EA036318B1 - 6-аминопиридин-3-илтиазолы в качестве модуляторов rort - Google Patents
6-аминопиридин-3-илтиазолы в качестве модуляторов rort Download PDFInfo
- Publication number
- EA036318B1 EA036318B1 EA201892438A EA201892438A EA036318B1 EA 036318 B1 EA036318 B1 EA 036318B1 EA 201892438 A EA201892438 A EA 201892438A EA 201892438 A EA201892438 A EA 201892438A EA 036318 B1 EA036318 B1 EA 036318B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- thiazole
- pyridin
- carbonyl
- trifluoromethyl
- amine
- Prior art date
Links
- -1 6-AMINOPYRIDIN-3-YL Chemical class 0.000 title claims description 1072
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 677
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 134
- 201000010099 disease Diseases 0.000 claims abstract description 74
- 238000000034 method Methods 0.000 claims abstract description 67
- 208000035475 disorder Diseases 0.000 claims abstract description 60
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 58
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 23
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 15
- 201000006417 multiple sclerosis Diseases 0.000 claims description 416
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 102000013691 Interleukin-17 Human genes 0.000 claims description 16
- 108050003558 Interleukin-17 Proteins 0.000 claims description 16
- 208000006673 asthma Diseases 0.000 claims description 14
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 11
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 7
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 150000003431 steroids Chemical class 0.000 claims description 5
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 108091008778 RORγ2 Proteins 0.000 claims 1
- 206010025135 lupus erythematosus Diseases 0.000 claims 1
- 125000002345 steroid group Chemical group 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 241000124008 Mammalia Species 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 813
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 491
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 314
- 238000005160 1H NMR spectroscopy Methods 0.000 description 300
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 271
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 description 245
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 191
- IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 description 163
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 112
- 238000005481 NMR spectroscopy Methods 0.000 description 107
- 239000000203 mixture Substances 0.000 description 92
- WEAZZOCWAJWPRL-UHFFFAOYSA-N 3-methylazetidin-3-ol;hydrochloride Chemical compound Cl.CC1(O)CNC1 WEAZZOCWAJWPRL-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 76
- 238000004808 supercritical fluid chromatography Methods 0.000 description 70
- 239000012071 phase Substances 0.000 description 69
- 230000005526 G1 to G0 transition Effects 0.000 description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- XOOXNICKWATYJX-UHFFFAOYSA-N N-(2-hydroxy-2-methylpropyl)-1,3-thiazole-2-carboxamide Chemical compound OC(CNC(=O)C=1SC=CN=1)(C)C XOOXNICKWATYJX-UHFFFAOYSA-N 0.000 description 57
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 229910002091 carbon monoxide Inorganic materials 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 44
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 44
- FYAHMXGTPZATDP-UHFFFAOYSA-N 5-bromo-N-(1-methylcyclobutyl)-4-(trifluoromethyl)pyridin-2-amine Chemical compound BrC=1C(=CC(=NC=1)NC1(CCC1)C)C(F)(F)F FYAHMXGTPZATDP-UHFFFAOYSA-N 0.000 description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000003814 drug Substances 0.000 description 30
- KPIJBKHHJXXREK-UHFFFAOYSA-N 5-bromo-2-chloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC(Br)=CN=C1Cl KPIJBKHHJXXREK-UHFFFAOYSA-N 0.000 description 29
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 27
- 229940079593 drug Drugs 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- GPDYYKIZRCAMSW-UHFFFAOYSA-N 3-(1-methylcyclobutyl)-4-(trifluoromethyl)pyridin-2-amine Chemical compound CC1(CCC1)C=1C(=NC=CC=1C(F)(F)F)N GPDYYKIZRCAMSW-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 21
- 229910052700 potassium Inorganic materials 0.000 description 21
- 239000011591 potassium Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 18
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- VIESMOHTDHXTQF-VKKIDBQXSA-N (1R,2R)-2-aminocyclobutan-1-ol hydrochloride Chemical compound Cl.N[C@@H]1CC[C@H]1O VIESMOHTDHXTQF-VKKIDBQXSA-N 0.000 description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
- 235000011089 carbon dioxide Nutrition 0.000 description 16
- 229920000856 Amylose Polymers 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 15
- XUMSHCRPQCZRGX-UHFFFAOYSA-N 3-aminocyclobutan-1-ol;hydrochloride Chemical compound Cl.NC1CC(O)C1 XUMSHCRPQCZRGX-UHFFFAOYSA-N 0.000 description 14
- SYBSBIJPNQAETE-UHFFFAOYSA-N 5-bromo-2-chloro-4-(trifluoromethyl)pyridine Chemical group FC(F)(F)C1=CC(Cl)=NC=C1Br SYBSBIJPNQAETE-UHFFFAOYSA-N 0.000 description 14
- LLDDQYYGMRELEU-UHFFFAOYSA-N 5-bromo-N-cyclopentyl-4-(difluoromethyl)pyridin-2-amine Chemical compound BrC=1C(=CC(=NC=1)NC1CCCC1)C(F)F LLDDQYYGMRELEU-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- NPXUJXXQDQHSKJ-UHFFFAOYSA-N 5-bromo-2-(cyclohexylamino)pyridine-4-carbonitrile Chemical compound BrC1=CN=C(C=C1C#N)NC1CCCCC1 NPXUJXXQDQHSKJ-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 210000000068 Th17 cell Anatomy 0.000 description 12
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- 108010065637 Interleukin-23 Proteins 0.000 description 11
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- LXQMHOKEXZETKB-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(O)CN LXQMHOKEXZETKB-UHFFFAOYSA-N 0.000 description 10
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
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- 239000012453 solvate Substances 0.000 description 10
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- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 9
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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| PCT/US2017/029531 WO2017189661A1 (en) | 2016-04-27 | 2017-04-26 | 6-AMINOPYRIDIN-3-YL THIAZOLES AS MODULATORS OF RORγT |
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| EA201892438A1 EA201892438A1 (ru) | 2019-04-30 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| TW201803869A (zh) | 2016-04-27 | 2018-02-01 | 健生藥品公司 | 作為RORγT調節劑之6-胺基吡啶-3-基噻唑 |
| WO2019177997A1 (en) | 2018-03-12 | 2019-09-19 | Escalier Biosciences B.V. | Spirocyclic ror-gamma modulators |
| US11230555B2 (en) | 2018-03-12 | 2022-01-25 | Escalier Biosciences B.V. | Bicyclic RORγ modulators |
| CA3103770A1 (en) | 2018-06-18 | 2019-12-26 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of roryt |
| JP2021528405A (ja) | 2018-06-18 | 2021-10-21 | ヤンセン ファーマシューティカ エヌ.ベー. | RORγtのモジュレータとしてのアミド置換チアゾール |
| CN112292183A (zh) | 2018-06-18 | 2021-01-29 | 詹森药业有限公司 | 作为RORγt的调节剂的6-氨基吡啶-3-基吡唑 |
| EP3807261B1 (en) * | 2018-06-18 | 2022-07-13 | Janssen Pharmaceutica NV | Pyridinyl pyrazoles as modulators of roryt |
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| EP3807261B1 (en) | 2018-06-18 | 2022-07-13 | Janssen Pharmaceutica NV | Pyridinyl pyrazoles as modulators of roryt |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013178362A1 (en) * | 2012-05-31 | 2013-12-05 | Phenex Pharmaceuticals Ag | Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma] |
| WO2016069974A1 (en) * | 2014-10-30 | 2016-05-06 | Janssen Pharmaceutica Nv | TRIFLUOROMETHYL ALCOHOLS AS MODULATORS OF RORyt |
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