KR20160133004A - 오토탁신의 치환된 스피로시클릭 억제제 - Google Patents

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Publication number

KR20160133004A

KR20160133004A KR1020167030589A KR20167030589A KR20160133004A KR 20160133004 A KR20160133004 A KR 20160133004A KR 1020167030589 A KR1020167030589 A KR 1020167030589A KR 20167030589 A KR20167030589 A KR 20167030589A KR 20160133004 A KR20160133004 A KR 20160133004A

Authority

KR

South Korea

Prior art keywords

methyl

triazaspiro

decan

alkyl

oxobutan

Prior art date

2014-04-04

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.)

Withdrawn

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• 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title claims description 34
• 239000003112 inhibitor Substances 0.000 title claims description 14
• 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title claims description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 188
• 238000000034 method Methods 0.000 claims abstract description 114
• 150000003839 salts Chemical class 0.000 claims abstract description 38
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
• 201000010099 disease Diseases 0.000 claims abstract description 24
• 201000011510 cancer Diseases 0.000 claims abstract description 22
• 208000004296 neuralgia Diseases 0.000 claims abstract description 19
• 208000021722 neuropathic pain Diseases 0.000 claims abstract description 19
• 230000003176 fibrotic effect Effects 0.000 claims abstract description 16
• 208000007536 Thrombosis Diseases 0.000 claims abstract description 14
• 208000037976 chronic inflammation Diseases 0.000 claims abstract description 14
• 230000006020 chronic inflammation Effects 0.000 claims abstract description 14
• 210000004698 lymphocyte Anatomy 0.000 claims abstract description 14
• 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
• 230000001404 mediated effect Effects 0.000 claims abstract description 9
• -1 heteroaryl Compound Chemical class 0.000 claims description 536
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 462
• 125000000217 alkyl group Chemical group 0.000 claims description 290
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 87
• 125000003118 aryl group Chemical group 0.000 claims description 73
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 60
• 125000001072 heteroaryl group Chemical group 0.000 claims description 57
• WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 52
• 229910052757 nitrogen Inorganic materials 0.000 claims description 50
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 46
• 229910052739 hydrogen Inorganic materials 0.000 claims description 45
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 44
• 125000005843 halogen group Chemical group 0.000 claims description 44
• 229910052760 oxygen Inorganic materials 0.000 claims description 44
• 229920006395 saturated elastomer Polymers 0.000 claims description 44
• 239000005711 Benzoic acid Substances 0.000 claims description 42
• 235000010233 benzoic acid Nutrition 0.000 claims description 42
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 37
• 125000005842 heteroatom Chemical group 0.000 claims description 32
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 30
• 229910052805 deuterium Inorganic materials 0.000 claims description 26
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 22
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 17
• 125000004432 carbon atom Chemical group C* 0.000 claims description 16
• 125000003342 alkenyl group Chemical group 0.000 claims description 15
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 239000001257 hydrogen Substances 0.000 claims description 15
• 125000000304 alkynyl group Chemical group 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 11
• 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 10
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 10
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 10
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• 241000124008 Mammalia Species 0.000 claims description 9
• 230000004761 fibrosis Effects 0.000 claims description 9
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 8
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 8
• 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 claims description 8
• 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 claims description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 7
• 230000033115 angiogenesis Effects 0.000 claims description 6
• 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 6
• BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
• 239000012453 solvate Substances 0.000 claims description 4
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
• QRMRRLXXFHXMBC-UHFFFAOYSA-N 3-methyl-1,3-benzoxazol-2-one Chemical compound C1=CC=C2OC(=O)N(C)C2=C1 QRMRRLXXFHXMBC-UHFFFAOYSA-N 0.000 claims description 3
• IGPACMIJADAUNA-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CNCCC21C(=O)N(C)CN2C1=CC=CC=C1 IGPACMIJADAUNA-UHFFFAOYSA-N 0.000 claims description 3
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 3
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
• 201000001352 cholecystitis Diseases 0.000 claims description 3
• 230000001587 cholestatic effect Effects 0.000 claims description 3
• 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 3
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 3
• VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 3
• 230000007803 itching Effects 0.000 claims description 3
• 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 3
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• ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
• 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
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• WAKRDDXHAXBEQA-UHFFFAOYSA-N benzoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C1=CC=CC=C1 WAKRDDXHAXBEQA-UHFFFAOYSA-N 0.000 claims 2
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• QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 claims 1
• PBAVCCPZRWNJOQ-UHFFFAOYSA-N 1-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)NC(=O)C11CCNCC1 PBAVCCPZRWNJOQ-UHFFFAOYSA-N 0.000 claims 1
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