WO2022100623A1 - Composés thiophène hétérocycliques substitués par azote et leur utilisation - Google Patents
Composés thiophène hétérocycliques substitués par azote et leur utilisation Download PDFInfo
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- WO2022100623A1 WO2022100623A1 PCT/CN2021/129863 CN2021129863W WO2022100623A1 WO 2022100623 A1 WO2022100623 A1 WO 2022100623A1 CN 2021129863 W CN2021129863 W CN 2021129863W WO 2022100623 A1 WO2022100623 A1 WO 2022100623A1
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- Prior art keywords
- och
- methyl
- alkyl
- substituted
- halogen
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- -1 heterocyclic thiophene compounds Chemical class 0.000 title claims description 114
- 150000001875 compounds Chemical class 0.000 claims abstract description 299
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 claims abstract description 18
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 claims abstract description 18
- 239000000651 prodrug Substances 0.000 claims abstract description 16
- 229940002612 prodrug Drugs 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 144
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 229910052736 halogen Inorganic materials 0.000 claims description 63
- 150000002367 halogens Chemical class 0.000 claims description 63
- 239000000460 chlorine Substances 0.000 claims description 56
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 35
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 33
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 31
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 23
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 21
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 18
- 208000004296 neuralgia Diseases 0.000 claims description 18
- 208000021722 neuropathic pain Diseases 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 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 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 17
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 15
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 15
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 239000011630 iodine Substances 0.000 claims description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 230000001605 fetal effect Effects 0.000 claims description 11
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 11
- 208000003906 hydrocephalus Diseases 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 claims description 9
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- 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 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 7
- 201000002793 renal fibrosis Diseases 0.000 claims description 7
- 230000003176 fibrotic effect Effects 0.000 claims description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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
- 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 2
- UNSHUWLBROGPRU-UHFFFAOYSA-N CCCCCOOC(C(CCCC(OCCCC)(OCC(C)C)OC(C)(C)C)(OC)OCC)(OCCC)OC(C)C Chemical compound CCCCCOOC(C(CCCC(OCCCC)(OCC(C)C)OC(C)(C)C)(OC)OCC)(OCCC)OC(C)C UNSHUWLBROGPRU-UHFFFAOYSA-N 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- ZHDSCPNAZAJOKO-UHFFFAOYSA-N [O]C(F)F Chemical compound [O]C(F)F ZHDSCPNAZAJOKO-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 168
- 239000000243 solution Substances 0.000 description 134
- 238000006243 chemical reaction Methods 0.000 description 129
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 83
- 238000003786 synthesis reaction Methods 0.000 description 80
- 230000015572 biosynthetic process Effects 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 239000012043 crude product Substances 0.000 description 54
- 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 description 53
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 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 35
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
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- 210000004027 cell Anatomy 0.000 description 13
- 239000005557 antagonist Substances 0.000 description 12
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 12
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 12
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- 101001038006 Homo sapiens Lysophosphatidic acid receptor 3 Proteins 0.000 description 11
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 11
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- 230000000052 comparative effect Effects 0.000 description 10
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- OXQRLBFDJMSRMM-NKWVEPMBSA-N methyl (1s,3r)-3-hydroxycyclohexane-1-carboxylate Chemical compound COC(=O)[C@H]1CCC[C@@H](O)C1 OXQRLBFDJMSRMM-NKWVEPMBSA-N 0.000 description 8
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- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229940099456 transforming growth factor beta 1 Drugs 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000006459 vascular development Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention belongs to the field of medicinal chemistry, in particular, the present invention relates to nitrogen-substituted heterocyclic thiophenes, more particularly, the present invention relates to nitrogen-substituted heterocyclic thiophenes and their use in preparing medicines.
- Lysophosphatidic acid is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which is widely present in various tissues of the human body intracellular and extracellular, such as various body fluids, saliva, urine, cerebrospinal fluid , blood, bronchoalveolar lavage fluid (BALF), etc. (Kaffe E et al. Cancers(Basel). 2019;11(11):1626.).
- LPA is mainly produced from membrane phospholipids through the following two pathways: (1) phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) PLA2-lysophospholipase D (LysoPLD) pathway.
- Autochemotactic protein (ATX) encoded by Enpp2 gene is a pyrophosphatase/phosphodiesterase, which has lysophospholipase D (LysoPLD) activity and can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., AnnuRev Pharmacol Toxicol. 2010;50:157186.), this response is the main source of LPA, and inhibition of ATX activity can inhibit LPA production in the body by more than 80% (Kaffe E et al. Cancers ( Basel). 2019;11(11):1626.).
- LPA mediates a variety of functions by interacting with G protein-coupled receptors, including cell survival, cell proliferation, cell adhesion, cell migration, cytoskeletal changes, calcium mobilization, increased vascular permeability and angiogenesis, immune function and myeloid Sheath formation, etc.
- LPA can bind and function with six lysophosphatidic acid receptors (LPARs), namely: LPAR1-LPAR6.
- LPA regulates a variety of physiological/pathological processes by binding to 6 LPARs, including vascular and neural development, hair follicle development, lymphocyte transport, bone development, fibrosis, fat mass regulation, cholestatic pruritus, neuropathic pain, embryo implantation , obesity and glucose homeostasis, sperm production, chronic inflammation, cell proliferation, cell chemotaxis, wound healing, tumor progression, fetal hydrocephalus, etc. (Fang Yang et al., Worldjournal of gastroenterology, 2018, 24(36):4132.) .
- LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein composed of 364 amino acids. It is widely expressed in various tissues and organs of the human body, among which the mRNA levels of brain, heart, colon, small intestine and placenta are high, while mRNA levels in other organs and tissues were relatively low. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling to G ⁇ I/o, G ⁇ Q/11, and G ⁇ 12/13, although LPA-LPAR1 signaling has been shown to play a role in the developmental stages of the nervous system. important effects, but no apparent toxicity was found for systemic inhibition in adults. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.
- the diseases that are significantly related to LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central diseases and the like.
- Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorders. The main manifestation is common interstitial pneumonia. IPF originates from repeated damage to the tissue of alveolar tissue, and this damage triggers a series of physiopathological events, including (I) disruption of homeostasis; (II) inflammatory response; (III) cell proliferation, migration and differentiation; ( IV) matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors at and around the injury site, in which LPA plays an important role.
- LPA extracellular matrix
- LPA induces endothelial cell barrier dysfunction and vascular leakage.
- increased vascular permeability can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibrosis development.
- bleomycin treatment resulted in a marked increase in LPA levels in bronchoalveolar lavage fluid following lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; LPAR1 antagonist AM966 reduced total protein content and LDH activity in bronchoalveolar lavage fluid in a bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in sexual lung disease.
- LPAR1 is a promising target for the treatment of IPF
- BMS-986278 is undergoing Phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol. 2010; 160(7): 1699-1713.).
- Radiation pulmonary fibrosis is a common and serious complication of radiation therapy for lung cancer.
- the LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibrocytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased fibroblast proliferation in mice and slowing the progression of radiation-induced pulmonary fibrosis, suggesting that LPAR1 antagonists are also therapeutic Potential for radiation pulmonary fibrosis (Xiang H et al, J Cancer. 2020;11(12):3519-3535.).
- LPAR1 is closely related to the occurrence of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the development of liver fibrosis, suggesting that antagonism of LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol.
- LPA promotes the progression of renal fibrosis through LPAR1.
- UUO unilateral ureteral obstruction
- TNF renal interstitial fibrosis
- ATX and LPA concentrations were elevated, LPAR1 was significantly up-regulated, and LPAR3 was significantly down-regulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.).
- ATX-LPA-LPAR1 signaling stimulates fibroblast migration and proliferation, and UUO-induced renal fibrosis is significantly attenuated on LPAR1 -/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling is blocked
- the expression of pro-fibrotic cytokines was also significantly down-regulated upon interruption. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
- Fetal hydrocephalus is a common neurological disease in neonates, and its occurrence is closely related to LPAR1 signaling.
- LPAR1 expressed by neural precursor cells NPCs
- NPCs neural precursor cells
- Ki16425 an LPAR1/3 antagonist
- PHL hemorrhagic hydrocephalus
- LPA-LPAR1 signaling has a significant tumor-promoting effect.
- LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and activates metalloproteinases, and promotes tumor cell resistance to cisplatin in vitro.
- LPAR1 signaling downregulates the expression of tumor suppressor p53 in hepatoma cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1 to promote MMP-9 expression and HCC invasion; LPA-LPAR1 can also activate GTPase RhoA and Rho-related protein kinase (ROCK) Promotes invasiveness; it also induces protein kinase C (PKC) and nuclear factor kappa B (NF-kB) to promote epithelial-to-mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis also promotes cancer development , because neovascularization is essential for the development of solid tumors.
- neuropathic pain a painful state
- symptoms including persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia
- LPAR1 signaling has been implicated in the development of neuropathic pain.
- Injury to the nervous system leads to serum leakage from the injury site, which exposes nerve cells to LPA and may be one of the causes of neuropathic pain.
- the study by Makoto Inoue et al. showed that the behavioral abnormalities and hyperalgesia induced by nerve injury in animal models can be eliminated by pretreatment with LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA.
- LPA-LPAR1 signaling plays a critical role in the initiation of neuropathic pain and that LPAR1 antagonists may hold promise as analgesics for the treatment of neuropathic pain (Inoue M et al., ERRATUM: Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J]. 2004, 10(7):755-755.).
- Rheumatoid arthritis is a chronic autoimmune disease
- LPAR1 signaling is related to the occurrence of RA.
- LPAR1 and/or LPAR2 expression levels are increased in the synovium of patients with rheumatoid arthritis
- preclinical studies have shown that gene knockout of LPAR1 completely abolished RA symptoms, and pharmacological antagonism of LPAR1 reduced the severity of the disease. Severity, inflammation and bone erosion were reduced (Kaffe E et al. Cancers(Basel). 2019; 11(11):1626. Published 2019 Oct 23.doi:10.3390/cancers11111626).
- Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
- the present invention aims to at least to some extent solve one of the above technical problems or at least provide a useful business option.
- the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):
- R 1 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), -ZR a , C 1-6 alkyl unsubstituted or substituted by R b ⁇ the "C 1- 6 alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R b is one or more ( The number is subject to the substituted group conforming to the valence bond theory and stable existence.
- halogen such as fluorine, chlorine, bromine or iodine
- R b when there are multiple R b , the R b is the same or different ⁇ , unsubstituted or C 3-6 cycloalkyl substituted by R b (the "C 3-6 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or C 1 substituted by R b -6 alkylamino (the "C 1-6 alkylamino" such as wherein m1 and m2 are each independently selected from integers from 0 to 6, the sum of m1 and m2 does not exceed 6, and/or m1 and m2 are not both zero), unsubstituted or substituted by R b C 1-6 alkoxy group (the "C 1-6 alkoxy group” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy
- Z is selected from a single bond, -O-, -S- or -CO-;
- R a is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl
- halogen is such as fluorine, chlorine, bromine or iodine
- the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as (e.g. 1, 2 or 3), when multiple halogens are present, the halogens are the same or different ⁇ , amino (eg -NH 2 ), C 1-3 alkylamino (eg );
- R b is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, pentyl, hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);
- halogen eg fluorine, chlorine, bromine or iodine
- C 1-6 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyloxy
- C 1-6 alkyl eg
- R 2 is selected from -H, -CN, halogen (eg fluorine, chlorine, bromine or iodine), -YR d , unsubstituted or substituted C 1-6 alkyl ⁇ the "C 1-6 alkane""base" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the Re is one or more (the The number is subject to the substituted group conforming to the valence bond theory and stable existence.
- halogen eg fluorine, chlorine, bromine or iodine
- -YR d unsubstituted or substituted C 1-6 alkyl ⁇ the "C 1-6 alkane""base” such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobuty
- the Re when there are multiple Re , the Re is the same or different ⁇ , unsubstituted or by Re -substituted C 3-6 cycloalkyl (the "C 3-6 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl), unsubstituted or R substituted C 1-6 Alkylamino (the "C 1-6 alkylamino” such as wherein n1 and n2 are each independently selected from integers from 0 to 6, the sum of n1 and n2 does not exceed 6, and/or n1 and n2 are not both zero), unsubstituted or substituted C 1-6 alkoxy group (the "C 1-6 alkoxy group” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy base, hexyloxy);
- Y is selected from a single bond, -O- or -S-;
- R d is selected from C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl), C 1 substituted by halogen -6 alkyl
- halogen is such as fluorine, chlorine, bromine or iodine
- the number of the halogen is one or more (the number of the substituted group conforms to the valence bond theory and exists stably as For example, 1, 2 or 3), when there are multiple halogens, the halogens are the same or different ⁇ ;
- R e is selected from -CN, halogen (eg fluorine, chlorine, bromine or iodine), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) butyl, pentyl, hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy, hexyloxy);
- X 1 , X 2 , and X 3 are independently selected from C or N, and X 1 , X 2 , and X 3 are not N at the same time;
- R g is selected from H, F, Cl, methyl
- L 1 is selected from a single bond, -N(R 3 )- or -O-;
- L 2 is selected from single bond, -O-, unsubstituted C 1-6 alkylene (for example ), C 1-6 alkylene substituted by C 1-3 alkyl (such as ), unsubstituted or cyclopropyl substituted by C 1-3 alkyl;
- R 3 is selected from -H, C 1-3 alkyl (eg methyl, ethyl, propyl);
- R 4 is selected from -H, -CN, halogen (such as fluorine, chlorine, bromine or iodine), unsubstituted or substituted C 1-6 alkyl ⁇ said "C 1-6 alkyl" such as methyl base, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, tert-butyl, pentyl, hexyl; the number of the R is one or more (the number is after the substitution
- the group conforms to the valence bond theory and is subject to stable existence.
- R h when there are multiple R h , the R h is the same or different ⁇ , unsubstituted or substituted by R h C 3-8 cycloalkyl (the "C 3-6 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl);
- R is selected from -H, halogen (eg fluorine, chlorine, bromine, iodine), C 1-6 alkyl (eg methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl), C1-6 alkyl substituted with halogen (eg trifluoromethyl), C1-6 alkoxy substituted with halogen (eg difluoromethoxy).
- halogen eg fluorine, chlorine, bromine, iodine
- C 1-6 alkyl eg methyl, ethyl, n -propyl, isopropyl, n-butyl, n-pentyl
- C1-6 alkyl substituted with halogen eg trifluoromethyl
- C1-6 alkoxy substituted with halogen eg difluoromethoxy
- R 1 is selected from fluorine, chlorine or bromine.
- R 1 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F. -OCH( CH3 )( CH2F ).
- R 1 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -SCH 2 CH 2 F, -S(CH 2 ) 2 CH 2 F, -SCH(CH 3 )(CH 2F ).
- R 1 is selected from -CO-NH 2 , -CO- NH- CH3 , -CO-N( CH3 ) 2 , -CO-NH- CH2 - CH3 , -CO-N( CH3 )( CH2CH3 ) ;
- R 1 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -NH-(CH 2 ) 2 CH 3 , -NH-CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 .
- R 1 is selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN), -NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F,
- R 2 is selected from fluorine, chlorine or bromine.
- R 2 is selected from -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 2 OCH 3 , -OCH 2 F, -OCH 2 CH 2 F, -O(CH 2 ) 2 CH 2 F. -OCH( CH3 )( CH2F ).
- R 2 is selected from -SCH 3 , -SCH 2 CH 3 , -S(CH 2 ) 2 CH 3 , -SCH(CH 3 ) 2 , -SCH 2 F, -SCH 2 CH 2 F, -S(CH 2 ) 2 CH 2 F, -SCH(CH 3 )(CH 2F ).
- R 2 is selected from -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -NH-(CH 2 ) 2 CH 3 , -NH-CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 ;
- R 2 is selected from -CH 2 CN, -CH 2 CH 2 CN, -(CH 2 ) 2 CH 2 CN, -CH(CH 3 )(CH 2 CN), -NH - CH2CN, -N( CH3 )( CH2CN ), -NH- CH2CH2CH2CN , -NH-( CH2 ) 2CH2CN , -NH- CH ( CH3 ) (CH 2 CN), -OCH 2 CN, -OCH 2 CH 2 CN, -O(CH 2 ) 2 CH 2 CN, -OCH(CH 3 )(CH 2 CN), -CH 2 F, -CHF 2 , CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -(CH 2 ) 2 CH 2 F,
- R 3 is selected from -H or methyl.
- R 4 is selected from methyl, ethyl, isopropyl , n-butyl.
- R 4 is selected from cyclopropyl, cyclobutyl, cyclopropyl amyl.
- R 4 is selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -(CH 2 ) 2 Cl, -( CH2 )3Cl, -CH( CH3 ) ( CH2Cl ).
- R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(
- R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(
- R 1 is selected from -H, -F, methyl, Cyclopropyl, -CO- NH2 , -CO-NH- CH3 , -CO-N( CH3 ) 2 .
- R 2 is selected from -H, -F, -Cl, -CH3 .
- L 1 is selected from a single bond, -NH- or -O -.
- R 4 is selected from -H, -F, methyl, Ethyl, isopropyl, cyclopropyl, n-butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
- R 2 is selected from -H, -F, -Cl, -CH 3 ; selected from L 1 is selected from single bond, -NH- or -O-; L 2 is selected from single bond, -O-, R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
- R 1 is methyl
- R 2 is selected from halogen
- selected from L 1 is selected from single bond, -NH- or -O-
- L 2 is selected from single bond, -O-
- R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F ;
- R 1 is selected from methyl, -CO-NH 2 ;
- R 2 is selected from -F, -Cl;
- selected from L 1 is selected from -NH- or -O-;
- L 2 is selected from -O-,
- R4 is selected from H, F, methyl, ethyl, isopropyl, cyclopropyl, n - butyl, cyclopropyl, cyclobutyl, -CHF2, -CF3 , -( CH2 ) 3F .
- the compound represented by the formula (I) is further the compound represented by the formula (I-0):
- R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F), -CO-NH 2 -, -CO,
- R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),
- R g is selected from H, F, Cl, methyl
- L 1 is selected from a single bond, -N(R 3 )- or -O-;
- L 2 is selected from single bond, -O-, unsubstituted or C 1-6 alkylene substituted by C 1-3 alkyl;
- R 3 is selected from H, C 1-3 alkyl
- R 4 is selected from -H, -CN, -F, -Cl, -Br, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -(CH 2 ) 2 F, -(CH 2 ) 3 F, -CH(CH 3 )(CH 2 F), -( CH 2 ) 2 Cl, -(CH 2 ) 3 Cl, -CH(CH 3 )(CH 2 Cl),
- the compound represented by the formula (I) is further the compound represented by the formula (I-0):
- R 1 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F), -CO-NH 2 -, -CO,
- R 2 is selected from -H, -CN, -F, -Cl, -Br, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(CH 2 ) 2 CH 2 F, -OCH(CH 3 )(CH 2 F),
- the compound represented by the formula (I) can be any of the following compounds:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.
- the compound represented by the formula (I), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) may be in a therapeutically effective dose.
- the present invention also provides a compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) in the preparation of therapeutic and Use in medicine for LPAR-related diseases.
- the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- said LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal brain volume water.
- the present invention also provides a method of treating or preventing LPAR-related diseases.
- the method comprises administering to the patient a pharmaceutically acceptable dose of the aforementioned compound, or the aforementioned pharmaceutical composition.
- the LPAR-related disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus .
- groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
- substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
- a number from 1 to 10 should be understood as not only reciting each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also reciting at least that each integer is respectively associated with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
- stereoisomers refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers and conformers.
- Stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, as defined by John Wiley & Sons, Inc., New York, 1994.
- the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory.
- the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
- Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids.
- Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
- Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist as two or more interconvertible species.
- Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
- Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the ketone form predominates; in phenols, the enol form predominates.
- the present invention encompasses all tautomeric forms of the compounds.
- composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
- an "effective dose” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
- the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
- active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
- solvate means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
- prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
- the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
- Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
- C 1-6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2 , 3, 4, 5 or 6 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbuty
- C3-6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- alkylamino refers to an amino group substituted with one or two hydrogen atoms by an alkyl group, including "N-alkylamino" and “N,N-dialkylamino", wherein the amino group
- the groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meanings as defined herein.
- Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.
- the alkylamino group is optionally substituted with one or more substituents described herein.
- C 1-6 alkylamino refers to “alkylamino” or “alkylamino” having 1 to 6 carbon atoms.
- C 1-6 alkoxy is to be understood as -O-(C 1-6 alkyl ) , wherein “C 1-6 alkyl " has the above definition.
- 4-8 membered heterocyclyl is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, of which 1, 2, 3, 4 or 5 rings Atoms are selected from N, O, and S, which, unless otherwise specified, may be attached through carbon or nitrogen, wherein the -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise specified, the ring nitrogen Atoms or ring sulfur atoms are optionally oxidized to form N-oxides or S-oxides or ring nitrogen atoms are optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl or methyl sulfonyl substitution; and the ring is optionally substituted with one or more halogens.
- heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic.
- heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
- 5-8 membered aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C 6 aryl”), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
- 5-8 membered heteroaryl is to be understood as having 5-8 ring atoms - in particular 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S
- a monovalent monocyclic, bicyclic or tricyclic aromatic ring group 1-3 monovalent monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and, in addition, in each case may be benzo-fused .
- heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.
- halo or halogen is fluorine, chlorine, bromine and iodine.
- haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
- the compound represented by formula (I), its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the present invention has a good antagonistic effect on LPAR1.
- the compound of the present invention has a good antagonistic effect on LPAR1, and a weak antagonistic effect on LPAR3, that is, the compound of the present invention shows excellent selectivity; the compound of the present invention has better safety and no cholestatic toxicity. Risk; the compounds of the present invention have excellent pharmacokinetic properties and good druggability; the compounds of the present invention can significantly inhibit LPA-induced histamine release by antagonizing LPAR1, and at the same time significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice.
- the embodiments of the present invention provide compounds represented by formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, to prepare formula (I) ) of the compound or its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs, methods and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicine.
- reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention.
- equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention.
- the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the units of NMR shifts are 10-6 (ppm).
- the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
- Liquid-mass spectrometry was determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, monitored using an ACQUITY UPLC BEH C18, 2.1*50mm, 1.7 ⁇ m chromatographic column. Gradient elution conditions: flow rate of 1.0mL/min, 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 for 0.5min, the percentage is the volume percentage of a certain solvent in the total solvent volume . Wherein solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentage is the volume percent of the solute in the solution.
- IC 50 half inhibitory concentration, refers to the concentration at which half of the maximum inhibitory effect is achieved
- n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
- M mol/L
- N equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
- DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
- PE petroleum ether
- Comparative Example 1 Comparative Compound 1 and its preparation
- Reference compound 1 was synthesized with reference to patent application WO2010141768A2.
- Comparative Example 2 Comparative Compound 2 and its preparation
- Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
- Comparative Example 3 Comparative Compound 3 and its preparation
- Reference compound 3 was synthesized with reference to patent application WO2017223016A1.
- Comparative Example 4 Comparative Compound 4 and its preparation
- Control compound 4 was synthesized with reference to patent application WO2019126098A1.
- Comparative Example 5 Comparative Compound 5 and its preparation
- Reference compound 5 was synthesized with reference to patent application WO2019126084A1.
- reaction solution was filtered through celite, concentrated, the residue was dissolved in methyl tert-butyl ether (100 mL), washed once with saturated sodium bicarbonate, once with saturated sodium sulfite, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain a white solid (1S,5R)-6-oxacyclo[3.2.1]octan-7-one (A-3) (3.88 g, 58.7% yield).
- the first step the synthesis of 2-bromo-4-methylpyrimidin-5-ol (I-1B)
- the second step the synthesis of methyl (1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1C) methyl( 1S,3S)-3-((2-bromo-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-1C)
- Step 5 (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of methyl 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-1F)
- Step 6 (1S,3S)-3-((2-(5-chloro-3-(((4-cyclopropoxypyrimidin-2-yl)amino)methyl)thiophen-2-yl)- Synthesis of 4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1)
- the synthetic route of the target compound I-2 is as follows:
- reaction solution was quenched with water (1 mL), and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was passed through a column to obtain compound (1S,3S)-3-((6-(5-chloro-3-((((4-isopropylpyrimidine- 2-yl)oxy)methyl)thiophen-2-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2D) (0.26 g, yield 99.73%).
- the synthetic route of the target compound I-3 is as follows:
- the first step Synthesis of (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (I-3B)
- reaction solution was extracted with ethyl acetate (20 mL ⁇ 2), and the organic layers were combined to obtain the compound 3-cyclopropylprop-1-ynyl(trimethyl)silane (I-3B) (1 g, yield 88.64%) . used directly in the next step.
- reaction solution was extracted with ethyl acetate (10 mL ⁇ 2), and the organic layers were combined to obtain compound (1S,3S)-3-((6-(3-(azidomethyl)-5-chlorothiophen-2-yl) )-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3D) (0.2 g, 94.37% yield).
- the synthetic route of the target compound I-4 is as follows:
- the synthetic route of the target compound I-6 is as follows:
- the first step the synthesis of 4-isopropylpyrimidin-2-amine (I-6B)
- the synthetic route of the target compound I-7 is as follows:
- the synthetic route of the target compound I-8 is as follows:
- the synthetic route of the target compound I-9 is as follows:
- 2,2,2-Trifluoro-1-ol (1.158 g, 11.58 mmol) was added to 10 mL of tetrahydrofuran, sodium hydrogen (0.278 g, 11.58 mmol) was added at 0°C, and after stirring for 30 minutes, 4-chloropyrimidine was added -2-amine (1 g, 7.72 mmol), stirred at 70°C for 12 hours.
- the synthetic route of the target compound I-11 is as follows:
- the synthetic route of the target compound I-12 is as follows:
- the first step Synthesis of 2-bromo-5-fluorothiophene-3-carbaldehyde (I-12B)
- the first step Synthesis of (N-((2-bromo-5-fluorothiophen-3-yl)methyl)-4-isopropylpyrimidin-2-amine (I-13B)
- Step 2 (1S,3S)-methyl 3-((6-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -2-methylpyridin-3-yloxy)cyclohexanecarboxylate (I-13C)
- the synthetic route of the target compound I-15 is as follows:
- the second step the synthesis of (1S,3S)-3-((2,4-dichloropyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15C)
- the third step the synthesis of (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy) cyclohexanecarboxylic acid methyl ester (I-15D)
- Methyl (1S,3S)-3-((2-chloro-4-cyanopyrimidin-5-yl)oxy)cyclohexanecarboxylate 400 mg, 1.35 mmol
- (3-formylthiophene-2 -yl)boronic acid 316.45 mg, 2.03 mmol
- potassium fluoride 471.50 mg, 8.12 mmol
- tetrahydrofuran 3 mL
- bis(tri-tert-butylphosphine)palladium 69.13 mg, 135.26 ⁇ mol
- the seventh step (1S,3S)-3-((4-carbamoyl-2-(5-chloro-3-(((5-(cyclobutylmethyl)-1,2,4-oxadiazole- Synthesis of 3-yl)amino)methyl)thiophen-2-yl)pyrimidin-5-yl)oxy)cyclohexanecarboxylic acid (target compound 1-15).
- the synthetic route of the target compound I-16 is as follows:
- Step 2 (1S,3S)-methyl 3-((2-(5-fluoro-3-(((4-isopropylpyrimidin-2-yl)amino)methyl)thiophen-2-yl) Synthesis of -4-methylpyrimidin-5-yloxy)cyclohexanecarboxylate (I-16B)
- the target compound I-17 was synthesized with reference to compound I-13, except that 4-isopropylpyrimidin-2-amine was replaced by 1-(cyclopropylmethyl)-1,4-dihydro-5H-tetrazole -5-keto.
- the target compound I-18 was synthesized with reference to compound I-11, except that 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine was replaced by 5-butyl-1,2,4 - oxadiazol-3-amine.
- the target compound I-19 was synthesized with reference to compound I-8, except that 2,2-difluoroethanol was replaced by 3-fluoro-1-propanol.
- Test Example 1 LPAR1 In Vitro Calcium Flux Assay
- the antagonism of compounds on LPAR1 was determined in a CHO cell line stably expressing human LPAR1. 18 hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours 20 ⁇ L/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, and then incubated at room temperature for 10 min in the dark. Add 10 ⁇ L/well of compounds of different final concentrations into the cells, and equilibrate.
- test compound IC50 (nM) Control compound 1 117.9 Control compound 2 243.8 Control compound 3 251.6 Control compound 4 243.3 Control compound 5 109.5 I-1 93.63 I-2 27.82 I-3 33.92 I-4 69.2 I-5 39.75 I-6 46.32 I-7 1697 I-8 82.06 I-9 47.49 I-10 288.1 I-11 35.18 I-12 11.29 I-13 22.16 I-14 49.29 I-16 91.3
- the results of the LPAR1 calcium flux test showed that the compounds of the present invention had a good antagonistic effect on LPAR1. Compared with the control compounds, most of the inventive compounds showed more excellent antagonistic effects on LPAR1.
- Test Example 2 LPAR3 In Vitro Calcium Flux Assay
- the antagonism of compounds on LPAR3 was determined in a CHO cell line stably expressing human LPAR3. Eighteen hours before the experiment, cells were seeded at a density of 15,000 cells/well in 384-well black-walled clear bottom plates containing 20 ⁇ L of DMEM/F12 (1:1) medium and kept at 37°C/5% CO for 18 hours. 20 ⁇ L/well of dye solution was added to each well of cells, placed back in a 37°C incubator for 30 min in the dark, then incubated at room temperature for 10 min in the dark, and 10 ⁇ L/well of different final concentrations of compounds were added to the cells and equilibrated.
- the results of the LPAR3 calcium flux assay showed that the compounds of the present invention had a weak antagonistic effect on LPAR3, and compared with the control compounds, the compounds of the present invention showed better selective inhibition of LPAR1.
- Test Example 3 Test test for the inhibitory effect of compounds on bile efflux transporters
- NC negative control
- PC positive control
- the assay was terminated with pre-chilled Buffer B1 (10 ⁇ Buffer B1 (Stopping and Washing Buffer): 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose). Transfer the test sample to a 96-well filter plate, filter it with a vacuum pump, and then repeatedly wash it with 0.2 mL of pre-cooled Buffer B1 for 5 times, dissolve the vesicles on the filter plate with 50 ⁇ L of 80% methanol, and centrifuge at 2000 rpm for 2 minutes after collection. The filtrate was collected and repeated once. The two filtrates were combined and mixed to obtain about 100 ⁇ L of the filtrate.
- Buffer B1 100 mM Hepes-Tris, 1000 mM KNO3, 500 mM Sucrose.
- mice pharmacokinetic test show that, compared with the control compound, the compound of the present invention exhibits better pharmacokinetic properties and better drug-forming properties.
- LPA-induced mouse histamine release assays were performed with 20-25 g female Balb/c mice. Compounds and positive control groups were set up in three administration groups, each group of 6 mice, orally administered 1, 3, 10mpk, respectively, blank group and negative control group were given the same volume of vehicle (5% DMSO + 5% Solutol+90%Saline). After 2 hours of administration, mice in each administration group were injected with 300 ⁇ g/mouse LPA through the tail vein, while the blank group and the negative control group were injected with an equal volume of vehicle (4 mg/ml BSA/PBS) through the tail vein.
- vehicle 5% DMSO + 5% Solutol+90%Saline
- the samples were stored at 2-8 degrees, centrifuged at 5000 rpm for 5 min within 20 min, and the plasma was collected, and the histamine concentration in the plasma was detected using the HTRF kit (Cisbio, 62HTMDPEG).
- the inhibition rates of different concentrations of compounds on LPA-induced histamine release were calculated using the histamine concentration data in plasma.
- Test Example 6 Efficacy test of bleomycin-induced pulmonary fibrosis
- mice were reared adaptively for 1 week, and after reaching the target body weight, they were randomly divided into the control group, the model group and the administration group according to the body weight of the animals.
- the model group and the administration group were evenly given 50 ⁇ L of bleomycin in the lungs to establish a mouse pulmonary fibrosis model, while the control group was evenly given 50 ⁇ L of normal saline in the lungs;
- the animals were deeply anesthetized with sodium pentobarbital, and the bronchoalveolar lavage fluid (BALF) was collected and temporarily stored in a wet ice box for subsequent index detection; some animal lungs were placed in 10% neutral fortification.
- BALF bronchoalveolar lavage fluid
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Abstract
L'invention concerne une nouvelle classe de composés qui antagonisent efficacement LPAR, ces composés étant représentés par la formule suivante, ou un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament des composés représentés par la formule suivante :
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Cited By (7)
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US11548871B2 (en) | 2019-11-15 | 2023-01-10 | Gilead Sciences, Inc. | Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof |
US11584738B2 (en) | 2020-06-03 | 2023-02-21 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
WO2023109878A1 (fr) * | 2021-12-15 | 2023-06-22 | 武汉人福创新药物研发中心有限公司 | Antagoniste de lpar1 triazaspiro et son utilisation |
US11702407B2 (en) | 2020-06-03 | 2023-07-18 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
CN117024409A (zh) * | 2023-10-10 | 2023-11-10 | 药康众拓(北京)医药科技有限公司 | 氘代lpa1抑制剂化合物及其用途 |
US11939318B2 (en) | 2021-12-08 | 2024-03-26 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11980609B2 (en) | 2021-05-11 | 2024-05-14 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
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AR128613A1 (es) | 2022-02-25 | 2024-05-29 | Lhotse Bio Inc | Compuestos y composiciones para el tratamiento de afecciones asociadas con la actividad del receptor de lpa |
CN117447450A (zh) * | 2022-07-25 | 2024-01-26 | 武汉人福创新药物研发中心有限公司 | 三氮唑类化合物及其作为lpar1拮抗剂的用途 |
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US11584738B2 (en) | 2020-06-03 | 2023-02-21 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11702407B2 (en) | 2020-06-03 | 2023-07-18 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
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US11980609B2 (en) | 2021-05-11 | 2024-05-14 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11939318B2 (en) | 2021-12-08 | 2024-03-26 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
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CN117024409A (zh) * | 2023-10-10 | 2023-11-10 | 药康众拓(北京)医药科技有限公司 | 氘代lpa1抑制剂化合物及其用途 |
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