CN108026099B - 经杂芳基取代的氨基吡啶化合物 - Google Patents
经杂芳基取代的氨基吡啶化合物 Download PDFInfo
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- CN108026099B CN108026099B CN201680043479.4A CN201680043479A CN108026099B CN 108026099 B CN108026099 B CN 108026099B CN 201680043479 A CN201680043479 A CN 201680043479A CN 108026099 B CN108026099 B CN 108026099B
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- Prior art keywords
- pyridin
- alkyl
- compound
- carbonitrile
- isopropylamino
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- -1 aminopyridine compounds Chemical class 0.000 title claims abstract description 53
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 19
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 18
- 238000006467 substitution reaction Methods 0.000 claims abstract description 16
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 15
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 10
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 10
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 76
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 201000005569 Gout Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000003566 oxetanyl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- XDESSKZUXMNMMO-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-(4-propyltriazol-1-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1N1N=NC(=C1)CCC)C1=CN=C2N1N=CC(=C2)C#N XDESSKZUXMNMMO-UHFFFAOYSA-N 0.000 claims description 8
- XDSRHSZBMTXRBP-UHFFFAOYSA-N 3-[5-[1-(oxan-4-yl)triazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1N=NN(C=1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N XDSRHSZBMTXRBP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- FUCFDTKIFAGVLY-UHFFFAOYSA-N 2-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-propan-2-yl-5-(4-propyltriazol-1-yl)pyridin-4-amine Chemical compound ClC=1C=NC=2N(C=1)N=CC=2C1=NC=C(C(=C1)NC(C)C)N1N=NC(=C1)CCC FUCFDTKIFAGVLY-UHFFFAOYSA-N 0.000 claims description 7
- RENRCXJODALGTE-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-5-[1-(oxan-4-yl)pyrazol-4-yl]-N-propan-2-ylpyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC(C)C)C=1C=NN(C=1)C1CCOCC1 RENRCXJODALGTE-UHFFFAOYSA-N 0.000 claims description 7
- XOYXADDAQJVPEI-UHFFFAOYSA-N 3-[5-[1-(3-hydroxy-3-methylbutyl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CCN1N=CC(=C1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C XOYXADDAQJVPEI-UHFFFAOYSA-N 0.000 claims description 7
- QSRKCOCAYVQGSS-UHFFFAOYSA-N 3-[5-[4-(2-hydroxypropan-2-yl)pyrazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound OC(C)(C)C=1C=NN(C=1)C=1C(=CC(=NC=1)C=1C=NN2C=1N=CC(=C2)C#N)NC(C)C QSRKCOCAYVQGSS-UHFFFAOYSA-N 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 5
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 5
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- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 208000024908 graft versus host disease Diseases 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- ZACIZZRZZPYFAZ-UHFFFAOYSA-N 1-[4-[6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-4-(propan-2-ylamino)pyridin-3-yl]pyrazol-1-yl]-2-methylpropan-2-ol Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=CC(=C(C=N1)C=1C=NN(C=1)CC(C)(O)C)NC(C)C ZACIZZRZZPYFAZ-UHFFFAOYSA-N 0.000 claims description 4
- SWYUCJNNROTAJE-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-[1-(2,2-difluoroethyl)pyrazol-4-yl]-5-(1-propylpyrazol-4-yl)pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC=1C=NN(C=1)CC(F)F)C=1C=NN(C=1)CCC SWYUCJNNROTAJE-UHFFFAOYSA-N 0.000 claims description 4
- DOTOFFAVTNZRLB-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-5-(1-propyltriazol-4-yl)pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC1CC1)C=1N=NN(C=1)CCC DOTOFFAVTNZRLB-UHFFFAOYSA-N 0.000 claims description 4
- ZBRIPMUNBFXCSD-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-propan-2-yl-5-(1-propyltriazol-4-yl)pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC(C)C)C=1N=NN(C=1)CCC ZBRIPMUNBFXCSD-UHFFFAOYSA-N 0.000 claims description 4
- KFILYRVIDVXHNI-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-propan-2-yl-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC(C)C)C=1C=NN(C=1)CC(F)(F)F KFILYRVIDVXHNI-UHFFFAOYSA-N 0.000 claims description 4
- JDHXZJLBUNAELN-UHFFFAOYSA-N 3-[4-(cyclopropylamino)-5-(1-propyltriazol-4-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C1(CC1)NC1=CC(=NC=C1C=1N=NN(C=1)CCC)C1=CN=C2N1N=CC(=C2)C#N JDHXZJLBUNAELN-UHFFFAOYSA-N 0.000 claims description 4
- TWOADEWSFFZZFG-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-(1-propylpyrazol-4-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1C=NN(C=1)CCC)C1=CN=C2N1N=CC(=C2)C#N TWOADEWSFFZZFG-UHFFFAOYSA-N 0.000 claims description 4
- QSMXMQMCCMIAQQ-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-(4-propyltriazol-1-yl)pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1N1N=NC(=C1)CCC)C=1C=NN2C=1N=CC(=C2)C#N QSMXMQMCCMIAQQ-UHFFFAOYSA-N 0.000 claims description 4
- PJWHSDHTZZMZIM-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1C=NN(C=1)CC(F)(F)F)C1=CN=C2N1N=CC(=C2)C#N PJWHSDHTZZMZIM-UHFFFAOYSA-N 0.000 claims description 4
- FRYFNOMIOVBKEM-UHFFFAOYSA-N 3-[4-[(3,3-difluorocyclobutyl)amino]-5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound FC1(CC(C1)NC1=CC(=NC=C1N1N=NC(=C1)CCC(C)(C)O)C=1C=NN2C=1N=CC(=C2)C#N)F FRYFNOMIOVBKEM-UHFFFAOYSA-N 0.000 claims description 4
- SOVIOGDRQIIPMO-UHFFFAOYSA-N 3-[4-[[1-(2,2-difluoroethyl)pyrazol-4-yl]amino]-5-(1-propylpyrazol-4-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound FC(CN1N=CC(=C1)NC1=CC(=NC=C1C=1C=NN(C=1)CCC)C1=CN=C2N1N=CC(=C2)C#N)F SOVIOGDRQIIPMO-UHFFFAOYSA-N 0.000 claims description 4
- FXJWDSCIKROGLP-UHFFFAOYSA-N 3-[5-[1-(1-acetylazetidin-3-yl)triazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(=O)N1CC(C1)N1N=NC(=C1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C FXJWDSCIKROGLP-UHFFFAOYSA-N 0.000 claims description 4
- KIFBHFOPKPWRAP-UHFFFAOYSA-N 3-[5-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CN1N=CC(=C1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C KIFBHFOPKPWRAP-UHFFFAOYSA-N 0.000 claims description 4
- VGDZIORKWAXUFJ-UHFFFAOYSA-N 3-[5-[1-(oxan-4-yl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1C=NN(C=1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N VGDZIORKWAXUFJ-UHFFFAOYSA-N 0.000 claims description 4
- PYJGADHQKPQSHH-UHFFFAOYSA-N 3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(oxetan-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound OC(CCC=1N=NN(C=1)C=1C(=CC(=NC=1)C=1C=NN2C=1N=CC(=C2)C#N)NC1COC1)(C)C PYJGADHQKPQSHH-UHFFFAOYSA-N 0.000 claims description 4
- BXPJRPWKDYCOMG-UHFFFAOYSA-N 3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CCC=1N=NN(C=1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C BXPJRPWKDYCOMG-UHFFFAOYSA-N 0.000 claims description 4
- RKHHFANTEKSOQG-UHFFFAOYSA-N 3-[5-[5-(oxan-4-yl)-1H-pyrazol-3-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C1=NNC(=C1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N RKHHFANTEKSOQG-UHFFFAOYSA-N 0.000 claims description 4
- CCXZYUPDEZUPCM-UHFFFAOYSA-N 4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(oxan-4-ylamino)pyridin-3-yl]triazol-4-yl]-2-methylbutan-2-ol Chemical compound ClC=1C=NC=2N(C=1)N=CC=2C1=CC(=C(C=N1)N1N=NC(=C1)CCC(C)(O)C)NC1CCOCC1 CCXZYUPDEZUPCM-UHFFFAOYSA-N 0.000 claims description 4
- WQSAYCODPMMYLW-UHFFFAOYSA-N 4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(oxetan-3-ylamino)pyridin-3-yl]triazol-4-yl]-2-methylbutan-2-ol Chemical compound ClC=1C=NC=2N(C=1)N=CC=2C1=CC(=C(C=N1)N1N=NC(=C1)CCC(C)(O)C)NC1COC1 WQSAYCODPMMYLW-UHFFFAOYSA-N 0.000 claims description 4
- WOKMOGOUIVJJGR-UHFFFAOYSA-N 4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(propan-2-ylamino)pyridin-3-yl]triazol-4-yl]-2-methylbutan-2-ol Chemical compound ClC=1C=NC=2N(C=1)N=CC=2C1=CC(=C(C=N1)N1N=NC(=C1)CCC(C)(O)C)NC(C)C WOKMOGOUIVJJGR-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- OVTPFOFMQCSSMS-MQNHUJCZSA-N methyl (3R)-4-[4-[6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-4-(cyclopropylamino)pyridin-3-yl]triazol-1-yl]-3-hydroxy-3-methylpiperidine-1-carboxylate Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=CC(=C(C=N1)C=1N=NN(C=1)C1[C@](CN(CC1)C(=O)OC)(C)O)NC1CC1 OVTPFOFMQCSSMS-MQNHUJCZSA-N 0.000 claims description 4
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- A—HUMAN NECESSITIES
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| AR105114A1 (es) | 2015-06-24 | 2017-09-06 | Bristol Myers Squibb Co | Compuestos de aminopiridina sustituida con heteroarilo |
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| WO2019111218A1 (en) | 2017-12-08 | 2019-06-13 | Cadila Healthcare Limited | Novel heterocyclic compounds as irak4 inhibitors |
| TWI842978B (zh) | 2018-07-13 | 2024-05-21 | 美商基利科學股份有限公司 | 衍生物 |
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| WO2020036830A1 (en) | 2018-08-13 | 2020-02-20 | Gilead Sciences, Inc. | Pyrrolo[1,2-b]pyridazine derivatives as irak4 inhibitors |
| TWI727392B (zh) | 2018-08-13 | 2021-05-11 | 美商基利科學股份有限公司 | 噻二唑irak4抑制劑 |
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| KR20220041124A (ko) * | 2019-07-23 | 2022-03-31 | 브리스톨-마이어스 스큅 컴퍼니 | Irak4 억제제로서 유용한 티에노피리디닐 및 티아졸로피리디닐 화합물 |
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| FR2896503B1 (fr) | 2006-01-23 | 2012-07-13 | Aventis Pharma Sa | Nouveaux derives soufres d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases |
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| WO2009046416A1 (en) | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| JPWO2010058846A1 (ja) | 2008-11-21 | 2012-04-19 | アステラス製薬株式会社 | ４，６−ジアミノニコチンアミド化合物 |
| EA021367B1 (ru) | 2008-11-28 | 2015-06-30 | Кова Компани, Лтд. | Производное пиридин-3-карбоксамида |
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| BR112012010220A2 (pt) | 2009-10-30 | 2021-02-23 | Janssen Pharmaceutical N.V. | piridinas fenóxi-substituídas como modulares do receptor opioide |
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| AU2012249240A1 (en) | 2011-04-29 | 2013-11-07 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitors |
| CN104159896B (zh) | 2012-01-13 | 2017-05-24 | 百时美施贵宝公司 | 用作激酶抑制剂的杂环取代的吡啶基化合物 |
| US8987311B2 (en) * | 2012-01-13 | 2015-03-24 | Bristol-Myers Squibb Company | Triazolyl-substituted pyridyl compounds useful as kinase inhibitors |
| ES2575604T3 (es) | 2012-01-13 | 2016-06-29 | Bristol-Myers Squibb Company | Compuestos de piridilo sustituidos con tiazolilo o tiadiazolilo útiles como inhibidores cinasa |
| SG11201503397YA (en) * | 2012-11-08 | 2015-05-28 | Bristol Myers Squibb Co | Heteroaryl substituted pyridyl compounds useful as kinase modulators |
| AU2013341185B2 (en) | 2012-11-08 | 2017-07-13 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of IL-12, IL-23 and/or IFNalpha responses |
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| TWI582077B (zh) | 2013-11-07 | 2017-05-11 | 必治妥美雅史谷比公司 | 作爲ＩＬ－１２、ＩＬ－２３及／或ＩＦＮα反應調節劑之經烷基－醯胺取代之吡啶化合物 |
| TW201609693A (zh) * | 2014-01-03 | 2016-03-16 | 必治妥美雅史谷比公司 | 雜芳基取代之菸鹼醯胺化合物 |
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