KR20160133004A - 오토탁신의 치환된 스피로시클릭 억제제 - Google Patents
오토탁신의 치환된 스피로시클릭 억제제 Download PDFInfo
- 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
- 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.)
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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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- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 8
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- 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
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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2015
- 2015-04-03 AP AP2016009496A patent/AP2016009496A0/en unknown
- 2015-04-03 EP EP15773254.6A patent/EP3125895A4/en not_active Withdrawn
- 2015-04-03 KR KR1020167030589A patent/KR20160133004A/ko not_active Withdrawn
- 2015-04-03 CA CA2943874A patent/CA2943874A1/en not_active Abandoned
- 2015-04-03 CR CR20160496A patent/CR20160496A/es unknown
- 2015-04-03 PE PE2016001885A patent/PE20170206A1/es unknown
- 2015-04-03 JP JP2017503794A patent/JP6616821B2/ja not_active Expired - Fee Related
- 2015-04-03 MD MDA20160116A patent/MD20160116A2/ro not_active Application Discontinuation
- 2015-04-03 MX MX2016013049A patent/MX2016013049A/es unknown
- 2015-04-03 CU CU2016000150A patent/CU24442B1/es unknown
- 2015-04-03 CN CN201580028170.3A patent/CN107106559A/zh active Pending
- 2015-04-03 SG SG11201607920RA patent/SG11201607920RA/en unknown
- 2015-04-03 WO PCT/US2015/024338 patent/WO2015154023A1/en not_active Ceased
- 2015-04-03 EA EA201691840A patent/EA201691840A1/ru unknown
- 2015-04-03 US US15/300,762 patent/US10011601B2/en not_active Expired - Fee Related
- 2015-04-03 AU AU2015240519A patent/AU2015240519B2/en not_active Ceased
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2016
- 2016-09-26 IL IL248050A patent/IL248050A0/en unknown
- 2016-09-28 PH PH12016501922A patent/PH12016501922A1/en unknown
- 2016-10-03 DO DO2016000270A patent/DOP2016000270A/es unknown
- 2016-10-04 CL CL2016002516A patent/CL2016002516A1/es unknown
- 2016-10-26 EC ECIEPI201684293A patent/ECSP16084293A/es unknown
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2018
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2019
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- 2019-11-08 JP JP2019203023A patent/JP2020040960A/ja active Pending
- 2019-11-15 AU AU2019264641A patent/AU2019264641A1/en not_active Abandoned
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| EP3125895A4 (en) | 2017-08-30 |
| CN107106559A (zh) | 2017-08-29 |
| US20180282332A1 (en) | 2018-10-04 |
| CR20160496A (es) | 2017-01-02 |
| AU2019264641A1 (en) | 2019-12-05 |
| CU24442B1 (es) | 2019-09-04 |
| US10011601B2 (en) | 2018-07-03 |
| DOP2016000270A (es) | 2016-12-15 |
| JP2017513932A (ja) | 2017-06-01 |
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| PE20170206A1 (es) | 2017-04-09 |
| US20170166568A1 (en) | 2017-06-15 |
| CA2943874A1 (en) | 2015-10-08 |
| MX2016013049A (es) | 2017-04-27 |
| AU2015240519B2 (en) | 2019-08-15 |
| SG11201607920RA (en) | 2016-10-28 |
| US20190225611A1 (en) | 2019-07-25 |
| AU2015240519A1 (en) | 2016-10-20 |
| US10233182B2 (en) | 2019-03-19 |
| EA201691840A1 (ru) | 2017-03-31 |
| JP6616821B2 (ja) | 2019-12-04 |
| MD20160116A2 (ro) | 2017-04-30 |
| EP3125895A1 (en) | 2017-02-08 |
| PH12016501922A1 (en) | 2016-12-19 |
| CL2016002516A1 (es) | 2017-05-12 |
| ECSP16084293A (es) | 2017-01-31 |
| JP2020040960A (ja) | 2020-03-19 |
| CU20160150A7 (es) | 2017-02-02 |
| AP2016009496A0 (en) | 2016-10-31 |
| IL248050A0 (en) | 2016-11-30 |
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