CN116640117A - 三氮唑类lpar1拮抗剂及其用途 - Google Patents

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Publication number

CN116640117A

CN116640117A CN202211617453.XA CN202211617453A CN116640117A CN 116640117 A CN116640117 A CN 116640117A CN 202211617453 A CN202211617453 A CN 202211617453A CN 116640117 A CN116640117 A CN 116640117A

Authority

CN

China

Prior art keywords

methyl

oxy

substituted

triazol

cyclopropyl

Prior art date

2021-12-15

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

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• 150000003852 triazoles Chemical class 0.000 title claims description 6
• 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 title abstract description 51
• 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 title abstract description 51
• 239000005557 antagonist Substances 0.000 title description 16
• 150000001875 compounds Chemical class 0.000 claims abstract description 466
• 150000003839 salts Chemical class 0.000 claims abstract description 19
• 239000000651 prodrug Substances 0.000 claims abstract description 15
• 229940002612 prodrug Drugs 0.000 claims abstract description 15
• 239000012453 solvate Substances 0.000 claims abstract description 12
• -1 chloro, bromo, iodo Chemical group 0.000 claims description 543
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 255
• 125000000217 alkyl group Chemical group 0.000 claims description 95
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 88
• 229910052736 halogen Inorganic materials 0.000 claims description 69
• 150000002367 halogens Chemical class 0.000 claims description 69
• 229910052757 nitrogen Inorganic materials 0.000 claims description 62
• 125000001072 heteroaryl group Chemical group 0.000 claims description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
• 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 claims description 15
• 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 claims description 15
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 208000004296 neuralgia Diseases 0.000 claims description 15
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 14
• 208000021722 neuropathic pain Diseases 0.000 claims description 14
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 14
• 201000010099 disease Diseases 0.000 claims description 13
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 238000011282 treatment Methods 0.000 claims description 12
• 125000002947 alkylene group Chemical group 0.000 claims description 11
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 125000005842 heteroatom Chemical group 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
• 239000000460 chlorine Substances 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 239000011737 fluorine Substances 0.000 claims description 10
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 229910052717 sulfur Inorganic materials 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 208000003906 hydrocephalus Diseases 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 7
• 230000001605 fetal effect Effects 0.000 claims description 7
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 206010016654 Fibrosis Diseases 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 230000004761 fibrosis Effects 0.000 claims description 5
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 5
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
• 206010023421 Kidney fibrosis Diseases 0.000 claims description 4
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 230000003176 fibrotic effect Effects 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 229930192474 thiophene Natural products 0.000 claims description 2
• 230000003042 antagnostic effect Effects 0.000 abstract description 5
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 485
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 307
• 238000006243 chemical reaction Methods 0.000 description 260
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 172
• 239000000243 solution Substances 0.000 description 159
• 238000003786 synthesis reaction Methods 0.000 description 152
• 230000015572 biosynthetic process Effects 0.000 description 151
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 148
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 129
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 114
• 239000012043 crude product Substances 0.000 description 112
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 108
• 239000012074 organic phase Substances 0.000 description 83
• 239000002904 solvent Substances 0.000 description 80
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 79
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 75
• 239000003208 petroleum Substances 0.000 description 74
• 238000005481 NMR spectroscopy Methods 0.000 description 67
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 66
• 239000011541 reaction mixture Substances 0.000 description 66
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
• 239000000203 mixture Substances 0.000 description 54
• 238000002360 preparation method Methods 0.000 description 49
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 42
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 41
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 37
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 36
• 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 36
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 36
• 238000004440 column chromatography Methods 0.000 description 35
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
• WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 28
• AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 28
• 239000012071 phase Substances 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 26
• NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 25
• 239000007864 aqueous solution Substances 0.000 description 24
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 22
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 21
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 21
• 235000019253 formic acid Nutrition 0.000 description 21
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
• 238000003756 stirring Methods 0.000 description 19
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 239000000741 silica gel Substances 0.000 description 18
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• 238000012360 testing method Methods 0.000 description 18
• 238000000034 method Methods 0.000 description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
• 238000004007 reversed phase HPLC Methods 0.000 description 17
• 239000000706 filtrate Substances 0.000 description 16
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
• 241000699670 Mus sp. Species 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• 210000004027 cell Anatomy 0.000 description 14
• 238000000605 extraction Methods 0.000 description 14
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
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• 238000001914 filtration Methods 0.000 description 12
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• 210000001519 tissue Anatomy 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
• 230000000694 effects Effects 0.000 description 11
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 11
• 238000000926 separation method Methods 0.000 description 11
• 230000011664 signaling Effects 0.000 description 11
• GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 10
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• 239000002253 acid Substances 0.000 description 10
• 210000004072 lung Anatomy 0.000 description 10
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• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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• 229960001561 bleomycin Drugs 0.000 description 9
• OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 9
• 125000004432 carbon atom Chemical group C* 0.000 description 9
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
• 238000002474 experimental method Methods 0.000 description 9
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
• 238000002156 mixing Methods 0.000 description 9
• DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 8
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
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• 208000005069 pulmonary fibrosis Diseases 0.000 description 8
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 8
• 238000010791 quenching Methods 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
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• 108010078791 Carrier Proteins Proteins 0.000 description 6
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• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
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• XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 5
• VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 5
• 150000003254 radicals Chemical class 0.000 description 5
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• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
• 125000001424 substituent group Chemical group 0.000 description 5
• 238000004808 supercritical fluid chromatography Methods 0.000 description 5
• KGQQKBSALJNKEH-ONEGZZNKSA-N (e)-4-ethoxy-1,1-difluorobut-3-en-2-one Chemical compound CCO\C=C\C(=O)C(F)F KGQQKBSALJNKEH-ONEGZZNKSA-N 0.000 description 4
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