EA033861B1 - Пиразины в качестве модуляторов gpr6 - Google Patents
Пиразины в качестве модуляторов gpr6 Download PDFInfo
- Publication number
- EA033861B1 EA033861B1 EA201691632A EA201691632A EA033861B1 EA 033861 B1 EA033861 B1 EA 033861B1 EA 201691632 A EA201691632 A EA 201691632A EA 201691632 A EA201691632 A EA 201691632A EA 033861 B1 EA033861 B1 EA 033861B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- piperidin
- isopropylamino
- pyrazine
- chloro
- cyano
- Prior art date
Links
- 150000003216 pyrazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 102100033861 G-protein coupled receptor 6 Human genes 0.000 claims abstract description 35
- 101001069613 Homo sapiens G-protein coupled receptor 6 Proteins 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 6
- -1 4- (4-chloro-2-fluorophenoxy) piperidin-1-yl Chemical group 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- CHDNZVHJOJQCDP-UHFFFAOYSA-N 5-[4-(4-chloro-2-fluorophenoxy)piperidin-1-yl]-6-(propan-2-ylamino)pyrazine-2,3-dicarbonitrile Chemical compound ClC1=CC(=C(OC2CCN(CC2)C=2N=C(C(=NC2NC(C)C)C#N)C#N)C=C1)F CHDNZVHJOJQCDP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- ZXGMCQPQJVWJRW-UHFFFAOYSA-N 3-chloro-6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-(propan-2-ylamino)pyrazine-2-carbonitrile Chemical compound ClC=1C(=NC(=C(N1)NC(C)C)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C#N ZXGMCQPQJVWJRW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- RSYHJQQMCPIHCU-UHFFFAOYSA-N 3-cyano-5-(cyclopropylamino)-6-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]pyrazine-2-carboxylic acid Chemical compound C(#N)C=1C(=NC(=C(N1)NC1CC1)N1CCN(CC1)CC1=C(C=C(C=C1)F)F)C(=O)O RSYHJQQMCPIHCU-UHFFFAOYSA-N 0.000 claims description 3
- ITPSILGGHCZPDK-UHFFFAOYSA-N 3-cyano-6-(cyclopropylamino)-5-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]pyrazine-2-carboxylic acid Chemical compound C(#N)C=1C(=NC(=C(N1)N1CCN(CC1)CC1=C(C=C(C=C1)F)F)NC1CC1)C(=O)O ITPSILGGHCZPDK-UHFFFAOYSA-N 0.000 claims description 3
- IBRDZKMXHKJPPD-UHFFFAOYSA-N 5-(cyclopropylamino)-6-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]pyrazine-2,3-dicarbonitrile Chemical compound C1(CC1)NC=1N=C(C(=NC1N1CCN(CC1)CC1=C(C=C(C=C1)F)F)C#N)C#N IBRDZKMXHKJPPD-UHFFFAOYSA-N 0.000 claims description 3
- RPUWWTNVKMGDOT-UHFFFAOYSA-N 5-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-(propan-2-ylamino)pyrazine-2,3-dicarbonitrile Chemical compound FC1=C(OC2CCN(CC2)C=2N=C(C(=NC2NC(C)C)C#N)C#N)C=CC(=C1)F RPUWWTNVKMGDOT-UHFFFAOYSA-N 0.000 claims description 3
- QANAFSVJIRJCBJ-UHFFFAOYSA-N 5-[4-(4-chloro-2-fluorophenoxy)piperidin-1-yl]-3-cyano-6-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound ClC1=CC(=C(OC2CCN(CC2)C=2N=C(C(=NC2NC(C)C)C(=O)O)C#N)C=C1)F QANAFSVJIRJCBJ-UHFFFAOYSA-N 0.000 claims description 3
- SXGCMIHWZXJJEA-UHFFFAOYSA-N 5-[4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl]-3-cyano-6-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound ClC=1C=CC(=C(C(=O)C2CCN(CC2)C=2N=C(C(=NC2NC(C)C)C(=O)O)C#N)C1)F SXGCMIHWZXJJEA-UHFFFAOYSA-N 0.000 claims description 3
- HUJMSSBPGWZSHG-UHFFFAOYSA-N 6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=CC(=N2)C(=O)O)NC(C)C)C=CC(=C1)F HUJMSSBPGWZSHG-UHFFFAOYSA-N 0.000 claims description 3
- ZGTSEKCLSOGFEK-UHFFFAOYSA-N 6-[4-(4-chloro-2-fluorophenoxy)piperidin-1-yl]-3-cyano-5-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound ClC1=CC(=C(OC2CCN(CC2)C2=C(N=C(C(=N2)C(=O)O)C#N)NC(C)C)C=C1)F ZGTSEKCLSOGFEK-UHFFFAOYSA-N 0.000 claims description 3
- DOSYINKMPAZWAS-UHFFFAOYSA-N 6-[4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl]-3-cyano-5-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound ClC=1C=CC(=C(C(=O)C2CCN(CC2)C2=C(N=C(C(=N2)C(=O)O)C#N)NC(C)C)C1)F DOSYINKMPAZWAS-UHFFFAOYSA-N 0.000 claims description 3
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- MKKLGVHYBCYOJR-UHFFFAOYSA-N 3-cyano-5-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound C(#N)C=1C(=NC(=C(N1)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)NC(C)C)C(=O)O MKKLGVHYBCYOJR-UHFFFAOYSA-N 0.000 claims description 2
- DILAMMRHDAEGSY-UHFFFAOYSA-N 3-cyano-6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-(propan-2-ylamino)pyrazine-2-carboxylic acid Chemical compound C(#N)C=1C(=NC(=C(N1)NC(C)C)N1CCC(CC1)OC1=C(C=C(C=C1)F)F)C(=O)O DILAMMRHDAEGSY-UHFFFAOYSA-N 0.000 claims description 2
- PJPUXSYJYLFQDS-UHFFFAOYSA-N 5-[4-(2,4-difluorophenoxy)piperidin-1-yl]-6-(propan-2-ylamino)pyrazine-2-carbonitrile Chemical compound FC1=C(OC2CCN(CC2)C=2N=CC(=NC2NC(C)C)C#N)C=CC(=C1)F PJPUXSYJYLFQDS-UHFFFAOYSA-N 0.000 claims description 2
- OGSYEOBSSCBGKI-UHFFFAOYSA-N 5-[4-(4-chloro-2-fluorophenoxy)piperidin-1-yl]-6-(cyclopropylamino)pyrazine-2-carbonitrile Chemical compound ClC1=CC(=C(OC2CCN(CC2)C=2N=CC(=NC2NC2CC2)C#N)C=C1)F OGSYEOBSSCBGKI-UHFFFAOYSA-N 0.000 claims description 2
- KYPYEURSCHOCEQ-UHFFFAOYSA-N 5-[4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl]-6-(propan-2-ylamino)pyrazine-2,3-dicarbonitrile Chemical compound ClC=1C=CC(=C(C(=O)C2CCN(CC2)C=2N=C(C(=NC2NC(C)C)C#N)C#N)C1)F KYPYEURSCHOCEQ-UHFFFAOYSA-N 0.000 claims description 2
- UUPPUNREICFVIO-UHFFFAOYSA-N 6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-morpholin-4-yl-5-(propan-2-ylamino)pyrazine-2-carbonitrile Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=C(C(=N2)C#N)N2CCOCC2)NC(C)C)C=CC(=C1)F UUPPUNREICFVIO-UHFFFAOYSA-N 0.000 claims description 2
- OGHPOGBIFGGUDI-UHFFFAOYSA-N 6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-(propan-2-ylamino)pyrazine-2-carbonitrile Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=CC(=N2)C#N)NC(C)C)C=CC(=C1)F OGHPOGBIFGGUDI-UHFFFAOYSA-N 0.000 claims description 2
- RYAJJIYVDSVRMA-UHFFFAOYSA-N [6-[4-(2,4-difluorophenoxy)piperidin-1-yl]-5-(propan-2-ylamino)pyrazin-2-yl]-(3-fluoroazetidin-1-yl)methanone Chemical compound FC1=C(OC2CCN(CC2)C2=C(N=CC(=N2)C(=O)N2CC(C2)F)NC(C)C)C=CC(=C1)F RYAJJIYVDSVRMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
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- 230000008520 organization Effects 0.000 claims 1
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- A61K31/4965—Non-condensed pyrazines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Neurology (AREA)
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- Epidemiology (AREA)
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- Addiction (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461940294P | 2014-02-14 | 2014-02-14 | |
| PCT/US2015/015841 WO2015123533A1 (en) | 2014-02-14 | 2015-02-13 | Pyrazines modulators of gpr6 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201691632A1 EA201691632A1 (ru) | 2017-02-28 |
| EA033861B1 true EA033861B1 (ru) | 2019-12-03 |
Family
ID=52598823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201691632A EA033861B1 (ru) | 2014-02-14 | 2015-02-13 | Пиразины в качестве модуляторов gpr6 |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US10000468B2 (enExample) |
| EP (1) | EP3105216B1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3105216B1 (en) * | 2014-02-14 | 2018-10-10 | Takeda Pharmaceutical Company Limited | Pyrazine modulators of gpr6 |
| EA202092442A3 (ru) | 2016-06-07 | 2021-08-31 | Джакобио Фармасьютикалс Ко., Лтд. | Новые гетероциклические производные, применимые в качестве ингибиторов shp2 |
| KR102317480B1 (ko) | 2017-03-23 | 2021-10-25 | 자코바이오 파마슈티칼스 컴퍼니 리미티드 | Shp2 억제제로서 유용한 신규한 헤테로환형 유도체 |
| CN110520127B (zh) * | 2017-03-26 | 2023-05-16 | 武田药品工业株式会社 | 作为gpr6的调节剂的经哌啶基取代的杂芳族羧酰胺和经哌嗪基取代的杂芳族羧酰胺 |
| JOP20180057A1 (ar) * | 2017-06-15 | 2019-01-30 | Takeda Pharmaceuticals Co | مركبات رابع هيدروبيريدو بيرازين والتي تعمل كمعدلات gpr6 |
| WO2020063760A1 (en) | 2018-09-26 | 2020-04-02 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
| KR20230017787A (ko) * | 2020-04-30 | 2023-02-06 | 오레곤 헬스 앤드 사이언스 유니버시티 | Gpr39 단백질의 길항제 |
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