -CH 2 -7 to 11-membered spirocyclic heterocycloalkyl, -CH 2 -7 to 11-membered bridged ring hetero Cycloalkyl, -CH 2 -4 to 6-membered monocyclic heterocycloalkyl connected through carbon atoms, -CH 2 CH 2 -7 to 8-membered monocyclic heterocycloalkyl, -CH 2 CH 2 -7 to 11 Membered spirocyclic heterocycloalkyl, -CH 2 CH 2 -7 to 11 membered bridged heterocycl
- R 2 is selected from C 1-6 alkyl, C 6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, C 3-10 carbocyclic ring, 5 to 10 membered heterocyclic ring, said R 2 Optionally substituted by 0 to 4 R 2a , the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
- R2 is selected from C 1-4 alkyl, benzene ring, naphthalene ring, 5 to 6 membered heteroaromatic ring, 9 to 10 membered heteroaromatic ring, C 3-10 non-aromatic carbocyclic ring, 5 to 10-membered non-aromatic heterocyclic ring, benzo C 4-6 carbocyclic group or benzo 4-6 membered heterocyclic group, the R 2 is optionally substituted by 0 to 4 R 2a , the heteroaromatic ring, heterocyclic group
- the ring contains 1 to 4 heteroatoms selected from O, S, and N;
- R is selected from benzene ring, naphthalene ring, 5- to 6-membered heteroaromatic ring, 9- to 10-membered heteroaromatic ring, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, benzene and C 4-6 carbocyclyl or benzo 4 to 6 membered heterocyclyl, the R 2 is optionally substituted by 0 to 4 R 2a , the heteroaromatic ring or heterocycloalkyl contains 1 to 4 Heteroatom selected from O, S, N; in some embodiments, R is selected from benzene ring, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furyl, oxazolyl , pyrrolyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopenty
- R is selected from Selected from
- R is selected from phenyl, pyridyl, pyridonyl, azepanyl, morpholinyl
- the R 2 is optionally 0 to 4 selected from deuterium, F, Cl, Br, OH, CF 3 , cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl Substituted by substituents;
- R is selected from The R 2 is optionally 1 to 4 selected from deuterium, CD 3 , -OCD 3 , F, Cl, Br, OH, CF 3 , cyano, methyl, ethyl, methoxy, ethoxy, Substituted with cyclopropyl or cyclobutyl substituents;
- R is selected from In some embodiments, R is selected from In some embodiments, R is selected from In some embodiments, R is selected from
- R 2a is selected from deuterium, halogen, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 6- cycloalkyl or 4- to 6-membered heterocycloalkyl.
- the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl groups are optionally substituted by 0 to 4 selected from deuterium, halogen , OH, CN, C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, N;
- R 2a is selected from deuterium, F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy;
- the cycloalkyl substituent is substituted, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, OH, cyano Substituted by substituents;
- the cycloalkyl substituent is substituted, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, OH, cyano Substituted by substituents;
- R 2a and R 2a are directly connected to form a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, and the said carbocyclic ring or
- R 3 is selected from H, C 1-4 alkyl, and the alkyl group is optionally 0 to 4 selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy , substituted by the substituent of the benzene ring;
- R3 is selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, benzyl;
- Ring A is selected from a C 8-10 cyclic carbocyclic ring (such as a benzo C 4-6 membered carbocyclic ring), and the Ring A is optionally substituted by 0 to 4 Ra5 ; in some embodiments In the scheme, ring A is selected from The Ring A is optionally substituted with 0 to 4 Ra5 ; in some embodiments, Ring A is selected from
- Ring A is selected from The ring A is substituted by 1 substituent selected from C 2-6 alkenyl or C 2-6 alkynyl, optionally substituted by 1 to 3 selected from R a5 ; in some embodiments, ring A is selected from since The Ring A is substituted with 1 R ak , optionally substituted with 1 to 3 R a5 selected from; in some embodiments, Ring A is selected from Ring A is optionally substituted by 1 to 3 R a5 ;
- R ak is selected from C 2-4 alkynyl (e.g., ethynyl, propynyl, propargyl)
- Ring A is selected from The ring A is substituted by 1 substituent selected from vinyl, ethynyl, propynyl, and propargyl, optionally substituted by 1 to 3 substituents selected from R a5 ;
- R a5 is each independently selected from F, Cl, Br, I, OH, CN, ethynyl, methyl, ethyl;
- R a5 is each independently selected from F, Cl, Br, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl;
- Ring A is selected from The upper left is directly connected to R 2 , and p2 is selected from 0, 1 or 2;
- R 1b is selected from
- R 1b is selected from
- R b1 is each independently selected from H, halogen, CN, C 1-6 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 0 to 4 Substituted with substituents selected from deuterium, halogen, OH, CN, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-4 alkyl, and C 1-6 alkoxy;
- R b1 is each independently selected from H, halogen, CN, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 0 to 4 Substituted with substituents selected from deuterium, halogen, OH, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, and C 1-4 alkoxy;
- the compound is not the structure shown in Table E-2 and its stereoisomers;
- the compound represented by the general formula (I) is selected from the compounds represented by the general formula (Ia), (Ib), (Ia-1), (Ib-1),
- the compound represented by general formula (I) is selected from the group consisting of general formula (If), (Ig), (If-1), (Ig-1), (Ih), (li), (Ih-1 ), the compound represented by (Ii-1),
- Formula (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1), (Ih ), (Ii), (Ih-1), and (Ii-1), the definitions of R 2a , R 1a , R ak , R a5 , R b2 , R b1 , and R 3 are the same as in any of the aforementioned embodiments;
- ring A in general formulas (I-a) and (I-b) is the same as any of the aforementioned embodiments of ring A;
- Formula (I), (I-a), (I-b), (I-a-1), (I-b-1), (I-f), (I-g), (I-f-1), (I-g-1 ), (I-h), (I-i), (I-h-1), (I-i-1), p1 is selected from 0, 1, 2, 3 or 4;
- Formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1 ), (Ih), (Ii), (Ih-1), (Ii-1), R 1a is selected from
- Formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (If), (Ig), (If-1), (Ig-1 ), (Ih), (Ii), (Ih-1), (Ii-1), R b1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, the alkyl or cycloalkyl
- the alkyl group is optionally selected from 0 to 4 deuterium, halogen, OH, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy Substituted by the substituent of the base;
- R b2 is selected from H, R ba , substituted or unsubstituted one of the following groups: methyl, ethyl, ethynyl, methoxy, ethoxy, -CH 2 NH(CH 2 CH 3 ), -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH (CH 2 CH 3 ), -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 N(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclobutyl, -CH 2 CH 2 -cyclopentyl,
- R ba and R k in (Ii-1) are the same as in any of the aforementioned embodiments;
- Formula (I), (la), (lb), (If), (Ig), (If-1), (Ig-1), (Ih), (li), (Ih -1), (Ii-1) R 2a is selected from deuterium, -CD 3 , -OCD 3 , F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy ;
- R ak in general formula (I), (Ig), (Ig-1), (Ii), (Ii-1) is selected from C 2-4 alkynyl;
- Formula (I), (If), (Ig), (If-1), (Ig-1), (Ih), (li), (Ih-1), (lii-1 ) in R a5 is selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, ethynyl;
- n1 in formula (I) is selected from 1, 2, or 3.
- the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- R 1 is selected from -CHR 1a R 1b or -NR 1a R 1b ;
- R 1b is selected from C 4-10 carbocyclic ring and 5 to 10 membered heterocyclic ring.
- the carbocyclic ring or heterocyclic ring is optionally substituted by 0 to 4 R b .
- the heterocyclic ring contains 1 to 4 R b selected from O , S, N heteroatoms;
- R ba is selected from -C 0-4 alkyl-7 to 12-membered heterocyclic ring, -C 0-4 alkyl-4 to 6-membered heterocyclic ring connected through carbon atoms,
- R 2 is selected from C 1-6 alkyl, C 6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, C 3-10 carbocyclic ring, 5 to 10 membered heterocyclic ring, and the R 2 is optionally replaced by 0 to 4
- Each R 2a is substituted, and the heteroaromatic ring or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
- Ring A is selected from C 8-10 paracyclic carbocyclic rings, and the ring A is optionally substituted by 0 to 4 R a5 ;
- Ring A is selected from The ring A is substituted by 1 substituent selected from C 2-6 alkenyl or C 2-6 alkynyl, optionally substituted by 1 to 3 R a5 ;
- the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- R 1 is selected from
- b is selected from 0, 1, 2, 3;
- R ba is selected from -C 0-2 alkyl-7 to 8-membered monocyclic heterocycloalkyl, -C 0-2 alkyl-7 to 11-membered spirocyclic heterocycloalkyl, -C 0-2 alkyl- 7 to 11 membered bridged cyclic heterocycloalkyl, -C 0-2 alkyl - 4 to 6 membered monocyclic heterocycloalkyl connected through carbon atoms,
- R 2 is selected from C 1-4 alkyl, benzene ring, naphthalene ring, 5 to 6 membered heteroaromatic ring, 9 to 10 membered heteroaromatic ring, C 3-10 nonaromatic carbocyclic ring, 5 to 10 membered nonaromatic heterocyclic ring , benzo C 4-6 carbocyclyl or benzo 4 to 6 membered heterocyclyl, the R 2 is optionally substituted by 0 to 4 R 2a , the heteroaromatic ring or heterocyclic ring contains 1 to 4 Heteroatom selected from O, S, N;
- Ring A is selected from benzo C 4-6 carbocyclic rings, and the ring A is optionally substituted by 0 to 4 R a5 ;
- Ring A is selected from The ring A is substituted by 1 substituent selected from C 2-4 alkenyl or C 2-4 alkynyl, optionally substituted by 1 to 3 selected from R a5 ;
- the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- Rba is selected from the group consisting of 7- to 8-membered monocyclic heterocycloalkyl, 7- to 11-membered spirocyclic heterocycloalkyl, 7- to 11-membered bridged heterocycloalkyl, and 4- to 6-membered monocyclic heterocycle connected through carbon atoms.
- R 2 is selected from benzene ring, naphthalene ring, 5 to 6 membered heteroaromatic ring, 9 to 10 membered heteroaromatic ring, C 3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, benzo C 4-6 carbon Ring group or benzo 4- to 6-membered heterocyclic group, the R 2 is optionally substituted by 0 to 4 R 2a , the heteroaromatic ring and heterocycloalkyl group contain 1 to 4 selected from O, S, N heteroatoms;
- R 2a and R 2a are directly connected to form a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring.
- R 3 is selected from H, C 1-4 alkyl, and the alkyl group optionally has 0 to 4 substituents selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, and benzene ring replaced;
- Ring A is selected from The ring A is optionally substituted by 0 to 4 R a5 ;
- Ring A is selected from The ring A is substituted by 1 substituent selected from C 2-4 alkenyl or C 2-4 alkynyl, optionally substituted by 1 to 3 selected from R a5 ;
- the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- R 1a is selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl;
- R 2 is selected from benzene ring, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, oxetanyl, oxetyl, oxetanyl, morpholinyl,
- the R 2 is optionally substituted by 0 to 4 R 2a ;
- R 3 is selected from H, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, and benzyl;
- Ring A is selected from The ring A is optionally substituted by 0 to 4 R a5 ;
- Ring A is selected from The ring A is substituted by 1 substituent selected from vinyl, ethynyl, propynyl, and propargyl, optionally substituted by 1 to 3 substituents selected from R a5 ;
- the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- R 1 is selected from
- R b is each independently selected from deuterium, F, Cl, Br, OH, cyano, R ba , or R b is each independently selected from one of the following substituted or unsubstituted groups: methyl, ethyl, ethynyl , methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl Pentyl, oxanyl, morpholinyl, phenyl, pyridyl, -CH 2 NH(CH 2 CH 3 ), -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 N
- R k is selected from -CH 2 N(CH 3 ) 2 , -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , azetidinyl, azetidinyl, oxetanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidine
- R 2 is selected from phenyl, pyridyl, pyridonyl, azocyclopentyl, morpholinyl,
- the R 2 is optionally 0 to 4 selected from deuterium, F, Cl, Br, OH, CF 3 , cyano, methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl Substituted by substituents;
- R 2 is selected from The R 2 is optionally 1 to 4 selected from deuterium, CD 3 , -OCD 3 , F, Cl, Br, OH, CF 3 , cyano, methyl, ethyl, methoxy, ethoxy, Substituted with cyclopropyl or cyclobutyl substituents;
- Ring A is selected from
- the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic,
- R 1 is selected from
- R 1 is selected from
- R 1 is selected from
- R 1 is selected from
- R 1 is selected from
- R 1 is selected from
- R 1 is selected from
- R 2 is selected from
- R 2 is selected from
- R 2 is selected from
- R 1a is selected from
- the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or Co-crystal is selected from the compounds represented by general formula (Ia), (Ib), general formula (Ia-1), (Ib-1),
- ring A and R 3 are the same as any one of two, three, four, five or six in the embodiment of the present invention.
- p1 is selected from 0, 1, 2, 3 or 4;
- R 2a is selected from deuterium, halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4 to 6-membered heterocycloalkyl, the alkyl, Alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 0 to 4 substituents selected from deuterium, halogen, OH, CN, C 1-4 alkyl, and C 1-4 alkoxy, so
- the heterocycloalkyl group contains 1 to 4 heteroatoms selected from O, S, and N;
- R 1a is selected from
- R b1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally 0 to 4 selected from deuterium, halogen, OH, CN, NHC 1- Substituted with substituents of 4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, and C 1-4 alkoxy;
- n1 is selected from 1, 2 or 3;
- R ba and R k are the same as any one of two, three, four, five or six in the embodiment of the present invention.
- the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or Co-crystal is selected from the compounds represented by the general formula (I-a), (I-b), (I-a-1), (I-b-1),
- R 2a is selected from deuterium, CD 3 , -OCD 3 , F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy;
- R b1 is selected from H, F, CH 2 F, CHF 2 , CF 3 , methyl, -CH 2 CH 2 N(CH 3 ) 2 ;
- R b2 is selected from H, R ba , one of the following substituted or unsubstituted groups: methyl, ethyl, ethynyl, methoxy, ethoxy, -CH 2 NH (CH 2 CH 3 ), -CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 N(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclobutyl, -CH 2 CH 2 -cyclopentyl, -CH 2 CH 2 -cyclohexyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 -azetidinyl, -CH 2
- the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or Co-crystal is selected from the group represented by the general formula (If), (Ig), (If-1), (Ig-1), (Ih), (Ii), (Ih-1), (Ii-1) Compounds:
- R 1b is selected from
- p2 is selected from 0, 1 or 2;
- Rak is selected from C 2-4 alkynyl
- R a5 is the same as any one of the first, second, third or fourth embodiments of the present invention.
- the compound represented by the above general formula (I) or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or Co-crystal is selected from the group represented by the general formula (I-f), (I-g), (I-f-1), (I-g-1), (I-h), (I-i), (I-h-1), (I-i-1) compound
- R ak is selected from ethynyl, propynyl, and propargyl
- R a5 is selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy, ethoxy, and ethynyl;
- R a6 is selected from H or F
- R 2 is selected from phenyl or The R 2 is optionally substituted by 1 to 4 C 1-4 alkyl selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, 1 to 4 halogen substituted C 1-4 alkyl, 1 to 4 halogen Substituted with substituents of C 1-4 alkoxy, 1 to 4 deuterium-substituted C 1-4 alkyl, and 1 to 4 deuterium-substituted C 1-4 alkoxy, preferably
- R b1 is selected from CH 2 F, CHF 2 , CF 3 , methyl; preferably CF 3 ;
- R b2 is selected from -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 -azetidinyl, -CH 2 -azetidinyl, - CH 2 -Azetidinyl, -CH 2 -morpholinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 -azetipentyl, -CH 2 CH 2 -azetidinyl ,
- the R b2 is optionally 1 to 4 selected from deuterium, F, Cl, Br, NHCH 2 CH 3 , N(CH 2 CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , methyl, ethanol base, isopropyl, methoxy, ethoxy, -CH 2 -cyclopropyl, Substituted with substituents; preferably
- the present invention relates to some specific compounds of general formula (I) selected from Table E-1.
- the present invention relates to some specific compounds of general formula (I), which compounds are selected from Table E-3, Table E-4, and Table E-5.
- the present invention relates to a pharmaceutical composition, including the compound of the present invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and Learn an acceptable medium.
- the present invention relates to a compound according to the invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal for use in the preparation of treatment with ⁇ 4 ⁇ 7 Application in drugs for diseases related to activity or expression level, preferably application in the preparation of drugs for intestinal inflammatory diseases.
- the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which contains a therapeutically effective amount of the compound of the present invention or its stereoisomer, racemate, deuterated product, solvate, pro- Drugs, metabolites, pharmaceutically acceptable salts or co-crystals and pharmaceutical excipients.
- the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation specification").
- the present invention also provides a method for treating diseases in a mammal, which includes administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, racemate, deuterated product, or solvate , prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals or pharmaceutical compositions.
- mammals of the present invention include humans.
- Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or condition being treated (eg, intestinal inflammatory disease). one or more symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, to treat An “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
- therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-
- the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics.
- a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite,
- the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably intestinal inflammatory disease.
- a method for treating diseases in mammals includes: using a compound of the present invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, metabolite, or pharmaceutically acceptable salt Or the cocrystal is administered to the subject at a daily dose of 1-1000 mg/day, which may be a single dose or divided dose.
- the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg /day, 10-800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day , 200-400 mg/day, in some embodiments, the daily dosage includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day , 160mg/day, 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
- the present invention relates to a kit, which may include a composition in a single dose or multiple dose form.
- the kit contains a compound of the invention or its stereoisomer, racemate, deuterated product, solvate, prodrug, Metabolites, pharmaceutically acceptable salts or co-crystals, of the compounds of the present invention or their stereoisomers, racemates, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals
- the amount is the same as in the above pharmaceutical composition.
- the amount of the compound of the invention or its stereoisomer, racemate, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is in each case in the form of a free base Conversion.
- Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
- R m1 is selected from Boc; Cbz; tert-butylsulfinyl, etc.;
- R m2 and R m3 are each independently selected from H, Cl, Br, I, OTf, B(OH) 2 , borate ester group, alkyl-substituted tin group, etc.;
- R m4 is selected from Cl, Br, I, OH, etc.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
- the isotopes of carbon include 12 C, 13 C and 14 C
- Alkyl refers to a linear or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched isomers; the alkyl group is optionally substituted by 0 to 6 members selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide , alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 8-membered carbocyclyl, 3 to 8-membered heterocyclyl, 3 to 8-membered Substituted with a carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group
- Alkylene refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10).
- alkylene include but are not limited to methylene, methylene Ethyl, propylene and butylene, etc.; the alkylene group is optionally selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, Substituted with alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylic acid ester substituents.
- Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, usually with 3 to 12 carbon atoms, including monocyclic cycloalkyl, pendent cycloalkyl, spirocyclic cycloalkyl or bridged cycloalkyl. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like.
- the cycloalkyl group is optionally substituted by 0 to 5 members selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl Substituted with a substituent of a group, an alkoxy group, a carbocyclyl group, a heterocyclyl group, a carbocyclyloxy group, a heterocyclyloxy group, a carboxyl group or a carboxylic acid ester group.
- alkenyl refers to straight-chain and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, and further preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
- alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl -3-Butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2- Methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-
- Alkynyl refers to straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain.
- alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl , 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2- Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-Methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl base, 3-octynyl, 1-nonynyl, 3-non
- Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
- the alkoxy group is optionally selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl Substituted with a substituent of a group, an alkoxy group, a carbocyclyl group, a heterocyclyl group, a carbocyclyloxy group, a heterocyclyloxy group, a carboxyl group or a carboxylic acid ester group.
- Carbocyclyl or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
- the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
- Bicyclic or 10 to 15-membered tricyclic system the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring.
- Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
- Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
- the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
- the optionally substituted N and S in the ring of the heterocyclyl can Oxidized into various oxidation states.
- the heterocyclyl group can be connected to a heteroatom or a carbon atom.
- the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
- the heterocyclyl group can be connected to a bridged ring or a spiro ring.
- Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl
- Heterocycloalkyl refers to a substituted or unsubstituted saturated heterocyclic group, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 Heteroatoms selected from N, O or S are preferably 3 to 8-membered heterocyclyl groups.
- the selectively substituted N and S in the ring of the heterocycloalkyl group can be oxidized into various oxidation states.
- the heterocycloalkyl group can be attached to a heteroatom or a carbon atom, and non-limiting examples include oxetyl, aziridyl, oxetanyl, azetidinyl, 1,3-dioxolane Cyclyl, 1,4-dioxanyl, 1,3-dioxanyl, azepanyl, piperidinyl, morpholinyl.
- n is selected from 0, 1 or 2.
- it is 6 to 14 yuan, further preferably 6 to 12 yuan, more preferably 6 to 10 yuan, and non-limiting examples thereof include:
- Non-limiting examples include:
- the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms.
- Non-limiting examples include and adamantane.
- the definition of bridge rings appearing in this article is consistent with this definition.
- Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
- Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
- Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
- Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system
- Heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
- Heterospirocycle refers to a “spirocycle” containing heteroatoms.
- Heterobridged ring refers to a “bridged ring” containing heteroatoms.
- Aryl or aromatic ring refers to a monovalent aromatic hydrocarbon group having a single or fused ring, usually 6 to 12 carbon atoms, and may be substituted or unsubstituted. Aryl groups or aromatic rings appearing herein are defined consistent with this definition.
- Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include
- Constant 1 to 4 heteroatoms selected from O, S, and N means containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N.
- Substituted by 0 to X substituents means substituted by 0, 1, 2, 3...X substituents, and X is selected from any integer between 1 and 10.
- substituted with 0 to 4 substituents means substituted with 0, 1, 2, 3 or 4 substituents.
- substituted with 0 to 5 substituents means substituted with 0, 1, 2, 3, 4 or 5 substituents.
- the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F. replace.
- Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
- “4-7 membered heteromonocyclic ring” refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings
- “5-10-membered heterocyclic ring” refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
- Alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
- “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components” refers to pharmaceutically acceptable Acceptable carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
- Animal is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
- Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
- the compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
- “Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXIA (Shanghai) ) Chemical Industrial Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
- NMR shift ( ⁇ ) is given by The unit of 10-6 (ppm) is given.
- NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments.
- the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and internal standards.
- TMS tetramethylsilane
- HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
- Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
- the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
- the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
- Boc tert-butoxycarbonyl
- Ts p-toluenesulfonyl
- Cbz benzyloxycarbonyl
- TMS trimethylsilyl
- TIPS triisopropylsilyl
- Bpin zonacol borate
- MOM methylene methyl ether
- THF tetrahydrofuran
- HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
- the * next to the chemical bond indicates that the chirality of the chiral atom is R or S;
- Retention time (Rt, retention time): There is no special explanation in the examples. It is the retention time of the analysis method. The method is as follows:
- mobile phase A is 0.05% TFA solution
- mobile phase B is acetonitrile
- Method 1 Instrument: waters 2767 preparation chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water ( Containing 0.1% ammonium acetate).
- Method 2 Instrument: waters 2767 preparation column: SunFire@Prep C18 (19mm ⁇ 150mm); (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoro Acetic acid.
- intermediate 1a (6.3g, 39.34mmol) was dissolved in dichloromethane (150mL), and anhydrous aluminum chloride (13.11g, 98.35mmol) was added. After reacting at room temperature for 5 min, a solution of elemental bromine (8.80 g, 55.08 mmol) in dichloromethane (50 mL) was added, and the reaction was carried out at room temperature for 2 h. Pour the reaction solution into ice water (200 mL), add dichloromethane (100 mL), wash with saturated brine (80 mL), dry over anhydrous sodium sulfate, filter and concentrate, and perform silica gel column chromatography to obtain 1B (8.0 g, 85.05% ).
- Dissolve 1B (8.1g, 33.88mmol) in DME (100mL), add 1M sodium hypochlorite solution (188mL) and 10N sodium hydroxide solution (18.5mL), and react at 50°C for 1 hour.
- Add water 150 mL
- extract with ether 200 mL
- adjust the pH of the aqueous phase to 1-2 with hydrochloric acid
- extract with ether 150 ml ⁇ 2
- combine the organic phases dry over anhydrous sodium sulfate, and concentrate to obtain 1C (7.6 g , 93.05%).
- Dissolve 4A (1.0g, 2.34mmol) in 3mL THF and 1mL water, add lithium hydroxide monohydrate (112mg, 4.68mmol), and react at room temperature for 5h. Adjust the pH to 5-6 with 1N hydrochloric acid, concentrate under reduced pressure, and obtain intermediate 4 (650 mg, 69.55%) by column chromatography.
- 1,4-oxaazepane hydrochloride 360 mg, 2.59 mmol was dissolved in 1,2-dichloroethane (8 mL), DIPEA was added, and the reaction was carried out at room temperature for 15 min. 1a (0.9 g, 2.59mmol, refer to the synthesis steps of WO2021076890A1) and 0.15mL acetic acid, stir at room temperature for 1h, add sodium triacetoxyborohydride (820mg, 3.86mmol), stir for 16h, concentrate under reduced pressure to obtain a crude product, and use a silica gel column for quick column chromatography of the crude product After analysis, 5A (0.49g, yield 43.75%) was obtained.
- the crude product 7E was dissolved in 1,2-dichloroethane (20 mL) and methanol (20 mL), and 3-fluoroazetidine hydrochloride (780 mg, 10.38 mmol) and acetic acid (0.5 mL), stir at room temperature for 1 h, add sodium triacetoxyborohydride (4.38g, 20.76mmol), and react overnight.
- 1a (3.0g, 8.64mmol, refer to WO2021076890A1 for synthesis steps) and methylamine hydrochloride (1.16g, 17.28mmol) were dissolved in 1,2-dichloroethane (30mL), and 5 Acetic acid was dropped and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.65g, 17.28mmol) was added and stirring was continued for 16 hours. Concentrate under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column flash column chromatography to obtain 1b (1.0g, yield 31.95%). ).
- Step 5 Preparation of compounds 1-1 and 1-2
- intermediate 1 80.0 mg, 0.23 mmol was dissolved in dry DMF (1.5 mL), and HOBt (62.16 mg, 0.46 mmol), EDCI (88.18 mg, 0.46 mmol) and DIPEA (118.90) were added in sequence. mg, 0.92mmol).
- 2e 100.0 mg, 0.23 mmol
- ethyl acetate 80 mL
- wash with water (20 mL ⁇ 2) and saturated brine (20 mL ⁇ 1) and dry over anhydrous sodium sulfate.
- filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 2g (50.0 mg, yield: 28.59%).
- Step 7 Synthesis of Compound 2-1 and Compound 2-2
- Dissolve 3b (1.05g, 2.55mmol) in ethanol (15mL) and water (1.5mL), add lithium hydroxide monohydrate (321mg, 7.65mmol), and react at room temperature for 5h. Concentrate under reduced pressure to remove the solvent, add 20 mL of water to the residue, adjust the pH to about 2-3 with 1N hydrochloric acid, extract the aqueous phase with ethyl acetate (50 mL ⁇ 2), and combine the organic phases. The organic phase was washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was prepared by reverse phase (0.1% trifluoroacetic acid) to obtain 3c (410 mg, yield 42 %).
- intermediate 3 (260 mg, 0.74 mmol, refer to WO2021076890A1 for synthesis steps) was dissolved in dry DMF (10 mL), and EDCI (280 mg, 1.46 mmol), HOBT (200 mg, 1.48 mmol) and DIPEA (290 mg) were added , 2.24mmol).
- EDCI 280 mg, 1.46 mmol
- HOBT 200 mg, 1.48 mmol
- DIPEA 290 mg
- 4g of crude product 250 mg, 0.74 mmol
- react at room temperature overnight add ethyl acetate (80 mL), wash with water (20 mL ⁇ 2) and saturated brine (20 mL ⁇ 1), and dry over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 4h (350 mg, yield: 70.83%)
- the crude product of compound 5 was obtained.
- the crude product of compound 6 was obtained.
- the crude product of compound 7 was obtained.
- the crude product of compound 8 was obtained.
- Dissolve 1a (3.0g, 8.64mmol) in 30mL of ultra-dry DCE, add diethylamine (0.95g, 12.96mmol) and AcOH (0.10mg, 1.73mmol) in sequence, react at room temperature for 1h, add triacetoxy hydroboration Sodium (3.66g, 17.28mmol), the reaction continued for 16h.
- intermediate 1 (300.0 mg, 0.84 mmol) was dissolved in dry DMF (5 mL), and HOBt (227.00 mg, 1.68 mmol), EDCI (322.06 mg, 1.68 mmol) and DIPEA (434.25 mg) were added in sequence. , 3.36mmol).
- HOBt 227.00 mg, 1.68 mmol
- EDCI 322.06 mg, 1.68 mmol
- DIPEA 434.25 mg
- compound 10b (1.0g, 3.54mmol) was dissolved in dry dichloromethane (10mL), and sodium bicarbonate (0.6g, 7.08mmol) and Dess-Martin oxidant (2.25g, 5.31) were added at room temperature. mmol), react at room temperature for 1 hour. Add saturated sodium thiosulfate solution (10mL) and saturated sodium bicarbonate solution (10mL), add dichloromethane for extraction (50mL ⁇ 3), dry with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and obtain by silica gel column chromatography. 10c (0.8g, yield: 80.58%).
- intermediate 3 (189.6 mg, 0.54 mmol) was dissolved in dry DMF (1.5 mL), and HOBt (147.08 mg, 1.090 mmol), EDCI (168.98 mg, 1.09 mmol) and DIPEA (220.3) were added in sequence. mg, 2.18mmol).
- HOBt 147.08 mg, 1.090 mmol
- EDCI 168.98 mg, 1.09 mmol
- DIPEA 220.3
- Step 8 Synthesis of Compound 10-1 and Compound 10-2
- the crude product of compound 12 was obtained.
- intermediate 1 250.0 mg, 0.70 mmol was dissolved in dry DMF (1.5 mL), and HOBt (190 mg, 1.41 mmol), EDCI (270 mg, 1.41 mmol) and DIPEA (270 mg, 2.09) were added in sequence. mmol).
- HOBt 190 mg, 1.41 mmol
- EDCI 270 mg, 1.41 mmol
- DIPEA 270 mg, 2.09
- 14f 270 mg, 0.70 mmol
- react at room temperature overnight add ethyl acetate (80 mL), wash with water (20 mL ⁇ 2) and saturated brine (20 mL ⁇ 1), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 14 g (368 mg, yield: 72.43%).
- the crude product of compound 15 was obtained.
- the crude product of compound 16 was obtained.
- the crude product of compound 17 was obtained.
- the crude product of compound 18 was obtained.
- the crude product of compound 19 was obtained.
- the crude product of compound 20 was obtained by referring to the preparation method of Example 21.
- 6G 400 mg, 0.89 mmol was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and 2.6-dimethyl-4-methoxyphenylboronic acid ( 240mg, 1.33mmol), XPhos Pd G2 (110mg, 0.13mmol), potassium phosphate (570mg, 2.67mmol), react at 100°C for 24h.
- intermediate 3 160 mg, 0.46 mmol was dissolved in dry DMF (8 mL), and HATU (350 mg, 0.92 mmol) and DIPEA (230 mg, 1.81 mmol) were added in sequence. After stirring at room temperature for 40 min, add 21b hydrochloride (185 mg, 0.46 mmol), react at room temperature overnight, add ethyl acetate (80 mL), wash with water (20 mL ⁇ 2) and saturated brine (20 mL ⁇ 1), and then anhydrous After drying over sodium sulfate and filtering, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 21c (240 mg, yield: 71.10%).
- compound 21-A is It is a racemate of four chiral isomers mixed in equal proportions.
- the crude product of compound 22 was obtained.
- the crude product of compound 23 was obtained.
- the crude product of compound 24 was obtained.
- Dissolve 26d (780 mg, 1.87 mmol) in 8 mL THF and 2 mL water, add lithium hydroxide monohydrate (235 mg, 5.61 mmol), and react at room temperature for 3 hours. Use 1N hydrochloric acid to adjust the pH to 5-6, and concentrate under reduced pressure to obtain a crude compound.
- the crude product is passed through a C18 column ((mobile Phase A: acetonitrile, mobile phase B: 0.5% NH 4 HCO 3 aqueous solution, gradient elution of 10% A to 40% B solution)) to obtain 26e (620 mg, 85.36%).
- 26e 155 mg, 0.40 mmol and intermediate 6 (157 mg, 0.40 mmol) were dissolved in dry DMF (3.0 mL), and EDCI (153 mg, 0.80 mmol), HOBT (108 mg, 0.80 mmol) and DIPEA were added. (155mg, 1.20mmol), react at room temperature overnight, add ethyl acetate (80mL), wash with water (20mL ⁇ 2) and saturated brine (20mL ⁇ 1) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , silica gel column chromatography obtained 26f (189 mg, 62.02%).
- Dissolve 26f (189 mg, 0.25 mmol) in 4 mL THF and 1 mL water, add lithium hydroxide monohydrate (32 mg, 0.75 mmol), and react at room temperature for 5 h. Adjust the pH to 5-6 with 1N hydrochloric acid, and concentrate under reduced pressure to obtain the crude compound 26.
- the crude product of compound 27 was obtained.
- the crude product of compound 28 was obtained.
- the crude product of compound 29 was obtained.
- the first step synthesis of 30b
- the crude compound 30 was obtained.
- the crude product of compound 32 was obtained by referring to the preparation method of Example 21.
- the crude compound 33 was obtained by referring to the preparation method of Example 21.
- the crude compound 36 was obtained with reference to the preparation method of Example 35.
- Example 20 a crude compound 37 was obtained.
- the first step synthesis of 38b
- Dissolve 38b (2.8g, 11.28mmol) in dichloromethane (20mL) solution, slowly add NaH (0.54g, 22.5mmol) in batches under ice bath, stir for 20 minutes, add deuterated iodomethane (3.27g , 22.56mmol), react overnight. Add water (20 mL), extract with ethyl acetate (30 ml rate 63.52%).
- the third to sixth steps refer to the preparation method of Example 21 to obtain the crude compound 38.
- the crude compound 39 was obtained.
- the crude product of compound 40 was obtained.
- the crude product of compound 41 was obtained.
- the crude product of compound 42 was obtained.
- the crude product of compound 42 was obtained.
- the crude compound 44 was obtained.
- Dissolve 46b (6.8g, 43.54mmoL) in a mixed solution of 1,4-dioxane and water (5:1, 200mL) at room temperature, add potassium peroxymonosulfonate (40.15g, 65.31mmoL), Reaction at 100°C for 4 hours. Add water and extract with ethyl acetate (50 mL .
- Dissolve 46f (1.8g, 5.32mmoL) in dichloromethane (20mL), slowly add trifluoroacetic acid (10mL, 134.19mmoL), and react at room temperature overnight. Concentrate under reduced pressure, add sodium bicarbonate aqueous solution to adjust the pH to neutral, extract with ethyl acetate (20 mL ⁇ 2 times), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 46 g of crude product, which can be directly Proceed to the next step of the reaction.
- the crude product of compound 47 was obtained.
- the crude product of compound 48 was obtained.
- substrate 49A (5.00g, 24.99mmo) was dissolved in 10% sulfuric acid aqueous solution (50mL), and then sodium nitrite (1.72g, 24.99mmol) was dissolved in water (10mL) and added dropwise to the system. After the addition is completed, continue the reaction in the ice bath for 1 hour; then add 50% sulfuric acid aqueous solution (50 mL) dropwise to the system. After the addition is completed, the temperature is raised to 100°C and the reaction is carried out for 1 hour. Cool the reaction system to room temperature, slowly pour the reaction solution into stirring ice water (300 mL), and continue stirring for 30 minutes.
- Substrate 49B (2.89g, 14.37mmo) was dissolved in acetonitrile (30mL), then potassium carbonate (3.97g, 28.72mmol) and methyl iodide (3.06g, 21.55mmol) were added. After addition, the temperature was raised to React at 60°C for 18 hours. Cool the reaction to room temperature, filter and wash the filter cake with ethyl acetate (5 mL ⁇ 2). Collect and concentrate the filtrate to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain 49C (2.65 g, yield 85.74%).
- Substrate 49C (2.65g, 12.32mmol) was dissolved in ultra-dry tetrahydrofuran (40mL), pre-cooled at -78°C for 10 minutes under a nitrogen atmosphere, n-butyllithium (0.89g, 13.91mmol) was slowly added dropwise, and the addition was completed , continue stirring at -78°C for 1 hour, and then add trimethyl borate (1.71g, 16.47mmol) dropwise to the system. After the addition is completed, the temperature is naturally raised to room temperature for 18 hours of reaction under a nitrogen atmosphere.
- the crude product of compound 49 was obtained.
- the crude product of compound 50 was obtained.
- TBS buffer containing 0.1% BSA Use TBS buffer containing 0.1% BSA to prepare 1ug/ml Biotinylated anti- ⁇ 7 antibody. Wash the plate three times with TBS buffer, add 50ul of antibody, and incubate at room temperature for 1 hour. Wash the plate three times with TBS buffer, add 50ul of Streptavidin-HRP, and incubate at room temperature for 20 minutes. Wash the plate three times with TBS buffer, add 50ul of TMB substrate, and incubate at room temperature for 5-30 minutes. Finally, add 25 ul of stop buffer (high-concentration phosphate solution), and read the OD value of the plate at 450 nm on a microplate reader. IC 50 values were calculated using GraphPad Prism 6 software.
- the compounds of the present invention have good inhibitory activity against integrin ⁇ 4 ⁇ 7.
- TBS buffer to prepare MAdCAM-1 to a final concentration of 2 ⁇ g/ml, transfer 50 ⁇ l of the solution to a 96-well plate, and coat at 4°C overnight. The plate was washed three times with TBS buffer, then 150 ⁇ l of blocking solution (TBS buffer containing 1% BSA) was added, and blocked at 37°C for 1 h.
- Collect RPMI8866 cells wash them twice with DPBS buffer, then resuspend the cells in TBS buffer to 4 ⁇ 10 5 cells/ml, transfer 50 ⁇ l of cell solution to a 96-well plate, so that the cell density is 2 ⁇ 10 5 cells/well , then add 1 ⁇ l of compounds of different concentrations or DMSO, and incubate at 37°C for 1 hour or 2 hours.
- VCAM coating buffer Prepare VCAM coating buffer to a final concentration of 0.5 ⁇ g/ml, transfer 50 ⁇ l of the solution to a 96-well plate, and coat at 4°C overnight. Wash the plate three times with coating buffer, then add 150 ⁇ l of blocking solution (coating buffer containing 1% BSA), and block at 37°C for 1 hour. Collect Jurkat cells, wash them twice with DPBS buffer, then resuspend the cells in buffer to 4 ⁇ 10 6 cells/ml, transfer 50 ⁇ l of cell solution to a 96-well plate, so that the cell density is 2 ⁇ 10 5 cells/well. Then add 1 ⁇ l of test compounds or DMSO at different concentrations and incubate at 37°C for 1 h.
- control compound A is
- the compounds of the present invention have good inhibitory effects on cell adhesion mediated by integrin ⁇ 4 ⁇ 7, and have better selectivity than the control compound A.
- the purpose of this study was to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP).
- the specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
- Test animals male BALB/c mice, 20-25g, 6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
- mice On the day of the experiment, 6 BALB/c mice were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
- Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline
- gastric administration vehicle 5% DMSO+95% (20% SBE- ⁇ -CD in saline)
- DMA dimethylacetamide
- Solutol polyethylene glycol-15-hydroxystearate
- Saline physiological saline
- DMSO Dimethyl sulfoxide
- SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
- the compounds of the present invention such as the example compounds, have better oral absorption performance and lower clearance rate in mice.
- Test animals male SD rats, about 220g, 6 to 8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
- Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline
- gastric administration vehicle 5% DMSO+95% (20% SBE- ⁇ -CD in saline)
- DMA dimethylacetamide
- Solutol polyethylene glycol-15-hydroxystearate
- Saline physiological saline
- DMSO Dimethyl sulfoxide
- SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
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Abstract
一种通式(I)所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与整合素α4β7活性或表达量相关疾病的药物中的应用。
Description
本发明涉及一种通式(I)所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与整合素α4β7活性或表达量相关疾病的药物中的应用。
整合素家族由α(120-185KD)和β(90-110KD)两个亚基单位形成的二聚体。哺乳动物种共18种α亚基和8种β亚基。按照不同的组合可以构成20余种整合素。α4β7是整合素/整联蛋白(integrin)家族成员之一,目前已经确定与α4β7有关的肠道炎症疾病包括克罗恩病(Crohn's disease),溃疡性结肠炎(ulcerative colitis)等。α4β7的主要配体为黏膜地址素细胞粘附分子(mucosal addressin cell adhesion molecule-1,MADCAM-1)。MAdCAM-1是选择性表达于黏膜淋巴器官高内皮静脉和肠道固有层静脉的一种跨膜糖蛋白分子。炎症情况下,多种细胞因子可以促进内皮细胞高表达MAdCAM-1,然后MAdCAM-1介导表达α4β7的白细胞向炎症部位迁移。无论是靶向整合素α4β7或者是MAdCAM-1都可以减轻肠道炎症程度。目前市场上并没有针对α4β7所介导炎症的特异性小分子化合物,临床上使用的Natalizumab是一种人源化的单克隆抗体,靶点为α4亚基,主要用于治疗多发性硬化症和克罗恩病,但在临床使用过程中出现过PML(进行性多灶性白质脑病)副作用。因此,有必要开发一种能够抑制整合素α4β7蛋白的小分子化合物,用于治疗与整合素α4β7活性或表达量相关的疾病。
发明内容
本发明开发了一种结构新颖的、药效好、α4β1/α4β7选择性更好、肝微粒体稳定性更好、更安全、无明显的hERG或CYP抑制活性的整合素α4β7抑制剂,这些化合物具有良好的药代动力学性能和良好的安全性,用于治疗与整合素α4β7相关疾病如肠道炎症疾病。
本发明的目的就是提供一种能够抑制整合素α4β7的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与整合素α4β7活性或表达量相关疾病的药物中的应用。
本发明提供一种通式(I)所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
在一些实施方案中,R1选自-CHR1aR1b或-NR1aR1b;
在一些实施方案中,R1选自
b选自0、1、2、3;
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,R1选自
在一些实施方案中,Rb1选自H、F、CH2F、CHF2、CF3、甲基、-CH2CH2N(CH3)2;
在一些实施方案中,Rb2、Rb各自独立地选自Rba、或任选取代的如下基团之一:乙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2-苯基、-CH2-吡啶基、-CH2CH2-苯基、-CH2CH2-吡啶基、当被取代时,被1至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
在一些实施方案中,Rb2、Rb各自独立地选自Rba、
在一些实施方案中,Rba选自
在一些实施方案中,Rb1选自H、C1-4烷基、C3-6环烷基,所述的烷基或者环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代;
在一些实施方案中,Rb2选自H、Rba、取代或者未取代的如下基团之一:C1-4烷基、C2-4炔基、C1-4烷氧基、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基,所述的CH2、烷基、环烷基或杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,R1a选自C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代;
在一些实施方案中,R1a选自甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、-CH2-环丙基、-CH2-环丁基;
在一些实施方案中,R1a选自
在一些实施方案中,R1b选自C4-10碳环、5至10元杂环,所述的碳环或者杂环任选被0至4个Rb取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-6烷基、-C0-4烷基-N(C1-6烷基)2、C1-6烷基、C2-6炔基、C1-6烷氧基、-C0-4烷基-C3-10碳环、-C0-4烷基-3至10元杂环或Rba,所述的烷基、炔基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、N(C1-6烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-4烷基、-C0-4烷基-N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、-C0-4烷基-C3-6碳环、-C0-4烷基-3至7元杂环或Rba,所述的烷基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rb选自Rba;
在一些实施方案中,Rb各自独立的选自氘、卤素、OH、=O、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、苯基、5至6元杂芳基、-CH2NHC1-4烷基、-CH2N(C1-4烷基)2、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、C3-6环烷基、3至7元杂环烷基、-CH2-C3-6环烷基、-CH2-3至7元杂环烷基、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基或Rba,所述的CH2、烷基、炔基、环烷基或杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rb各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基,当被取代时,被0至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的或Rk取代基所取代;
在一些实施方案中,Rb各自独立的选自氘、F、Cl、Br、OH、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-
氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基,当被取代时,被0至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
在一些实施方案中,Rb选自Rb2;
在一些实施方案中,Rba选自-C0-4烷基-7至12元杂环、-C0-4烷基-通过碳原子连接的4至6元杂环,、所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rba选自-C0-2烷基-7至8元单环杂环烷基、-C0-2烷基-7至11元螺环杂环烷基、-C0-2烷基-7至11元桥环杂环烷基、-C0-2烷基-通过碳原子连接的4至6元单环杂环烷基、所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rba选自7至8元单环杂环烷基、7至11元螺环杂环烷基、7至11元桥环杂环烷基、通过碳原子连接的4至6元单环杂环烷基、-CH2-7至8元单环杂环烷基、-CH2-7至11元螺环杂环烷基、-CH2-7至11元桥环杂环烷基、-CH2-通过碳原子连接的4至6元单环杂环烷基、-CH2CH2-7至8元单环杂环烷基、-CH2CH2-7至11元螺环杂环烷基、-CH2CH2-7至11元桥环杂环烷基、-CH2CH2-通过碳原子连接的4至6元单环杂环烷基、
所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rba选自任选取代的如下基团之一:
当被取代时,任选被1至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、
NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代;
在一些实施方案中,Rba选自任选取代的如下基团之一:
当被取代时,任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
在一些实施方案中,Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-6烷基、-C1-4烷基-N(C1-6烷基)2、-C0-4烷基-C3-10碳环或-C0-4烷基-3至10元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rk选自-C1-2烷基-NH2、-C1-2烷基-NHC1-4烷基、-C1-2烷基-N(C1-4烷基)2、-C0-2烷基-C3-6碳环或-C0-2烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-4烷基、-C1-4烷基-N(C1-4烷基)2、-C0-4烷基-C3-6碳环或-C0-4烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、或环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基任选被1至4个选自氘、卤素、OH、=O、氰基、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代;
在一些实施方案中,Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、
CH2F、CHF2、CF3、甲基、乙基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基的取代基所取代;
在一些实施方案中,R2选自C1-6烷基、C6-10芳环、5至10元杂芳环、C3-10碳环、5至10元杂环,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,R2选自C1-4烷基、苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-10非芳香碳环、5至10元非芳香杂环、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;
在一些实施方案中,R2选自苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-6环烷基、3至7元杂环烷基、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环烷基含有1至4个选自O、S、N的杂原子;在一些实施方案中,R2选自苯环、吡啶基、吡啶酮基、吡嗪基、嘧啶基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、
所述R2任选被0至4个R2a取代;在一些实施方案中,R2选自p1选自0、1、2、3或4;
在一些实施方案中,R2选自选自
在一些实施方案中,R2选自苯基、吡啶基、吡啶酮基、氮杂环戊基、吗啉基、所述R2任选被0至4个选自氘、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;
在一些实施方案中,R2选自
所述R2任选被1至4个选自氘、CD3、-OCD3、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;
在一些实施方案中,R2选自
在一些实施方案中,R2选自在一些实施方案中,R2选自
在一些实施方案中,R2选自
在一些实施方案中,R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
在一些实施方案中,R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
在一些实施方案中,R2a选自氘、卤素、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或者4至6元杂环烷基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、烯基、炔基、烷氧基、环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;
在一些实施方案中,R2a各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基,所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;
在一些实施方案中,R2a选自氘、F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基;
在一些实施方案中,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;
在一些实施方案中,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;
在一些实施方案中,R2a与R2a直接连接形成4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基(如F、Cl、Br、I、OH、氰基)所取代;
在一些实施方案中,R3选自H、C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6碳环的取代基所取代;
在一些实施方案中,R3选自H、C1-4烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环的取代基所取代;
在一些实施方案中,R3选自H、C1-4烷基,所述的烷基任选0至4个选自氘、卤素、C1-4烷基、C1-4烷氧基、苯环的取代基所取代;
在一些实施方案中,R3选自H、甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、苄基;
在一些实施方案中,环A选自C8-10并环碳环(如苯并C4-6元碳环),所述的环A任选被0至4个Ra5取代;在一些实施方案中,环A选自所述环A任选被0至4个Ra5取代;在一些实施方案中,环A选自
在一些实施方案中,环A选自所述环A被1个选自C2-6烯基或C2-6炔基的取代基所取代、任选被1至3个选自Ra5取代;在一些实施方案中,环A选自所述环A被1个Rak取代,任选被1至3个选自Ra5取代;在一些实施方案中,环A选自环A任选被1至3个选自Ra5取代;
在一些实施方案中,Rak选自C2-4炔基(例如乙炔基、丙炔基、炔丙基)
在一些实施方案中,环A选自所述环A被1个选自乙烯基、乙炔基、丙炔基、炔丙基的取代基所取代,任选被1至3个选自Ra5取代;
在一些实施方案中,Ra5选自卤素、OH、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
在一些实施方案中,Ra5选自卤素、OH、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
在一些实施方案中,Ra5选自卤素、OH、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代;
在一些实施方案中,Ra5各自独立的选自F、Cl、Br、I、OH、CN、乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基,所述的乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基任选被1至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代
在一些实施方案中,Ra5各自独立的选自F、Cl、Br、I、OH、CN、乙炔基、甲基、乙基;
在一些实施方案中,Ra5各自独立的选自H、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、卤素取代的C1-6烷基、氰基取代的C1-6烷基、C1-6烷氧基、C3-6环烷基;
在一些实施方案中,Ra5各自独立的选自H、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基;
在一些实施方案中,Ra5各自独立的选自F、Cl、Br、OH、氰基、CF3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基;
在一些实施方案中,环A选自左上方与R2直接连接,p2选自0、1或2;
在一些实施方案中,R1b选自
在一些实施方案中,R1b选自
在一些实施方案中,Rb1各自独立的选自H、卤素、CN、C1-6烷基、C3-6环烷基,所述的烷基或环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-6烷基、N(C1-6烷基)2、C1-4烷基、C1-6烷氧基的取代基所取代;
在一些实施方案中,Rb1各自独立的选自H、卤素、CN、C1-4烷基、C3-6环烷基,所述的烷基或环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代;
在一些实施方案中,化合物不为表E-2所示结构及其立体异构体;
在一些实施方案中,通式(I)示的化合物选自通式(I-a)、(I-b)、(I-a-1)、(I-b-1)所示的化合物,
在一些实施方案中,通式(I)示的化合物选自通式(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)所示的化合物,
在一些实施方案中,通式(I-a)、(I-b)、(I-a-1)、(I-b-1)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中R2a、R1a、Rak、Ra5、Rb2、Rb1、R3定义与前述任意一种实施方案相同;
在一些实施方案中,通式(I-a)、(I-b)中环A的定义与前述环A的任意一种实施方案相同;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-a-1)、(I-b-1)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中p1选自0、1、2、3或4;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-a-1)、(I-b-1)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中R2a选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或者4至6元杂环烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-a-1)、(I-b-1)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中R1a选自
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-a-1)、(I-b-1)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中Rb1选自H、C1-4烷基、C3-6环烷基,所述的烷基或者环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中Rb1选自H、F、CH2F、CHF2、CF3、甲基、-CH2CH2N(CH3)2;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中Rb2选自H、Rba、取代或者未取代的如下基团之一:C1-4烷基、C2-4炔基、C1-4烷氧基、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基,所述的CH2、烷基、环烷基或杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;
在一些实施方案中,通式式(I)、(I-a)、(I-b)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中Rb2选自H、Rba、取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉,当被取代时,被1、2或3个选自氘、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、Rk的取代基所取代;
在一些实施方案中,通式(I-a)、(I-b)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中的Rba、Rk的定义与前述任意一种实施方案相同;
在一些实施方案中,通式(I)、(I-a)、(I-b)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中R2a选自氘、-CD3、-OCD3、F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基;
在一些实施方案中,通式(I)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中p2选自0、1或2;
在一些实施方案中,通式(I)、(I-g)、(I-g-1)、(I-i)、(I-i-1)中Rak选自C2-4炔基;
在一些实施方案中,通式(I)、(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)中Ra5选自F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基、乙炔基;
在一些实施方案中,通式(I)中n1选自1、2或3。
作为本发明的第一种实施方案,前述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1选自-CHR1aR1b或-NR1aR1b;
R1a选自C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代;
R1b选自C4-10碳环、5至10元杂环,所述的碳环或者杂环任选被0至4个Rb取代,所述的杂环含有1至4个选自O、S、N的杂原子;
Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-6烷基、-C0-4烷基-N(C1-6烷基)2、C1-6烷基、C2-6炔基、C1-6烷氧基、-C0-4烷基-C3-10碳环、-C0-4烷基-3至10元杂环或Rba,所述的烷基、炔基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、N(C1-6烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
Rba选自-C0-4烷基-7至12元杂环、-C0-4烷基-通过碳原子连接的4至6元杂环、
所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、
C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-6烷基、-C1-4烷基-N(C1-6烷基)2、-C0-4烷基-C3-10碳环或-C0-4烷基-3至10元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
R2选自C1-6烷基、C6-10芳环、5至10元杂芳环、C3-10碳环、5至10元杂环,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;
R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
作为选择,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;
R3选自H、C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6碳环的取代基所取代;
环A选自C8-10并环碳环,所述的环A任选被0至4个Ra5取代;
或者环A选自所述环A被1个选自C2-6烯基或C2-6炔基的取代基所取代、任选被1至3个Ra5取代;
Ra5选自卤素、OH、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子。
作为本发明的第二种实施方案,前述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1选自
b选自0、1、2、3;
Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-4烷基、-C0-4烷基-N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、-C0-4烷基-C3-6碳环、-C0-4烷基-3至7元杂环或Rba,所述的烷基、炔基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
Rba选自-C0-2烷基-7至8元单环杂环烷基、-C0-2烷基-7至11元螺环杂环烷基、-C0-2烷基-7至11元桥环杂环烷基、-C0-2烷基-通过碳原子连接的4至6元单环杂环烷基、
所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
Rk选自-C1-2烷基-NH2、-C1-2烷基-NHC1-4烷基、-C1-2烷基-N(C1-4烷基)2、-C0-2烷基-C3-6碳环或-C0-2烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;
R2选自C1-4烷基、苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-10非芳香碳环、5至10元非芳香杂环、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;
R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
作为选择,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;
R3选自H、C1-4烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环的取代基所取代;
环A选自苯并C4-6碳环,所述的环A任选被0至4个Ra5取代;
或者环A选自所述环A被1个选自C2-4烯基或C2-4炔基的取代基所取代、任选被1至3个选自Ra5取代;
Ra5选自卤素、OH、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;
其余取代基的定义与本发明方案一一致。
作为本发明的第三种实施方案,前述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
Rb各自独立的选自氘、卤素、OH、=O、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、苯基、5至6元杂芳基、-CH2NHC1-4烷基、-CH2N(C1-4烷基)2、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、苯基、5至6元杂芳基、C3-6环烷基、3至7元杂环烷基、-CH2-苯基、-CH2-5至6元杂芳基、-CH2-C3-6环烷基、-CH2-3至7元杂环烷基、-CH2CH2-苯基、-CH2CH2-5至6元杂芳基、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基、Rba,所述的CH2、烷基、炔基、苯基、杂芳基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;
Rba选自7至8元单环杂环烷基、7至11元螺环杂环烷基、7至11元桥环杂环烷基、通过碳原子连接的4至6元单环杂环烷基、-CH2-7至8元单环杂环烷基、-CH2-7至11元螺环杂环烷基、-CH2-7至11元桥环杂环烷基、-CH2-通过碳原子连接的4至6元单环杂环烷基、-CH2CH2-7至8元单环杂环烷基、-CH2CH2-7至11元螺环杂环烷基、-CH2CH2-7至11元桥环杂环烷基、-CH2CH2-通过碳原子连接的4至6元单环杂环烷基、所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-4烷基、-C1-4烷基-N(C1-4烷基)2、-C0-4烷基-C3-6碳环或-C0-4烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、
N的杂原子;
R2选自苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-6环烷基、3至7元杂环烷基、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环烷基含有1至4个选自O、S、N的杂原子;
R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、烯基、炔基、烷氧基、环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;
作为选择,R2a与R2a直接连接形成4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;
R3选自H、C1-4烷基,所述的烷基任选0至4个选自氘、卤素、C1-4烷基、C1-4烷氧基、苯环的取代基所取代;
环A选自所述环A任选被0至4个Ra5取代;
或者环A选自所述环A被1个选自C2-4烯基或C2-4炔基的取代基所取代、任选被1至3个选自Ra5取代;
Ra5选自卤素、OH、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代;
其余取代基的定义与本发明方案一或二中的任一种相同。
作为本发明的第四种实施方案,前述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1a选自甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、-CH2-环丙基、-CH2-环丁基;
Rb各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2-苯基、-CH2-吡啶基、-CH2CH2-苯基、-CH2CH2-吡啶基,当被取代时,被0至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4
烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代;
Rba选自任选取代的如下基团之一:
当被取代时,任选被1至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代;
Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基任选被1至4个选自氘、卤素、OH、=O、氰基、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代;
R2选自苯环、吡啶基、吡啶酮基、吡嗪基、嘧啶基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、
所述R2任选被0至4个R2a取代;
R2a各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基,所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;
R3选自H、甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、苄基;
环A选自所述环A任选被0至4个Ra5取代;
或者环A选自所述环A被1个选自乙烯基、乙炔基、丙炔基、炔丙基的取代基所取代、任选被1至3个选自Ra5取代;
Ra5各自独立的选自F、Cl、Br、I、OH、CN、乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基,所述的乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基任选被1至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代;
其余取代基的定义与本发明方案一、二或三中的一种相同。
作为本发明的第五种实施方案,前述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1选自
Rb各自独立的选自氘、F、Cl、Br、OH、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2-苯基、-CH2-吡啶基、-CH2CH2-苯基、-CH2CH2-吡啶基、当被取代时,被0至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、
乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
Rba选自任选取代的如下基团之一:
当被取代时,任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基的取代基所取代;
R2选自苯基、吡啶基、吡啶酮基、氮杂环戊基、吗啉基、所述R2任选被0至4个选自氘、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;
或者R2选自
所述R2任选被1至4个选自氘、CD3、-OCD3、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;
环A选自
其余取代基的定义与本发明方案一、二、三或四中的一种相同。
作为本发明的第六种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1选自
或者R1选自
或者R1选自
或者R1选自
或者R1选自
或者R1选自
或者R1选自
R2选自
或者R2选自
或者R2选自
R1a选自
其余取代基的定义与本发明方案一、二、三、四或五中的一种相同。
作为本发明的第七种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-a)、(I-b)、通式(I-a-1)、(I-b-1)所示的化合物,
环A、R3的定义与本发明实施方案中的二、三、四、五或六中任意一项相同;
p1选自0、1、2、3或4;
R2a选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或者4至6元杂环烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;
R1a选自
Rb1选自H、C1-4烷基、C3-6环烷基,所述的烷基或者环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代;
Rb2选自H、Rba、取代或者未取代的如下基团之一:C1-4烷基、C2-4炔基、C1-4烷氧基、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基,所述的CH2、烷基、环烷基或杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;
n1选自1、2或3;
Rba、Rk的定义与本发明实施方案中的二、三、四、五或六中任意一项相同。
作为本发明的第八种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-a)、(I-b)、(I-a-1)、(I-b-1)所示的化合物,
R2a选自氘、CD3、-OCD3、F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基;
Rb1选自H、F、CH2F、CHF2、CF3、甲基、-CH2CH2N(CH3)2;
Rb2选自H、Rba、取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉,当被取代时,被1、2或3个选自氘、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;
其余基团的定义与本发明实施方案七相同。
作为本发明的第九种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)所示的化合物:
R1b选自
p2选自0、1或2;
Rak选自C2-4炔基;
Ra5定义与本发明第一、二、三或四种实施方案中任一种相同;
其余基团定义与本发明第七或八种实施方案中任一种相同。
作为本发明的第十种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)所示的化合物
Rak选自乙炔基、丙炔基、炔丙基;
Ra5选自F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基、乙炔基;
其余基团定义与本发明第九种实施方案相同。
作为本发明的第十种实施方案,上述通式(I)所示的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-j)或(I-k)
Ra6选自H或F;
R2选自苯基或所述R2任选被1至4个选自卤素、C1-4烷基、C1-4烷氧基、1至4个卤素取代的C1-4烷基、1至4个卤素取代的C1-4烷氧基、1至4个氘取代C1-4烷基、1至4个氘取代C1-4烷氧基的取代基所取代,优选
Rb1选自CH2F、CHF2、CF3、甲基;优选CF3;
Rb2选自-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-吗啉基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、所述Rb2任选被被1至4个选自氘、F、Cl、Br、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、甲氧基、乙氧基、-CH2-环丙基、的取代基所取代;优选
本发明涉及通式(I)的一些具体化合物,该化合物选自表E-1。
本发明涉及通式(I)的一些具体化合物,该化合物选自表E-3、表E-4、表E-5。
表E-1
表E-2
表E-3
表E-4
表E-5
本发明涉及一种药物组合物,包括本发明所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及要学上可接受的载体。
本发明涉及一种本发明所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与α4β7活性或表达量相关疾病的药物中的应用,优选用于制备肠道炎症疾病药物中的应用。
本发明涉及一种药物组合物或药物制剂,所述的药物组合物或药物制剂包含治疗有效量的本发明所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和药用赋型剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。
本发明还提供一种用于治疗哺乳动物的疾病的方法,其包括向所述哺乳动物给予治疗有效量的本发明所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或药物组合物。一些实施方案中,本发明中所述哺乳动物包括人。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物,其将在某种程度上缓解所治疗的疾病或病症(例如肠道炎症疾病)的一种或多种症状。在一些实施方案中,结果是减少和/或缓和疾病的体征、症状或原因,或生物***的任何其它希望改变。例如,针对治
疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。
在一些实施方案中,该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
一种用于治疗哺乳动物的疾病的方法,所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,治疗有效量优选1-1500mg,所述的疾病优选肠道炎症疾病。
一种用于治疗哺乳动物的疾病的方法所述方法包括,将药物本发明化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1000mg/天的日剂量给予受试者,所述日剂量可以为单剂量或分剂量,在一些实施方案中,日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天,在一些实施方案中,日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。
本发明涉及一种试剂盒,该试剂盒可以包括单剂量或多剂量形式的组合物,该试剂盒包含本发明化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,本发明化合物的或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
本发明化合物的合成方法:
通式化合物(Z-1)与通式化合物(Z-2)通过偶联或取代反应得到通式化合物(Z-3);
通式化合物(Z-3)脱除保护基得到通式化合物(Z-4);
通式化合物(Z-4)与通式化合物(Z-5)通过偶联或取代反应得到通式化合物(I)
Rm1选自Boc;Cbz;叔丁基亚磺酰基等;
Rm2,Rm3各自独立选自H、Cl、Br、I、OTf、B(OH)2,硼酸酯基,烷基取代的锡基等;
Rm4选自Cl、Br、I、OH等;
其余基团的定义与上述通式(I)中任意一种实施方案中相同。
除非有不同的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;所述的烷基任选被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“亚烷基”是指直链和支链的二价饱和烃基,包括-(CH2)v-(v为1至10的整数),亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等;所述的亚烷基任选被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“环烷基”是指一价饱和的碳环烃基,通常有3至12个碳原子,包括了单环环烷基、并环环烷基、螺环环烷基或桥环环烷基,非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基任选被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“烯基”是指直链和支链的一价不饱和烃基,其具有至少1个,通常有1、2或3个碳碳双键,主链包括2至10个碳原子,进一步优选2至6个碳原子,更优选在主链上有2至4个碳原子,烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、
1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等;所述的烯基任选被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“炔基”是指直链和支链的不饱和烃基,其具有至少1个,通常有1、2或3个碳碳三键,主链包括2至10个碳原子,进一步优选2至6个碳原子,更优选在主链上有2至4个碳原子,炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等;所述的炔基任选被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的炔基,其定义与本定义一致。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷氧基任选被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,碳环基可以连接在芳香环上或者非芳香环上,芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、
所述的碳环任选被0至5个选自F、Cl、Br、I、=O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接在芳香环上或者非芳香环上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪
唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、
所述的杂环基任选被0至5个选自F、Cl、Br、I、=O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“杂环烷基”是指取代的或未取代的饱和的杂环基,可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基,杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上,非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、吗啉基。所述的杂环烷基任选被0至5个选自F、Cl、Br、I、=O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。
“螺环”是指取代的或未取代的单环之间共用一个原子(称螺原子)的5至20元多环基团,其可以包含0至5个双键,且可以含有0至5个选自N、O或S(=O)n的杂原子(n选自0、1或2)。优选为6至14元,进一步优选为6至12元,更优选6至10元,其非限定性实例包括:
“并环”是指***中的每个环与体系中的其他环共享毗邻的一对原子的多环基团,其中一个或多个环可以含有0个或多个双键,且可以是取代的或未取代,并环体系中的各个环可以含0至5个选自N、S(=O)n或O的杂原子(n选自0、1或2)。优选为5至20元,进一步优选为5至14元,更有选5至12元,再进一步优选5至10元。非限定性实例包括:
“桥环”是指任意两个不直接连接的原子的多环基团,可以含有0个或多个双键,且可以是取代的或未取代的,桥环体系中的任意环可以含0至5个选自N、S(=O)n或O杂原子或基团(其中n为0、1、2)。环原子包含5至20个原子,优选为5至14个原子,进一步优选5至12个,在进一步优选5至10个。非限定性实例包括
和金刚烷。本文中出现的桥环,其定义与本定义一致。
“碳螺环”、“螺环碳环基“、“螺碳环基“或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。
“碳并环”、“并环碳环基“、“并碳环基“或者“碳并环基”是指环体系仅有碳原子组成的“并环”。
“碳桥环”、“桥环碳环基“、“桥碳环基“或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。
“杂单环”、“单环杂环基“或“杂单环基”是指单环体系的“杂环基”或“杂环”
“杂并环”、“杂并环基”“并环杂环基“或“并杂环基”是指含有杂原子的“并环”。
“杂螺环”、“杂螺环基”、“螺环杂环基“或“螺杂环基”是指含有杂原子的“螺环”。
“杂桥环”、“杂桥环基”、“桥环杂环基是指含有杂原子的“桥环”。
“芳基”或“芳环”是指具有单环或稠合环的一价芳香族烃基,通常有6至12个碳原子,且可以是取代的或未取代的。本文中出现的芳基或芳环,其定义与本定义一致。
“杂芳基”是指取代或未取代的5至15元芳香环,且含有1至5个选自N、O或S(=O)n杂原子或基团,优选5至10元杂芳香环,进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含
“含有1至4个选自O、S、N的杂原子”是指含有1、2、3或4个选自O、S、N的杂原子。
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代,取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、
氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环基、Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代,X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选被0至4个选自H或F的取代基所取代”是指杂桥环任选被0、1、2、3或4个选自H或F的取代基所取代。
X-Y元的环(X选自小于Y大于等于3的整数,Y选自4至12之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环,“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“动物”是指包括哺乳动物,例如人、陪伴动物、动物园动物和家畜,优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
为了完成本发明的目的,根据本领域技术人员已知的有机合成技术,从市售的化学品和/或化学文献中描述的化合物开始,制备本文所述反应中使用的化合物“商业上可用的化学品”是从标准的商业来源获得的,包括上海阿拉丁生化科技股份有限公司,上海麦克林生化科技有限公司,Sigma-Aldrich,阿法埃莎(中国)化学有限公司,梯希爱(上海)化成工业发展有限公司,安耐吉化学,上海泰坦科技股份有限公司,科龙化工,百灵威科技有限公司等。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以
10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
Boc:叔丁氧基羰基;Ts:对甲苯磺酰基;Cbz:苄氧羰基;TMS:三甲基硅基;
TIPS:三异丙基硅基;Bpin:嚬哪醇硼酸酯;MOM:亚甲基甲醚;THF:四氢呋喃
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐;
PdCl2(dppf):CAS 72287-26-4。XPhos Pd G2:CAS 1310584-14-5
化学键旁边*代表手性原子的手性为R或S;
保留时间(Rt,retention time):实施例中无特殊说明,为分析方法的保留时间,方法如下所示:
检测波长:254nm/210nm 流速:1.0ml/min 柱温:35℃
进样量:2μl 采集时间:10min
梯度洗脱程序:
酸性条件:流动相A为0.05%TFA溶液,流动相B为乙腈
色谱柱品牌:月旭,色谱柱型号:Xtimate C18 4.6*50mm,3μm
仪器型号1:岛津LC-20AT,仪器编码:CH-Y-J0460
仪器型号2:安捷伦1260Infinity,仪器编码:CH-Y-J0692
制备HPLC(prep-HPLC)的具体方法如下:方法1:仪器:waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm);(流动相组成:流动相A:乙腈,流动相B:水(含0.1%醋酸铵)。方法2:仪器:waters 2767制备色谱柱:SunFire@Prep C18(19mm×150mm);(流动相组成:流动相A:乙腈,流动相B:水(含0.1%三氟乙酸。
中间体1:中间体1的制备
第一步:1B的合成
氮气保护下,将中间体1a(6.3g,39.34mmol)溶于二氯甲烷(150mL)中,加入无水氯化铝(13.11g,98.35mmol)。室温反应5min后,加入单质溴(8.80g,55.08mmol)的二氯甲烷(50mL)溶液,室温反应2h。将反应液倒入冰水(200mL)中,加入二氯甲烷(100mL),饱和食盐水(80mL)洗涤,无水硫酸钠干燥,过滤浓缩,经硅胶柱层析得1B(8.0g,85.05%)。
LC-Ms m/z(ESI):241.1[M+H]+
第二步:1C的合成
将1B(8.1g,33.88mmol)溶于DME(100mL)中,加入1M次氯酸钠溶液(188mL)和10N的氢氧化钠溶液(18.5mL),50℃反应1h。加入水(150mL),用***(200mL)萃取,水相用盐酸调pH为1-2,用***萃取(150ml×2),合并有机相,经无水硫酸钠干燥、浓缩得到1C(7.6g,93.05%)。
LC-Ms m/z(ESI):240.9[M+H]+
第三步:1D的合成
将1C(7.6g,31.52mmol)溶于甲醇(50mL)中,加入二氯亚砜(11.25g,94.56mmol),70℃反应2h。减压浓缩,经硅胶柱层析得1D(8.0g,99.49%)。
LC-Ms m/z(ESI):255.0[M+H]+
第四步:1E的合成
在氮气保护下,将1D(2g,7.84mmol),4-氟2,6-二甲基苯硼酸(2.63g,15.68mmol),碳酸铯(7.66g,23.52mmol)加入到1,4-二氧六环(30.0mL)和水(3.0mL)中,加入Pd(PPh3)4(1.81g,1.57mmol),100℃封管反应5h。冷却至室温后,硅藻土过滤,加入乙酸乙酯(50mL),依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱快速层析得到1E(2.2g,收率:94.05%)。
第五步:1F的合成
在氮气保护下,将1E(2.13g,7.14mmol)溶于干燥的THF(30mL)中,0℃缓慢加入四氢锂铝(406mg,10.71mmol),室温反应1h。加入10%的硫酸钠水溶液(20mL),过滤,减压除去溶剂,得到粗品1F。
第六步:1g的合成
在氮气保护下,将粗品1F(1.87g,6.92mmol)溶于干燥的二氯甲烷(35mL)中,室温加入碳酸氢钠(1.16g,13.84mmol)和戴斯-马丁氧化剂(3.81g,9.00mmol),室温反应1h。加入饱和硫代
硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL),加二氯甲烷萃取(50mL×3),无水硫酸钠干燥,过滤,减压除去溶剂,硅胶柱层析得到1G(1.63g,87.68%)。
第七步:1H的合成
在氮气保护下,将1G(1.61g,6.00mmol)和R-叔丁基亚磺酰胺(1.01g,9.00mmol)溶于THF(35mL)中,缓慢加入钛酸四乙酯(2.05g,9.00mmol),45℃反应15h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到1H(1.73g,收率77.61%)。
LC-Ms m/z(ESI):329.3[M+H]+
第八步:1I的合成
将锌粉(915mg,14mmol)加入干燥THF(5mL)中,置换氮气3次,加入CuCl(297mg,3mmol),60℃反应2h。冷却至室温,缓慢加入溴乙酸乙酯(835mg,5mmol),60℃反应1h,冷却至0℃,加入1H(371mg,1mmol)的THF(1mL)溶液,0℃搅拌3h。硅藻土过滤,加入饱和氯化铵溶液(20mL),乙酸乙酯萃取(30ml×3),饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到1I(386mg,收率83.98%)。
LC-Ms m/z(ESI):460.2[M+H]+
第九步:中间体1的合成
将1I(272mg,0.27mmol)溶于THF(2mL)中,加入4N盐酸二氧六环溶液(2mL),室温搅拌3h。减压浓缩得到粗品中间体1。
LC-Ms m/z(ESI):356.3[M+H]+
中间体2:中间体2的制备
第一步:2B的合成
氮气保护下,2A(25g,91.94mmol),CuI(3.5g,18.39mmol),PdCl2(PPh3)2(6.45g,9.19mmol),1-(三甲基硅基)丙炔(9.29g,82.75mmol),氟化铯(41.90g,275.82mmol)溶于THF(250mL)中,60℃反应72h后,减压浓缩,经硅胶柱层析得2B(8.5g,40.02%)。
第二步:2C的合成
氮气保护下,将2B(8.5g,36.79mmol)溶于THF(75mL)中,-78℃加入二异丙基氨基锂(5.91g,55.19mmol),搅拌1h,滴加DMF(5.38g,73.58mmol),搅拌30min。加入饱和氯化铵水溶液(150mL),用乙酸乙酯(200mL×3)萃取,合并有机相,经无水硫酸钠干燥、浓缩得到2C(7.2g,75.55%)。
第三步:2D的合成
在氮气保护下,将2C(7.2g,27.79mmol)和R-叔丁基亚磺酰胺(4.04g,33.35mmol)溶于THF(75mL)中,缓慢加入钛酸四乙酯(9.51g,41.69mmol),45℃反应3h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到2D(6.80g,收率67.55%)。
第四步:2E的合成
将锌粉(17.19g,262.78mmol)加入干燥THF(45mL)中,置换氮气3次,加入CuCl(5.57g,56.31mmol),60℃反应2h。冷却至室温,缓慢加入溴乙酸乙酯(15.67g,93.85mmol),60℃反应1h,冷却至0℃,加入2D(6.8g,18.77mmol)的THF(10mL)溶液,0℃搅拌3h。硅藻土过滤,加入饱和氯化铵溶液(200mL),乙酸乙酯萃取(300ml×3),饱和食盐水洗涤(200mL),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到2E(7.0g,收率82.81%)。
第五步:2F的合成
将2E(3.0g,6.66mmol)溶于二氯甲烷(10mL)中,加入4N盐酸二氧六环溶液(5mL),室温搅拌3h。减压浓缩得到粗品2F。
第六步:2G的合成
在氮气保护下,将粗品2F(2.0g,5.78mmol)溶于干燥二氯甲烷(35mL)中,室温加入三乙胺(1.75g,17.34mmol)和二碳酸二叔丁酯(1.51g,6.94mmol),室温反应3h。减压除去溶剂,硅胶柱柱层析得到2G(1.3g,50.40%)。
第七步:2H的合成
在氮气保护下,将2G(0.45g,1.11mmol)和2,6-二甲基苯基硼酸(0.50g,3.33mmol),磷酸钾(0.47g,2.21mmol),RuPhos Pd G3(0.19g,0.22mmol)溶于DMF(8mL)和水(0.8mL)中,75℃搅拌3h,加入水(20mL),乙酸乙酯萃取(30ml×3),饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到2H(0.3g,收率57.38%)。
第八步:中间体2的合成
将2H(300mg,0.64mmol)溶于二氯甲烷(2mL)中,加入4N盐酸二氧六环溶液(2mL),室温搅拌3h。减压浓缩得到粗品中间体2。
LC-Ms m/z(ESI):372.2[M+H]+
中间体4:
第一步:4A的合成
在氮气保护下,将1a(1.5g,4.32mmol,合成步骤参照WO2021076890A1)和5-氮杂螺[2.4]庚烷(0.42g,4.32mmol)溶于1,2-二氯乙烷(10mL)中,滴加0.5mL乙酸,室温搅拌2h,加入三乙酰氧基硼氢化钠(1.82g,8.64mmol),搅拌16h,减压浓缩后用硅胶柱快速柱层析得到4A(1.0g,收率54.05%)。
LC-Ms m/z(ESI):429.2[M+H]+
第二步:中间体4的合成
将4A(1.0g,2.34mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(112mg,4.68mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩,柱层析得到中间体4(650mg,69.55%)。
LC-Ms m/z(ESI):401.2[M+H]+
中间体5:中间体5的制备
第一步:5A的合成
在氮气保护下,1,4-氧氮杂环庚烷盐酸盐(360mg,2.59mmol)溶于1,2-二氯乙烷(8mL)中,加入DIPEA,室温反应15min,加入1a(0.9g,2.59mmol,合成步骤参照WO2021076890A1)和0.15mL乙酸,室温搅拌1h,加入三乙酰氧基硼氢化钠(820mg,3.86mmol),搅拌16h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到5A(0.49g,收率43.75%)。
LC-Ms m/z(ESI):433.7[M+H]+
第二步:中间体5的合成
将5A(0.72g,1.66mmol)溶于6mL乙醇和0.6mL水中,加入一水氢氧化锂(210mg,4.98mmol),室温反应3h。用1N盐酸调pH为4,减压浓缩,柱层析得到中间体5(530mg,收率:78.95%)。
LC-Ms m/z(ESI):405.6[M+H]+
中间体6:中间体6的制备
第一步:6B的合成
将6A(1720mg,6.96mmol)溶解在三氟乙酸(25mL)中,加入三乙基硅烷(25mL),室温下反应48h后继续加入三乙基硅烷(15mL)搅拌反应过夜。在30℃下减压浓缩,残余物经硅胶柱柱层析分离纯化得化合物6B(1700mg)粗品。
第二步:6C的合成
在氮气保护下,将粗品6B(1700mg,7.29mmol)溶解在干燥的THF(70mL)中,-78℃下缓慢加入二异丙基氨基锂(1.56g,14.58mmol),在该温度下搅拌0.5h后加入干燥的DMF(2.6g,36.45mmol),-78℃继续反应1h,加入氯化铵溶液淬灭反应(50mL)。用乙酸乙酯萃取(80mL×3),无水硫酸钠干燥,过滤,减压除去溶剂,硅胶柱柱层析分离纯化得6C(1.58g,两步收率:83.02%)。
第三步:6D的合成
在氮气保护下,将6C(1580mg,6.05mmol)和R-叔丁基亚磺酰胺(1100mg,9.7mmol)溶于THF(35mL)中,缓慢加入钛酸四乙酯(2070mg,9.07mmol),45℃反应15h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到6D(2100mg,收率95.29%)。
LC-Ms m/z(ESI):364.2[M+H]+
第四步:6E的合成
将锌粉(1.2g,18.34mmol)加入干燥THF(8mL)中,置换氮气3次,加入CuCl(389mg,3.93mmol),60℃反应2h。冷却至室温,缓慢加入溴乙酸乙酯(1.09g,6.55mmol),60℃反应1h,冷却至0℃,加入6D(478mg,1.31mmol)的THF(3mL)溶液,0℃搅拌3h。硅藻土过滤,加入饱和氯化铵溶液(30mL),乙酸乙酯萃取(40mL×3),饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到6E(498mg,收率84.04%)。
LC-Ms m/z(ESI):452.4[M+H]+
第五步:6F的合成
将6E(448mg,0.99mmol)溶于二氯甲烷(3mL)中,加入4N盐酸二氧六环溶液(2.5mL),室温搅拌3h。减压浓缩得到粗品6F的盐酸盐。
LC-Ms m/z(ESI):348.3[M+H]+
第六步:6G的合成
将6F溶于THF(4mL)和水(4mL)中,加入碳酸钠(210mg,1.98mmol),Boc2O(240mg,1.09mmol),室温搅拌3h。加入水(10mL),乙酸乙酯萃取(20mL×3),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到6G(420mg,两步收率86.31%)。
LC-Ms m/z(ESI):350.0[M+H-Boc]+
第七步:6H的合成
在氮气保护下,将6G(230mg,0.51mmol),2,6-二甲基-4-氟苯硼酸(128mg,0.77mmol),磷酸钾(325mg,1.53mmol)加入到1,4-二氧六环(2.5mL)和水(0.25mL)中,加入Xphos-G2-Pd(40mg,0.051mmol),100℃封管反应24h。冷却至室温后,加入乙酸乙酯(40mL),依次用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱快速层析得到6H(210mg,收率83.77%)。
LC-Ms m/z(ESI):392.6[M+H-Boc]+
第八步:中间体6的合成
将6H(210mg,0.43mmol)溶于THF(3mL)中,加入4N盐酸二氧六环溶液(2.5mL),室温搅拌3h。减压浓缩得到粗品中间体6的盐酸盐。
LC-Ms m/z(ESI):392.6[M+H]+
中间体7:中间体7的制备
第一步:7C的合成
氮气保护下,将7A(1.0g,6.92mmol)和7B(2.14g,9.0mmol)溶于超干DMF(42mL)中,加入碳酸钾(1.91g,13.84mmol),氮气氛围80℃反应4h。加入100mL乙酸乙酯稀释体系,加入50mL×3水洗有机相,有机相饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤浓缩,经硅胶柱层析得7C(2.18g,99%)。
LC-Ms m/z(ESI):287.1[M+H]+
第二步:7D的合成
将7C(2g,6.92mmol)和(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(2.06g,10.38mmol)溶于甲苯(30mL)和水(6mL)的混合溶液中,加入碳酸钠(2.2g,20.76mmol)和PdCl2(dppf)(506mg,0.692mmol),氮气氛围100℃反应过夜,加入50mL水稀释体系,加入乙酸乙酯80mL×3萃取,有机相饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤浓缩,经硅胶柱层析得7D(2.27g,99%)。
LC-Ms m/z(ESI):309.1[M+H]+
第三步:7E的合成
将7D(2.27g,6.92mmol)溶于二氯甲烷(50mL)中,加入三氟乙酸(15mL),室温下反应2h。减压浓缩,得到中间体7E的粗品。
LC-Ms m/z(ESI):295.1[M+H]+
第四步:7F的合成
在氮气保护下,将粗品7E溶于1,2-二氯乙烷(20mL)和甲醇(20mL)中,加入3-氟氮杂环丁烷盐酸盐(780mg,10.38mmol)和醋酸(0.5mL),室温搅拌1h,加入三乙酰氧基硼氢化钠(4.38g,20.76mmol),反应过夜。加入100mL水稀释体系,加入饱和碳酸氢钠溶液调节pH=9-10,用二氯甲烷100mL×3萃取,有机相饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤浓缩,经硅胶柱层析得7F(1.25g,两步48%)。
LC-Ms m/z(ESI):354.2[M+H]+
第五步:中间体7的合成
将7F(1.25g,3.54mmol)溶于15mL乙醇和1.5mL水中,加入一水氢氧化锂(446mg,10.62mmol),室温反应3h。用1N盐酸调pH为4,减压浓缩,柱层析得到中间体7(700mg,61%)。
LC-Ms m/z(ESI):362.2[M+H]+
实施例1:化合物1的制备
第一步:1b的制备
在氮气保护下,将1a(3.0g,8.64mmol,合成步骤参照WO2021076890A1)和甲胺盐酸盐(1.16g,17.28mmol)溶于1,2-二氯乙烷(30mL)中,滴加5滴乙酸,室温搅拌2h,加入三乙酰氧基硼氢化钠(3.65g,17.28mmol)继续搅拌16h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到1b(1.0g,收率31.95%)。
LC-Ms m/z(ESI):363.2[M+H]+
第二步:1d的制备
在氮气保护下,将1b(1.0g,2.76mmol)和1c(1.02g,5.52mmol)溶于DMF(30mL)中,碳酸钾(1.14g,8.28mmol),60℃搅拌24h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到1d(1.0g,收率80.08%)。
LC-Ms m/z(ESI):453.2[M+H]+
第三步:1e的制备
将1d(1.0g,2.21mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(112mg,4.68mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩,柱层析得到1e(700mg,74.62%)。
LC-Ms m/z(ESI):425.2[M+H]+
第四步:1f的制备
在氮气保护下,将1e(280mg,0.66mmol)溶于干燥的DMF(1.5mL)中,加入HATU(376mg,0.99mmol)和DIPEA(225mg,1.74mmol)。室温搅拌40min后,加入中间体1(234mg,0.66mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到1f(300mg)
LC-Ms m/z(ESI):762.4[M+H]+
第五步:化合物1-1和1-2的制备
将1f(300mg)溶于3mL THF和1mL水中,加入一水氢氧化锂(45mg,1.08mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物1粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物1-1(15mg,Rt=4.325min,收率5.19%)和化合物1-2(15mg,Rt=4.429min,收率5.19%)。
化合物1-1:
LC-Ms m/z(ESI):734.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.93(s,1H),7.17(s,1H),6.84–6.72(m,4H),5.75(t,1H),5.34–5.28(m,1H),3.54–3.43(m,1H),3.40–3.33(m,2H),3.09–2.95(m,5H),2.95–2.89(m,2H),2.86–2.80(m,2H),2.44–2.36(m,2H),2.19–2.08(m,1H),2.02–1.93(m,4H),1.88(s,3H),1.80(s,4H),1.55–1.41(m,2H),1.01–0.91(m,6H).
化合物1-2:
LC-Ms m/z(ESI):734.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.93(s,1H),7.22(s,1H),6.89(s,1H),6.85(s,1H),6.84–6.79(m,2H),5.73(t,1H),5.31(t,1H),3.53–3.45(m,1H),3.41–3.33(m,3H),3.08–2.95(m,7H),2.89–2.76(m,2H),2.49–2.42(m,2H),2.21–2.09(m,1H),2.06–2.00(m,2H),1.94(s,6H),1.85–1.78(m,3H),1.54–1.45(m,1H),1.38–1.27(m,1H),0.92–0.83(m,6H).
实施例2:化合物2的制备
第一步:2b的合成
在氮气保护下,将2a(6.0g,15.62mmol,合成步骤参照WO2021076890A1)溶于1,4-二氧六环(60mL)和水(6mL)中,依次加入N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(5.8g,18.74mmol),Pd(PPh3)4(1.8g,1.56mmol)和碳酸钾(6.48g,46.86mmol),70℃反应30h。待反应完全结束后,加入乙酸乙酯(180mL)进行萃取,水(50mL×2)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到2b(5.0g,收率:65.79%)。
LC-Ms m/z(ESI):487.3[M+H]+
第二步:2c的合成
在氢气条件下,将2b(5.0g,10.28mmol)溶于甲醇(50mL)中,加入等质量的Pd/C,室温反应2h。过滤除去固体,滤液浓缩,经层析柱纯化得2c(2.5g,产率:49.78%)。
LC-Ms m/z(ESI):489.3[M+H]+
第三步:2d的合成
将2c(480.0mg,0.98mmol)溶于二氯甲烷(5mL)中,加入盐酸-1,4-二氧六环(3mL),反应1h。待反应完全结束后,减压除去溶剂,获得粗品化合物2d。
LC-Ms m/z(ESI):389.2[M+H]+
第四步:2e的合成
将2d(350.0mg,0.90mmol)溶于甲醇(4mL)中,依次加入三乙胺(273.21mg,2.7mmol)和(2,2-二氟环丙基)甲磺酸甲酯(201.07mg,1.08mmol),60℃反应16h。待反应完全结束后,经层析柱纯化得2e(280.0mg,产率:65.02%)。
LC-Ms m/z(ESI):465.90[M+H]+
第五步:2f的合成
将2e(280.0mg,0.60mmol)溶于甲醇(2mL)和水(1mL)中,加入氢氧化锂(28.47mg,1.20mmol),室温反应1-2h。待反应完全结束后,经反相层析柱纯化得2f(100.0mg,产率:37.0%)。
LC-Ms m/z(ESI):451.70[M+H]+
第六步:2g的合成
在氮气保护下,将中间体1(80.0mg,0.23mmol)溶于干燥的DMF(1.5mL)中,依次加入HOBt(62.16mg,0.46mmol)、EDCI(88.18mg,0.46mmol)和DIPEA(118.90mg,0.92mmol)。
室温搅拌40min后,加入2e(100.0mg,0.23mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到2g(50.0mg,收率:28.59%)。
LC-Ms m/z(ESI):788.4[M+H]+
第七步:化合物2-1和化合物2-2的合成
将化合物2g(50.0mg,0.063mmol)溶于1mL甲醇和0.5mL水中,加入一水氢氧化锂(3.02mg,0.13mmol),室温反应30min。用1N盐酸调pH为5-6,减压浓缩得到化合物2粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物2-1的三氟乙酸盐(4.0mg,Rt=5.955min,收率8.36%)和化合物2-2的三氟乙酸盐(3.0mg,Rt=5.989min,收率6.27%)。
化合物2-1的三氟乙酸盐:
LC-Ms m/z(ESI):760.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.16(d,1H),7.81(s,1H),7.16(d,1H),6.83–6.74(m,3H),6.72(d,1H),5.76(t,1H),5.38–5.29(m,1H),4.55–4.45(m,1H),3.77–3.61(m,2H),3.50–3.39(m,1H),3.26–3.10(m,3H),3.04–2.79(m,6H),2.45–2.35(m,2H),2.22–2.07(m,2H),2.04–1.93(m,4H),1.88–1.81(m,4H),1.78(s,3H),1.65(d,1H),1.53–1.41(m,2H),1.04–0.91(m,6H).
化合物2-2的三氟乙酸盐:
LC-Ms m/z(ESI):760.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.87(s,1H),7.23(d,1H),6.91–6.74(m,4H),5.77–5.70(m,1H),5.36–5.24(m 1H),4.56–4.45(m,1H),3.79–3.64(m,2H),3.48–3.39(m,1H),3.26–3.12(m,2H),3.00–2.93(m,2H),2.90–2.76(m,2H),2.49–2.38(m,2H),2.22–1.99(m,5H),1.94(s,6H),1.88–1.78(m,2H),1.77–1.68(m,1H),1.68–1.61(m,2H),1.55–1.43(m,1H),1.37–1.26(m,2H),0.96–0.78(m,6H).
实施例3:化合物3的制备
第一步:3b的制备
将1a(1.4g粗品)、3a(1.2g,7.2mmol)和冰醋酸(220mg,3.6mmol)溶于1,2-二氯乙烷(20mL)中,氮气保护室温搅拌30min,加入三乙酰氧基硼氢化钠(1.5g,7.2mmol)。室温搅拌过夜。加入
50mL乙酸乙酯,依次用水(30mL×1)、饱和食盐水(30mL×1)洗涤,有机层用无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析得到3b(1.05g,产率71%)。
LCMS m/z=413.2[M+H]+
第二步:3c的制备
将3b(1.05g,2.55mmol)溶于乙醇(15mL)和水(1.5mL)中,加入一水合氢氧化锂(321mg,7.65mmol),室温反应5h。减压浓缩除去溶剂,向残留物中加入20mL水,用1N的盐酸调节pH至2-3左右,用乙酸乙酯(50mL×2)萃取水相,合并有机相。有机相用饱和食盐水(30mL×1)洗涤,有机层用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物经反相(0.1%三氟乙酸)制备得到3c(410mg,产率42%)。
LCMS m/z=385.2[M+H]+;
第三步:3d的制备
将3c(0.200g,0.52mmol),中间体1(0.18g,0.52mmol)溶于5mL DMF,在加入HOBT(0.14g,1.04mmol),DIPEA(0.27g,2.05mmol)和EDCI(0.20g,1.04mmol)室温搅拌2h。加入30ml乙酸乙酯,水洗2次(20ml×2),无水硫酸钠干燥,减压浓缩,柱层析得目标化合物3d,黄色油状物(0.21g,产率:55.95%)。
LCMS m/z=722.90[M+H]+;
第四步:化合物3-1和3-2的制备
将3d(0.18g,0.25mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(31.5mg,0.75mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物3粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物3-1(25mg,Rt=4.300min,收率:14%)和化合物3-2(30mg,Rt=4.398min,收率:17%)。
化合物3-1:
LC-Ms m/z(ESI):694.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.16(d,1H),δ7.89(s,1H),7.19(d,1H),6.87–6.73(m,4H),5.80–5.69(m,1H),5.40–5.29(m,1H),4.54–4.33(m,2H),4.29–4.12(m,2H),3.79–3.70(m,1H),3.49–3.35(m,2H),2.98–2.90(m,3H),2.88–2.76(m,4H),2.44–2.37(m,2H),2.04–1.93(m,4H),1.89(s,3H),1.82(s,3H),1.52–1.39(m,1H),1.01–0.92(m,6H).
化合物3-2:
LC-Ms m/z(ESI):694.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.89(s,1H),7.24(d,1H),6.93–6.79(m,4H),5.78–5.69(m,1H),5.38–5.29(m,1H),4.57–4.35(m,2H),4.31–4.16m,2H),3.85–3.69(m,1H),3.54–3.35(m,2H),3.07–2.94(m,3H),2.94–2.77(m,4H),2.49–2.41(m,2H),2.08–1.98(m,2H),1.94(s,6H),1.85–1.76(m,2H),1.39–1.27(m,1H),0.93–0.81(m,6H).
实施例4:化合物4的制备
第一步:4b的合成
在氮气保护下,将1D(1.8g,7.06mmol),2,6-二甲基苯硼酸(1.27g,8.47mmol),碳酸铯(6.90g,21.18mmol)加入到1,4-二氧六环(40.0mL)和水(4.0mL)中,加入Pd(PPh3)4(1.63g,1.41mmol),100℃封管反应5h。冷却至室温后,硅藻土过滤,加入乙酸乙酯(50mL),依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱快速层析得到4b(1.4g,收率:70.73%)。
第二步:4c的合成
在氮气保护下,将4b(1.4g,4.99mmol)溶于干燥THF(30mL)中,0℃缓慢加入四氢锂铝(380mg,10.03mmol),室温反应1h。加入10%的硫酸钠水溶液(20mL),过滤,减压除去溶剂,得到4c(800mg,67.27%)。
第三步:4d的合成
在氮气保护下,将4c(800mg,3.17mmol)溶于干燥的二氯甲烷(20mL)中,加入碳酸氢钠(0.53g,6.31mmol)和戴斯-马丁氧化剂(1.75g,4.13mmol),室温反应1h。加入饱和硫代硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL),加二氯甲烷萃取(50mL×3),无水硫酸钠干燥,过滤,减压除去溶剂,硅胶柱柱层析得到4d(650mg,81.91%)。
第四步:4e的合成
在氮气保护下,将4d(600mg,2.40mmol)和R-叔丁基亚磺酰胺(0.35g,2.88mmol)溶于THF(20mL)中,缓慢加入钛酸四乙酯(1.64g,7.22mmol),45℃反应15h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到4e(800mg,收率94.29%)。
LC-Ms m/z(ESI):354.5[M+H]+
第五步:4f的合成
将锌粉(1.81g,27.72mmol)加入干燥THF(5mL)中,置换氮气3次,加入CuCl(590mg,5.94mmol),60℃反应2h。冷却至室温,缓慢加入溴乙酸乙酯(1.65g,9.9mmol),60℃反应1h,冷却至0℃,加入4e(700mg,1.98mmol)的THF(1mL)溶液,0℃搅拌3h。硅藻土过滤,加入饱和氯化铵溶液(20mL),乙酸乙酯萃取(30ml×3),饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到4f(750mg,收率85.77%)。
LC-Ms m/z(ESI):442.6[M+H]+
第六步:4g的合成
将4f(600mg,1.36mmol)溶于THF(2mL)中,加入4N盐酸二氧六环溶液(2mL),室温搅拌3h。减压浓缩得到粗品4g。
LC-Ms m/z(ESI):338.4[M+H]+
第七步:化合物4h的合成
在氮气保护下,将中间体3(260mg,0.74mmol,合成步骤参照WO2021076890A1)溶于干燥的DMF(10mL)中,加入EDCI(280mg,1.46mmol),HOBT(200mg,1.48mmol)和DIPEA(290mg,2.24mmol)。室温搅拌40min后,加入粗品4g(250mg,0.74mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到4h(350mg,收率:70.83%)
LC-Ms m/z(ESI):668.8[M+H]+
第八步:化合物4-1和4-2的合成
将4h(350mg,0.52mmol)溶于6mL THF和2mL水中,加入一水氢氧化锂(31mg,1.29mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物4粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物4-1的三氟乙酸盐(16mg,Rt=4.135min,收率4.81%)和化合物4-2(18mg,Rt=4.039min,收率5.41%)。
化合物4-1的三氟乙酸盐:
LC-Ms m/z(ESI):640.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.15(d,1H),7.92(s,1H),7.22(s,1H),7.15–7.05(m,3H),6.88(s,1H),6.84–6.79(m,1H),5.74(t,1H),5.35–5.28(m,1H),3.66–3.27(m,2H),3.05–2.91(m,10H),2.90–2.77(m,2H),2.49–2.40(m,2H),2.07–1.98(m,2H),1.93(s,6H),1.86–1.78(m,2H),1.39–1.28(m,1H),0.93–0.81(m,6H).
化合物4-2的三氟乙酸盐:
LC-Ms m/z(ESI):640.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.17(d,1H),7.92(s,1H),7.16(d,1H),7.13–6.99(m,3H),6.79(s,1H),6.76(d,1H),5.75(t,1H),5.38–5.27(m,1H),3.31–3.19(m,2H),3.06–2.87(m,10H),2.87–2.75(m,2H),2.44–2.34(m,2H),2.04–1.92(m,4H),1.87(s,3H),1.80(s,3H),1.50–1.41(m,1H),1.01–0.90(m,6H).
实施例5:化合物5的制备
参照化合物3的制备方法,得到化合物5的粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物5-1(2mg,Rt=4.184min)和化合物5-2(2mg,Rt=4.283min)。
化合物5-1:
LC-Ms m/z(ESI):710.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.85(s,1H),7.17(t,1H),7.12–7.02(m,3H),6.83(s,1H),5.83–5.76(m,1H),5.73–5.67(m,1H),5.36–5.32(m,1H),4.46–4.37(m,1H),4.26–4.15(m,2H),3.79–3.72(m,1H),3.49–3.38(m,2H),3.15–3.08(m,1H),2.95–2.93(m,1H),2.89–2.81(m,2H),2.19(t,1H),2.09–2.00(m,4H),1.99–1.91(m,4H),1.89(s,3H),1.65–1.55(m,1H),1.00–0.91(m,6H).
化合物5-2:
LC-Ms m/z(ESI):710.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.88(s,1H),7.23–7.03(m,4H),6.89(s,1H),5.84–5.77(m,1H),5.71(t,1H),5.34(t,1H),4.51–4.37(m,1H),4.27–4.16(m,1H),3.82–3.71(m,1H),3.52–3.39(m,3H),3.15–3.03(m,2H),2.97–2.83(m,3H),2.24–2.14(m,2H),2.10–1.95(m,7H),1.92–1.78(m,2H),1.66–1.53(m,1H),0.95–0.79(m,6H).
实施例6:化合物6的制备
参照化合物3的制备方法,得到化合物6的粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物6-1(20mg,Rt=4.255min)和化合物6-2(20mg,Rt=4.342min)。
化合物6-1:
LC-Ms m/z(ESI):726.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.75(s,1H),7.14(t,1H),7.10–7.01(m,2H),6.96(t,1H),6.78(s,1H),5.77–5.70(m,1H),5.68–5.62(m,1H),2.89–2.80(m,1H),2.81–2.73(m,3H),2.74–2.62(m,3H),2.61–2.51(m,4H),2.02(s,3H),1.99(s,3H),1.97–1.89(m,2H),1.86–1.79(m,4H),1.44–1.36(m,1H),0.98–0.91(m,6H),0.62–0.52(m,4H).
化合物6-2:
LC-Ms m/z(ESI):726.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.83(s,1H),7.20–7.15(m,1H),7.13–7.05(m,3H),6.90(s,1H),5.84–5.75(m,1H),5.64(t,1H),3.56–3.47(m,2H),3.44–3.37(m,1H),3.25(s,2H),3.03–2.94(m,2H),2.88–2.78(m,1H),2.60–2.51(m,1H),2.09–1.97(m,11H),1.94-1.84(m,1H),1.77–1.63(m,1H),1.40–1.32(m,1H),0.94–0.85(m,6H),0.85–0.70(m,4H).
实施例7:化合物7的制备
参照化合物1的制备方法,得到化合物7的粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物7-1(20mg,Rt=4.323min)和化合物7-2(20mg,Rt=4.240min)。
化合物7-1:
LC-Ms m/z(ESI):750.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.85(d,1H),7.20–7.13(m,1H),7.12–7.01(m,3H),6.80(s,1H),5.77(t,1H),5.65(t,1H),3.34(s,3H),2.88–2.55(m,6H),2.49–2.38(m,1H),2.36–2.30(m,2H),2.10–1.94(m,9H),1.82–1.75(m,2H),1.55–1.44(m,1H),1.32–1.23(m,1H),1.10–1.01(m,1H),0.93–0.80(m,6H).
化合物7-2:
LC-Ms m/z(ESI):750.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.75(d,1H),7.14(t,1H),7.09–7.01(m,2H),6.96(t,1H),6.78(s,1H),5.74(t,1H),5.69–5.60(m,1H),3.34(s,3H),2.91–2.82(m,1H),2.74–2.51(m,5H),2.48–2.34(m,1H),2.35–2.28(m,2H),2.02(s,3H),1.98(s,3H),1.93(t,1H),1.84(s,3H),1.77–1.68(m,1H),1.53–1.35(m,2H),1.09–0.99(m,1H),0.98–0.85(m,6H).
实施例8:化合物8的制备
参照化合物4的制备方法,得到化合物8的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物8-1的三氟乙酸盐(25mg,Rt=4.269min,收率6.53%)和化合物8-2的三氟乙酸盐(28mg,Rt=4.171min,收率7.32%)。
化合物8-1的三氟乙酸盐:
LC-Ms m/z(ESI):696.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.90(s,1H),7.21(s,1H),7.15–7.02(m,3H),6.87(s,1H),6.83(d,1H),5.74–5.66(m,1H),5.34(t,1H),3.93–3.87(m,2H),3.83(t,2H),3.49–3.42(m,2H),3.42–3.37(m,2H),3.35–3.30(m,2H),3.05–2.90(m,4H),2.80–2.74(m,2H),2.45(t,2H),2.19–2.09(m,2H),2.08–1.96(m,2H),1.93(s,6H),1.89–1.74(m,2H),1.39–1.28(m,1H),0.92–0.84(m,6H).
化合物8-2的三氟乙酸盐:
LC-Ms m/z(ESI):696.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.92(s,1H),7.16(s,1H),7.13–6.99(m,3H),6.81–6.72(m,2H),5.78–5.70(m,1H),5.37–5.28(m,1H),3.95–3.87(m,2H),3.86–3.77(m,2H),3.48–3.42(m,2H),3.42–3.37(m,2H),3.30–3.20(m,2H),3.06–2.88(m,4H),2.87–2.77(m,2H),2.43–2.36(m,2H),2.17–2.09(m,2H),2.03–1.91(m,4H),1.87(s,3H),1.80(s,3H),1.51–1.39(m,1H),0.99-0.91(m,6H).
实施例9:化合物9的制备
第一步:9a的合成
将1a(3.0g,8.64mmol)溶于30mL超干DCE中,依次加入二乙胺(0.95g,12.96mmol)和AcOH(0.10mg,1.73mmol),常温反应1h,加入三乙酰氧基硼氢化钠(3.66g,17.28mmol),持续反应16h。加入乙酸乙酯200mL和100mL饱和NaHCO3水溶液进行萃取分离,水相再用乙酸乙酯(100mL×1)萃取,合并乙酸乙酯层,乙酸乙酯层用饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,减压浓缩后,残余物经层析柱纯化得到9a(2.8g,产率:80.12%)。
LC-Ms m/z(ESI):405.3[M+H]+
第二步:9b的合成
将9a(2.8g,6.92mmol)溶于THF(30mL)和水(10mL)中,加入氢氧化锂(331.55mg,13.85mmol),持续反应30min。经反相层析柱纯化得9b(1.2g,产率:46.05%)。
LC-Ms m/z(ESI):377.2[M+H]+
第三步:9c的合成
在氮气保护下,将中间体1(300.0mg,0.84mmol)溶于干燥的DMF(5mL)中,依次加入HOBt(227.00mg,1.68mmol)、EDCI(322.06mg,1.68mmol)和DIPEA(434.25mg,3.36mmol)。室温搅拌40min后,加入化合物9b(316.18mg,0.84mmol),室温反应过夜,加入乙酸乙酯(100mL),依次用水(40mL×2)和饱和食盐水(40mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到9c(400.0mg,产率:66.71%)。
LC-Ms m/z(ESI):714.4[M+H]+
第四步:化合物9-1和化合物9-2的合成
将9d(400.0mg,0.56mmol)溶于3mL甲醇和1mL水中,加入一水氢氧化锂(27.0mg,1.12mmol),室温反应30min。用1N盐酸调pH为5-6,减压浓缩得到化合物9粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物9-1的三氟乙酸盐(76.0mg,收率8.36%)和化合物9-2的三氟乙酸盐(81.0mg,收率6.27%)。
化合物9-1的三氟乙酸盐:
LC-Ms m/z(ESI):686.2[M+H]+
1H NMR(400MHz,CD3OD)δ7.91(s,1H),7.19(s,1H),6.82–6.73(m,4H),5.74–5.66(m,1H),5.35–5.27(m,1H),3.21–3.06(m,6H),3.00–2.85(m,4H),2.73–2.63(m,2H),2.43–2.35(m,2H),2.02–1.92(m,4H),1.89(s,3H),1.82(s,3H),1.48–1.36(m,1H),1.26(t,6H),0.99–0.90(m,6H).
化合物9-2的三氟乙酸盐:
LC-Ms m/z(ESI):686.2[M+H]+
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.22(s,1H),6.90–6.77(m,4H),5.66–5.57(m,1H),5.41–5.33(m,1H),3.30–3.17(m,6H),3.03–2.90(m,4H),2.68–2.53(m,2H),2.48–2.38(m,2H),2.07–1.89(m,9H),1.78–1.67(m,1H),1.43–1.34(m,1H),1.29(t,6H),0.92–0.82(m,6H).
实施例10:化合物10的制备
第一步:10a的合成
在氮气保护下,将1D(2.0g,7.84mmol),2.6-二甲基-4-甲氧基苯硼酸(2.82g,15.68mmol),碳酸铯(7.66g,23.52mmol)加入到1,4-二氧六环(30.0mL)和水(3.0mL)中,加入Pd(PPh3)4(0.29g,0.78mmol),100℃封管反应12h。冷却至室温后,硅藻土过滤,加入乙酸乙酯(50mL),依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱快速层析得到10a(1.6g,收率:65.75%)。
第二步:10b的合成
在氮气保护下,将10a(1.6g,5.15mmol)溶于干燥的THF(10mL)中,0℃缓慢加入四氢锂铝(8mL),室温反应1h。加入10%的硫酸钠水溶液(20mL),过滤,减压除去溶剂,硅胶柱快速层析得到10b(1.0g,收率:68.76%)。
第三步:10c的合成
在氮气保护下,将化合物10b(1.0g,3.54mmol)溶于干燥的二氯甲烷(10mL)中,室温加入碳酸氢钠(0.6g,7.08mmol)和戴斯-马丁氧化剂(2.25g,5.31mmol),室温反应1h。加入饱和硫代硫酸钠溶液(10mL)和饱和碳酸氢钠溶液(10mL),加二氯甲烷萃取(50mL×3),无水硫酸钠干燥,过滤,减压除去溶剂,硅胶柱柱层析得到10c(0.8g,产率:80.58%)。
第四步:10d的合成
在氮气保护下,将10c(1.4g,4.99mmol)和R-叔丁基亚磺酰胺(0.82g,5.99mmol)溶于THF(15mL)中,缓慢加入钛酸四乙酯(1.71g,7.50mmol),45℃反应15h,减压浓缩得到粗品,粗品用硅胶柱快速柱层析得到10d(1.9g,收率:99.27%)。
第五步:10e的合成
将锌粉(4.77g,72.94mmol)加入干燥THF(5mL)中,置换氮气3次,加入CuCl(1.55g,15.63mmol),60℃反应2h。冷却至室温,缓慢加入溴乙酸乙酯(4.35g,26.05mmol),60℃反应1h,冷却至0℃,加入10d(2.0g,5.21mmol)的THF(1mL)溶液,0℃搅拌3h。硅藻土过滤,加入饱和氯化铵溶液(80mL),乙酸乙酯萃取(100ml×3),饱和食盐水洗涤(80mL),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到10e(2.0g,收率:81.39%)。
第六步:10f的合成
将10e(500.0mg,1.06mmol)溶于THF5mL)中,加入4N盐酸二氧六环溶液(5mL),室温搅拌3h。减压浓缩得到粗品10f。
LC-Ms m/z(ESI):368.0[M+H]+
第七步:10g的合成
在氮气保护下,将中间体3(189.6mg,0.54mmol)溶于干燥的DMF(1.5mL)中,依次加入HOBt(147.08mg,1.090mmol)、EDCI(168.98mg,1.09mmol)和DIPEA(220.3mg,2.18mmol)。室温搅拌40min后,加入粗品10f(200.0mg,0.54mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到10g(180.0mg,收率:47.39%)
LC-Ms m/z(ESI):698.3[M+H]+
第八步:化合物10-1和化合物10-2的合成
将10g(180.0mg,0.26mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(12.45mg,0.52mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物10粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物10-1的三氟乙酸盐(17mg,收率:9.76%)和化合物10-2的三氟乙酸盐(15mg,收率:8.61%)。
化合物10-1的三氟乙酸盐:
LC-Ms m/z(ESI):670.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.14(s,1H),6.80(s,1H),6.74(s,1H),6.67–6.56(m,2H),5.79–5.70(m,1H),5.37–5.27(m,1H),3.77(s,3H),3.29–3.20(m,2H),3.05–2.88(m,10H),2.87–2.76(m,2H),2.46–2.35(m,2H),2.04–1.89(m,4H),1.85(s,3H),1.78(s,3H),1.51–1.39(m,1H),1.02–0.91(m,6H).
化合物10-2的三氟乙酸盐:
LC-Ms m/z(ESI):670.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.20(s,1H),6.88(s,1H),6.82(s,1H),6.66(s,2H),5.78–5.69(m,1H),5.37–5.24(m,1H),3.78(s,3H),3.35–3.24(m,2H),3.05–2.92(m,10H),2.89–2.76(m,2H),2.50–2.42(m,2H),2.09–1.96(m,2H),1.91(s,6H),1.86–1.77(m,2H),1.39–1.25(m,1H),0.95–0.81(m,6H).
实施例11:化合物11的制备
第一步:11a的合成
在氮气保护下,将2g(300.0mg,0.67mmol),2.6-二甲基-4-甲氧基苯硼酸(242.0mg,1.34mmol),碳酸铯(0.65g,2.01mmol)加入到1,4-二氧六环(5.0mL)和水(0.5mL)中,加入Pd(PPh3)4(77.0mg,0.067mmol),100℃封管反应12h。冷却至室温,硅藻土过滤,加入乙酸乙酯(50mL),依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱快速层析得到11a(300.0mg,收率:92.22%)。
第二步:11b的合成
将11a(300.0mg,0.60mmol)溶解在乙腈(3mL)中,加入盐酸-1,4-二氧六环溶液(2mL),室温搅拌30min。减压干燥除去溶剂获得粗品11b。
LC-Ms m/z(ESI):402.7[M+H]+
第三步:11c的合成
在氮气保护下,将中间体3(174.18mg,0.50mmol)溶于干燥DMF(5mL)中,依次加入HOBt(135.12mg,1.00mmol)、EDCI(191.70mg,1.00mmol)和DIPEA(258.48mg,2.00mmol)。室温搅拌40min后,加入粗品11b(200.0mg,0.50mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到11c(300.0mg,收率:81.99%)
LC-Ms m/z(ESI):732.3[M+H]+
第四步:化合物11-1和化合物11-2的合成
将11c(300.0mg,0.41mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(19.46mg,0.82mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物11粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物11-1的三氟乙酸盐(23mg,Rt=4.024min,收率:7.97%)和化合物11-2的三氟乙酸盐(27mg,Rt=4.165min,收率:9.36%)。
化合物11-1的三氟乙酸盐:
LC-Ms m/z(ESI):704.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.03(t,1H),6.84(s,1H),6.69–6.63(m,2H),5.76–5.62(m,2H),3.78(s,3H),3.24–3.14(m,2H),3.03–2.89(m,3H),2.85(s,6H),2.81–2.70(m,1H),2.03(s,3H),2.01–1.92(m,5H),1.87(s,3H),1.46–1.32(m,1H),0.99–0.88(m,6H).
化合物11-1的三氟乙酸盐:
LC-Ms m/z(ESI):704.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.83(s,1H),7.08(t,1H),6.90(s,1H),6.69(s,2H),5.81–5.74(m,1H),5.70–5.61(m,1H),3.79(s,3H),3.30–3.17(m,2H),3.05–2.95(m,2H),2.91–2.78(m,7H),2.69–2.58(m,1H),2.06(s,3H),2.02–1.96(m,6H),1.94–1.82(m,1H),1.81–1.70(m,1H),1.41–1.25(m,1H),0.94–0.82(m,6H).
实施例12:化合物12的合成
参照化合物9的制备方法,得到化合物12的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物12-1的三氟乙酸盐(11mg,Rt=4.191min)和化合物12-2的三氟乙酸盐(17mg,Rt=4.332min)。
化合物12-1的三氟乙酸盐:
LC-Ms m/z(ESI):702.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.88(s,1H),7.19–7.11(m,1H),7.10–6.98(m,3H),6.84(s,1H),5.77–5.64(m,2H),3.22–3.10(m,6H),3.03–2.87(m,3H),2.72–2.63(m,1H),2.03(s,3H),2.00–1.93(m,5H),1.89(s,3H),1.46–1.34(m,1H),1.27(t,6H),0.98–0.87(m,6H).
化合物12-2的三氟乙酸盐:
LC-Ms m/z(ESI):702.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.89–7.83(m,1H),7.20–7.14(m,1H),7.13–7.02(m,3H),6.89(s,1H),5.80–5.72(m,1H),5.69–5.62(m,1H),3.29–3.18(m,6H),3.01-2.92(m,2H),2.90–2.80(m,1H),2.68–2.57(m,1H),2.06(s,3H),2.03–1.98(m,6H),1.94–1.83(m,1H),1.78–1.67(m,1H),1.39–1.24(m,7H),0.93–0.82(m,6H).
实施例13:化合物13的制备
第一步:13b的制备
将2a(2.0g,5.2mmol)、13a(1.9g,10.4mmol)、三乙胺(1.4mL,10.4mmol)、碘化亚铜(4.0g,20.8mmol)、无水氯化锂(1.76g,41.6mmol)和(PPh3)2PdCl2(730mg,1.04mmol)置于封管中,加入DMF(30mL)和水(3mL)。氮气保护80℃搅拌3h。冷却至室温,加入100mL乙酸乙酯稀释,依次用水(50mL×3)、饱和食盐水(50mL×1)洗涤,有机层用无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析得到13b(1.86g,产率74%)。
LCMS m/z=485.2[M+H]+
第二步:13c的制备
将13b(1.86g,3.84mmol)溶于20mL二氯甲烷中,加入5mL三氟乙酸,室温搅拌3h。减压浓缩得到13c粗品(1.8g)。
LCMS m/z=385.2[M+H]+
第三步:13d的制备
将13c(1.8g)粗品、甲醛水溶液(5mL)和冰醋酸(230mg,3.84mmol)溶于甲醇(20mL)中,氮气保护室温搅拌30min,加入三乙酰氧基硼氢化钠(1.62g,7.68mmol)。室温下继续搅拌过夜。减压浓缩除去溶剂,加入30mL水,用乙酸乙酯(50mL×2)萃取水相,合并有机相。有机相用饱和食盐水(30mL×1)洗涤,有机层用无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析得到13d(0.91g,两步产率60%)。
LCMS m/z=399.2[M+H]+
第四步:13e的制备
将13d(0.91g,2.29mmol)溶于乙醇(15mL)和水(1.5mL)中,加入一水合氢氧化锂(288mg,6.86mmol),室温反应5h。减压浓缩除去溶剂,向残留物中加入20mL水,用1N的盐酸调节pH至2-3左右,用乙酸乙酯(50mL×2)萃取水相,合并有机相。有机相用饱和食盐水(30mL×1)洗涤,有机层用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物经反相(0.1%三氟乙酸)制备得到13e,(200mg,产率24%)。
LCMS m/z=371.2[M+H]+;
第五步:13f的制备
将13e(0.160g,0.43mmol),中间体1(0.15g,0.43mmol)溶于5mL DMF,加入HOBT(0.12g,0.86mmol),DIPEA(0.22g,1.72mmol)和EDCI(0.16g,0.86mmol)室温搅拌2h,反应结束后,加入
30ml乙酸乙酯,水洗2次(20mL×2),无水硫酸钠干燥,减压浓缩,柱层析得13f(0.13g,产率:42.71%)。
LCMS m/z=708.9[M+H]+;
第六步:化合物13-1和13-2的制备
将13f(0.13g,0.18mmol)溶于3mL THF和1mL水中,加入一水氢氧化锂(23mg,0.55mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物13粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物13-1(0.55mg,Rt=4.271min)和化合物13-2(0.6mg,Rt=4.358min)。
化合物13-1:
LC-Ms m/z(ESI):680.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ8.03(s,1H),7.15(s,1H),6.84–6.70(m,4H),5.72–5.65(m,1H),5.31(t,1H),3.93–3.81(m,1H),3.58–3.48(m,2H),3.15–3.12(m,1H),2.95–2.85(m,2H),2.70(d,2H),2.52(s,3H),2.42-2.35(m,2H),2.03–1.91(m,4H),1.89(s,3H),1.79(s,3H),1.48–1.29(m,2H),1.00–0.90(m,6H)
化合物13-2:
LC-Ms m/z(ESI):680.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ8.08(s,1H),7.23(s,1H),6.86–6.78(m,4H),5.69–5.58(m,1H),5.40–5.29(m,1H),3.96–3.87(m,1H),3.70-3.47(m,2H),3.14–3.10(m,1H),2.99–2.91(m,2H),2.72–2.64(m,2H),2.55(s,3H),2.48–2.39(m,2H),2.22–2.14(m,1H),2.06–1.98(m,3H),1.96–1.90(m,6H),1.77–1.69(m,1H),1.66–1.55(m,1H),0.91–0.83(m,6H).
实施例14:化合物14的制备
第一步:14b的合成
在氮气保护下,将2a(20.0g,52.04mmol)溶于DMF(60mL)中,依次加入14a(10.56g,62.44mmol),醋酸钯(3.32g,10.4mmol),三(邻甲基苯基)膦(6.32g,20.8mmol)和三乙胺(15.8g,156.12mmol),100℃反应24h。加入乙酸乙酯(180mL)进行萃取,水(50mL×2)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到14b(4.0g,收率:16.27%)。
LC-Ms m/z(ESI):473.5[M+H]+
第二步:14c的合成
将14b(4.0g,8.46mmol)溶于甲醇(10mL)中,加入Pd/C(2.0g),氢气氛围室温反应0.5h。过滤除去固体,滤液浓缩,经层析柱纯化得14c(3.6g,产率:89.68%)。
LC-Ms m/z(ESI):475.5[M+H]+
第三步:14d的合成
将14c(3.6g,7.59mmol)溶于二氯甲烷(5mL)中,加入盐酸-1,4-二氧六环(3mL),反应1h。减压除去溶剂,获得粗品14d的盐酸盐。
第四步:14e的合成
将14d的盐酸盐(1.3g,3.47mmol)溶于超干1,2-二氯乙烷(30mL)中,依次加入丙酮(400mg,6.87mmol)和冰醋酸(21.0mg,0.35mmol),60℃反应2h。冷却至室温后,加入三乙酰氧基硼氢化钠(1.84g,8.68mmol),室温过夜反应。加入乙酸乙酯(20mL)进行萃取,水(30mL×2)和饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到14e(1.0g,收率:69.20%)。
LC-Ms m/z(ESI):417.4[M+H]+
第五步:14f的合成
将14e(1.0g,2.40mmol)溶于THF(9mL)和水(3mL)中,加入氢氧化锂(170mg,7.10mmol),室温反应2h。经反相层析柱纯化得14f(800mg,产率:85.82%)。
LC-Ms m/z(ESI):389.4[M+H]+
第六步:14g的合成
在氮气保护下,将中间体1(250.0mg,0.70mmol)溶于干燥的DMF(1.5mL)中,依次加入HOBt(190mg,1.41mmol)、EDCI(270mg,1.41mmol)和DIPEA(270mg,2.09mmol)。室温搅拌40min后,加入14f(270mg,0.70mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到14g(368mg,收率:72.43%)。
LC-Ms m/z(ESI):726.8[M+H]+
第七步:化合物14-1和化合物14-2的合成
将化合物14g(368mg,0.51mmol)溶于1.5mL甲醇和0.5mL水中,加入一水氢氧化锂(31mg,1.27mmol),室温反应30min。用1N盐酸调pH为5-6,减压浓缩得到化合物14粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物14-1的三氟乙酸盐(20mg,Rt=4.295min,收率5.62%)和化合物14-2的三氟乙酸盐(25mg,Rt=4.378min,收率7.02%)。
化合物14-1的三氟乙酸盐:
LC-Ms m/z(ESI):698.8[M+H]+
1H NMR(400MHz,CD3OD)δ7.90–7.68(m,1H),7.20(s,1H),6.88–6.73(m,4H),5.84–5.75(m,1H),5.39–5.27(m,1H),4.32–3.83(m,4H),3.52–3.34(m,1H),3.20–2.81(m,7H),2.49–2.34(m,2H),2.10–1.92(m,4H),1.90(m,3H),1.83(s,3H),1.52–1.35(m,1H),1.30–1.11(m,6H),1.05–0.93(m,6H).
化合物14-2的三氟乙酸盐:
LC-Ms m/z(ESI):698.8[M+H]+
1H NMR(400MHz,CD3OD)δ7.91–7.76(m,1H),7.25(s,1H),6.92–6.78(m,4H),5.84–5.73(m,1H),5.39–5.26(m,1H),4.34–3.85(m,4H),3.53–3.35(m,1H),3.24–2.95(m,4H),2.94–2.77(m,3H),2.53–2.43(m,2H),2.12–2.00(m,2H),1.96(s,6H),1.91–1.78(m,2H),1.40–1.20(m,7H),0.96–0.85(m,6H).
实施例15:化合物15的制备
参照化合物14的制备方法,得到化合物15的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物15-1的三氟乙酸盐(15mg,Rt=4.354min)和化合物15-2的三氟乙酸盐(17mg,Rt=4.455min)。
化合物15-1的三氟乙酸盐:
LC-Ms m/z(ESI):710.8[M+H]+
1H NMR(400MHz,CD3OD)δ7.89–7.72(s,1H),7.20(s,1H),6.89–6.72(m,4H),5.84–5.75(m,1H),5.38–5.28(m,1H),4.36–3.84(m,4H),3.27–2.79(m,9H),2.48–2.37(m,2H),2.09–1.93(m,4H),1.92–1.81(m,6H),1.51–1.38(m,1H),1.07–0.94(m,7H),0.74–0.63(m,2H),0.44–0.34(m,2H).
化合物15-2的三氟乙酸盐:
LC-Ms m/z(ESI):710.8[M+H]+
1H NMR(400MHz,CD3OD)δ7.92–7.74(s,1H),7.25(s,1H),6.93–6.77(m,4H),5.83–5.73(m,1H),5.38–5.28(m,1H),4.36–3.86(m,4H),3.30–2.76(m,9H),2.52–2.43(m,2H),2.12–2.01(m,2H),1.96(s,6H),1.93–1.74(m,2H),1.41–1.27(m,1H),1.11–0.84(m,7H),0.76–0.61(m,2H),0.47–0.38(m,2H).
实施例16:化合物16的制备
参照化合物3的制备方法,得到化合物16的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物16-1的三氟乙酸盐(15mg,Rt=4.077min)和化合物16-2的三氟乙酸盐(16mg,Rt=4.178min)。
化合物16-1的三氟乙酸盐:
LC-Ms m/z(ESI):728.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.23–7.15(m,1H),7.14–7.03(m,3H),6.86(s,1H),5.87–5.76(m,1H),5.75–5.64(m,1H),4.77–4.68(m,1H),4.61–4.47(m,1H),4.23–4.02(m,1H),3.97–3.84(m,1H),3.77–3.35(m,4H),3.19–2.86(m,4H),2.38–2.18(m,2H),2.12–1.84(m,11H),1.50–1.35(m,1H),1.05–0.90(m,6H).
化合物16-2的三氟乙酸盐:
LC-Ms m/z(ESI):728.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.95(s,1H),7.25–7.07(m,4H),6.92(s,1H),5.87–5.78(m,1H),5.75–5.66(m,1H),4.77–4.70(m,1H),4.62–4.51(m,1H),4.26–4.04(m,1H),3.94–3.85(m,1H),3.75–3.36(m,4H),3.14–2.89(m,4H),2.39–2.18(m,2H),2.12–1.98(m,9H),1.97–1.73(m,2H),1.41–1.25(m,1H),0.94–0.85(m,6H).
实施例17:化合物17的制备
参照化合物3制备方法,得到化合物17的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物17-1的三氟乙酸盐(17mg,Rt=4.035min)和化合物17-2的三氟乙酸盐(18mg,Rt=4.118min)。
化合物17-1的三氟乙酸盐:
LC-Ms m/z(ESI):728.7[M+H]+
1H NMR(400MHz,CD3OD)δ8.01–7.80(s,1H),7.23–7.15(m,1H),7.14–7.03(m,3H),6.86(s,1H),5.88–5.78(m,1H),5.76–5.64(m,1H),4.79–4.65(m,1H),4.62–4.46(m,1H),4.41–3.97(m,1H),3.96–3.64(m,2H),3.60–3.40(m,2H),3.32–3.22(m,1H),3.19–2.85(m,4H),2.45–2.13(m,2H),2.11–1.85(m,11H),1.50–1.37(m,1H),1.04–0.90(m,6H).
化合物17-2的三氟乙酸盐:
LC-Ms m/z(ESI):728.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.93(s,1H),7.25–7.06(m,4H),6.92(s,1H),5.88-5.77(m,1H),5.75–5.64(m,1H),4.79–4.68(m,1H),4.62–4.48(m,1H),4.24–3.98(m,1H),3.97–3.84(m,1H),3.82–3.62(m,1H),3.62–3.37(m,3H),3.15–2.89(m,4H),2.44–2.16(m,2H),2.09(s,3H),2.04(s,6H),1.95–1.71(m,2H),1.38–1.26(m,1H),0.98–0.84(m,6H).
实施例18:化合物18的制备
参照化合物14的制备方法,得到化合物18的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物18-1的三氟乙酸盐(12mg,Rt=4.164min)和化合物18-2的三氟乙酸盐(13mg,Rt=4.268min)。
化合物18-1的三氟乙酸盐:
LC-Ms m/z(ESI):714.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.97–7.77(m,1H),7.25–7.18(m,1H),7.18–7.09(m,3H),
6.89(s,1H),5.89–5.79(m,1H),5.77–5.65(m,1H),4.34–4.05(m,2H),4.03–3.85(m,2H),3.55–3.36(m,1H),3.24–3.03(m,2H),3.00–2.79(m,3H),2.08(s,3H),2.04(s,6H),1.93–1.71(m,2H),1.39–1.20(m,7H),0.97–0.85(m,6H).
化合物18-2的三氟乙酸盐:
LC-Ms m/z(ESI):714.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.91–7.72(m,1H),7.22–7.15(m,1H),7.14–7.04(m,3H),6.84(s,1H),5.88–5.79(m,1H),5.75–5.65(m,1H),4.33–4.14(m,1H),4.10–3.81(m,3H),3.51–3.35(m,1H),3.22–3.07(m,2H),3.06–2.81(m,3H),2.14–2.04(m,4H),2.02–1.83(m,7H),1.48–1.35(m,1H),1.32–1.17(m,6H),1.04–0.93(m,6H).
实施例19:化合物19的制备
参照化合物14的制备方法,得到化合物19的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物19-1的三氟乙酸盐(18mg,Rt=4.218min)和化合物19-2的三氟乙酸盐(19mg,Rt=4.297min)。
化合物19-1的三氟乙酸盐:
LC-Ms m/z(ESI):726.8[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.36–9.20(m,1H),7.88-7.69(m,1H),7.23–7.04(m,4H),6.88-6.77(m,1H),5.87–5.76(m,1H),5.75-5.65(m,1H),4.34–3.85(m,4H),3.26–2.87(m,7H),2.12-2.01(m,4H),2.01–1.93(m,4H),1.92-1.84(m,3H),1.46–1.35(m,1H),1.06-1.93(m,7H),0.74-0.64(m,2H),0.47–0.35(m,2H).
化合物19-2的三氟乙酸盐:
LC-Ms m/z(ESI):726.8[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.51–9.33(m,1H),7.94–7.77(m,1H),7.27-7.04(m,4H),6.89(d,1H),5.88-5.78(m,1H),5.76-5.65(m,1H),4.37–3.90(m,4H),3.29–2.82(m,7H),2.08(s,3H),2.04(s,6H),1.92–1.69(m,2H),1.39-1.25(m,1H),1.11-0.96(m,1H),0.96–0.86(m,6H),0.75-0.64(m,2H),0.45-0.36(m,2H).
实施例20:化合物20的制备
参考实施例21的制备方法得到化合物20粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物20-1的三氟乙酸盐(16mg,Rt=4.007min,收率5.51%)和化合物20-2的三氟乙酸盐(17mg,Rt=4.095min,收率5.85%)。
化合物20-1的三氟乙酸盐:
LC-Ms m/z(ESI):676.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.20(d,1H),7.89(s,1H),7.20–7.04(m,3H),6.82(s,1H),5.82-5.73(m,1H),5.74-5.64(m,1H),3.29–3.23(m,2H),3.16–2.82(m,12H),2.50-2.35(m,2H),2.08–1.88(m,7H),1.86(s,3H),1.47-1.34(m,1H),1.00-0.89(m,6H).
化合物20-2的三氟乙酸盐:
LC-Ms m/z(ESI):676.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.33(d,1H),7.91(s,1H),7.20–7.07(m,3H),6.88(s,1H),5.82–5.66(m,2H),3.37–3.30(m,2H),3.08–2.86(m,12H),2.48(t,2H),2.14–2.01(m,2H),1.98(s,6H),1.86–1.73(m,2H),1.36-1.23(m,1H),0.93-0.81(m,6H).
实施例21:化合物21的制备
第一步:21a的合成
在氮气保护下,将6G(400mg,0.89mmol)溶于1,4-二氧六环(6mL)和水(0.6mL)中,依次加入2.6-二甲基-4-甲氧基苯硼酸(240mg,1.33mmol),XPhos Pd G2(110mg,0.13mmol),磷酸钾(570mg,2.67mmol),100℃反应24h。加入乙酸乙酯(80mL)进行萃取,水(50mL×2)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到21a(230mg,收率:51.32%)。
LC-Ms m/z(ESI):404.5[M+H-Boc]+
第二步:21b的合成
将21a(230mg,0.46mmol)溶于二氯甲烷(6mL)中,加入盐酸-1,4-二氧六环(6mL),反应1h。减压除去溶剂,获得粗品21b的盐酸盐。
第三步:21c的合成
在氮气保护下,将中间体3(160mg,0.46mmol)溶于干燥的DMF(8mL)中,依次加入HATU(350mg,0.92mmol)、DIPEA(230mg,1.81mmol)。室温搅拌40min后,加入21b的盐酸盐(185mg,0.46mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到21c(240mg,收率:71.10%)。
LC-Ms m/z(ESI):734.8[M+H]+
第四步:化合物21-1和化合物21-2的合成
将化合物21c(240mg,0.33mmol)溶于6mL THF和2mL水中,加入一水氢氧化锂(20mg,0.83mmol),室温反应30min。用1N盐酸调pH为5-6,减压浓缩得到化合物21粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物21-1的三氟乙酸盐(19mg,Rt=3.973min,收率8.16%)和化合物21-2的三氟乙酸盐(20mg,Rt=4.051min,收率8.59%)。
化合物21-1的三氟乙酸盐:
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.89(s,1H),6.82(s,1H),6.67(s,2H),5.82-5.74(m,1H),5.72-5.63(m,1H),3.78(s,3H),3.32–3.24(m,2H),3.14–2.83(m,12H),2.49-2.38(m,2H),2.08–1.92(m,4H),1.90(s,3H),1.83(s,3H),1.47–1.35(m,1H),1.01-0.86(m,6H).
化合物21-2的三氟乙酸盐:
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.33(d,1H),7.91(s,1H),6.88(s,1H),6.70(s,2H),5.82-5.75(m,1H),5.74-5.63(m,1H),3.79(s,3H),3.36-3.29(m,2H),3.10–2.83(m,12H),2.53-2.43(m,2H),2.13–2.01(m,2H),1.95(s,6H),1.87–1.74(m,2H),1.35-1.23(m,1H),0.93-0.82(m,6H)
化合物21-A结构为为4个手性异构体等比例混合的外消旋体。
实施例22:化合物22的制备
参照化合物14的制备方法,得到化合物22的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物22-1的三氟乙酸盐(10mg,Rt=4.334min)和化合物22-2的三氟乙酸盐(10mg,Rt=4.411min)。
化合物22-1的三氟乙酸盐:
LC-Ms m/z(ESI):726.4[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.74(s,1H),7.18(s,1H),6.86–6.70(m,4H),5.76(t,1H),5.33(t,1H),3.50–3.35(m,3H),3.06–2.97(m,1H),2.96–2.81(m,5H),2.61–2.49(m,2H),2.40(t,2H),2.07–1.90(m,6H),1.86(s,3H),1.81(s,3H),1.55–1.37(m,4H),1.34(s,3H),1.32(s,3H),1.00-0.92(m,6H).
化合物22-2的三氟乙酸盐:
LC-Ms m/z(ESI):726.4[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.12(d,1H),7.79(s,1H),7.23(d,1H),6.88–6.79(m,4H),5.76(t,1H),5.31(q,1H),3.52–3.41(m,3H),3.10–2.94(m,4H),2.86–2.78(m,2H),2.65–2.42(m,4H),2.11–1.98(m,4H),1.96–1.90(m,6H),1.83–1.77(m,2H),1.57–1.26(m,10H),0.92–0.83(m,6H).
实施例23:化合物23的制备
参照化合物14的制备方法,得到化合物23的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物23-1的三氟乙酸盐(10mg,Rt=4.233min)和化合物23-2的三氟乙酸盐(10mg,Rt=4.411min)。
化合物23-1的三氟乙酸盐:
LC-Ms m/z(ESI):742.4[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.29(d,1H),7.74(s,1H),7.20–7.03(m,4H),6.81(s,1H),5.84–5.75(m,1H),5.73–5.63(m,1H),3.51–3.38(m,2H),3.13–2.87(m,5H),2.60–2.48(m,2H),2.04(s,3H),2.02–1.89(m,6H),1.88–1.71(m,5H),1.55–1.25(m,10H),1.00–0.89(m,6H).
化合物23-2的三氟乙酸盐:
LC-Ms m/z(ESI):742.4[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.79(s,1H),7.24–7.07(m,4H),6.86(s,1H),5.83–5.74(m,1H),5.76–5.64(m,1H),3.55–3.40(m,3H),3.12–2.87(m,4H),2.65–2.47(m,2H),2.15–1.96(m,11H),1.90–1.72(m,3H),1.58–1.44(m,2H),1.41–1.21(m,7H),0.95–0.81(m,6H).
实施例24:化合物24的制备
参照化合物14的制备方法,得到化合物24的粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物24-1(34mg,Rt=4.300min)和化合物24-2(35mg,Rt=4.374min)。
化合物24-1:
LC-Ms m/z(ESI):760.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.71(s,1H),6.89–6.82(m 2H),6.81(s,1H),5.81–5.74(m,1H),5.73–5.67(m,1H),3.31–3.24(m,2H),3.04–2.93(m,3H),2.80–2.73(m,1H),2.70–2.53(m,2H),2.54–2.43(m,4H),2.23–2.16(m,1H),2.12–2.02(m,2H),2.01–1.91(m,5H),1.86(s,3H),1.82–1.77(m,2H),1.70–1.61(m,1H),1.41–1.25(m,3H),0.98–0.93(m,6H),0.77–0.65(m,4H).
化合物24-2:
LC-Ms m/z(ESI):760.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.78(s,1H),6.91(s,1H),6.89–6.85(m,2H),5.81–5.75(m,1H),5.75–5.68(m,1H),3.47–3.38(m,2H),3.01(t,2H),2.94–2.84(m,1H),2.82–2.58(m,4H),2.57–2.47(m,3H),2.33–2.26(m,1H),2.15–2.05(m,2H),2.02–1.96(m,6H),1.89–1.71(m,4H),1.59–1.50(m,1H),1.40–1.24(m,3H),0.91–0.85(m,6H),0.84–0.79(m,2H),0.77–0.71(m,2H).
实施例25:化合物25的制备
第一步:25a的合成
在氮气保护下,将9b(140mg,0.33mmol),中间体6(124mg,0.33mmol),溶于干燥的DMF(3.0mL)中,加入EDCI(126mg,0.66mmol),HOBT(90mg,0.66mmol)和DIPEA(128mg,0.99mmol)室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到25a粗品(250mg)。
LC-Ms m/z(ESI):750.2[M+H]+
第二步:化合物25-1和25-2的制备
将上述粗品25a粗品(250mg)溶于4mL THF和1mL水中,加入一水氢氧化锂(45mg,1.08mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩,残余物经prep-HPLC分离提纯(方法1)得到化合物25-1(29mg,Rt=4.237min,两步收率:10.86%)和化合物25-2(36mg,Rt=4.294min,两步收率:13.48%)。
化合物25-1:
LC-Ms m/z(ESI):722.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.91(s,1H),6.90–6.76(m,3H),5.78–5.68(m,2H),3.26–3.11(m,6H),3.02–2.89(m,5H),2.71–2.62(m,1H),2.50–2.43(m,2H),2.11–1.98(m,4H),1.97(s,3H),1.90(s,3H),1.45–1.34(m,1H),1.34–1.28(m,6H),0.99–0.90(m,6H).
化合物25-2:
LC-Ms m/z(ESI):722.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ7.88(s,1H),6.93–6.86(m,3H),5.83–5.75(m,1H),5.70–5.61(m,1H),3.29–3.15(m,6H),3.05–2.94(m,4H),2.89–2.79(m,1H),2.64–2.55(m,1H),2.56-2.46(m,2H),2.14–2.04(m,2H),2.02–1.97(m,6H),1.95–1.87(m,1H),1.78–1.69(m,1H),1.39–1.28(m,7H),0.93–0.86(m,6H).
实施例26:化合物26的制备
第一步:26a的合成
在氮气保护下,将2a(1.68g,4.72mmol)溶于DMF(29mL)和水(2.9mL)中,依次加入1-BOC-3-乙炔基吡咯烷(1.84g,9.44mmol),碘化亚铜(3.6g,18.88mmol),氯化锂(1.6g,37.76mmol)和PdCl2(dppf)(578mg,0.71mmol),80℃反应5h。硅藻土过滤,加入乙酸乙酯(100mL),依次用水(30mL×2)和饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到26a(1.7g,收率:72.24%)。
LC-Ms m/z(ESI):443.2[M+H-t-Bu]+
第二步:26b的合成
在氮气保护下,将26a(1.3g,2.61mmol)溶于甲醇(22mL)中,加入10%w/w Pd/C(2.2g,2.09mmol),氢气置换三次,在氢气球保护下,室温反应0.5h。过滤除去固体,滤液浓缩得26b粗品(1.3g)。
LC-Ms m/z(ESI):447.2[M+H-t-Bu]+
第三步:26c的合成
将上一步粗品26b(1.3g)溶于二氯甲烷(14mL)中,加入盐酸-1,4-二氧六环(10mL),反应3h。减压除去溶剂,获得26c粗品(1.4g)。
LC-Ms m/z(ESI):403.6[M+H]+
第四步:26d的合成
将粗品26c(1.4g,3.48mmol)溶于DCE(23mL)中,依次加入多聚甲醛(209mg,6.96mmol),醋酸(105mg,1.74mmol)和三乙酰氧基硼氢化钠(1475mg,6.96mmol),60℃反应16h。加入二氯甲烷(80mL)和水(30mL),饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到26d(750mg,三步收率:51.75%)。
LC-Ms m/z(ESI):417.6[M+H]+
第五步:26e的合成
将26d(780mg,1.87mmol)溶于8mL THF和2mL水中,加入一水氢氧化锂(235mg,5.61mmol),室温反应3h。用1N盐酸调pH为5-6,减压浓缩得到化合物粗品,粗品经C18柱((流动
相A:乙腈,流动相B:0.5%的NH4HCO3水溶液,A的10%至40%的B溶液梯度洗脱))分离得到26e(620mg,85.36%)。
LC-Ms m/z(ESI):389.4[M+H]+
第六步:26f的合成
在氮气保护下,将26e(155mg,0.40mmol),中间体6(157mg,0.40mmol)溶于干燥DMF(3.0mL),加入EDCI(153mg,0.80mmol),HOBT(108mg,0.80mmol)和DIPEA(155mg,1.20mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到26f(189mg,62.02%)。
LC-Ms m/z(ESI):762.7[M+H]+
第七步:化合物26-1和26-2的制备
将26f(189mg,0.25mmol)溶于4mL THF和1mL水中,加入一水氢氧化锂(32mg,0.75mmol),室温反应5h。用1N盐酸调pH为5-6,减压浓缩得到化合物26粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物26-1的三氟乙酸盐(30mg,Rt=4.218min,两步收率:16.35%)和化合物26-2的三氟乙酸盐(30mg,Rt=4.305min,两步收率:16.35%)。
化合物26-1的三氟乙酸盐:
LC-Ms m/z(ESI):734.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.16(t,1H),7.76(d,1H),6.91–6.83(m,2H),6.81(s,1H),5.84–5.76(m,1H),5.75–5.67(m,1H),3.87–3.63(m,2H),3.29–3.01(m,3H),3.01–2.86(m,5H),2.81–2.53(m,3H),2.53–2.42(m,2H),2.38–2.18(m,2H),2.12–2.03(m,3H),2.02–1.99(m,1H),1.94(d,3H),1.89(d,3H),1.82–1.69(m,2H),1.45–1.33(m,2H),1.01–0.93(m,6H).
化合物26-2的三氟乙酸盐:
LC-Ms m/z(ESI):734.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.32(d,1H),7.85(s,1H),6.96–6.84(m,3H),5.80(t,1H),5.75–5.66(m,1H),3.88–3.64(m,2H),3.25–2.83(m,8H),2.82–2.56(m,3H),2.54–2.45(m,2H),2.41–2.18(m,1H),2.17–2.06(m,2H),2.00(s,6H),1.90–1.70(m,5H),1.40–1.23(m,2H),0.95–0.83(m,6H).
实施例27:化合物27的制备
参照化合物26的制备方法,得到化合物27的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物27-1的三氟乙酸盐(58mg,Rt=4.134min)和化合物27-2的三氟乙酸盐(86mg,Rt=4.243min)。
化合物27-1的三氟乙酸盐:
LC-Ms m/z(ESI):714.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.27(t,1H),7.75(s,1H),7.19(t,1H),7.13–7.04(m,3H),6.82(s,1H),5.83–5.74(m,1H),5.74–5.63(m,1H),3.87–3.55(m,2H),3.26–3.02(m,2H),3.00–2.88(m,4H),2.81–2.46(m,3H),2.46–2.15(m,2H),2.06(s,3H),2.00–1.91(m,4H),1.90–1.84(m,4H),1.79–1.66(m,2H),1.47–1.33(m,2H),1.01–0.92(m,6H).
化合物27-2的三氟乙酸盐:
LC-Ms m/z(ESI):714.3[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.47–9.37(m,1H),7.84(d,1H),7.26–7.09(m,4H),6.87(s,1H),5.86–5.76(m,1H),5.76–5.65(m,1H),3.90–3.54(m,2H),3.25–3.03(m,2H),3.02–2.88(m,4H),2.84–2.51(m,3H),2.52–2.18(m,2H),2.14–2.00(m,9H),1.92–1.60(m,5H),1.42–1.22(m,2H),0.96–0.82(m,6H).
实施例28:化合物28的制备
参照化合物26的制备方法,得到化合物28的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物28-1的三氟乙酸盐(37mg,Rt=4.218min),化合物28-2的三氟乙酸盐(50mg,Rt=4.343min)。
化合物28-1的三氟乙酸盐:
LC-Ms m/z(ESI):734.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.20(t,1H),7.84(d,1H),6.91–6.78(m,3H),5.86–5.78(m,1H),5.76–5.65(m,1H),3.75–3.63(m,1H),3.41–3.37(m,1H),3.21–3.06(m,2H),3.01–2.94(m,3H),2.93–2.86(m,2H),2.78–2.61(m,2H),2.56–2.44(m,2H),2.41–2.15(m,3H),2.13–2.00(m,4H),1.99–1.92(m,4H),1.89(d,3H),1.85–1.74(m,2H),1.47–1.33(m,2H),1.01–0.94(m,6H).
化合物28-2的三氟乙酸盐:
LC-Ms m/z(ESI):734.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.35(d,1H),7.87(s,1H),6.94–6.81(m,3H),5.81(t,1H),5.74–5.65(m,1H),3.75–5.65(m,1H),3.23–3.14(m,1H),3.11–2.98(m,4H),2.94–2.86(m,3H),2.85–2.74(m,1H),2.70–2.61(m,1H),2.52(t,J=7.4Hz,3H),2.25–2.04(m,5H),2.00(s,6H),1.87–1.76(m,4H),1.41–1.26(m,2H),0.95–0.84(m,6H).
实施例29:化合物29的制备
参照化合物26的制备方法,得到化合物29的粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物29-1的三氟乙酸盐(60mg,Rt=4.181min),化合物29-2的三氟乙酸盐(88mg,Rt=4.279min)
化合物29-1的三氟乙酸盐:
LC-Ms m/z(ESI):714.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.31(t,1H),7.83(d,1H),7.19(t,1H),7.14–7.03(m,3H),6.83(s,1H),5.86–5.78(m,1H),5.73–5.64(m,1H),3.75–3.64(m,1H),3.22–3.10(m,2H),2.98(s,1H),2.96–2.88(m,1H),2.86(s,1H),2.81–2.51(m,3H),2.36–2.33(m,1H),2.24–2.09(m,2H),2.08–2.01(m,5H),2.01–1.91(m,4H),1.88(d,3H),1.85–1.74(m,2H),1.49–1.31(m,2H),1.01-0.93(m,6H).
化合物29-2的三氟乙酸盐:
LC-Ms m/z(ESI):714.2[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.45(d,1H),7.88(d,1H),7.25–7.09(m,4H),6.88(d,1H),5.86–5.78(m,1H),5.73–5.64(m,1H),3.75–3.64(m,1H),3.43–3.37(m,1H),3.24–3.03(m,2H),3.01–2.90(m,4H),2.86–2.50(m,3H),2.41–2.29(m,1H),2.25–2.11(m,2H),2.11–1.97(m,9H),1.89–1.73(m,4H),1.39–1.26(m,2H),0.95–0.86(m,6H).
实施例30:化合物30及异构体的制备
第一步:30b的合成
在氮气保护下,将30a(1.76g,8.26mmol)溶于1,4-二氧六环(60mL)中,依次加入联硼酸频那醇酯(3.15g,12.39mmol),PdCl2(dppf)(0.60g,0.83mmol)和乙酸钾(2.43g,24.78mmol),100℃反应2h。加入乙酸乙酯(180mL)进行萃取,水(50mL×2)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到22b(1.35g,收率:62.86%)。
参考化合物20的制备方法,以30b和中间体6为起始原料,得到化合物30粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物30-1的三氟乙酸盐(10mg,Rt=4.121min,收率10.4%)和化合物30-2的三氟乙酸盐(10mg,Rt=4.175min,收率10.4%)。
化合物30-1的三氟乙酸盐:
LC-Ms m/z(ESI):704.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.90(d,1H),7.04(s,1H),6.84(s,1H),6.76(d,1H),5.85–5.76(m,1H),5.75–5.65(m,1H),4.52–4.42(m,2H),3.30–3.25(m,1H),3.24–3.15(m,2H),3.05–3.05(m,1H),3.05–2.87(m,10H),2.87–2.74(m,2H),2.69–2.55(m,1H),2.30–2.22(m,3H),2.11–1.86(m,4H),1.47–1.33(m,1H),1.00–0.89(m,6H).
化合物30-2的三氟乙酸盐:
LC-Ms m/z(ESI):704.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.90(s,1H),7.06(s,1H),6.88(s,1H),6.77(d,1H),5.84–5.74(m,1H),5.73–5.61(m,1H),4.54–4.44(m,2H),3.37–3.31(m,1H),3.26–3.18(m,2H),3.14–2.91(m,11H),2.90–2.75(m,2H),2.73–2.54(m,1H),2.32–2.24(m,3H),2.14–2.00(m,2H),1.87–1.77(m,2H),1.38–1.24(m,1H),0.98–0.83(m,6H).
实施例32:化合物32及异构体制备
参考实施例21的制备方法得到化合物32粗品,粗品经prep-HPLC分离提纯(方法2)得到化合物32-1的三氟乙酸盐(19mg,Rt=4.790min,收率8.93%)和化合物32-2的三氟乙酸盐(20mg,Rt=4.862min,收率8.46%)。
化合物32-1的三氟乙酸盐:
LC-Ms m/z(ESI):734.8[M+H]+
1H NMR(400MHz,CD3OD)δ9.23–9.07(m,1H),7.82(s,1H),6.89–6.78(m,3H),5.85–5.76(m,1H),5.74–5.64(m,1H),4.33–3.83(m,4H),3.51–3.35(m,1H),3.18–2.81(m,7H),2.50–2.39(m,2H),2.13–1.99(m,3H),1.94–1.83(m,6H),1.40–1.29(m,2H),1.27–1.16(m,6H),1.02–0.88(m,6H).
化合物32-2的三氟乙酸盐:
LC-Ms m/z(ESI):734.8[M+H]+
1H NMR(400MHz,CD3OD)δ7.94–7.73(m,1H),6.93–6.83(m,3H),5.84–5.65(m,2H),4.26–4.07(m,2H),4.00–3.83(m,2H),3.46–3.35(m,1H),3.19–2.77(m,7H),2.53–2.43(m,2H),2.16–2.03(m,2H),1.98(s,6H),1.87–1.70(m,2H),1.38–1.18(m,7H),0.97–0.81(m,6H).
实施例33:化合物33及异构体的制备
参考实施例21的制备方法得到化合物33粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物33-1(20mg,Rt=3.714min,收率7.50%)和化合物33-2(25mg,Rt=3.765min,收率9.38%)。
化合物33-1:
LC-Ms m/z(ESI):702.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.84(d,1H),7.52–7.42(m,2H),7.36–7.30(m,1H),6.87–6.80(m,1H),5.76–5.61(m,2H),3.05–2.83(m,7H),2.76–2.58(m,7H),2.54–2.41(m,2H),2.19–1.91(m,7H),1.43–1.31(m,1H),0.97–0.85(m,6H).
化合物33-2:
LC-Ms m/z(ESI):702.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.83–7.78(m,1H),7.53–7.45(m,2H),7.40–7.33(m,1H),6.92–6.87(m,1H),5.87–5.79(m,1H),5.68–5.58(m,1H),3.28–3.14(m,2H),3.06–2.94(m,4H),2.85–2.75(m,7H),2.62–2.42(m,3H),2.21–2.16(m,3H),2.13–2.02(m,2H),1.97–1.85(m,1H),1.81–1.70(m,1H),1.40–1.27(m,1H),0.94–0.81(m,6H).
实施例35:化合物35的制备
第一步:35b的合成
在氮气保护下,将中间体9(合成参照WO2021076902)(390mg,1.08mmol)溶于干燥的DMF(5mL)中,依次加入HATU(750mg,1.97mmol)、DIPEA(510mg,3.98mmol)。室温搅拌40min后,加入中间体21a(400mg,0.99mmol),室温反应过夜,加入乙酸乙酯(80mL),依次用水(20mL×2)和饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,硅胶柱柱层析得到35b(500mg,收率:67.72%)。
LC-Ms m/z(ESI):746.8[M+H]+
第二步:化合物35-1和化合物35-2的合成
将35b(500mg,0.67mmol)溶于9mL THF和3mL水中,加入一水氢氧化锂(40mg,1.68mmol),室温反应30min。用1N盐酸调pH为5-6,减压浓缩得到化合物35粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物35-1(21mg,Rt=4.109min,收率4.37%)和化合物35-2(22mg,Rt=4.204min,收率4.57%)。
化合物35-1的
LC-Ms m/z(ESI):718.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.77(s,1H),6.88(s,1H),6.68(s,2H),5.75–5.68(m,1H),5.68–5.60(m,1H),4.06–3.95(m,4H),3.78(s,3H),3.00–2.82(m,5H),2.69–2.59(m,1H),2.51–2.37(m,4H),2.11–2.01(m,2H),2.00–1.86(s,9H),1.46–1.34(m,1H),0.97–0.86(m,6H).
化合物35-2的
LC-Ms m/z(ESI):718.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.66(s,1H),6.92(s,1H),6.70(s,2H),5.92–5.85(m,1H),5.63–5.56(m,1H),4.17–4.06(m,4H),3.79(s,3H),3.46–3.32(m,2H),3.02–2.88(m,3H),2.87–2.72(m,2H),2.53–2.39(m,5H),2.14–2.03(m,2H),2.00–1.90(m,7H),1.77–1.68(m,1H),1.43–1.31(m,1H),0.93–0.84(m,6H).
实施例36:化合物36的制备
参照实施例35的制备方法得到化合物36粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物36-1(19mg,Rt=5.540min,收率6.57%)和化合物36-2(21mg,Rt=5.599min,收率7.26%)。
化合物36-1的
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.86(s,1H),6.91–6.78(m,3H),5.83–5.66(m,2H),4.43–4.01(m,4H),3.45–3.33(m,2H),3.15–3.04(m,1H),2.99–2.76(m,5H),2.68–2.54(m,1H),2.53–2.37(m,3H),2.11–1.99(m,3H),1.97–1.83(m,7H),1.47–1.33(m,1H),1.00–0.89(m,6H).
化合物36-2的
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.67(s,1H),6.95–6.84(m,3H),5.94–5.85(m,1H),5.64–5.55(m,1H),4.17–4.04(m,4H),3.46–3.33(m,2H),3.04–2.71(m,5H),2.53–2.39(m,5H),2.16–2.03(m,2H),2.01–1.87(m,7H),1.77–1.67(m,1H),1.42–1.30(m,1H),0.93–0.82(m,6H).
实施例37:化合物37的制备
参考实施例20的制备方法,得到化合物37粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物37-1(18mg,Rt=5.359min,收率6.21%)和化合物37-2(19mg,Rt=5.401min,收率6.56%)。
化合物37-1的:
LC-Ms m/z(ESI):690.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.12(s,1H),6.98(d,1H),6.83(s,1H),6.73(d,1H),5.74–5.64(m,2H),4.56(t,2H),3.26–3.17(m,2H),3.12–3.02(m,2H),2.98–2.84(m,5H),2.79–2.65(m,9H),2.08–1.94(m,4H),1.46–1.35(m,1H),0.97–0.91(m,6H).
化合物37-2的:
LC-Ms m/z(ESI):690.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.80(s,1H),7.16(s,1H),7.02(d,1H),6.91(s,1H),6.77(d,1H),5.85–5.77(m,1H),5.69–5.60(m,1H),4.58(t,2H),3.29–3.12(m,4H),3.05–2.89(m,4H),2.83–2.72(m,9H),2.57–2.48(m,1H),2.11–2.00(m,2H),1.96–1.88(m,1H),1.81–1.70(m,1H),1.41–1.28(m,1H),0.93–0.82(m,6H).
实施例38:化合物38的制备
第一步:38b的合成
在氮气保护下,将38a(3g,14.91mmol)和联硼酸频那醇酯(4.54g,17.88mmol),碳酸钾(2.06g,14.91mmol),PdCl2(dppf).DCM(CAS:95464-05-4))(1.22g,1.49mmol)溶于1.4-二氧六环(30mL)和水(3mL)中,100℃回流过夜反应,加入水(20mL),乙酸乙酯萃取(30ml×3),饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到38b(2.8g,收率75.68%)。
第二步:38c的合成
将38b(2.8g,11.28mmol)溶于二氯甲烷(20mL)溶液中,冰浴下分批缓缓加入NaH(0.54g,22.5mmol),搅拌20分钟后,加入氘代碘甲烷(3.27g,22.56mmol),过夜反应。加入水(20mL),乙酸乙酯萃取(30ml×3),饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,减压浓缩后,快速柱层析得到38c(1.9g,收率63.52%)。
第三步至第六步参照实施例21的制备方法得到化合物38粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物38-1(20mg,Rt=4.048min,收率9.41%)和化合物38-2(25mg,Rt=4.301min,收率11.76%)。
化合物38-1的:
LC-Ms m/z(ESI):709.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.83(s,1H),6.82(s,1H),6.68–6.62(m,2H),5.74–5.63(m,2H),3.00–2.83(m,7H),2.71–2.58(m,7H),2.48–2.39(m,2H),2.08–1.93(m,4H),1.91(s,3H),1.83(s,3H),1.46–1.34(m,1H),0.97–0.88(m,6H).
化合物38-2的:
LC-Ms m/z(ESI):709.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.85(s,1H),6.90(s,1H),6.69(s,2H),5.81–5.74(m,1H),5.71–5.64(m,1H),3.29–3.18(m,2H),3.06–2.82(m,11H),2.73–2.62(m,1H),2.53–2.43(m,2H),2.13–2.01(m,2H),1.94(s,6H),1.91–1.82(m,1H),1.82–1.72(m,1H),1.41–1.26(m,1H),0.94–0.82(m,6H).
实施例39:化合物39的制备
参照中间体6及化合物21的制备方法,得到化合物39粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物39-1(28mg,Rt=4.070min)和化合物39-2(30mg,Rt=4.143min)。
化合物39-1的:
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.85(s,1H),6.83(s,1H),6.67(s,2H),5.72–5.63(m,2H),3.78(s,3H),3.11–2.99(m,2H),2.98–2.86(m,5H),2.75–2.62(m,7H),2.48–2.40(m,2H),2.09–2.00(m,2H),1.99–1.94(m,2H),1.92(s,3H),1.85(s,3H),1.47–1.33(m,1H),0.99–0.87(m,6H).
化合物39-2的:
LC-Ms m/z(ESI):706.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.80(s,1H),6.90(s,1H),6.69(s,2H),5.86–5.79(m,1H),5.65–5.59(m,1H),3.79(s,3H),3.28–3.10(m,2H),3.02–2.93(m,4H),2.83–2.72(m,7H),2.58–2.44(m,3H),2.13–2.01(m,2H),1.97–1.87(m,7H),1.79–1.70(m,1H),1.41–1.29(m,1H),0.93–0.83(m,6H).
实施例40:化合物40的制备
参照化合物38的制备方法,得到化合物40粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物40-1(11mg,Rt=4.152min)和化合物40-2(10mg,Rt=4.238min)。
化合物40-1的:
LC-Ms m/z(ESI):721.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.76(s,1H),6.88(s,1H),6.67(s,2H),5.75–5.68(m,1H),5.67–5.59(m,1H),4.03–3.90(m,4H),3.35–3.22(m,2H),3.00–2.92(m,2H),2.92–2.80(m,3H),2.67–2.59(m,1H),2.51–2.36(m,4H),2.11–2.00(m,2H),1.99–1.92(m,5H),1.89(s,3H),1.47–1.35(m,1H),0.98–0.87(m,6H).
化合物40-2的:
LC-Ms m/z(ESI):721.7[M+H]+
1H NMR(400MHz,CD3OD)δ7.66(s,1H),6.92(s,1H),6.69(s,2H),5.89(dd,1H),5.59(t,1H),4.16–4.03(s,4H),3.45–3.33(m,2H),3.03–2.70(m,5H),2.53–2.38(m,5H),2.13–2.03(m,2H),2.00–1.88(m,7H),1.79–1.68(m,1H),1.43–1.33(m,1H),0.95–0.83(m,6H).
实施例41:化合物41的制备
参照化合物9制备方法,得到化合物41的粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物41-1(20mg,Rt=4.286min)和化合物41-2(25mg,Rt=4.371min)。
化合物41-1的:
LC-Ms m/z(ESI):750.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.80(s,1H),6.80(s,1H),6.69–6.63(m,2H),5.74–5.66(m,2H),3.78(s,3H),3.73–3.47(m,4H),3.05–2.87(m,5H),2.82–2.74(m,1H),2.73–2.60(m,2H),2.48–2.40(m,2H),2.09–1.98(m,2H),1.98–1.88(m,5H),1.83(s,3H),1.63–1.52(m,3H),1.47–1.36(m,1H),0.99–0.90(m,6H).
化合物41-2的:
LC-Ms m/z(ESI):750.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.74(s,1H),6.88(s,1H),6.69(s,2H),5.84–5.76(m,1H),5.70–5.62(m,1H),4.03–3.75(m,7H),3.20–3.13(m,2H),3.02–2.94(m,2H),2.91–2.70(m,3H),2.68–2.59(m,1H),2.53–2.45(m,2H),2.13–2.02(m,2H),1.97–1.83(m,7H),1.81–1.71(m,1H),1.66–1.55(m,3H),1.40–1.29(m,1H),0.95–0.83(m,6H).
实施例42:化合物42的制备
参照化合物35的制备方法,得到化合物42粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物42-1(15mg,Rt=4.071min)和化合物42-2(18mg,Rt=4.228min)。
化合物42-1的:
LC-Ms m/z(ESI):683.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.29(s,1H),6.69(s,2H),5.56(dd,1H),5.49(t,1H),5.34–5.12(m,1H),4.32–4.08(m,2H),3.93–3.82(m,1H),3.80–3.69(m,4H),3.49–3.33(m,2H),3.00–2.85(m,3H),2.85–2.75(m,1H),2.66–2.43(m,4H),2.24–2.14(m,4H),2.12–2.02(m,2H),1.96–1.90(m,6H),1.79–1.70(m,1H),1.41–1.28(m,1H),0.91–0.83(m,6H).
化合物42-2的:
LC-Ms m/z(ESI):683.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.28–7.24(m,1H),6.69(s,2H),5.73(dd,1H),5.66–5.59(m,1H),5.40–5.17(m,1H),4.43–4.26(m,2H),4.10–3.88(m,2H),3.79(s,3H),3.49–3.40(m,2H),3.02–2.83(m,4H),2.70–2.60(m,1H),2.55–2.44(m,3H),2.21–2.15(m,3H),2.14–2.02(m,3H),1.96–1.91(m,6H),1.88–1.78(m,1H),1.41–1.27(m,1H),0.91–0.82(m,6H).
实施例43:化合物43的制备
参照化合物35的制备方法,得到化合物42粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物43-1(98mg,Rt=4.126min)和化合物43-2(103mg,Rt=4.303min)。
化合物43-1:
LC-Ms m/z(ESI):671.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.32–7.27(m,1H),6.92–6.82(m,2H),5.60–5.47(m,2H),5.33–5.08(m,1H),4.19–3.96(m,2H),3.81–3.61(m,2H),3.37–3.23(m,2H),3.02–2.92(m,2H),2.90–2.70(m,2H),2.67–2.54(m,2H),2.52–2.41(m,2H),2.24–2.13(m,4H),2.13–2.02(m,2H),1.99–1.94(m,6H),1.80–1.70(m,1H),1.42–1.26(m,1H),0.92–0.81(m,6H).
化合物43-2:
LC-Ms m/z(ESI):671.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.29–7.25(m,1H),6.90–6.84(m,2H),5.76–5.69(m,1H),5.65–5.58(m,1H),5.41–5.19(m,1H),4.44–4.31(m,2H),4.12–3.92(m,2H),3.50–3.44(m,2H),3.02–2.84(m,4H),2.70–2.61(m,1H),2.54–2.45(m,3H),2.20–2.16(m,3H),2.14–2.03(m,3H),1.99–1.93(m,6H),1.88–1.79(m,1H),1.40–1.27(m,1H),0.90–0.83(m,6H).
实施例44:化合物44的制备
参照化合物35的制备方法,得到化合物44粗品,粗品经prep-HPLC分离提纯(方法1)得到化合物44-1(84mg,Rt=4.315min)和化合物44-2(96mg,Rt=4.398min)。
化合物44-1的:
LC-Ms m/z(ESI):738.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.79(s,1H),6.88–6.80(m,2H),6.79(s,1H),5.74–5.64(m,2H),3.63–3.38(m,4H),3.02–2.90(m,3H),2.88–2.80(m,2H),2.80–2.71(m,1H),2.71–2.57(m,2H),2.49–2.39(m,2H),2.10–2.01(m,2H),2.00–1.91(m,5H),1.85–1.82(m,3H),1.56(d,3H),1.47–1.36(m,1H),0.99–0.89(m,6H).
化合物44-2的:
LC-Ms m/z(ESI):738.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.74(s,1H),6.91–6.84(m,3H),5.83–5.76(m,1H),5.70–5.61(m,1H),4.02–3.75(m,4H),3.20–3.13(m,2H),3.04–2.94(m,2H),2.91–2.70(m,3H),2.69–2.60(m,1H),2.53–2.44(m,2H),2.14–2.03(m,2H),1.98(s,6H),1.94–1.84(m,1H),1.83–1.71(m,1H),1.63–1.58(m,3H),1.42–1.28(m,1H),0.94–0.84(m,6H).
实施例45:化合物45的制备
以(S)-叔丁基亚磺酰胺及6c为起始原料,参照中间体6及化合物35的制备方法,得到化合物45粗品,粗品经prep-HPLC分离提纯(方法1)化合物45-1(5mg,保留时间=3.918min)和化合物45-2(6mg,保留时间=4.001min)。
化合物45-1:LC-Ms m/z(ESI):718.3[M+H]+
化合物45-2:LC-Ms m/z(ESI):718.3[M+H]+
实施例46:化合物46的合成
第一步:46b的合成
室温下,将2-硫脲嘧啶(10g,78.03mmoL),碳酸钾(32g,234.02mmoL)溶于四氢呋喃溶液(500mL)中,加入碘甲烷(15mL,234.04mmoL)反应3小时。加水用乙酸乙酯(50mL×3次)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物经硅胶柱层析纯化得到46b(6.8g,收率:55.79%)。
LC-Ms m/z(ESI):157.2[M+H]+
第二步:46c的合成
室温下,将46b(6.8g,43.54mmoL)溶于1,4-二氧六环和水的混合溶液(5:1,200mL)中,加入过氧单磺酸钾(40.15g,65.31mmoL),100℃反应4小时。加水用乙酸乙酯(50mL×3次)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物经硅胶柱层析纯化得到化合物46c(4.9g,收率:89.24%)。
LC-Ms m/z(ESI):127.2[M+H]+
第三步:46d的合成
室温下,将46c(4.9g,38.87mmoL)溶于50mL乙腈中,分别加入N-溴代丁二酰亚胺(6.92g,38.87mmoL),冰醋酸(0.22mL,3.85mmoL)反应4个小时。加入碳酸氢钠水溶液淬灭反应,乙酸乙酯(50毫升×3次)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物经硅胶柱层析纯化得化合物46d(5.5g,收率:69.02%)。
LC-Ms m/z(ESI):206.1[M+H]+
第四步:46e的合成
室温下,将46d(5.5g,26.83mmoL),中间体2-(甲磺酰氧基)-4-甲基戊酸乙酯(7.67g,32.20mmoL)溶于乙腈(80mL)中,加入碳酸钾(11.12g,80.53mmoL),随后升至80℃过夜反应。硅藻土过滤反应液,乙酸乙酯(30mL×3次)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物经硅胶柱层析纯化得到化合物46e(4.7g,收率:50.45%)。
LC-Ms m/z(ESI):348.2[M+H]+
第五步:46f的合成
将46e(4.7g,13.54mmoL),(E)-1-乙氧乙烯基-2-硼酸频那醇酯(3.22g,16.25mmoL)溶于1,4-二氧六环和水中(v/v=10:1,110mL),加入碳酸钾(5.61g,40.62mmoL),四三苯基膦钯(1.56g,1.35mmoL),氮气置换3次,70℃反应24小时。加水淬灭,乙酸乙酯(30mL×3次)萃取,合并有机相,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残余物经硅胶柱层析纯化得46f(1.8g,收率:39.28%)。
LC-Ms m/z(ESI):339.4[M+H]+
第六步:化合物46g的合成
将46f(1.8g,5.32mmoL)溶于二氯甲烷(20mL)中,缓缓加入三氟乙酸(10mL,134.19mmoL),室温下过夜反应。减压浓缩,加入碳酸氢钠水溶液调节pH至中性,乙酸乙酯(20mL×2次)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得46g的粗品,无需纯化直接进行下一步反应。
第七至十步:化合物46的合成
以46g为起始原料,参照化合物3的合成路线及制备方法,得到化合物46的粗品,粗品经prep-HPLC分离提纯((制备方法1)得到化合物46-1(20mg,保留时间=4.122min)和化合物46-2(18mg,保留时间=4.250min)。
化合物46-1的:
LC-Ms m/z(ESI):713.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.70(s,1H),6.68(s,2H),5.73–5.65(m,1H),5.45–5.37(m,1H),4.47–4.26(m,4H),3.79(s,3H),3.56–3.38(m,2H),3.25(s,3H),3.12–3.02(m,1H),2.99–2.91(m,2H),2.89–2.81(m,1H),2.80–2.71(m,1H),2.66–2.56(m,1H),2.52–2.39(m,2H),2.10–2.01(m,2H),2.00–1.90(m,4H),1.89–1.75(m,4H),1.71–1.61(m,3H),1.54–1.43(m,1H),1.00–0.91(m,6H).
化合物46-2的:
LC-Ms m/z(ESI):713.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.71(s,1H),6.70(s,2H),5.74–5.64(m,1H),5.48–5.40(m,1H),4.52–4.26(m,4H),3.79(s,3H),3.58–3.38(m,2H),3.32(s,3H),3.09–3.01(m,1H),3.00–2.93(m,2H),2.91–2.72(m,2H),2.66–2.56(m,1H),2.53–2.44(m,2H),2.12–2.01(m,2H),1.94(s,6H),1.83–1.73(m,1H),1.71–1.60(m,4H),1.45–1.32(m,1H),0.95–0.85(t,6H).
实施例47:化合物47的制备
参照化合物35的合成路线及制备方法,得到化合物47粗品,粗品经prep-HPLC分离提纯((制备方法2))得到化合物47-1(40mg,保留时间=4.179min)和化合物47-2(45mg,保留时间=4.271min)。
化合物47-1的三氟乙酸盐:
LC-Ms m/z(ESI):706.3[M+H]+
1H NMR(400MHz,CD3OD)δ9.26(d,1H),7.86(s,1H),7.15–7.05(m,1H),7.02–6.93(m,1H),6.82(s,1H),5.85–5.65(m,2H),4.42–4.03(m,4H),3.44–3.33(m,2H),3.15–3.05(m,1H),3.00–2.78(m,5H),2.67–2.53(m,1H),2.51–2.36(m,3H),2.13–1.99(m,3H),1.97–1.76(m,7H),1.47–1.35(m,1H),1.00–0.90(m,6H).
化合物47-2的三氟乙酸盐:
LC-Ms m/z(ESI):706.3[M+H]+
1H NMR(400MHz,CD3OD)δ9.38(d,1H),7.88(s,1H),7.17–7.10(m,1H),7.04–6.96(m,1H),6.88(s,1H),5.83–5.66(m,2H),4.42–4.05(m,4H),3.50–3.33(m,2H),3.11–2.95(m,3H),2.95–2.80(m,3H),2.71–2.56(m,1H),2.53–2.39(m,3H),2.15–2.04(m,2H),1.95(s,3H),1.90(d,3H),1.87–1.71(m,2H),1.37–1.23(m,1H),0.98–0.83(m,6H).
实施例48:化合物48的制备
参照化合物35的合成路线及制备方法,得到化合物48粗品,粗品经prep-HPLC分离提纯(制备方法2)得到化合物48-1(54mg,保留时间=4.179min)和化合物48-2(62mg,保留时间=4.271min)。
化合物48-1的三氟乙酸盐:
LC-Ms m/z(ESI):694.3[M+H]+
1H NMR(400MHz,CD3OD)δ9.23(d,1H),7.90(s,1H),7.13–7.04(m,1H),7.01–6.91(m,1H),6.82(s,1H),5.82–5.74(m,1H),5.73–5.64(m,1H),3.36–3.22(m,2H),3.15–2.83(m,12H),2.52–2.36(m,2H),2.13–1.98(m,3H),1.97–1.74(m,7H),1.48–1.35(m,1H),1.01–0.94(m,6H).
化合物48-2的三氟乙酸盐:
LC-Ms m/z(ESI):694.3[M+H]+
1H NMR(400MHz,CD3OD)δ9.35(d,1H),7.92(s,1H),7.16–7.08(m,1H),7.04–6.94(m,1H),6.88(s,1H),5.82–5.64(m,2H),3.39–3.24(m,2H),3.10–2.84(m,12H),2.55–2.45(m,2H),2.16–2.03(m,2H),1.95(s,3H),1.90(d,3H),1.87–1.71(m,2H),1.38–1.23(m,1H),0.98–0.81(m,6H).
实施例49:化合物49的制备
第一步:化合物49B的合成
冰浴下,将底物49A(5.00g,24.99mmo)溶于10%硫酸水溶液(50mL),然后将亚硝酸钠(1.72g,24.99mmol)溶于水(10mL)中滴加至体系中,加毕,冰浴下继续反应1小时;再向体系滴加50%硫酸水溶液(50mL),加毕,升温至100℃反应1小时。冷却反应体系至室温,将反应液缓慢倒入搅拌的冰水(300mL)中,继续搅拌30分钟,乙酸乙酯(50mL×3)萃取水相,合并有机相,无水硫酸钠干燥,过滤浓缩得粗品,粗品经硅胶柱层析纯化得49B(2.89g,产率57.52%)。
第二步:化合物49C的合成
将底物49B(2.89g,14.37mmo)溶于乙腈(30mL)中,然后加入碳酸钾(3.97g,28.72mmol)和碘甲烷(3.06g,21.55mmol),加毕,氮气氛围下,升温至60℃反应18小时。冷却反应至室温,过滤并用乙酸乙酯(5mL×2)洗涤滤饼,收集并浓缩滤液得粗品,粗品经硅胶柱层析纯化得49C(2.65g,产率85.74%)。
第三步:化合物49D的合成
将底物49C(2.65g,12.32mmol)溶于超干四氢呋喃(40mL)中,氮气氛围下,-78℃预冷10分钟,缓慢滴加正丁基锂(0.89g,13.91mmol),加毕,-78℃继续搅拌1小时,再向体系滴加硼酸三甲酯(1.71g,16.47mmol),加毕,氮气氛围下,自然升温至室温反应18小时。冰浴下,将反应倒入10%盐酸水溶液(50mL)中,冰浴下搅拌30分钟,乙酸乙酯(30mL 3)萃取,合并有机相,无水硫酸钠干燥,过滤浓缩得粗品,粗品经硅胶柱层析纯化得49D(0.84g,产率37.88%)。
参照化合物35的合成路线及制备方法,得到化合物49粗品,粗品经prep-HPLC分离提纯(制备方法1)得到化合物49-1(32mg,保留时间=4.218min)和化合物49-2(35mg,保留时间=4.303min)。
化合物49-1:
LC-Ms m/z(ESI):718.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.76(s,1H),7.06(d,1H),6.88(s,1H),6.85(d,1H),5.75–5.68(m,1H),5.67–5.59(m,1H),4.05–4.39(m,4H),3.82(s,3H),3.37–3.31(m,2H),2.96(t,2H),2.92–2.82(m,3H),2.69–2.60(m,1H),2.49–2.36(m,4H),2.12–2.01(m,2H),2.00–1.92(m,2H),1.89–1.76(m,6H),1.47–1.34(m,1H),0.97–0.87(m,6H).
化合物49-2:
LC-Ms m/z(ESI):718.3[M+H]+
1H NMR(400MHz,CD3OD)δ7.66(s,1H),7.08(d,1H),6.92(s,1H),6.86(d,1H),5.92–5.86(m,1H),5.60(t,1H),4.11(t,4H),3.83(s,3H),3.46–3.32(m,2H),3.03–2.87(m,3H),2.86–2.71(m,2H),2.53–2.39(m,5H),2.13–2.02(m,2H),1.99–1.92(m,1H),1.91–1.81(m,6H),1.78–1.67(m,1H),1.43–1.32(m,1H),0.93–0.84(m,6H).
实施例50:化合物50的制备
参照化合物35的合成路线及制备方法,得到化合物50粗品,粗品经prep-HPLC分离提纯((制备方法1))得到化合物50-1(35mg,保留时间=4.184min)和化合物50-2(37mg,保留时间=4.260min)。
化合物50-1:
LC-Ms m/z(ESI):706.4[M+H]+
1H NMR(400MHz,CD3OD)δ7.85(s,1H),7.08–7.02(m,1H),6.87–6.81(m,2H),5.72–5.63(m,2H),3.82(s,3H),3.14–3.00(m,2H),2.99–2.87(m,5H),2.71(m,6H),2.70–2.63(m,1H),2.46–2.39(m,2H),2.09–2.00(m,2H),1.99–1.91(m,2H),1.89–1.72(m,6H),1.47–1.35(m,1H),0.97–0.88(m,6H).
化合物50-2:
LC-Ms m/z(ESI):706.4[M+H]+
1H NMR(400MHz,CD3OD)δ7.79(s,1H),7.08(d,1H),6.90(s,1H),6.86(d,1H),5.87–5.78(m,1H),5.61(t,1H),3.83(s,3H),3.25–3.11(m,2H),3.03–2.92(m,4H),2.83–2.72(m,7H),2.58–2.50(m,1H),2.46(t,2H),2.14–2.02(m,2H),1.98–1.91(m,1H),1.90–1.81(m,6H),1.79–1.69(m,1H),1.42–1.31(m,1H),0.94–0.81(m,6H).
生物测试:
1.整合素α4β7ELISA检测试验:
将MAdCAM用TBS缓冲液配置成2.5ug/ml的终浓度,转移50ul溶液到96孔板中,在4℃过夜包被。TBS缓冲液清洗板子3次,然后加入150ul的封闭液(含有1%BSA的TBS缓冲液),
在37℃封闭1h。TBS缓冲液清洗板子3次,使用含有0.1%BSA的TBS缓冲液配置1ug/ml的α4β7整合素蛋白,转移50ul整合素蛋白到96孔板,再加入1ul不同浓度的化合物或者DMSO,在常温下孵育2h。使用含有0.1%BSA的TBS缓冲液配置1ug/ml的Biotinylated anti-β7抗体,将板子用TBS缓冲液清洗3次,加入50ul的抗体,在常温孵育1h。TBS缓冲液清洗板子3次,加入50ul的Streptavidin-HRP,在常温孵育20min。TBS缓冲液清洗板子3次,加入50ul的TMB底物,在常温孵育5-30min。最后加入25ul的终止缓冲液(高浓度的磷酸盐溶液),在酶标仪450nm处,读取板子的OD值。运用GraphPad Prism 6软件计算IC50值。
结论:本发明化合物,例如实施例化合物对整合素α4β7具有良好的抑制活性。
2.整合素α4β7细胞粘附试验
将MAdCAM-1用TBS缓冲液配置成2μg/ml的终浓度,转移50μl溶液到96孔板中,在4°C过夜包被。TBS缓冲液清洗板子3次,然后加入150μl的封闭液(含有1%BSA的TBS缓冲液),在37℃封闭1h。收集RPMI8866细胞,使用DPBS缓冲液清洗2次,然后用TBS缓冲液重悬细胞至4×105cells/ml,转移50μl的细胞液到96孔板,使细胞密度为2×105cells/well,再加入1μl不同浓度的化合物或者DMSO,在37℃孵育1h或2h。TBS缓冲液清洗板子,去除没有粘附的细胞,加入50μl的底物(4-nitrophenyl-N-acetyl-β-D-glucosaminide),在37℃下孵育2h,最终加入90μl的终止液(50mM glycine and 5mM EDTA,pH 10.4),酶标仪405nm处,读取板子的OD值。运用GraphPad Prism 6软件计算IC50值,结果见表1。
3.整合素α4β1细胞粘附实验
将VCAM用包被液Buffer配置成0.5μg/ml的终浓度,转移50μl溶液到96孔板中,在4℃过夜包被。包被液Buffer清洗板子3次,然后加入150μl的封闭液(含有1%BSA的包被液Buffer),在37℃封闭1h。收集Jurkat细胞,使用DPBS缓冲液清洗2次,然后用作用buffer重悬细胞至4×106cells/ml,转移50μl的细胞液到96孔板,使细胞密度为2×105cells/well,再加入1μl不同浓度的受试化合物或者DMSO,在37℃孵育1h。包被液Buffer清洗板子,去除没有粘附的细胞,加入50μl的底物(4-nitrophenyl-N-acetyl-β-D-glucosaminide),在37℃下孵育2h,最终加入90μl的终止液(50mM glycine and 5mM EDTA,pH 10.4),在405nm处,读取板子的OD值。
包被液Buffer:DMEM+20mM HEPES+0.4mM MnCl2
作用Buffer:DMEM+20mM HEPES+0.1%BSA+0.4mM MnCl2
DMEM:dulbecco's modified eagle medium;
HEPES:2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
表1化合物对α4β7和α4β1细胞粘附结果
A<10nM;对照化合物A为
结论:本发明化合物,例如实施例化合物对整合素α4β7介导的细胞粘附具有良好的抑制作用,且与对照化合物A相比,具有更好的选择性。
4.CYP450酶抑制测试
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育,加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应,在反应结束后,通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物,测定CYP酶活性的变化,计算IC50值,评价受试物对各CYP酶亚型CYP1A2、CYP2C9、CYP2D6、CYP3A4-M(以咪达***为底物)的抑制潜能。
结论:本发明化合物,例如实施例化合物对CYP酶各亚型均无明显的抑制作用。
5.小鼠药代动力学测试
试验动物:雄性BALB/c小鼠,20~25g,6只/化合物。购于成都达硕实验动物有限公司。
试验设计:试验当天,6只BALB/c小鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
表2.给药信息
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL,置于EDTAK2离心管中,5000rpm,4℃离心10min,收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前,所有样品存于-80℃,用LC-MS/MS对样品进行定量分析。
表3
结论:本发明化合物,例如实施例化合物在小鼠体内具有较好的口服吸收性能和清除率更低。
6.大鼠药代动力学测试
试验动物:雄性SD大鼠,220g左右,6~8周龄,6只/化合物。购于成都达硕实验动物有限公司。
试验设计:试验当天,6只SD大鼠/化合物,按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
表4.给药信息
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
于给药前及给药后异氟烷麻醉经眼眶取血0.10mL,置于EDTAK2离心管中,5000rpm,4℃离心10min,收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前,所有样品存于-80℃,用LC-MS/MS对样品进行定量分析。
表5
*对照化合物A iv 2.5mg/kg;PO:10mg/kg
*对照化合物A iv 2.5mg/kg;PO:10mg/kg
结论:本发明化合物,例如实施例化合物在大鼠体内具有较好的口服吸收性能或/和清除率更低。
7.比格犬药代动力学测试
试验动物:雄性比格犬,8~11kg左右,5-6只/化合物,购于北京玛斯生物技术有限公司。
试验方法:试验当天,比格犬5-6只/化合物按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
表6给药信息
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
于给药前及给药后通过颈静脉或四肢静脉取血1ml,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。G1和G2组静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h,48,72h。G3和G4组静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前,所有样品存于-80℃,用LC-MS/MS对样品进行定量分析。
结论:本发明化合物,例如实施例化合物在比格犬体内具有较好的口服吸收性能。
8.猴药代动力学测试
试验动物:雄性食蟹猴,3~5kg,3~6年龄,4-6只/化合物。购于苏州西山生物技术有限公司。
试验方法:试验当天,猴4-6只/化合物按体重随机分组。给药前1天禁食不禁水14~18h,给药后4h给食。
表7.给药信息
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
*剂量以游离碱计。
注:静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:5%DMSO+95%(20%
SBE-β-CD in saline)
(DMA:二甲基乙酰胺;Solutol:聚乙二醇-15-羟基硬脂酸酯;Saline:生理盐水;DMSO:
二甲亚砜;SBE-β-CD:磺丁基-β-环糊精)
*剂量以游离碱计。
于给药前及给药后通过四肢静脉取血1.0mL,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。静脉组和灌胃组采血时间点均为:0,5min,15min,30min,1,2,4,6,8,10,12,24h。分析检测前,所有样品存于-80℃,用LC-MS/MS对样品进行定量分析。
结论:本发明化合物,例如实施例化合物在猴体内具有较好的口服吸收性能。
9.hERG钾离子通道作用测试
实验平台:电生理手动膜片钳***
细胞系:稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系
实验方法:稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞,在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10,Sutter)经拉制仪拉制而成,灌注电极内液后的尖端电阻为2-5MΩ左右,将玻璃微电极***放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录,采样频率为10kHz,滤波频率为2kHz。在得到全细胞记录后,细胞钳制在-80mV,诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV,再复极化到-50mV,持续1s后回到-80mV。每10s给予此电压刺激,确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟,每个浓度至少测试2个细胞(n≥2)。
数据处理:数据分析处理采用pClamp 10,GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算:
Inhibition%=[1–(I/Io)]×100%
Inhibition%=[1–(I/Io)]×100%
其中,Inhibition%代表化合物对hERG钾电流的抑制百分率,I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
其中,X为供试品检测浓度的Log值,Y为对应浓度下抑制百分率,Bottom和Top分别为最小和最大抑制百分率。
结论:本发明化合物,例如实施例化合物无明显的hERG抑制活性。
10.肝微粒体稳定性测试
本实验采用猴、大鼠和小鼠三个种属肝微粒体作为体外模型来评价受试物的代谢稳定性。
在37℃条件下,1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育,反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应,采用LC-MS/MS方法检测样品中受试物浓度,以孵育体系中药物剩余率的ln值和孵育时间求得T1/2,并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。
表8肝微粒体稳定性结果
结论:本发明化合物,例如实施例化合物在猴、小鼠和大鼠的肝微粒体中具有较好的稳定性。
Claims (15)
- 一种化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I)所示的化合物,其中
R1选自-CHR1aR1b或-NR1aR1b;R1a选自C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代;R1b选自C4-10碳环、5至10元杂环,所述的碳环或者杂环任选被0至4个Rb取代,所述的杂环含有1至4个选自O、S、N的杂原子;Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-6烷基、-C0-4烷基-N(C1-6烷基)2、C1-6烷基、C2-6炔基、C1-6烷氧基、-C0-4烷基-C3-10碳环、-C0-4烷基-3至10元杂环或Rba,所述的烷基、炔基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、N(C1-6烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;Rba选自-C0-4烷基-7至12元杂环、-C0-4烷基-通过碳原子连接的4至6元杂环、 所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-6烷基、CON(C1-6烷基)2、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6炔基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-6烷基、-C1-4烷基-N(C1-6烷基)2、-C0-4烷基-C3-10碳环或-C0-4烷基-3至10元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基、C1-6烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;R2选自C1-6烷基、C6-10芳环、5至10元杂芳环、C3-10碳环、5至10元杂环,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;作为选择,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;R3选自H、C1-6烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C3-6碳环的取代基所取代;环A选自C8-10并环碳环,所述的环A任选被0至4个Ra5取代;或者环A选自所述环A被1个选自C2-6烯基或C2-6炔基的取代基所取代、任选被1至3个Ra5取代;Ra5选自卤素、OH、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子。 - 根据权利要求1所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,R1选自b选自0、1、2、3;Rb各自独立的选自氘、卤素、OH、=O、氰基、COOH、NH2、-C0-4烷基-NHC1-4烷基、-C0-4烷基-N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、-C0-4烷基-C3-6碳环、-C0-4烷基-3至7元杂环或Rba,所述的烷基、炔基、烷氧基、碳环或杂环任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环含有1至4个选自O、 S、N的杂原子;Rba选自-C0-2烷基-7至8元单环杂环烷基、-C0-2烷基-7至11元螺环杂环烷基、-C0-2烷基-7至11元桥环杂环烷基、-C0-2烷基-通过碳原子连接的4至6元单环杂环烷基、 所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;Rk选自-C1-2烷基-NH2、-C1-2烷基-NHC1-4烷基、-C1-2烷基-N(C1-4烷基)2、-C0-2烷基-C3-6碳环或-C0-2烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;R2选自C1-4烷基、苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-10非芳香碳环、5至10元非芳香杂环、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环含有1至4个选自O、S、N的杂原子;R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子;作为选择,R2a与R2a直接连接形成C4-7元碳环或者4至7元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;R3选自H、C1-4烷基,所述的烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环的取代基所取代;环A选自苯并C4-6碳环,所述的环A任选被0至4个Ra5取代;或者环A选自所述环A被1个选自C2-4烯基或C2-4炔基的取代基所取代、任选被1至3个选自Ra5取代;Ra5选自卤素、OH、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基或3至7元杂环基,所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、卤素取代的C1-4烷基、氰基取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代,所述杂环基含有1至3个选自N、O或S的杂原子。
- 根据权利要求2所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,Rb各自独立的选自氘、卤素、OH、=O、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、苯基、5至6元杂芳基、-CH2NHC1-4烷基、-CH2N(C1-4烷基)2、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、苯基、5至6元杂芳基、C3-6环烷基、3至7元杂环烷基、-CH2-苯基、-CH2-5至6元杂芳基、-CH2-C3-6环烷基、-CH2-3至7元杂环烷基、-CH2CH2-苯基、-CH2CH2-5至6元杂芳基、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基、Rba,所述的CH2、烷基、炔基、苯基、杂芳基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;Rba选自7至8元单环杂环烷基、7至11元螺环杂环烷基、7至11元桥环杂环烷基、通过碳原子连接的4至6元单环杂环烷基、-CH2-7至8元单环杂环烷基、-CH2-7至11元螺环杂环烷基、-CH2-7至11元桥环杂环烷基、-CH2-通过碳原子连接的4至6元单环杂环烷基、-CH2CH2-7至8元单环杂环烷基、-CH2CH2-7至11元螺环杂环烷基、-CH2CH2-7至11元桥环杂环烷基、-CH2CH2-通过碳原子连接的4至6元单环杂环烷基、所述Rba任选被1至4个选自H、卤素、OH、=O、氰基、COOH、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;Rk选自-C1-4烷基-NH2、-C1-4烷基-NHC1-4烷基、-C1-4烷基-N(C1-4烷基)2、-C0-4烷基-C3-6碳环或-C0-4烷基-3至6元杂环,所述的烷基、碳环或者杂环任选被1至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代,所述的杂环含有1至4个选自O、S、N的杂原子;R2选自苯环、萘环、5至6元杂芳环、9至10元杂芳环、C3-6环烷基、3至7元杂环烷基、苯并C4-6碳环基或苯并4至6元杂环基,所述R2任选被0至4个R2a取代,所述的杂芳环、杂环烷基含有1至4个选自O、S、N的杂原子;R2a各自独立的选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、烯基、炔基、烷氧基、环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;作为选择,R2a与R2a直接连接形成4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环,所说的碳环或杂环任选被1至4个选自氘、卤素、OH、氰基、=O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6环烷基、3至7元杂环烷基的取代基所取代,所述的烷基、烯基、炔基、烷氧基、环烷基或杂环烷基任选被1至4个选自氘、卤素、OH、氰基的取代基所取代;R3选自H、C1-4烷基,所述的烷基任选0至4个选自氘、卤素、C1-4烷基、C1-4烷氧基、苯环的取代基所取代;环A选自所述环A任选被0至4个Ra5取代;或者环A选自所述环A被1个选自C2-4烯基或C2-4炔基的取代基所取代、任选被1至3个选自Ra5取代;Ra5选自卤素、OH、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、C3-6环烷基,所述的烷基、炔基、烷氧基、环烷基、杂环基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代。
- 根据权利要求3所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,R1a选自甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、-CH2-环丙基、-CH2-环丁基;Rb各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2-苯基、-CH2-吡啶基、-CH2CH2-苯基、-CH2CH2-吡啶基,当被取代时,被0至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代;Rba选自任选取代的如下基团之一: 当被取代时,任选被1至4个选自氘、卤素、OH、=O、氰基、CONH2、CONHC1-4烷基、CON(C1-4烷基)2、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代;Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮 杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基任选被1至4个选自氘、卤素、OH、=O、氰基、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基的取代基所取代;R2选自苯环、吡啶基、吡啶酮基、吡嗪基、嘧啶基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、 所述R2任选被0至4个R2a取代;R2a各自独立的选自氘、F、Cl、Br、I、OH、=O、氰基、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基,所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基或环丁基任选被0至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基的取代基所取代;R3选自H、甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、苄基;环A选自所述环A任选被0至4个Ra5取代;或者环A选自所述环A被1个选自乙烯基、乙炔基、丙炔基、炔丙基的取代基所取代、任选被1至3个选自Ra5取代;Ra5各自独立的选自F、Cl、Br、I、OH、CN、乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基,所述的乙炔基、丙炔基、炔丙基、甲基、乙基、环丙基、甲氧基、乙氧基任选被1至4个选自氘、卤素、OH、=O、氰基、C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代。
- 根据权利要求4所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,R1选自Rb各自独立的选自氘、F、Cl、Br、OH、氰基、Rba,或者Rb各自独立的选自取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吗啉基、苯基、吡啶基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-氮杂环戊基、-CH2-氮杂环己基、-CH2-氧杂环丁基、-CH2-氧杂环戊基、-CH2-氧杂环己基、-CH2-吗啉基、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2-苯基、-CH2-吡啶基、-CH2CH2-苯基、-CH2CH2-吡啶基、当被取代时,被0至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;Rba选自任选取代的如下基团之一: 当被取代时,任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、CONH2、CONHCH3、CON(CH3)2、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代;Rk选自-CH2N(CH3)2、-CH2-环丙基、-CH2-环丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基,所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基任选被1至4个选自氘、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基的取代基所取代;R2选自苯基、吡啶基、吡啶酮基、氮杂环戊基、吗啉基、所述R2任选被0至4个选自氘、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;或者R2选自 所述R2任选被1至4个选自氘、CD3、-OCD3、F、Cl、Br、OH、CF3、氰基、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基的取代基所取代;环A选自
- 根据权利要求5所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,R1选自或者R1选自或者R1选自或者R1选自或者R1选自或者R1选自或者R1选自R2选自或者R2选自或者R2选自R1a选自
- 根据权利要求1所述化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-a)、(I-b)、通式(I-a-1)、(I-b-1)所示的化合物,
环A、R3的定义与权利要求2至6任意一项相同;p1选自0、1、2、3或4;R2a选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或者4至6元杂环烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被0至4个选自氘、卤素、OH、CN、C1-4烷基、C1-4烷氧基的取代基所取代,所述的杂环烷基含有1至4个选自O、S、N的杂原子;R1a选自Rb1选自H、C1-4烷基、C3-6环烷基,所述的烷基或者环烷基任选被0至4个选自氘、卤素、OH、CN、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基的取代基所取代;Rb2选自H、Rba、取代或者未取代的如下基团之一:C1-4烷基、C2-4炔基、C1-4烷氧基、苯基、5至6元杂芳基、-CH2CH2-苯基、-CH2CH2-5至6元杂芳基、-CH2CH2-NHC1-4烷基、-CH2CH2-N(C1-4烷基)2、-CH2CH2-C3-6环烷基、-CH2CH2-3至7元杂环烷基,所述的CH2、烷基、环烷基或杂环烷基任选被0至4个选自氘、卤素、OH、=O、氰基、COOH、NH2、NHC1-4烷基、N(C1-4烷基)2、N(C1-4烷基)(C3-6环烷基)、NH(C3-6环烷基)、C1-4烷基、C2-4炔基、C1-4烷氧基、卤素取代的C1-4烷基、卤素取代的C1-4烷氧基、C1-4烷氧基烷基或Rk的取代基所取代,所述的杂芳基或杂环烷基含有1至4个选自O、S、N的杂原子;Rba、Rk的定义与权利要求2至6任意一项相同。 - 根据权利要求7所述化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,R2a选自氘、-CD3、-OCD3、F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基;Rb1选自H、F、CH2F、CHF2、CF3、甲基、-CH2CH2N(CH3)2;Rb2选自H、Rba、取代或者未取代的如下基团之一:甲基、乙基、乙炔基、甲氧基、乙氧基、-CH2NH(CH2CH3)、-CH2N(CH2CH3)2、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-CH2CH2NH(CH2CH3)、-CH2CH2N(CH2CH3)2、-CH2CH2N(CH3)(CH2CH3)、-CH2CH2-环丙基、-CH2CH2-环丁基、-CH2CH2-环戊基、-CH2CH2-环己基、-CH2CH2-氮杂环丁基、-CH2CH2-氮杂环戊基、-CH2CH2-氮杂环己基、-CH2CH2-氧杂环丁基、-CH2CH2-氧杂环戊基、-CH2CH2-氧杂环己基、-CH2CH2-吗啉基、-CH2CH2-苯基、-CH2CH2-吡啶基,当被取代时,被1、2或3个选自H、F、Cl、Br、OH、=O、氰基、NH2、NHCH3、N(CH3)2、N(CH3)(环丙基)、NHCH2CH3、N(CH2CH3)2、CH2F、CHF2、CF3、甲基、乙基、异丙基、乙炔基、甲氧基、乙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基或Rk的取代基所取代。
- 根据权利要求1所述化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I-f)、(I-g)、(I-f-1)、(I-g-1)、(I-h)、(I-i)、(I-h-1)、(I-i-1)所示的化合物,
R1b选自p2选自0、1或2;Rak选自C2-4炔基;Ra5的定义与权利要求1至4任一项相同;其余基团的定义与权利要求7或8相同。 - 根据权利要求9所述化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,Rak选自乙炔基、丙炔基、炔丙基;Ra5选自F、Cl、Br、I、OH、氰基、甲基、乙基、甲氧基、乙氧基、乙炔基。
- 根据权利要求1所述化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中该化合物表E-1、表E-3、表E-4、表E-5所示结构之一。
- 一种药物组合物,包括权利要求1-11任意一项所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及要学上可接受的载体,优选地,药物组合物中包含1-1500mg的权利要求1-11任意一项所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
- 根据权利要求1-12任意一项所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求12所述的药物组合物在用于制备治疗与α4β7活性或表达量相关疾病的药物中的应用。
- 根据权利要求13所述的应用,其中,所述的疾病选自肠道炎症疾病。
- 一种用于治疗哺乳动物的疾病的方法,所述方法包括给予受试者治疗有效量的权利要求 1-11任意一项所述的化合物或者其立体异构体、消旋体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求12所述的药物组合物,治疗有效量优选1-1500mg,所述的疾病优选肠道炎症疾病。
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