EA036172B1 - Спирогептансалициламиды и родственные соединения как ингибиторы rock - Google Patents

Info

Publication number

EA036172B1

EA036172B1 EA201891557A EA201891557A EA036172B1 EA 036172 B1 EA036172 B1 EA 036172B1 EA 201891557 A EA201891557 A EA 201891557A EA 201891557 A EA201891557 A EA 201891557A EA 036172 B1 EA036172 B1 EA 036172B1

Authority

EA

Eurasian Patent Office

Prior art keywords

spiro

oxy

pyridine

carboxamide

heptan

Prior art date

2016-01-13

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 155
• -1 Spiroheptane salicylamides Chemical class 0.000 title claims description 785
• 239000011435 rock Substances 0.000 title abstract description 38
• 239000003112 inhibitor Substances 0.000 title abstract description 11
• 150000003839 salts Chemical class 0.000 claims abstract description 57
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
• 210000002460 smooth muscle Anatomy 0.000 claims abstract description 6
• 230000003176 fibrotic effect Effects 0.000 claims abstract description 5
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
• 230000002981 neuropathic effect Effects 0.000 claims abstract 2
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 930
• 125000003003 spiro group Chemical group 0.000 claims description 609
• 235000005152 nicotinamide Nutrition 0.000 claims description 472
• 239000011570 nicotinamide Substances 0.000 claims description 472
• 125000000217 alkyl group Chemical group 0.000 claims description 203
• 125000000623 heterocyclic group Chemical group 0.000 claims description 179
• 125000004432 carbon atom Chemical group C* 0.000 claims description 98
• 125000005842 heteroatom Chemical group 0.000 claims description 82
• 125000003545 alkoxy group Chemical group 0.000 claims description 81
• 229910052760 oxygen Inorganic materials 0.000 claims description 69
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 67
• 229910052799 carbon Inorganic materials 0.000 claims description 67
• 229910052736 halogen Inorganic materials 0.000 claims description 67
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 67
• 150000002367 halogens Chemical class 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 229910052717 sulfur Inorganic materials 0.000 claims description 61
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 54
• 239000004305 biphenyl Substances 0.000 claims description 49
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 46
• 229910052757 nitrogen Inorganic materials 0.000 claims description 42
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 41
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 32
• JVOGPCAZHXALIS-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C1=CC=CC2=C(C(=O)N)C=NN21 JVOGPCAZHXALIS-UHFFFAOYSA-N 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 30
• 201000010099 disease Diseases 0.000 claims description 26
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 26
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 23
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
• 125000003342 alkenyl group Chemical group 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 19
• 230000000694 effects Effects 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
• 125000003368 amide group Chemical group 0.000 claims description 16
• LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 claims description 16
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 15
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 15
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
• 206010020772 Hypertension Diseases 0.000 claims description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 12
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 11
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
• 125000004414 alkyl thio group Chemical group 0.000 claims description 11
• 125000001188 haloalkyl group Chemical group 0.000 claims description 11
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 10
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 10
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 108010041788 rho-Associated Kinases Proteins 0.000 claims description 10
• 102000000568 rho-Associated Kinases Human genes 0.000 claims description 10
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 9
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
• 125000001072 heteroaryl group Chemical group 0.000 claims description 9
• WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical group CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 9
• 208000006011 Stroke Diseases 0.000 claims description 8
• 208000035475 disorder Diseases 0.000 claims description 8
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 230000002265 prevention Effects 0.000 claims description 8
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 229910006074 SO2NH2 Inorganic materials 0.000 claims description 6
• 230000001594 aberrant effect Effects 0.000 claims description 6
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
• 206010019280 Heart failures Diseases 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 claims description 5
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
• 206010002383 Angina Pectoris Diseases 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 208000029078 coronary artery disease Diseases 0.000 claims description 4
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
• 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
• 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 3
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
• 150000003857 carboxamides Chemical class 0.000 claims description 3
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
• 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• PGWGORHIOVHAEI-UHFFFAOYSA-N N-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound N1=CC(=C2N1C=CC=C2)C(=O)NOCC(C)(C)O PGWGORHIOVHAEI-UHFFFAOYSA-N 0.000 claims description 2
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
• KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 claims description 2
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
• VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
• DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 235000019260 propionic acid Nutrition 0.000 claims description 2
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 2
• GEBGCSXVYUDDPU-UHFFFAOYSA-N pyridazine-4-carboxamide Chemical compound NC(=O)C1=CC=NN=C1 GEBGCSXVYUDDPU-UHFFFAOYSA-N 0.000 claims description 2
• BLTDCIWCFCUQCB-UHFFFAOYSA-N quionoline-3-carboxamide Natural products C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 claims description 2
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 15
• DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 claims 3
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 3
• 235000010290 biphenyl Nutrition 0.000 claims 3
• HETDBWJUJKUELN-UHFFFAOYSA-N N-[2-[2-carbamoyl-5-(3-carbamoylphenyl)phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(CC(C2)OC=2C=C(C=CC=2C(=O)N)C2=CC(=CC=C2)C(=O)N)C1)(C)C HETDBWJUJKUELN-UHFFFAOYSA-N 0.000 claims 2
• 235000001968 nicotinic acid Nutrition 0.000 claims 2
• 239000011664 nicotinic acid Substances 0.000 claims 2
• PMHRADVIAUMGFC-IZZDOVSWSA-N (E)-3-[3-[4-carbamoyl-3-[6-[[6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonyl]amino]spiro[3.3]heptan-2-yl]oxyphenyl]phenyl]prop-2-enoic acid Chemical compound C(N)(=O)C1=C(C=C(C=C1)C1=CC(=CC=C1)/C=C/C(=O)O)OC1CC2(C1)CC(C2)NC(=O)C=1C=NN2C=1C=CC(=C2)OCC(C)(C)O PMHRADVIAUMGFC-IZZDOVSWSA-N 0.000 claims 1
• PYJSTJLJZLTFLC-UHFFFAOYSA-N 1-(1-methylpyrazol-4-yl)indazole-3-carboxamide Chemical compound CN1N=CC(=C1)N1N=C(C2=CC=CC=C12)C(=O)N PYJSTJLJZLTFLC-UHFFFAOYSA-N 0.000 claims 1
• YJMMVZPKVOLBKJ-UHFFFAOYSA-N 1-(3,3,3-trifluoropropoxy)indazole-3-carboxamide Chemical compound FC(CCON1N=C(C2=CC=CC=C12)C(=O)N)(F)F YJMMVZPKVOLBKJ-UHFFFAOYSA-N 0.000 claims 1
• KPPOMCPGQCSUSQ-UHFFFAOYSA-N 1-[1-(difluoromethyl)pyrazol-4-yl]indazole-3-carboxamide Chemical compound FC(N1N=CC(=C1)N1N=C(C2=CC=CC=C12)C(=O)N)F KPPOMCPGQCSUSQ-UHFFFAOYSA-N 0.000 claims 1
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
• 208000023275 Autoimmune disease Diseases 0.000 claims 1
• 208000029578 Muscle disease Diseases 0.000 claims 1
• 208000021642 Muscular disease Diseases 0.000 claims 1
• 208000031481 Pathologic Constriction Diseases 0.000 claims 1
• 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
• 206010047163 Vasospasm Diseases 0.000 claims 1
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims 1
• 208000026106 cerebrovascular disease Diseases 0.000 claims 1
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
• WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims 1
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims 1
• 208000010125 myocardial infarction Diseases 0.000 claims 1
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
• 208000037804 stenosis Diseases 0.000 claims 1
• 230000036262 stenosis Effects 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 43
• 230000002526 effect on cardiovascular system Effects 0.000 abstract description 4
• 230000001363 autoimmune Effects 0.000 abstract 1
• 230000000771 oncological effect Effects 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 181
• 239000000543 intermediate Substances 0.000 description 141
• 239000011541 reaction mixture Substances 0.000 description 127
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
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• 238000002360 preparation method Methods 0.000 description 52
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• 239000000203 mixture Substances 0.000 description 43
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• 235000002639 sodium chloride Nutrition 0.000 description 41
• 238000005481 NMR spectroscopy Methods 0.000 description 39
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• 125000003118 aryl group Chemical group 0.000 description 15
• 125000001424 substituent group Chemical group 0.000 description 15
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• 239000012267 brine Substances 0.000 description 14
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• 239000011734 sodium Substances 0.000 description 14
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• 238000003786 synthesis reaction Methods 0.000 description 13
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• 125000004429 atom Chemical group 0.000 description 12
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