CN117279923A - Derivative of six-membered heteroaromatic urea ring and application thereof - Google Patents
Derivative of six-membered heteroaromatic urea ring and application thereof Download PDFInfo
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- CN117279923A CN117279923A CN202280031344.1A CN202280031344A CN117279923A CN 117279923 A CN117279923 A CN 117279923A CN 202280031344 A CN202280031344 A CN 202280031344A CN 117279923 A CN117279923 A CN 117279923A
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- 125000001072 heteroaryl group Chemical group 0.000 title description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 14
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 5
- 206010055171 Hypertensive nephropathy Diseases 0.000 claims abstract description 5
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 150
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- -1 2 -pyridinyl Chemical group 0.000 claims description 21
- 229910052740 iodine Inorganic materials 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 94
- 239000000243 solution Substances 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 239000000203 mixture Substances 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 29
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 21
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 20
- 239000012071 phase Substances 0.000 description 19
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 15
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000012131 assay buffer Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 108010044467 Isoenzymes Proteins 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 210000001853 liver microsome Anatomy 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
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- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
A six-membered heteroaromatic urea ring derivative shown in formula (I) and application thereof in preparing medicaments for treating diabetic nephropathy or hypertensive nephropathy.
Description
The present application claims priority as follows:
CN202110462009.4, 2021, 04, 27;
CN202210307799.3, 2022, 25 days 03.
The invention discloses a six-membered heteroaromatic urea ring derivative and application thereof, and particularly discloses a compound shown in a formula (I) and pharmaceutically acceptable salts thereof.
Soluble guanylate cyclase (sGC) is widely found in mammalian cytosol and is a heterodimer composed of two subunits, α and β, which in turn have two subunits α1, α2 and β1, β2, respectively. α1β1 dimer is mainly distributed in cardiovascular tissues, the expression level is positively correlated with the degree of tissue vascularization, while α2β1 dimer is mainly expressed in brain and nervous system. Although there are large differences in tissue distribution and cell localization, they have a similar role in maintaining sGC enzyme function.
Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway, and sGC catalyzes the conversion of Guanosine Triphosphate (GTP) to cyclic guanosine phosphate (cGMP) upon activation in vivo. cGMP is an important secondary messenger molecule that initiates a downstream cascade of physiological functions in the gastrointestinal system, the blood circulation system and the nervous system, such as promotion of vasodilation of blood vessels and smooth muscle, inhibition of platelet aggregation, vascular remodeling, apoptosis and inflammation occurrence, and participation in neurotransmission, etc., by activating various effector molecules downstream thereof, such as Phosphodiesterase (PDE), cyclic nucleotide-gated ion Channel (CNG), protein Kinase G (PKG), etc. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction, etc. In recent two years, studies have shown that sGC-mediated abnormalities in signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
Conventional stimulatory treatments for soluble guanylate cyclases use only compounds whose effect is based on NO, such as organic nitrates. This is formed by bioconversion and activates the soluble guanylate cyclase by attacking the central iron atom of heme. In addition to side effects, the development of tolerance is also one of the decisive drawbacks of such therapeutic methods.
A new guanylate cyclase stimulant, named riociquat (WO 2003095451 A1), was approved by the FDA 10 in 2013 and is a pyrazolopyridine compound used for treating pulmonary hypertension, but has a short half-life in humans and a high clearance rate, requiring 3 times a day.
Aiming at the unsatisfied demands of the current market and clinic for the soluble guanylate cyclase stimulators, the invention provides a novel compound which can be used as the stimulator of the soluble guanylate cyclase, has good in vitro stimulatory activity on the guanylate cyclase and has excellent pharmacokinetic properties.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein R is 1 H, F or Cl;
R 2 Is C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl or-CH 2 -pyrimidinyl, wherein said C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl or-CH 2 -pyrimidinyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5R a Substituted;
each R is a Is independently H, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-C(＝O)OH、C 1-3 Alkoxy or optionally is substituted with 1, 2 or 3 groups independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group;
R 3 and R is 4 Each independently is H, F, cl, br, I, -OH, -CN or-NH 2 ；
R 5 is-L-R b ；
L is a single bond, -NR c C (=O) O-or-NR c C(＝O)-；
R b Is C 1-6 Alkyl group,Wherein said C 1-6 Alkyl group, R is each independently optionally substituted with 1, 2 or 3R c Is H, -CH 3 or-CH 2 CH 3 ；
Each R is independently F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、C 1-3 Alkoxy or optionally is substituted with 1, 2 or 3 groups independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group;
or R is 3 And R is 5 Linked to carbon atoms to which they are attached, to form structural unitsSelected from the group consisting of
R 6 、R 7 And R is 8 Each independently is F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 Or optionally 1, 2 or 3 independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group.
In some embodiments of the invention, L is a single bond, -NH-C (=O) O-, -NH-C (=O) -, -N (CH) 3 ) -C (=O) O-or-N (CH) 3 ) -C (=o) -, other variables being as defined herein.
In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof has a structure represented by the formulas (I-1) to (I-4):
wherein R is 1 、R 2 、R 4 And R is b As defined herein.
In some embodiments of the invention, each R is independently F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-CH 2 CF 3 、-CH 2 CH 2 CF 3 、-CH 2 OH or-CH 2 CH 2 OH, and other variables are as defined herein.
In some aspects of the invention, R is as defined above b Is C 1-4 Alkyl group,Wherein said C 1-4 Alkyl group,Each independently optionally substituted with 1, 2 or 3R, R and other variables are as defined herein.
In some aspects of the invention, R is as defined above b is-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-C(CH 3 ) 3 、 R and other variables are as defined herein.
In some aspects of the invention, R is as defined above b is-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-C(CH 3 ) 3 、 The other variables are as defined herein.
In some aspects of the invention, R is as defined above 5 is-NH-C (=O) O-C 1-4 Alkyl, -NHC (=o) -C 1-4 Alkyl, -N (CH) 3 )-C(＝O)O-C 1- 4 Alkyl, -NH-C (=o) - (C) 3-6 Cycloalkyl), -N (CH) 3 )C(＝O)-(C 3-6 Cycloalkyl), -NH-C (=o) -phenyl, -N (CH) 3 ) -C (=o) -phenyl or 5-6 membered heterocycloalkyl, wherein said NH-C (=o) O-C 1-4 Alkyl, -NHC (=o) -C 1-4 Alkyl, -N (CH) 3 )-C(＝O)O-C 1-4 Alkyl, -NH-C (=o) - (C) 3-6 Cycloalkyl), -N (CH) 3 )C(＝O)-(C 3-6 Cycloalkyl), -NH-C (=o) -phenyl, -N (CH) 3 ) -C (=o) -phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3R, R and the other variables are as defined herein.
In some aspects of the invention, R is as defined above 5 is-NH-C (=O) O-CH 3 、-NH-C(＝O)O-CH 2 CH 3 、-NH-C(＝O)O-CH 2 CH 2 CH 3 、-NH-C(＝O)O-CH(CH 3 ) 2 、-NH-C(＝O)-CH 3 、-NH-C(＝O)-CH 2 CH 3 、-NH-C(＝O)-CH 2 CH 2 CH 3 、-NH-C(＝O)-CH(CH 3 ) 2 、-N(CH 3 )-C(＝O)O-CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH(CH 3 ) 2 、 R and other variables are as defined herein.
In some aspects of the invention, R is as defined above 5 -NH-C(＝O)O-CH 3 、-NH-C(＝O)O-CH 2 CH 3 、-NH-C(＝O)O-CH 2 CH 2 CH 3 、-NH-C(＝O)O-CH(CH 3 ) 2 、-NH-C(＝O)-CH 3 、-NH-C(＝O)-CH 2 CH 3 、-NH-C(＝O)-CH 2 CH 2 CH 3 、-NH-C(＝O)- CH(CH 3 ) 2 、-N(CH 3 )-C(＝O)O-CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH(CH 3 ) 2 、 The other variables are as defined herein.
In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof has a structure represented by the formulas (I-5) to (I-13):
wherein p is 0, 1 or 2; r is R 4 Is H or-NH 2 ；R 2 And R is as defined herein.
In some embodiments of the invention, the above-described compounds, or pharmaceutically acceptable salts thereof, have the structures of formulas (I-14) to (I-15):
wherein R is 1 、R 2 、R 4 、R 6 、R 7 And R is 8 As defined herein.
In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof has a structure represented by the formulas (I-16) to (I-19):
wherein R is 2 、R 6 、R 7 And R is 8 As defined herein.
In some aspects of the invention, the structural units described aboveIs that The other variables are as defined herein.
In some aspects of the invention, the structural units described above Is thatThe other variables are as defined herein.
In some aspects of the invention, R is as defined above 6 、R 7 And R is 8 Each independently is F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-CH 3 、-CH 2 CH 3 、-CF 3 、-CH 2 CF 3 or-CH 2 CH 2 OH, and other variables are as defined herein.
In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof has a structure represented by the formulas (I-20) to (I-25):
wherein R is 2 The invention is defined.
In some aspects of the invention, each R is a Is independently H, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-C(＝O)OH、-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-CH 2 CF 3 、-CF 2 CF 3 、-CH 2 CH 2 CF 3 、 -CH 2 OH or-CH 2 CH 2 OH, and other variables are as defined herein.
In some aspects of the invention, each R is a Is independently H, F, cl, or-NH 2 The other variables are as defined herein.
In some aspects of the invention, R is as defined above 2 Is C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl, -CH 2 Pyrimidinyl or-CH 2 -pyrazinyl, wherein the C 1-6 Alkyl, phenyl, pyridinyl, pyrimidinyl and pyrazinyl are optionally substituted with 1, 2, 3, 4 or 5R a Substituted, R a And other variables are as defined herein.
In some aspects of the invention, R is as defined above 2 Is that R a And other variables are as defined herein.
In some aspects of the invention, R is as defined above 2 Is that The other variables are as defined herein.
In some aspects of the invention, R is as defined above 3 And R is 4 Each independently is H or-NH 2 The other variables are as defined herein.
In some embodiments of the invention, the above-described compounds have the structure of formula (I-15-a), (I-15-b), (I-15-c), or (I-15-d):
wherein R is 1 、R 4 、R 7 、R 8 And R is a As defined herein.
Still other embodiments of the present invention are derived from any combination of the variables described above.
In some embodiments of the invention, the above compound or pharmaceutically acceptable salt thereof is selected from:
the invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing a medicament for treating diabetic nephropathy or hypertensive nephropathy.
The present invention also provides a method of treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, the method comprising providing to the subject an effective dose of a compound as defined in any of the above claims, or a pharmaceutically acceptable salt thereof.
Technical effects
The novel soluble guanylate cyclase stimulators disclosed by the invention have remarkable in-vitro stimulation activity on guanylate cyclase, excellent pharmacokinetic properties and weaker inhibition degree on five CYP isozymes.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.
Unless otherwise indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.
Unless otherwise indicated, with solid wedge bonds And a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysAnd straight dotted line key
The compounds of the invention may be present in particular. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomer (valance tautomer) includes the interconversion by recombination of some of the bond-forming electrons. A specific example of where keto-enol tautomerization is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.
Unless otherwise indicated, the terms "enriched in one isomer", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, such as- (CRR) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A. When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.
When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group formed by linking the rings A and B in the same direction as the reading order from left to rightThe ring A and the ring B may be connected in a direction opposite to the reading order from left to rightCombinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line keyOr wave linesAnd (3) representing. For example-OCH 3 The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group;the straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group; The wavy line in (2) represents the attachment to other groups through carbon atoms at positions 1 and 2 in the phenyl group.It means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection modes, even though H atom is drawn on-N-, areStill includeThe group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.
Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "5-7 membered ring" refers to a "ring" of 5-7 atoms arranged around a ring.
Unless otherwise specified, "3-12 membered ring" means cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl consisting of 3 to 12 ring atoms. The rings include monocyclic rings, and also include bicyclic or polycyclic ring systems such as spiro, fused and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S and N. The 3-12 membered ring includes 3-10 membered, 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 4-10 membered, 4-9 membered, 4-8 membered, 4-7 membered, 4-6 membered, 4-5 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-10 membered, 6-9 membered, 6-8 membered, 6-7 membered ring, etc. The term "5-7 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems comprising at least one ring, each of which independently meets the definition set forth above.
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises C 1- 3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 And C 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring, and the like.
Unless otherwise specified, the term "C 1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is 1-6 Alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 And C 5 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.
Unless otherwise specified, the term "C 1-4 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C is 1-4 Alkyl includes C 1-2 、C 1-3 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g. methyl), divalent (e.g. methylene) or multivalent (e.g.Methine). C1C 1 - Examples of 4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1- 3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-2 、C 2-3 、C 3 And C 2 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).
The solvent used in the present invention is commercially available.
The invention adopts the following abbreviations: DMF represents N, N-dimethylformamide; k (K) 2 CO 3 Represents potassium carbonate; meI represents methyl iodide; etOAc represents ethyl acetate; EA represents ethyl acetate; THF represents tetrahydrofuran; naHMDS substitution Sodium epihexamethyldisilazide; meOH represents methanol; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; PE represents petroleum ether; etOH stands for ethanol; ACN represents acetonitrile; TFA represents trifluoroacetic acid; FA represents formic acid; NH (NH) 3 ·H 2 O represents ammonia water; TEA represents triethylamine; DIPEA stands for N, N-diisopropylethylamine; boc 2 O represents di-tert-butyl dicarbonate; boc represents tert-butoxycarbonyl, a protecting group for amino; EDCI stands for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; CDI represents N, N' -carbonyldiimidazole; DDQ represents 2, 3-dichloro-5, 6-dicyano-p-benzoquinone; LCMS represents liquid chromatography; HPLC represents liquid chromatography; TLC stands for thin layer chromatography; MEC represents the minimum effective concentration; lnCap represents prostate cancer cells; sGC represents a soluble guanylate cyclase; cGMP stands for guanosine cyclophosphate.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
Example 1
The synthetic route is as follows:
step A: to a solution of 1-1 (2 g,12.61mmol,1 eq) in toluene (20 mL) was added 2-fluorobenzylamine (1.89g,15.14mmol,1.72 mL,1.2eq) and cesium carbonate (6.17 g,18.92mmol,1.5 eq). The nitrogen was replaced and stirred at 80℃for 12 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, extracted with EtOAc (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etOAc=50:1-20:1), and the obtained crude product was stirred with petroleum ether (10 mL), filtered and dried to obtain compound 1-a.
And (B) step (B): reduced iron powder (3.44 g,61.56mmol,8 eq) and NH were added to a mixture of 1-a (2.5 g,7.70mmol,1 eq) EtOH (20 mL) and water (5 mL) 4 Cl (4.94 g,92.35mmol,3.23mL,12 eq). To the reaction solution, water (20 mL) and EtOAc (50 mL) were added under stirring at 70 ℃ for 3 hours with nitrogen replaced, the solution was separated after filtration, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated after filtration, and the residue was purified by silica gel column chromatography (PE: etoac=10:1 to 5:1) to give compound 1-b.
Step C: to a solution of 1-b (1.1 g,3.93mmol,1 eq) in THF (50.00 mL) was slowly added CDI (955.69 mg,5.89mmol,1.5 eq). After the addition was complete, the mixture was stirred at 70℃for 12 hours. The reaction was concentrated and the residue was purified by column chromatography on silica gel (PE: etoac=4:1-2:1) to give compound 1-c.
Step D: to a solution of 1-2 (5.0 g,28.89mmol,1 eq) of phosphorus oxychloride (49.50 g,322.83mmol,30.00mL,11.18 eq) was slowly added dropwise 2, 6-lutidine (13.80 g,128.79mmol,15.00mL,4.46 eq) at 30℃and after the addition was completed, nitrogen was replaced 3 times, and the reaction solution was stirred at 80℃for 12 hours. The reaction solution was cooled to 30 ℃, then concentrated under reduced pressure to remove the excess solvent, finally the reaction solution was slowly added to ice water (100 mL) at 0-5 ℃, then extracted with PE/EA (100 mL, 1/1), the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by silica gel column chromatography (PE/ea=1/0 to 20/1) to give compound 1-f.
Step E: to an ethanol (20 mL) solution of compound 1-f (3.3 g,14.45mmol,1 eq) at-20℃was added an ethanol solution of NH3 (20 mL), the reaction solution was stirred at-20℃for 50 minutes, the reaction solution was filtered, and the cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to give compound 1-g.
Step F: to a solution of 1-c (200 mg, 800.87. Mu. Mol,1 eq) in DMF (1.00 mL) was added 1-g (403.76 mg, 800.87. Mu. Mol,1.0 eq), cesium carbonate (521.88 mg,1.60mmol,2 eq), cuprous iodide (15.25 mg, 80.09. Mu. Mol,0.10 eq) and 1, 10-phenanthroline (28.86 mg, 160.17. Mu. Mol,0.2 eq). After nitrogen was replaced, stirred at 90℃for 3 hours, water (20 mL) was added to the reaction mixture, extracted with EtOAc (50 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1-d.
Step G: reduced iron powder (845.42 mg,15.14mmol,20 eq) and NH were added to a mixture of 1-d (300 mg, 756.94. Mu. Mol,1 eq) MeOH (9 mL) and water (3 mL) 4 Cl (809.79 mg,15.14mmol,20 eq). After nitrogen was replaced and stirred at 70℃for 2 hours, water (10 mL) was added to the reaction solution, extracted with EtOAc (25 mL. Times.2), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by thin layer chromatography (DCM: meOH=10:1) to give compound 1-e.
Step H: methyl chloroformate (41.65 mg, 440.72. Mu. Mol, 34.14. Mu.L, 1.5 eq) was added to a solution of 1-e (120 mg, 293.82. Mu. Mol,1 eq) in pyridine (1.5 mL) at 0deg.C, stirred for half an hour at 0deg.C, water (10 mL) was added to the reaction solution, extracted with EtOAc (50 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was added to EtOAc (10 mL) and stirred, filtered and dried to give compound 1. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.08-8.01(m，2H)，7.95(br s，1H)，7.35(m，1H)，7.28-7.19(m，2H)，7.18-7.08(m，2H)，6.33(br s，4H)，5.15(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：425.3[M+1] + 。
Example 2
The synthetic route is as follows:
compound 1 (50 mg, 115.04. Mu. Mol,to a solution of 1 eq) in DMF (1 mL) was added NaH (6.90 mg, 172.55. Mu. Mol,60% purity, 1.5 eq), stirred at 0deg.C for 10 min, then methyl iodide (24.49 mg, 172.55. Mu. Mol, 10.74. Mu.L, 1.5 eq) was added, the resulting mixture was stirred at 0deg.C for half an hour, water (5 mL) was added to the reaction, extracted with EtOAc (10 mL. Times.2), the combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by thin layer chromatography (EtOAc) to give compound 2. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.09-8.02(m，2H)，7.39-7.30(m，1H)，7.27-7.19(m，2H)，7.18-7.08(m，2H)，6.55(br s，4H)，5.15(s，2H)，3.66(s，1H)，3.55(s，2H)，3.00(s，3H)；LCMS(ESI)m/z：439.3[M+1] + 。
Example 3
The synthetic route is as follows:
step A: to a solution of compound 3-1 (2 g,11.33mmol,1 eq) in toluene (20.00 mL) under nitrogen protection was added cesium carbonate (5.54 g,16.99mmol,1.5 eq) and 2-fluorobenzylamine (1.70 g,13.60mmol,1.55mL,1.2 eq). The mixture was stirred at 80℃for 12 hours. After cooling, water (40 mL) was added, extracted with EtOAc (40 mL), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was isolated by column chromatography (PE: etoac=50:1-5:1) to give compound 3-a.
And (B) step (B): reduced iron powder (1.26 g,22.62mmol,4 eq) and NH were added to a mixture of 3-a (1.50 g,5.66mmol,1 eq) in THF (20 mL) and water (10 mL) 4 Cl (1.51 g,53.49mmol,5 eq). The reaction was filtered, the filter cake was washed with EtOAc (40 mL), the filtrate was added again with saturated brine (50 mL), extracted with EtOAc (40 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etoac=10:1-4:1) to give compound 3-b.
Step C: to a solution of 3-b (1.00 g,4.25mmol,1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g,6.38mmol,1.5 eq). After the addition was complete, the mixture was stirred at 70℃for 12 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=5:1-2:1) to give compound 3-c. 1 H NMR(400MHz，CDCl 3 )：δppm 9.99(br s，1H)，7.96(t，J＝2.1Hz，1H)，7.33-7.29(m，1H)，7.28-7.24(m，1H)，7.16(dd，J＝2.5，8.0Hz，1H)，7.12-7.05(m，2H)，5.27(s，2H)。
Step D: to a solution of 3-c (113 mg, 432.57. Mu. Mol,1 eq) in DMF (4.00 mL) was added 1-g (261.70 mg, 519.09. Mu. Mol,1.0 eq), cesium carbonate (281.88 mg, 865.15. Mu. Mol,2 eq), cuprous iodide (8.24 mg, 43.26. Mu. Mol,0.10 eq) and 1, 10-phenanthroline (15.59 mg, 86.51. Mu. Mol,0.2 eq). After stirring at 100deg.C for 3 hours with nitrogen replaced, the reaction mixture was cooled, saturated brine (20 mL) was added to the reaction mixture, extracted with EtOAc (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etOAc=5:1-2:1) to give compound 3-d.
Step E: reduced iron powder (64.70 mg,1.16mmol,4 eq) and NH were added to a mixture of 3-d (120 mg, 289.63. Mu. Mol,1 eq) in MeOH (6 mL) and water (2 mL) 4 Cl (77.46 mg,1.45mmol,5 eq). The reaction was stirred at 70℃for 3 hours with nitrogen replaced, the reaction was filtered, the filter cake was washed with methanol (10 mL) and dichloromethane (10 mL), saturated brine (10 mL) was added to the filtrate, extracted with DCM (10 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by thin layer chromatography (DCM: meOH=10:1) to give compound 3-e.
Step F: to a solution of 3-e (42 mg, 91.06. Mu. Mol,1 eq) in pyridine (1.5 mL) was added methyl chloroformate (12.91 mg, 136.60. Mu. Mol, 10.58. Mu.L, 1.5 eq) at 0deg.C, stirred for 1 hour at 0deg.C, the reaction solution was poured into ice water (20 mL), saturated brine (10 mL) was added, extracted with EtOAc (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated after filtration, and the residue was purified by preparative HPLC [ mobile phase: water (0.22)5％FA)-ACN]Compound 3 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.18(dd，J＝2.5，9.4Hz，1H)，8.07(s，1H)，7.96(br s，1H)，7.41-7.31(m，1H)，7.30-7.11(m，3H)，6.37(br s，4H)，5.14(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：443.1[M+1] + 。
Example 4
The synthetic route is as follows:
step A: to a solution of 3-1 (2 g,11.33mmol,1 eq) in toluene (20.00 mL) under nitrogen was added cesium carbonate (5.54 g,16.99mmol,1.5 eq) and 2-trifluoromethylbenzylamine (2.38 g,13.60mmol,1.55mL,1.2 eq). The mixture was stirred at 80℃for 12 hours. After cooling, water (40 mL) was added, extracted with EtOAc (40 mL), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was isolated by column chromatography (PE: etoac=50:1-5:1) to give compound 4-a.
And (B) step (B): reduced iron powder (1.20 g,21.57mmol,4eq) and NH were added to a mixture of 4-a (1.70 g,5.39mmol,1 eq) in THF (20 mL) and water (10 mL) 4 Cl (1.44 g,26.97mmol,5 eq). The reaction was stirred at 60℃for 3 hours with nitrogen replaced, the reaction was filtered, the filter cake was washed with EtOAc (40 mL), the filtrate was added further with saturated brine (60 mL), extracted with EtOAc (50 mL), the organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etOAc=10:1-4:1) to give compound 4-b.
Step C: to a solution of 4-b (1.21 g,4.25mmol,1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g,6.38mmol,1.5 eq). After the addition was complete, the mixture was stirred at 70℃for 12 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=4:1-2:1) to give compound 4-c. 1 H NMR(400MHz，DMSO-d 6 )：δppm 11.60(br s，1H)，7.91(t，J＝2.0Hz，1H)，7.80(d，J＝7.7Hz，1H)，7.63-7.53(m，1H)，7.53-7.40(m，2H)，7.02(d，J＝7.7Hz，1H)，5.19(s，2H)。
Step D: to a solution of 4-c (140 mg, 449.82. Mu. Mol,1 eq) in DMF (1.00 mL) was added 1-g (226.78 mg, 449.82. Mu. Mol,1.0 eq), cesium carbonate (293.12 mg, 899.64. Mu. Mol,2 eq), cuprous iodide (8.57 mg, 44.98. Mu. Mol,0.10 eq) and 1, 10-phenanthroline (16.21 mg, 89.96. Mu. Mol,0.2 eq). The nitrogen was replaced, the reaction mixture was stirred at 100deg.C for 3 hours, cooled, filtered, the filter cake was washed with MeOH (10 mL) and EtOAc (10 mL), saturated brine (20 mL) was added to the filtrate, extracted with EtOAc (30 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 4-d.
Step E: reduced iron powder (360.84 mg,6.46mmol,20 eq) and NH were added to a mixture of 4-d (150 mg, 323.04. Mu. Mol,1 eq) MeOH (9 mL) and water (3 mL) 4 Cl (345.59 mg,6.46mmol,20 eq). The reaction was stirred at 70℃for 3 hours with nitrogen replaced, filtered, the filter cake was washed with methanol (10 mL) and EtOAc (10 mL), and the filtrate was concentrated and purified by thin layer chromatography (DCM: meOH=10:1) to give compound 4-e.
Step F: methyl chloroformate (12.91 mg, 136.60. Mu. Mol, 10.58. Mu.L, 1.5 eq) was added to a solution of 4-e (39.55 mg, 91.06. Mu. Mol,1 eq) in pyridine (1.0 mL) at 0deg.C, stirred for 1 hour at 0deg.C, the reaction mixture was poured into ice water (10 mL), saturated brine (10 mL) was added, extracted with EtOAc (5 mL. Times.3), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated after filtration, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 4 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.18(dd，J＝2.5，9.4Hz，1H)，8.07(s，1H)，7.96(br s，1H)，7.41-7.31(m，1H)，7.30-7.11(m，3H)，6.37(br s，4H)，5.14(s，2H)，3.62(br s，3H)；LCMS(ESI)m/z：493.1[M+1] + 。
Example 5
The synthetic route is as follows:
step A: to a solution of 1-f (1.3 g,5.69mmol,1 eq) in DCM (100.00 mL) was slowly added a solution of p-methoxybenzylamine (1.56 g,11.38mmol,1.47mL,2 eq) in DCM (100.00 mL) at-20deg.C, the mixture was stirred for 1 hour, water (50.00 mL) was added to wash, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was stirred with EtOAc (15 mL) and filtered and dried to give compound 5-b.
And (B) step (B): in CoCl 2 ·6H 2 To a solution of O (1.71 g,7.19mmol,0.1 eq) in THF (200.00 mL) and water (100.00 mL) was added 5-2 (10 g,71.89mmol,8.00mL,1 eq) followed by addition of NaBH in portions 4 (13.60 g,359.45mmol,5 eq) and the reaction was stirred at 30℃for 12 hours, NH was added slowly to the reaction 3 ·H 2 O (25%, 20 mL), water (100 mL) was added, extracted with EtOAc (100 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: etOAc=10:1-3:1) to give compound 5-c.
Step C: to a solution of 5-c (3.65 g,25.49mmol,2.99mL,1.5 eq) in toluene (30.00 mL) was added cesium carbonate (8.31 g,25.49mmol,1.5 eq) and 3-1 (3.0 g,16.99mmol,1 eq). The mixture was stirred for 12 hours at 80℃and concentrated after filtration, and the residue was isolated by column chromatography (PE: etOAc=100:1-10:1) to give compound 5-d.
Step D: reduced iron powder (1.97 g,35.30mmol,5 eq) and NH were added to a mixture of 5-d (2.0 g,7.06mmol,1 eq) EtOH (100 mL) and water (50 mL) 4 Cl (1.89 g,35.30mmol,1.23mL,5 eq) was stirred at 70℃for 1 hour, extracted with EtOAc (100 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etOAc=10:1-3:1) to give compound 5-e.
Step E: to a solution of 5-e (1.0 g,3.95mmol,1 eq) in THF (100.00 mL) was slowly added CDI (960.51 mg,5.92mmol,1.5 eq). After the addition was complete, the mixture was stirred at 70℃for 2 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=20:1-3:1) to give compound 5-f.
Step F: to a solution of 5-f (450 mg,1.61mmol,1 eq) in DMF (10.00 mL) was added 5-b (1.04 g,2.42mmol,1.5 eq), cesium carbonate (630.13 mg,1.93mmol,1.2 eq), cuprous iodide (30.69 mg, 161.16. Mu. Mol,0.1 eq) and 8-hydroxyquinoline (23.39 mg, 161.16. Mu. Mol, 27.85. Mu.L, 0.1 eq), nitrogen was replaced, stirred at 100℃for 3 hours, water (50 mL) was added to the reaction solution, extracted with EtOAc (50 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: etOAc=10:1-3:1) to give compound 5-g.
Step G: to a solution of 5-g (900 mg,1.34mmol,1 eq) of DCM (50.00 mL) and water (5.00 mL) was added DDQ (1.52 g,6.69mmol,5 eq), stirred at 30℃for 12 hours, saturated aqueous sodium bicarbonate solution (20 mL) was added, extracted with DCM (50 mL. Times.2), the combined organic phases were washed with water (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was stirred with EtOAc (10 mL) and filtered and dried to give compound 5-h.
Step H: reduced iron powder (95.59 mg,1.71mmol,20 eq) and NH were added to a mixture of 5-h (50 mg, 85.59. Mu. Mol,1 eq) of MeOH (3 mL) and water (1 mL) 4 Cl (91.56 mg,1.71mmol,20 eq) was stirred at 70℃for 1 hour, the reaction was cooled and filtered, the filtrate was added with water (20 mL), extracted with DCM (25 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give compound 5-i.
Step I: to a solution of 5-i (20 mg, 49.71. Mu. Mol,1 eq) in pyridine (1.0 mL) was added methyl chloroformate (7.05 mg, 74.57. Mu. Mol, 5.78. Mu.L, 1.5 eq) at 0deg.C, stirred for 30 min at 0deg.C, water (10 mL) was added to the reaction solution, extracted with EtOAc (10 mL. Times.2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Obtaining the productAnd (5) a compound. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.20(dd，J＝2.6，9.4Hz，1H)，8.07(t，J＝2.1Hz，1H)，7.98(br s，1H)，7.44-7.30(m，1H)，7.22-7.08(m，2H)，6.37(br s，4H)，5.17(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：461.1[M+1] + 。
Example 6
The synthetic route is as follows:
to a solution of compound 5 (15 mg, 32.58. Mu. Mol,1 eq) in DMF (1.00 mL) was added NaH (1.95 mg, 48.87. Mu. Mol,60% purity, 1.5 eq) at 0deg.C, methyl iodide (6.94 mg, 48.87. Mu. Mol, 3.04. Mu.L, 1.5 eq) after stirring for 30 min at 0deg.C, continuing stirring for 30 min at 0deg.C, the reaction solution was slowly poured into water (30 mL) and then extracted with EtOAc (30 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated after filtration, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 6 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.47(br s，1H)，8.22(br dd，J＝2.6，9.4Hz，1H)，7.45-7.30(m，1H)，7.22-7.06(m，2H)，6.64-6.49(m，4H)，5.17(s，2H)，3.66-3.55(s，3H)，3.00(s，3H)。LCMS(ESI)m/z：475.1[M+1] + 。
Example 7
The synthetic route is as follows:
step A: DIPEA (2.20 g,16.99mmol,2.96mL,1.5 eq) and 2-chlorobenzylamine (1.60 g,11.33mmol,1.37mL,1 eq) were added to a solution of 3-1 (2 g,11.33mmol,1 eq) in toluene (20.00 mL) under nitrogen. The mixture was stirred at 80℃for 17 hours. After cooling, water (20 mL) was added, extracted with EtOAc (20 mL. Times.3) and combined The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: etoac=100:1-50:1) to give compound 7-a, 1 H NMR(400MHz，CDCl 3 )δppm 4.94(d，J＝6.02Hz，2H)7.17-7.34(m，2H)7.37-7.47(m，2H)8.22(dd，J＝7.91，2.89Hz，1H)8.40(d，J＝2.89Hz，1H)8.47-8.67(m，1H)。
and (B) step (B): reduced iron powder (2.24 g,40.03mmol,5 eq) and NH were added to a mixture of 7-a (3.13 g,8.01mmol,1 eq) in THF (45 mL) and water (15 mL) 4 Cl (1.71 g,32.02mmol,1.12mL,4 eq). The reaction was stirred at 80℃for 17 hours with nitrogen replaced, the filtrate was filtered, water (80 mL) was added to the filtrate, extracted with EtOAc (80 mL. Times.3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by column chromatography (PE: etOAc=100:1-5:1) to give compound 7-b, 1 H NMR(400MHz，DMSO-d 6 )：δppm 7.44-7.38(m，1H)，7.35-7.30(m，1H)，7.28-7.24(m，2H)，7.22(d，J＝2.6Hz，1H)，6.64(dd，J＝2.8，10.4Hz，1H)，6.09(t，J＝5.6Hz，1H)，5.22(s，2H)，4.58(d，J＝5.6Hz，2H)。
step C: to a solution of 7-b (1.16 g,3.75mmol,1 eq) in THF (30.00 mL) was slowly added CDI (911.37 mg,5.62mmol,1.5 eq). After the addition was complete, the mixture was stirred at 75℃for 4 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=20:1-4:1) to give compound 7-c.
Step D: to a solution of 7-c (0.3 g,1.08mmol,1 eq) in DMF (5.00 mL) was added 1-g (245.76 mg,1.30mmol,1.2 eq), cesium carbonate (704.01 mg,2.16mmol,2.0 eq), cuprous iodide (20.58 mg, 108.04. Mu. Mol,0.1 eq) and 1, 10-phenanthroline (38.94 mg, 216.08. Mu. Mol,0.2 eq). After stirring at 90℃for 3 hours with nitrogen replaced, the reaction mixture was cooled and filtered, water (10 mL) was added to the filtrate, the mixture was extracted with DCM: meOH=5:1 (10 mL. Times.4), the combined organic phases were washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 7-d.
Step E: to a mixture of 7-d (276.00 mg, 640.70. Mu. Mol,1 eq) MeOH (8 mL) and water (2 mL) was addedReduced iron powder (715.60 mg,12.81mmol,20 eq) and NH were charged 4 Cl (685.44 mg,12.81mmol, 448.00. Mu.L, 20 eq) was stirred at 75℃for 1.5 hours, the reaction was cooled and filtered, the filtrate was concentrated and water (10 mL) was added, extracted with DCM: meOH=10:1 (10 mL. Times.3), the combined organic phases were washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by thin layer chromatography (DCM: meOH=10:1) to give compound 7-e.
Step F: to a solution of 7-e (20 mg, 49.90. Mu. Mol,1 eq) in pyridine (1.0 mL) was added methyl chloroformate (4.72 mg, 49.95. Mu. Mol, 3.87. Mu.L, 1.00 eq) at 0deg.C, stirred for 30 min at 0deg.C, the reaction solution was poured into water (1 mL), extracted with EtOAc (2 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 7 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 8.23(dd，J＝9.47，2.57Hz，1H)，7.98-8.14(m，1H)，7.96(br s，1H)，7.51(dd，J＝7.84，1.32Hz，1H)，7.19-7.43(m，2H)，7.08(d，J＝6.40Hz，1H)，6.37(br s，4H)，5.15(s，2H)，3.62(br s，3H)；LCMS(ESI)m/z：459.0[M+1] + 。
Example 8
The synthetic route is as follows:
step A: to a solution of 3-e (40 mg, 104.06. Mu. Mol,1 eq) in DMF (1 mL) was added sequentially trifluoroethyl triflate (48.31 mg, 208.15. Mu. Mol,2.0 eq) and DIPEA (40.35 mg, 312.22. Mu. Mol, 54.38. Mu.L, 3.0 eq). The mixture was stirred at 80℃for 12 hours. After cooling, water (20 mL) was added, extracted with EA (10 ml×2), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (dichloromethane: methanol=15:1) to give compound 8-a.
And (B) step (B): to a solution of 8-a (15 mg, 32.16. Mu. Mol,1 eq) in DMF (1 mL)CDI (10.43 mg, 64.33. Mu. Mol,2.0 eq) was added and the mixture stirred at 90℃for 6 hours. The reaction mixture was added with saturated brine (10 mL), extracted with EA (8 mL. Times.2), and the organic phase was washed with brine (10 mL), anhydrous Na 2 SO 4 Dried, filtered and concentrated to give a residue. The residue was purified by preparative HPLC [ mobile phase: water (10 mM NH) 4 HCO 3 )-ACN]Compound 8 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.19(dd，J＝2.4，9.3Hz，1H)，8.10(d，J＝1.9Hz，1H)，7.40-7.26(m，1H)，7.26-7.19(m，1H)，7.26-7.19(m，1H)，7.18-7.12(m，1H)，7.43-7.12(m，1H)，7.12-7.04(m，1H)，7.09(br s，1H)，5.16(s，2H)，4.91(q，J＝9.0Hz，2H)；LCMS(ESI)m/z：493.1[M+1] + 。
Example 9
The synthetic route is as follows:
step A: ammonia (3.64 g,103.86mmol,4.00mL,4.03 eq) and diisopropylethylamine (5.00 g,38.66mmol,6.73mL,1.5 eq) were dissolved in dichloromethane (80 mL) to give solution 1, 9-1 (5 g,25.78mmol,1 eq) was dissolved in dichloromethane (15 mL) to give solution 2, solution 1 was slowly added dropwise to solution 2 at 0deg.C, and stirred at 0deg.C for 1 hour, and the reaction solution was filtered to give compound 9-a. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.57(br s，1H)9.01(s，1H)9.19(br s，1H)。
And (B) step (B): 9-a (0.2 g,1.15mmol,1.2 eq), compound 3-c (249.44 mg, 954.86. Mu. Mol,1 eq) and anhydrous potassium carbonate (263.94 mg,1.91mmol,2 eq) were dissolved in DMF (5 mL) and replaced 3 times with nitrogen and stirred at 25℃for 2 hours. The reaction was added dropwise to 40mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.
Step C: compound 9-b (400 mg, 879.52. Mu. Mol,1 eq) was dissolved in MeOH (9 mL) and H 2 O (3 mL) into the solutionFe (982.33 mg,17.59mmol,20 eq) and NH were added thereto 4 Cl (940.93 mg,17.59mmol, 614.99. Mu.L, 20 eq) was stirred at 75℃for 1 hour. The reaction solution was cooled to 25 ℃, filtered through celite, and the filtrate was concentrated and purified by thin layer chromatography (DCM: meoh=10:1) to give compound 9-c.
Step D: compound 9-c (45 mg, 121.84. Mu. Mol,1 eq) was dissolved in pyridine (2 mL), methyl chloroformate (17.27 mg, 182.76. Mu. Mol, 14.16. Mu.L, 1.5 eq) was added dropwise at 0℃and stirred at that temperature for 30 minutes, the reaction solution was dropped into 2mL of water, extracted with EA (3 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 9 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 3.68(s，3H)5.15(s，2H)7.09-7.43(m，6H)8.09(d，J＝1.88Hz，1H)8.16(dd，J＝9.35，2.45Hz，1H)8.28(br s，1H)8.85(br s，1H)；LCMS(ESI)m/z：428.0[M+1] + 。
Example 10
The synthetic route is as follows:
step A: to a solution of compound 3-e (203 mg, 512.33. Mu. Mol,1 eq) in pyridine (2.0 mL) was added compound 10-1 (219.74 mg,1.54mmol, 158.09. Mu.L, 3 eq) at one time under nitrogen protection at 0deg.C, and the mixture was stirred at 0deg.C for 1 hour, and the resultant reaction solution was added dropwise to water (20 mL) and then extracted with ethyl acetate (10 mL. Times.3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to thin layer chromatography (SiO 2 DCM/meoh=15/1) to give the crude compound 10-a, which was used in the next reaction without further purification. LCMS (ESI) m/z:491.0[ M+1 ]] + 。
And (B) step (B): at 0 ℃ under the protection of nitrogenTo a solution of compound 10-a (65 mg, 132.42. Mu. Mol,1 eq) in THF (4.0 mL) was added NaHMDS (1M, 264.85. Mu.L, 2 eq) in one portion, and the mixture was reacted at 0℃for 1 hour. Then added dropwise to an ice bath (10 mL), then extracted with ethyl acetate (10 mL. Times.3), and the combined organic layers were washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 Drying, suction filtration, and the residue after concentrating the filtrate under reduced pressure was subjected to preparative HPLC [ mobile phase: water (0.04% NH) 3 ·H 2 O+10mM NH 4 HCO 3 )-ACN]Purification gave compound 10. 1 H NMR(400MHz，DMSO-d 6 )：δppm 11.77(br s，1H)，8.17-8.05(m，2H)，7.40-7.26(m，2H)，7.26-7.12(m，2H)，6.95(br s，2H)，5.35(t，J＝4.9Hz，1H)，5.15(s，2H)，3.97(t，J＝4.8Hz，2H)，3.68-3.56(m，2H)；
LCMS(ESI)m/z：455.2[M+1] + 。
Example 11
The synthetic route is as follows:
compound 9-c (200 mg, 349.28. Mu. Mol,1 eq) was dissolved in pyridine (2 mL), 11-1 (55.82 mg, 523.92. Mu. Mol,1.5 eq) was added dropwise at 0℃and stirred at that temperature for 30 minutes. After completion of the reaction, the reaction mixture was dropped into 2mL of water, extracted with EA (4 mL. Times.3), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 11 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.13(d，J＝6.78Hz，6H)2.67(quin，J＝6.78Hz，1H)5.15(s，2H)7.10-7.18(m，1H)7.17-7.39(m，5H)8.09(s，1H)8.16(dd，J＝9.29，2.38Hz，1H)8.37(s，1H)9.33(s，1H)。LCMS(ESI)m/z：440.1[M+1] + 。
Example 12
The synthetic route is as follows:
compound 9-c (200 mg, 349.28. Mu. Mol,1 eq) was dissolved in pyridine (2 mL), 12-1 (76.81 mg, 523.92. Mu. Mol, 69.83. Mu.L, 1.5 eq) was added dropwise at 0℃and stirred at that temperature for 30 minutes. The reaction solution was dropped into 2mL of water, extracted with EA (4 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (10 mM NH) 4 HCO 3 )-ACN]Compound 12 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 1.15-1.56(m，3H)1.40(q，J＝12.05Hz，2H)1.66(br d，J＝11.67Hz，1H)1.76(br d，J＝12.67Hz，2H)1.88(br d，J＝11.17Hz，2H)2.31-2.43(m，1H)5.14(s，2H)7.06-7.43(m，6H)8.09(t，J＝2.07Hz，1H)8.15(dd，J＝9.22，2.45Hz，1H)8.36(s，1H)9.15(br s，1H)。LCMS(ESI)m/z：480.0[M+1] + 。
Example 13
The synthetic route is as follows:
compound 9-c (0.036 g, 94.06. Mu. Mol,1 eq) was dissolved in DMF (1 mL), DIEA (48.63 mg, 376.25. Mu. Mol, 65.54. Mu.L, 4 eq) and 13-1 (24.00 mg, 103.47. Mu. Mol, 12.97. Mu.L, 1.1 eq) were added and the resulting mixture was stirred at 130℃for 2 hours. The reaction solution was purified by preparative HPLC [ mobile phase: water (0.05% Ammonia water) -ACN]Compound 13 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.19-8.06(m，2H)，7.99(s，1H)，7.39-7.32(m，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，5.15(s，2H)，3.83-3.71(m，4H)，2.95-2.80(m，4H)；LCMS(ESI)m/z：440.2[M+1] + 。
Example 14
The synthetic route is as follows:
14-1 (0.159 g,1.03mmol,1 eq) was dissolved in DCM (1 mL) at 25℃and oxalyl chloride (117.88 mg, 928.70. Mu. Mol, 81.29. Mu.L, 0.9 eq) and DMF (7.54 mg, 103.19. Mu. Mol, 7.94. Mu.L, 0.1 eq) were added, stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (119.09 mg, 206.38. Mu. Mol,0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25℃for 2 hours. To the reaction was added 2mL of water and extracted with DCM (4 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [ mobile phase: water (0.04% NH) 3 H 2 O)-ACN]Compound 14 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.31-1.38(m，2H)1.68(br s，2H)5.15(s，2H)7.11-7.18(m，2H)7.17-7.40(m，4H)8.05-8.12(m，2H)8.22(dd，J＝9.35，2.57Hz，1H)9.10(br s，1H)；LCMS(ESI)m/z：506.0[M+1] + 。
Example 15
The synthetic route is as follows:
step A: tribromopyridine (12.50 g,7.81mmol,4 eq) was added to a solution of compound 15-1 (1.50 g,9.77mmol,1 eq) in t-butanol (54 mL) and stirred at 25℃for 6 hours. The reaction mixture was filtered, the cake was washed with EA (20 mL), water (30 mL) was added to the filtrate, and ethyl acetate (50 mL) was used for extraction. The organic phase was collected, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO 2 PE: EA=5:1-3:1) to give compound 15-a.
And (B) step (B): compound 15-a (1.5 g,4.58mmol,1 eq) and ammonium chloride (1.23 g,22.91mmol,5 eq) were dissolved in tetrahydrofuran (16 mL) and water (8 mL), then zinc powder (1.50 g,22.91mmol,5 eq) and the reaction system was stirred for 1 hour at 25 ℃. The reaction solution was filtered, the filtrate was extracted with ethyl acetate (20 mL. Times.2), the organic phase was collected, washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (SiO 2 PE: EA=5:1-1:1) to give compound 15-b.
Step C: compound 15-b (150 mg,0.885mmol,1 eq) was dissolved in anhydrous DMF (15 mL) and NaH (35.38 mg,0.885mmol,60% purity, 1 eq) was added to the reaction at 0deg.C in place of nitrogen and stirred at 25deg.C for 30 min. 2- (trimethylsilyl) ethoxymethyl chloride (147.5 mg,0.885mmol, 156.6. Mu.L, 1 eq) was then added dropwise and stirred for 1 hour at 25 ℃. NaH (70.76 mg,1.77mmol,60% purity, 2 eq) was added to the above reaction system under nitrogen protection after cooling to 0℃and after stirring for 30 minutes methyl iodide (263.67 mg,1.86mmol, 115.65. Mu.L, 2.1 eq) was added dropwise and the reaction system was stirred at 25℃for 1 hour. Pouring the reaction solution into H 2 O (45 mL) was extracted with ethyl acetate (40 mL. Times.2). The combined organic phases were washed with saturated brine (40 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: ea=5:1) to give compound 15-c.
Step D: to a solution of compound 15-c (70 mg, 213.49. Mu. Mol,1 eq) and compound 3-c (66.92 mg, 256.19. Mu. Mol,1.2 eq) in DMF (5.0 mL) was added cesium carbonate (139.12 mg, 426.98. Mu. Mol,2.0 eq) in place of nitrogen. The reaction system was stirred at 100℃for 15 hours under nitrogen atmosphere. H is added into the reaction system 2 O (20 mL), ethyl acetate extraction (20 mL. Times.2). The combined organic phases were washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE: ea=5:1) to give compound 15-d; 1 H NMR(400MHz，CDCl 3 )：δppm 8.43(s，1H)，8.15(dd，J＝8.85，2.57Hz，1H)，8.04(dd，J＝2.45，1.57Hz，1H)，7.38-7.42(m，1H)，7.23-7.25(m，1H)，7.04-7.09(m，2H)，5.31(s，2H)，5.28(s，2H)，3.70(t，J＝8.4Hz，2H)，1.52(s，6H)，0.99(t，J＝8.0Hz，2H)，0.02(s，9H)。
step E: trifluoroacetic acid (154 mg,1.35mmol,18.66 eq) was added to a solution of compound 15-d (40 mg, 72.38. Mu. Mol,1 eq) in anhydrous dichloromethane (5.0 mL) and stirred at 25℃for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (0.04% NH) 3 ·H 2 O)-ACN]Compound 15 was obtained. 1 H NMR(400MHz，CDCl 3 )：δppm 8.35(s，1H)，8.17(d，J＝2.8Hz，1H)，8.15(d，J＝2.8Hz，1H)，8.05-8.04(m，1H)，7.27-7.24(m，1H)，7.07-7.03(m，2H)，5.29(s，2H)，1.51(s，6H)；LCMS(ESI)m/z：423.2[M+1] + 。
Example 16
The synthetic route is as follows:
parafluorobenzoic acid (245.45 mg,1.75mmol,1 eq) was dissolved in DCM (1 mL) at 25℃and DMF (7.54 mg, 103.19. Mu. Mol, 7.94. Mu.L, 0.1 eq) and oxalyl chloride (200.12 mg,1.58mmol, 138.01. Mu.L, 0.9 eq) were added, stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (0.2 g, 350.37. Mu. Mol,0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25℃for 2 hours. To the reaction was added 2mL of water and extracted with DCM (4 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [ mobile phase: water (0.04% NH) 3 .H 2 O)-ACN]Compound 16 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 5.16(s，2H)7.12-7.18(m，1H)7.19-7.26(m，1H)7.27-7.43(m，6H)8.04-8.18(m，3H)8.18-8.34(m，2H)9.82(s，1H)。LCMS(ESI)m/z：492.2[M+1] + 。
Example 17
The synthetic route is as follows:
step A: naH (2.07 g,51.67mmol,60% purity, 2 eq) was carefully added slowly to a solution of 17-1 (3 g,25.84mmol,1 eq) in DMF (30 mL) at 0deg.C, stirred for 0.5 hours at 0deg.C, methyl iodide (4.40 g,31.00mmol,1.93mL,1.2 eq) was added to the solution, gradually brought back to room temperature and stirred for 0.5 hours at 45deg.C, stirred for 3 hours, cooled to room temperature, quenched with saturated ammonium chloride solution (60 mL), diluted with water (10 mL), extracted with DCM (30 mL. Times.3), the combined organic phases were washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated below 10deg.C to give compound 17-a. 1 HNMR(400MHz，DMSO-d 6 )：δ3.65(s，3H)，3.30(s，3H)，1.31-1.27(dd，J＝4.8Hz，8.4Hz，2H)，1.17-1.14(dd，J＝4Hz，7.2Hz，2H)。
And (B) step (B): to a solution of 17-a (0.56 g,4.30mmol,1 eq) in MeOH (5 mL) was slowly added a solution of KOH (483.19 mg,8.61mmol,2 eq) in water (2.5 mL). After the addition was complete, the mixture was stirred at 20℃for 15 hours. The reaction was concentrated at below 40 ℃, the concentrate was washed with petroleum ether (15 mL), then the aqueous phase was poured into ice water (15 mL), the solution was pH adjusted to 5-6 with 3M aqueous hydrochloric acid, extracted with DCM (12 mL), the organic phase was dried over anhydrous sodium sulfate filtered and concentrated to give compound 17-b. 1 H NMR(400MHz，DMSO-d 6 )：δ12.55(s，1H)，3.29(s，3H)，1.14-1.12(dd，J＝6Hz，8.8Hz，2H)，1.07-1.04(dd，J＝3.2Hz，6.4Hz，2H)。
Step C: to a solution of 17-b (350 mg,3.01mmol,1 eq) in DCM (2.00 mL) and DMF (22.03 mg, 301.43. Mu. Mol, 23.19. Mu.L, 0.1 eq) at 0deg.C was added oxalyl chloride (344.33 mg,2.71mmol, 237.47. Mu.L, 0.9 eq), nitrogen was replaced, stirred at 0deg.C for 0.5 hours, a solution of 9-c (261.94 mg, 602.85. Mu. Mol,0.2 eq) in DCM (3 mL) was added dropwise thereto, pyridine (476.85 mg,6.03mmol, 486.59. Mu.L, 2 eq) was added thereto, the mixture was stirred at 20deg.C for 5 hours, the reaction was quenched with water (20 mL), extracted with EtOAc (15 mL. Times.3), the combined organic phase was washed with saturated brine (15 mL. Times 3), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated by column chromatography (P) E: etoac=10:1-0.1:1) purification of the crude product obtained further by preparative HPLC [ mobile phase: water (0.05% Ammonia water) -ACN]Purifying to obtain a compound 17. 1 H NMR(400MHz，CD 3 OD)：δppm 1.23-1.25(dd，J＝2.8Hz，7.2Hz，2H)，1.32-1.35(dd，J＝4Hz，6.8Hz，2H)，2.03(s，1H)，3.50(s，3H)，5.28(s，2H)，7.09-7.14(t，J＝6Hz，2H)，7.29-7.36(dd，J＝7.2Hz，14.8Hz，2H)，8.01(s，1H)，8.19(s，1H)，8.35-8.37(d，J＝2.4Hz，1H)；LCMS(ESI)m/z：468.0[M+1] + 。
Example 18
The synthetic route is as follows:
to a solution of 3-e (100 mg, 260.18. Mu. Mol,1 eq) in pyridine (4 mL) were added EDCI (399.02 mg,2.08mmol,8 eq) and 14-1 (80.18 mg, 520.37. Mu. Mol,2 eq) and the reaction mixture was stirred at 30℃for 2 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 ml×2), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]]Compound 18 is obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.60(br s，1H)，8.22(dd，J＝2.3，9.4Hz，1H)，8.08(s，1H)，7.39-7.31(m，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，6.26(br s，4H)，5.14(s，2H)，1.74(br s，2H)，1.32-1.15(m，2H)；LCMS(ESI)m/z：521.2[M+1] + 。
Example 19
The synthetic route is as follows:
EDCI (418.62 mg,2.18mmol,8 eq) and 14-1 (84.12 mg, 545.92. Mu. Mol,2 eq) and the reaction mixture was stirred at 30℃for 2 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 ml×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 19 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 8.58(br s，1H)，8.14-8.01(m，2H)，7.38-7.32(m，1H)，7.29-7.20(m，2H)，7.18-7.11(m，2H)，6.22(br s，4H)，5.16(s，2H)，1.77-1.69(m，2H)，1.31-1.20(m，2H)；LCMS(ESI)m/z：503.2[M+1] + 。
Example 20
The synthetic route is as follows:
compound 9 (169 mg, 395.45. Mu. Mol,1 eq) was dissolved in THF (2 mL) at 0deg.C, then NaH (20.56 mg, 514.08. Mu. Mol,60% purity, 1.3 eq) was added to the resulting solution, stirred for 90min, then 2, 2-trifluoroethyl triflate (110.14 mg, 474.54. Mu. Mol,1.2 eq) was added, and the temperature was raised to 20deg.C and stirred for 36 hours. To the reaction solution was added 2mL of water, and the pH was adjusted to 6-7 with 1M aqueous hydrochloric acid, followed by extraction with EA (4 ml×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC [ mobile phase: water (0.04% NH) 3 H 2 O+10mM NH 4 HCO 3 )-ACN]Compound 20 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 4.85(q，J＝9.03Hz，2H)5.18(s，2H)7.14-7.19(m，1H)7.21-7.27(m，1H)7.30-7.40(m，2H)7.99(dd，J＝9.10，2.45Hz，1H)8.12(t，J＝2.13Hz，1H)8.52(s，1H)；LCMS(ESI)m/z：478.2[M+1] + 。
Example 21
The synthetic route is as follows:
21-1 (203 mg,2.03mmol,1 eq) was dissolved in DCM (1 mL) at 25℃and oxalyl chloride (231.63 mg,1.82mmol, 159.74. Mu.L, 0.9 eq) and DMF (14.82 mg, 202.77. Mu. Mol, 15.60. Mu.L, 0.1 eq) were added, stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (176.20 mg, 405.53. Mu. Mol,0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25℃for 2 hours. To the reaction was added 2mL of water and extracted with DCM (4 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water (0.04% nh) 3 ·H 2 O+10mM NH 4 HCO 3 )-ACN]The method comprises the steps of carrying out a first treatment on the surface of the Acetonitrile: 35% -62%,10 min) to obtain compound 21. 1 H NMR(400MHz，DMSO-d 6 )：δppm 0.53-0.75(m，2H)1.14(br d，J＝2.38Hz，2H)1.44(s，3H)5.16(s，2H)7.12-7.28(m，4H)7.27-7.40(m，2H)8.07(s，1H)8.11(s，1H)8.21(dd，J＝9.29，2.38Hz，1H)8.85(br s，1H)；LCMS(ESI)m/z：452.2[M+1] + 。
Example 22
The synthetic route is as follows:
compound 3-e (0.1 g, 260.18. Mu. Mol,1 eq) was dissolved in pyridine (2 mL), ethyl chloroformate (42.35 mg, 390.28. Mu. Mol, 37.15. Mu.L, 1.5 eq) was added dropwise at 0℃and stirred at that temperature for 30 minutes. After completion of the reaction, the reaction solution was dropped into 4mL of water, extracted with ethyl acetate (5 ml×3), the organic phase was washed with saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [ [ mobile phase: water (0.225% FA) -ACN ]Compound 22 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 1.02-1.33(m，3H)4.06(br d，J＝6.78Hz，2H)5.13(s，2H)6.33(br s，4H)7.10-7.17(m，1H)7.18-7.29(m，2H)7.30-7.39(m，1H)7.92(br s，1H)8.06(s，1H)8.18(br d，J＝9.03Hz，1H)；LCMS(ESI)m/z：457.0[M+1] + 。
Example 23
The synthetic route is as follows:
compound 3-e (100 mg, 260.18. Mu. Mol,1 eq) and 23-1 (57.81 mg, 520.37. Mu. Mol,2 eq) were dissolved in pyridine (4 mL), EDCI (399.02 mg,2.08mmol,8 eq) was added thereto, and the reaction solution was reacted at 30℃for 2 hours. Dropping the reaction solution into H 2 O (4 mL) was then extracted with EA (5 mL. Times.3), and the organic phase was washed with saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 23 was obtained. 1 H NMR(400MHz，DMSO-d 6 )：δppm 1.50-1.64(m，2H)1.64-1.87(m，2H)5.14(s，2H)6.47(br s，4H)7.10-7.19(m，1H)7.18-7.30(m，2H)7.35(q，J＝6.48Hz，1H)8.07(s，1H)8.22(dd，J＝9.35，2.20Hz，1H)8.60(br s，1H)；LCMS(ESI)m/z：478.0[M+1] + 。
Example 24
The synthetic route is as follows:
to a solution of 3-e (100 mg, 260.18. Mu. Mol,1 eq) in pyridine (5 mL) were added EDCI (399.02 mg,2.08mmol,8 eq) and 17-b (90.63 mg, 780.55. Mu. Mol,3 eq). The reaction solution was stirred at 20℃for 1 hour. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL. Times.2). The organic phase is exposed to anhydrous Na 2 SO 4 Drying, filtration and concentration to give the crude compound by preparative HPLC [ mobile phase: water (10 mM ammonium bicarbonate) -acetonitrile]After separation, the mixture was purified by thin layer chromatography (SiO 2 ，DCM∶MeOH＝101) purifying to obtain the compound 24. 1 H NMR(400MHz，MeOH-d 4 )δ＝8.28-8.22(m，1H)，7.98-7.93(m，1H)，7.30(t，J＝7.5Hz，1H)，7.27-7.20(m，1H)，7.07-7.00(m，2H)，5.24(s，2H)，3.46(s，3H)，1.41-1.31(m，2H)，1.26-1.16(m，2H)。LCMS(ESI)m/z：483.4[M+1] + 。
Example 25
The synthetic route is as follows:
to a solution of 3-e (150 mg, 390.28. Mu. Mol,1 eq) in pyridine (5 mL) were added EDCI (598.53 mg,3.12mmol,8 eq) and 1-methylcyclopropyl-1-carboxylic acid (117.22 mg,1.17mmol,3 eq) and the reaction mixture was stirred at 20℃for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 ml×2), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN ]Compound 25 is obtained. 1 H NMR(400MHz，DMSO-d 6 )δ＝8.29(s，1H)，8.20(dd，J＝2.4，9.3Hz，1H)，8.08(d，J＝1.7Hz，1H)，7.35(q，J＝7.3Hz，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，6.21(br s，4H)，5.14(s，2H)，1.43(s，3H)，1.11(br d，J＝2.4Hz，2H)，0.63-0.46(m，2H)。LCMS(ESI)m/z：467.4[M+1] + 。
Example 26
The synthetic route is as follows:
step A: malononitrile (14.93 g,225.98mmol,14.22mL,1 eq) was dissolved in THF (100 mL), then potassium tert-butoxide (27.89 g,248.58mmol,1.1 eq) was added, the reaction stirred at 50℃for 0.5 h, then compound 26-1 (45 g,248.58mmol,32.14mL,1.1 eq) was added, the reaction stirred at 50℃for 11.5 h, after completion of the reaction 100mL water quench was added, then extracted with EtOAc (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated after filtration, and the residue was purified by column chromatography (PE/EtOAc=10/1-5/1) to give compound 26-a.
And (B) step (B): compound 26-a (20 g,120.35mmol,1 eq), S-methyl thiourea (27.04 g,144.42mmol,1.2eq, HSO) 4 ) And triethylamine (24.36 g,240.71mmol,33.50mL,2 eq) were dissolved in DMF (60 mL), after 3-fold nitrogen substitution, stirred at 100 ℃ for 12 hours, after completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (PE/etoac=10/1-1/1) to give compound 26-b.
Step C: compound 26-b (3.8 g,16.94mmol,1 eq) was dissolved in DCM (50 mL) and then m-chloroperoxybenzoic acid (6.88 g,33.89mmol,85% purity, 2 eq) was added. The reaction solution was stirred at 20℃for 12 hours. After completion of the reaction, filtration, a cake was collected, stirred with methylene chloride (100 mL), and dried by filtration to give compound 26-c. LCMS (ESI) m/z:257.2[ M+1 ] ] + 。
Step D: to a solution of 3-c (5.74 g,21.98mmol,1.1 eq) in DMF (30 mL) at 20℃were added potassium carbonate (8.28 g,59.93mmol,3 eq) and 26-c (5.12 g,19.98mmol,1.0 eq), the reaction was warmed to 120℃and incubated for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with methanol (20 mL) and DMF (20 mL), the filtrates were combined and concentrated under reduced pressure to remove methanol, and the residue was purified by preparative HPLC [ mobile phase: water (0.1% FA) -ACN]Compound 26 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δ＝11.15(s，1H)，8.27(dd，J＝2.5，9.4Hz，1H)，8.10(t，J＝2.0Hz，1H)，7.39-7.32(m，1H)，7.29(t，J＝7.6Hz，1H)，7.25-7.20(m，1H)，7.18-7.12(m，1H)，7.03(br s，2H)，5.15(s，2H)，1.35(s，6H)。LCMS(ESI)m/z：428.4[M+1] + 。
Example 27
The synthetic route is as follows:
to a solution of 5-f (200 mg, 670.45. Mu. Mol,1 eq) in DMF (2 mL) was added 26-c (2793 mg, 858.58. Mu. Mol,1.28 eq) and potassium carbonate (200 mg,1.45mmol,2.16 eq). The nitrogen was replaced and stirred at 120℃for 12 hours. The reaction was filtered and the filter cake was washed with 2mL of DMF and the filtrate was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 27 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.34(s，6H)5.18(s，2H)6.94-7.22(m，4H)7.37(q，J＝8.23Hz，1H)8.10(t，J＝2.14Hz，1H)8.27(dd，J＝9.48，2.63Hz，1H)；LCMS(ESI)m/z：456.1[M+1] + 。
Example 28
The synthetic route is as follows:
step A: to a mixture of 28-1 (3.5 g,31.79mmol,1 eq) in dichloromethane (100.00 mL) and toluene (10 mL) was added diphenyl azide phosphate (17.49 g,63.57mmol,13.78mL,2 eq) and 1.8-diazabicyclo [5.4.0] undec-7-ene (9.68 g,63.57mmol,9.58mL,2 eq). The reaction solution was stirred at 20℃for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: etoac=5:1 to 1:1) to give compound 28-a.
And (B) step (B): to a solution of 28-a (3.0 g,22.20mmol,1 eq) in methanol (10 mL) under nitrogen protection was added wet Pd/C (1.0 g,10% purity), the reaction mixture was replaced 3 times with hydrogen, and after completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to give compound 28-b under 15psi pressure and stirring at 20℃for 2 hours.
Step C: 3-1 (2.5 g,14.16mmol,1 eq) and 28-b (1.85 g,16.99mmol,1.2 eq) were dissolved in toluene (100 mL) and the mixture was warmed to 80℃and stirred for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: etoac=1:1) to give compound 28-c.
Step D: pd/C (1.0 g,9.63mmol,10% purity) was added to 28-C (2.4 g,9.63mmol,1 eq) in methanol (10 mL) under nitrogen. The reaction mixture was replaced with hydrogen gas 3 times, stirred at 15psi for 2 hours at 30℃and, after completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to give compound 28-d.
Step E: to a solution of 28-d (2.1 g,9.58mmol,1 eq) in THF (100 mL) was added CDI (3.11 g,19.16mmol,2 eq). The mixture was stirred at 70℃for 12 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=1:1 to 0:1) to give compound 28-e.
Step F: to a solution of 28-e (200 mg, 815.62. Mu. Mol,1 eq) in DMF (3 mL) was added 26-c (399 mg,1.63mmol,2 eq) and potassium carbonate (338 mg,2.45mmol,3 eq). The nitrogen was replaced and stirred at 120℃for 12 hours. The reaction solution was filtered, the filter cake was washed with 2ml dmf, and the filtrate was purified by preparative HPLC [ mobile phase: water (0.225% FA) -ACN]Compound 28 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.34(s，6H)5.16(s，2H)7.01(br s，2H)8.06-8.17(m，1H)8.29(dd，J＝9.48，2.63Hz，1H)8.84(s，2H)9.12(s，1H)；LCMS(ESI)m/z：422.1[M+1] + 。
Example 29
The synthetic route is as follows:
step A: diisopropylethylamine (2.11 g,16.31mmol,2.84mL,4 eq) and 3-fluoro-2-pyridylmethylamine hydrochloride (893 mg,4.49mmol,1.1 eq) were added to a solution of 3-1 (720 mg,4.08mmol,1 eq) in toluene (20.00 mL) under nitrogen. The mixture was stirred at 70℃for 12 hours. After cooling, water (100 mL) was added, extracted with EtOAc (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was isolated and purified by column chromatography (petroleum ether: ethyl acetate=20:1-5:1) to give compound 29-a.
And (B) step (B): to 29-a (650 mg,2.44mmol,1 eq) of tetrahydrofuran (15 mL) and water (5 mL) were added zinc reduction powder (428 mg,9.77mmol,4 eq) and ammonium chloride (653 mg,12.21mmol,5 eq). The reaction solution was stirred at 70℃for 12 hours, the reaction solution was filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate=4:1-2:1) to give compound 29-b.
Step C: to a solution of 29-b (430 mg,1.82mmol,1 eq) in THF (20.00 mL) was added CDI (442 mg,2.73mmol,1.5 eq). The mixture was stirred at 70℃for 12.5 hours, with a nitrogen displacement of 3 times. The reaction mixture was concentrated and the residue was purified directly by column chromatography (petroleum ether: ethyl acetate=4:1-1:1) to give compound 29-c.
Step D: to a solution of 29-c (200 mg, 762.73. Mu. Mol,1 eq) in DMF (3 mL) were added potassium carbonate (316 mg,2.29mmol,3 eq) and 26-c (481 mg,1.53mmol,2 eq) which were then reacted at 120℃for 12 hours. The reaction was filtered and the filter cake was washed with DMF (2 mL) and the filtrate was purified by preparative HPLC [ mobile phase: water (0.225% FA) -acetonitrile]Compound 29 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.22-1.48(m，6H)5.30(s，2H)7.02(br s，2H)7.26-7.52(m，1H)7.76(ddd，J＝10.06，8.53，1.10Hz，1H)7.94-8.13(m，1H)8.15-8.36(m，2H)11.12(br s，1H)。LCMS(ESI)m/z：439.1[M+1] + 。
Example 30
The synthetic route is as follows:
step A: to a solution of 3-c (250 mg, 957.02. Mu. Mol,1 eq) in DMF (2.00 mL) was added 2-chloro-4-amino-5-bromopyrimidine (199.49 mg, 957.02. Mu. Mol,1 eq) and potassium carbonate (264.53 mg,1.91mmol,2 eq). The reaction was stirred at 120deg.C for 12 hours, the reaction solution was cooled, diluted with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by thin layer chromatography (SiO 2 PE: etOAc=2:1) to afford compound 30-a.
Step (a)B: 30-a (200 mg, 461.67. Mu. Mol,1 eq), cyclopropylboronic acid (118.97 mg,1.39mmol,3 eq), potassium carbonate (191.42 mg,1.39mmol,3 eq) and bis (triphenylphosphine) palladium dichloride (162.02 mg, 230.84. Mu. Mol,0.5 eq) were dissolved in 1, 4-dioxane (5 mL), and after 3 times nitrogen substitution, stirred at 100℃for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 ml×2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by preparative HPLC [ mobile phase: water (0.1% TFA) -ACN]]Compound 30 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δ＝8.55(br d，J＝9.3Hz，1H)，8.22(d，J＝1.7Hz，1H)，7.85(s，1H)，7.41-7.33(m，2H)，7.24(m，1H)，7.20-7.11(m，1H)，5.19(s，2H)，1.67(m，1H)，0.96(dd，J＝1.9，8.3Hz，2H)，0.63(dd，J＝1.7，5.3Hz，2H)。LCMS(ESI)m/z：395.3[M+1] + 。
Example 31
The synthetic route is as follows:
step A: to a solution of 3-1 (2 g,11.33mmol,1 eq) in toluene (20 mL) was added m-fluorobenzylamine (1.56 g,12.46mmol,1.42mL,1.1 eq) and N, N-diisopropylethylamine (4.39 g,33.99mmol,5.92mL,3 eq). After the addition was complete, the mixture was stirred at 100℃for 2 hours. The reaction was concentrated and the residue was purified by column chromatography (PE: etoac=100:1-30:1) to give compound 31-a.
And (B) step (B): to a solution of 31-a (1.62 g,6.52mmol,1 eq) in methanol (30 mL) under nitrogen was added wet palladium on carbon (300 mg), after the addition was completed, the hydrogen was replaced three times by vacuum and the reaction was stirred under an atmosphere of hydrogen (15 psi) at 45℃for 12 hours. The reaction solution was filtered through celite, and the cake was washed with methanol (10 mL. Times.3), and the filtrate was concentrated to give compound 31-b.
Step C: to a solution of compound 31-b (2 g,8.50mmol,1 eq) in tetrahydrofuran (20 mL) was added CDI (2.76 g,17.00mmol,2 eq), the reaction was warmed to 70℃andStirring is carried out for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by column chromatography (PE/ea=5/1-1/1) to obtain compound 31-c. LCMS (ESI) m/z:262.5[ M+1 ]] + 。
Step F: to a solution of 31-c (260 mg, 995.30. Mu. Mol,1 eq) in DMF (3 mL) under nitrogen protection was added 26-c (510 mg,1.99mmol,2 eq) and potassium carbonate (413 mg,2.99mmol,3 eq). The reaction solution was stirred at 120℃for 12 hours. The reaction solution was filtered and the filtrate was purified by preparative HPLC [ mobile phase: water (0.225% FA) -acetonitrile]Compound 31 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δppm 1.35(s，6H)5.10(s，2H)7.00(br s，2H)7.07-7.14(m，1H)7.15-7.23(m，2H)7.38(td，J＝8.01，6.24Hz，1H)8.10(t，J＝2.08Hz，1H)8.26(dd，J＝9.35，2.51Hz，1H)11.12(br s，1H)；LCMS(ESI)m/z：438.1[M+1] + 。
Example 32
The synthetic route is as follows:
step A: to a solution of 3-1 (1.4 g,7.93mmol,1 eq) in toluene (40 mL) under nitrogen was added 2, 4-dimethoxybenzylamine (1.33 g,7.93mmol,1.19mL,1 eq) and triethylamine (1.60 g,15.86mmol,2.21mL,2 eq) and the reaction was stirred at 100deg.C for 4 hours. The reaction solution was cooled, washed with water (40 mL), separated, and the organic phase was concentrated under reduced pressure, then methanol was added and stirred for 1 hour, filtered, and the filter cake was dried under vacuum to give compound 32-a.
And (B) step (B): to a solution of 32-a (2 g,6.51mmol,1 eq) in tetrahydrofuran (60 mL) and water (20 mL) were added zinc powder (2.13 g,32.54mmol,5 eq) and ammonium chloride (1.74 g,32.54mmol,5 eq) and the reaction was stirred at 60℃for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to give compound 32-b.
Step C: to a solution of 32-b (1.6 g,5.77mmol,1 eq) in tetrahydrofuran (30 mL) under nitrogen was added CDI (1.87 g,11.54mmol,2 eq). The reaction mixture was stirred at 60℃for 16 hours, then quenched by addition of water (2 mL), concentrated under reduced pressure, the residue was stirred with methanol (20 mL) for 2 hours, filtered, and the cake was dried under vacuum to give compound 32-c.
Step D: to a solution of 32-c (1.1 g,3.63mmol,1 eq) in DMF (10 mL) under nitrogen protection were added 26-c (1.73 g,5.44mmol,1.5 eq) and potassium carbonate (1.50 g,10.88mmol,3 eq), the reaction was stirred at 120℃for 4 hours, water (40 mL) was added to the reaction to dilute, filtered, and the filter cake was dried in vacuo to give compound 32-d.
Step E: to a solution of 32-d (1.6 g,3.34mmol,1 eq) in DMF (4 mL) was added potassium carbonate (922.41 mg,6.67mmol,2 eq) and p-methoxybenzyl chloride (731.66 mg,4.67mmol, 636.23. Mu.L, 1.4 eq), stirred at 50℃for 2 hours under nitrogen protection, the reaction was diluted with water (25 mL), filtered and the filter cake dried in vacuo to give compound 32-e.
Step F: a solution of 32-e (1.8 g,3.00mmol,1 eq) in TFA (27.72 g,243.11mmol,18.00mL,80.98 eq) was stirred at 30℃for 3 hours, the reaction was concentrated and the residue was separated by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give compound 32-f.
Step G: to a solution of 32-f (0.6 g,1.34mmol,1 eq) in DMF (5 mL) was added 1, 2-pentafluoro-4-iodobutane (1.46 g,5.34mmol,4 eq) and potassium carbonate (922.55 mg,6.68mmol,5 eq). The reaction solution was reacted at 50℃for 1 hour under nitrogen protection. The reaction solution was neutralized by adding dilute hydrochloric acid (30 ml,1 mol/L), then extracted with ethyl acetate, dried over sodium sulfate and concentrated, and the residue was separated by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 32-g of a compound.
Step H: to a solution of 32-g (0.2 g, 335.85. Mu. Mol,1 eq) in TFA (2 mL) under nitrogen was added trifluoromethanesulfonic acid (3.40 g,22.66mmol,2mL,67.45 eq). The reaction solution was stirred at 50℃for 16 hours. The reaction mixture was neutralized by pouring into an aqueous solution of sodium hydroxide (80 mL,1 mol/L), extracted with ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure and purified by preparative HPLC [ water (0.075% TFA) -acetonitrile]Compound 32 was obtained. 1 H NMR(400MHz，DMSO-d 6 )δ＝11.14(s，1H)，8.26(dd，J＝2.6，9.4Hz，1H)，8.15(t，J＝2.1Hz，1H)，7.01(br s，2H)，4.22(t，J＝6.9Hz，2H)，2.90-2.72(m，2H)，1.35(s，6H).LCMS(ESI)m/z：476.2[M+1] + 。
Biological testing
Experimental example 1: in vitro Activity test
cGMP expression test based on lnCap cells
1. Experimental procedure
1) Solution preparation
● 10% BSA (bovine serum albumin)
10g BSA was dissolved in 100mL double distilled water (ddH 2 O) gives 10% BSA.
● 5mM DETA (diethylenetriamine) -NO
10mg of DETA-NO was weighed out and dissolved in 12.2mL double distilled water (ddH) 2 O) 5mM DETA-NO was obtained, dispensed and frozen in a-20deg.C freezer.
● Washing Buffer (Washing Buffer,50 mL)
● Assay Buffer (Assay Buffer,50 mL)
● Detection Buffer (Detection Buffer)
a) mu.L of cGMP-D2 (D2 labeled cyclic guanosine monophosphate) was added to 1mL of the lysate (lysia buffer) and mixed well.
b) 50. Mu.L of anti-cGMP cryptate (Eu) 3+ The cryptate-labeled anti-cyclophosphaguanosine antibody) was added to 1mL of lysate (lysies buffer) and mixed well.
2) Dilution of the Compounds
(1) The compound was diluted to 5mM with DMSO. Transfer 10 μl of compound to a shallow well plate for Echo.
(2) Compounds were diluted in gradients using Echo, 10 concentration gradients of each compound were diluted and added to 50nL to 384 microwell plates, respectively.
3) Preparation of LNCap cells
(1) LNCap medium: RPMI1640+10% foetal calf serum+1% double antibody
(2) And (5) placing phosphate buffer solution, pancreatin and culture medium used in the process of cell passage into a water bath kettle at 37 ℃ for preheating.
(3) From 37℃5% CO 2 Cells (14 th generation) were removed from the incubator, and old culture medium in the flask was aspirated by a pipette.
(4) 5mL of phosphate buffer was aspirated and added to the flask to rinse the cells, and the liquid was discarded.
(5) 3mL of pancreatin was aspirated, added to the flask, the liquid was discarded after shaking, and the flask was placed in an incubator.
(6) After about 2 minutes the flask was removed and after observing that the cells had all been separated, 9mL of medium was aspirated into the flask and repeatedly blown several times to transfer the cell suspension into a 50mL centrifuge tube.
(7) Aspirate 0.7mL of cell suspension into a counting cup and count on ViCell XR. The remaining cells were centrifuged at 1000rpm for 5min and the supernatant was removed.
(8) Cells were washed by adding 10mL of wash buffer (washing buffer), centrifuging at 1000rpm for 5min, and removing the supernatant.
(9) Add assay buffer (assay buffer) and adjust cell concentration to 1.25X10 6 /mL. 8. Mu.L/well was added to the microplate.
4) DETA-NO formulation and addition
(1) mu.L of 5mM DETA-NO was added to 1240. Mu.L and 1657. Mu.L of assay buffer (assay buffer), respectively, to give 40. Mu.M and 30. Mu.M DETA-NO.
(2) 2. Mu.L/well of DETA-NO was transferred to 384 microwell plates using Bravo.
(3) Centrifuge at 1500rpm for 5min. The microwell plates were incubated at 37℃for 30min.
5) Preparation of cGMP standard curve
(1) 1mM of cGMP stock solution was diluted to 10. Mu.M with assay buffer (assay buffer). Then 4-fold gradient diluted 11 concentration gradients.
(2) Diluted cGMP was added to the microplate at 10. Mu.L/well.
6) Adding detection reagent and reading the plate
(1) 5. Mu.L/well of cGMP-D2 was transferred to 384 microwell plates using Bravo. Centrifuge at 1500rpm for 1min.
(2) 5. Mu.L/well of anti-cGMP cryptate was transferred to 384 microwell plates using Bravo. Centrifuge at 1500rpm for 1min.
(3) Incubating for 1h at normal temperature.
(4) 665/615 are read with envision.
7) Data analysis
(1) cGMP standard curve: standard curves were made with Graphpad prism according to the ratio of cGMP concentration to 665/615.
(2) HTRF (homogeneous time resolved fluorescence technique) ratio (665/615) is converted to cGMP concentration: in Graphpad prism, HTRF ratios (665/615) are copied into the ratio column of the cGMP standard curve, run analysis "Log inhibitor vs response-variable slope", select "interface", and convert HTRF ratios (665/615) to cGMP concentrations.
(3) Compound activation profile: the concentration of converted cGMP was plotted against the concentration of compound using the "Log agonist vs response-variable slope" assay in Graphpad prism.
TABLE 1 MEC values of the compounds of the invention for sGC stimulatory activity
| Numbering of compounds | MEC(nM) |
| Compound 2 | 320.6 |
| Compound 8 | 12 |
| Compound 9 | 66 |
| Compound 10 | 293 |
| Compound 11 | 234 |
| Compound 12 | 94 |
| Compound 14 | 39 |
| Compound 15 | 61 |
| Compound 16 | 150 |
| Compound 17 | 95 |
| Compound 18 | 48 |
| Compound 19 | 101 |
| Compound 21 | 151 |
| Compound 22 | 346 |
| Compound 23 | 299 |
| Compound 26 | 5 |
| Compound 27 | 3.8 |
| Compound 28 | 37 |
| Compound 29 | 73 |
| Compound 31 | 27.6 |
| Compound 32 | 12.9 |
From the experimental results, the compound has good stimulation activity to sGC.
Experimental example 2: in vivo pharmacokinetic evaluation in rats
The purpose of the experiment is as follows:
detection of pharmacokinetic parameters of Compounds of the invention in rats
Experimental protocol:
1) Experimental animals: 6 male SD rats of 7-9 weeks of age were randomly divided into 2 groups of 3;
2) Preparing the medicine: weighing a proper amount of medicine, dissolving in 10% DMSO+50% PEG400+40% H 2 The mixed solvent of O is configured to be 0.2mg/mL; weighing appropriate amount of the medicine, dissolving in 10% EtOH+40% PEG400+50% H 2 The mixed solvent of O is configured to be 0.3mg/mL;
experimental operation:
group 1 animals were given a dose of 1.0mg/kg and a concentration of 0.2mg/mL of drug via a single injection into the tail vein, and group 2 animals were given a dose of 3mg/kg and a concentration of 0.3mg/mL of compound via gavage. Plasma samples were collected at 0.0833 (tail-vein-only group), 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-dose.
Data analysis:
the LC-MS/MS method was used to determine the drug concentration in plasma samples and the kinetic parameters of the test drugs are shown in table 2.
TABLE 2 pharmacokinetic test results of the inventive compounds
-indicating absence of
Conclusion: the compounds of the present invention have good pharmacokinetic properties in rats.
Experimental example 3: human liver microsome CYP inhibition assay
The objective of the study was to evaluate the inhibition of human liver microsomal cytochrome P450 isozymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6, CYP3 A4) by the test sample using a 5 in 1 probe substrate for the CYP isozymes.
Mixed Human Liver Microsomes (HLM) were purchased from Corning Inc. (Steuben, new York, USA) or from other suppliers and were stored at temperatures below-70℃until use.
The diluted serial concentration working solution of the test sample is added into an incubation system containing human liver microsomes, a probe substrate and auxiliary factors of a circulating system, and a control containing no test sample and solvent is taken as an enzyme activity control (100%). The concentration of the metabolite produced by the probe substrate in the sample is determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Non-linear regression analysis was performed on the mean percent activity versus concentration of the test samples using SigmaPlat (V.11). Calculation of IC by three-parameter or four-parameter sigmoid logarithmic equation 50 Values. Test results seeTable 3:
TABLE 3 in vitro detection of inhibition of CYP isozymes by the compounds of the invention
Conclusion: the compounds of the present invention have a weak inhibition of five CYP isozymes.
Claims (24)
- A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,wherein R is 1 H, F or Cl;R 2 is C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl or-CH 2 -pyrimidinyl, wherein said C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl or-CH 2 -pyrimidinyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5R a Substituted;each R is a Is independently H, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-C(＝O)OH、C 1-3 Alkoxy or optionally is substituted with 1, 2 or 3 groups independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group;R 3 and R is 4 Each independently is H, F, cl, br, I, -OH, -CN or-NH 2 ；R 5 is-L-R b ；L is a single bond, -NR c C (=O) O-or-NR c C(＝O)-；R b Is C 1-6 Alkyl group,Wherein said C 1-6 Alkyl group, Each independently optionally substituted with 1, 2 or 3R;R c is H, -CH 3 or-CH 2 CH 3 ；Each R is independently F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、C 1-3 Alkoxy or optionally is substituted with 1, 2 or 3 groups independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group;or R is 3 And R is 5 Linked to carbon atoms to which they are attached, to form structural unitsSelected from the group consisting ofR 6 、R 7 And R is 8 Each independently is F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 Or optionally 1, 2 or 3 independently selected from F, cl, br, I, -OH, -CN, -NH 2 and-OCH 3 C substituted by substituent(s) 1-3 An alkyl group.
- The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a single bond, -NH-C (=o) O-, -NH-C (=o) -, -N (CH) 3 ) -C (=O) O-or-N (CH) 3 )-C(＝O)-。
- The compound according to claim 1, having the structure represented by formulae (I-1) to (I-4):wherein R is 1 、R 2 、R 4 And R is b As defined in claim 1.
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is independently F, cl, br, -OH, -CN, -NH 2 、-NO 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-CH 2 CF 3 、-CH 2 CH 2 CF 3 、-CH 2 OH or-CH 2 CH 2 OH。
- The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R b Is C 1-4 Alkyl group, Wherein said C 1-4 Alkyl group,Each independently optionally substituted with 1, 2 or 3R.
- The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein said R b is-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-C(CH 3 ) 3 、
- The compound according to claim 4 or 6, or a pharmaceutically acceptable salt thereof, wherein R b is-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、 -CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH(CH 3 )CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-C(CH 3 ) 3 、
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the R 5 is-NH-C (=O) O-C 1-4 Alkyl, -NHC (=o) -C 1-4 Alkyl, -N (CH) 3 )-C(＝O)O-C 1-4 Alkyl, -NH-C (=o) - (C) 3-6 Cycloalkyl), -N (CH) 3 )C(＝O)-(C 3-6 Cycloalkyl), -NH-C (=o) -phenyl, -N (CH) 3 ) -C (=o) -phenyl or 5-6 membered heterocycloalkyl, wherein said NH-C (=o) O-C 1-4 Alkyl, -NHC (=o) -C 1-4 Alkyl, -N (CH) 3 )-C(＝O)O-C 1-4 Alkyl, -NH-C (=o) - (C) 3-6 Cycloalkyl), -N (CH) 3 )C(＝O)-(C 3-6 Cycloalkyl), -NH-C (=o) -phenyl, -N (CH) 3 ) -C (=o) -phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3R.
- The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the R 5 is-NH-C (=O) O-CH 3 、-NH-C(＝O)O-CH 2 CH 3 、-NH-C(＝O)O-CH 2 CH 2 CH 3 、-NH-C(＝O)O-CH(CH 3 ) 2 、-NH-C(＝O)-CH 3 、-NH-C(＝O)-CH 2 CH 3 、-NH-C(＝O)-CH 2 CH 2 CH 3 、-NH-C(＝O)-CH(CH 3 ) 2 、-N(CH 3 )-C(＝O)O-CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH(CH 3 ) 2 、
- The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the R 5 is-NH-C (=O) O-CH 3 、-NH-C(＝O)O-CH 2 CH 3 、-NH-C(＝O)O-CH 2 CH 2 CH 3 、-NH-C(＝O)O-CH(CH 3 ) 2 、-NH-C(＝O)-CH 3 、-NH-C(＝O)-CH 2 CH 3 、-NH-C(＝O)-CH 2 CH 2 CH 3 、-NH-C(＝O)-CH(CH 3 ) 2 、-N(CH 3 )-C(＝O)O-CH 3 、-N(CH 3 )-C(＝O)O-CH 2 CH 3 、-N(CH 3 )- C(＝O)O-CH 2 CH 2 CH 3 、-N(CH 3 )-C(＝O)O-CH(CH 3 ) 2 、
- The compound according to claim 1, having the structure of formulae (I-5) to (I-13):wherein p is 0, 1 or 2; r is R 4 Is H or-NH 2 ；R 2 As defined in claim 1; r is as defined in claim 1 or 4.
- The compound according to claim 1, having the structure of formulae (I-14) to (I-15):wherein R is 1 、R 2 、R 4 、R 6 、R 7 And R is 8 As defined in claim 1.
- The compound according to claim 12, having the structure of formulae (I-16) to (I-19):wherein R is 2 、R 6 、R 7 And R is 8 As defined in claim 12.
- The compound of claim 1 or 12, or a pharmaceutically acceptable salt thereof, wherein the building blockIs that
- The compound of claim 1 or 12, or a pharmaceutically acceptable salt thereof, wherein the building block Is that
- The compound according to any one of claims 1, 12 or 13, or a pharmaceutically acceptable salt thereof, wherein said R 6 、R 7 And R is 8 Each independently is F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-CH 3 、-CH 2 CH 3 、-CF 3 、-CH 2 CF 3 or-CH 2 CH 2 OH。
- The compound according to claim 13, having the structure of formulae (I-20) to (I-25):wherein R is 2 As defined in claim 13.
- The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R a Is independently H, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 、-C(＝O)OH、-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-CH 2 CF 3 、-CF 2 CF 3 、-CH 2 CH 2 CF 3 、-CH 2 OH or-CH 2 CH 2 OH。
- The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein each R a H, F, cl or-CF independently 3 。
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the R 2 Is that
- The compound of claim 18 or 20, or a pharmaceutically acceptable salt thereof, wherein the R 2 Is that
- A compound of the formula:
- use of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetic nephropathy or hypertensive nephropathy.
- A method of treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, the method comprising providing to the subject an effective dose of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.
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| CN2021104620094 | 2021-04-27 | ||
| CN202210307799 | 2022-03-25 | ||
| CN2022103077993 | 2022-03-25 | ||
| PCT/CN2022/088918 WO2022228365A1 (en) | 2021-04-27 | 2022-04-25 | Derivative of six-membered heteroaromatic urea ring and application thereof |
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| DE10220570A1 (en) * | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamate-substituted pyrazolopyridines |
| CN101076334A (en) * | 2004-05-28 | 2007-11-21 | 默克公司 | Benzoureas having anti-diabetic activity |
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