CA2749837C - Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases - Google Patents
Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases Download PDFInfo
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- CA2749837C CA2749837C CA2749837A CA2749837A CA2749837C CA 2749837 C CA2749837 C CA 2749837C CA 2749837 A CA2749837 A CA 2749837A CA 2749837 A CA2749837 A CA 2749837A CA 2749837 C CA2749837 C CA 2749837C
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- Prior art keywords
- substituted
- fluoro
- tetrazol
- alkyl
- phenyl
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 109
- 201000010099 disease Diseases 0.000 title claims description 59
- 230000002757 inflammatory effect Effects 0.000 title claims description 23
- 238000011282 treatment Methods 0.000 title abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title description 13
- 230000002062 proliferating effect Effects 0.000 title description 12
- 230000001363 autoimmune Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 334
- 108090000315 Protein Kinase C Proteins 0.000 claims abstract description 118
- 102000003923 Protein Kinase C Human genes 0.000 claims abstract description 118
- 238000000034 method Methods 0.000 claims abstract description 74
- 230000000694 effects Effects 0.000 claims abstract description 41
- 230000001404 mediated effect Effects 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 230000002459 sustained effect Effects 0.000 claims abstract description 6
- -1 amino, substituted amino, carboxyl Chemical group 0.000 claims description 408
- 125000000217 alkyl group Chemical group 0.000 claims description 366
- 125000000623 heterocyclic group Chemical group 0.000 claims description 239
- 229910052739 hydrogen Inorganic materials 0.000 claims description 231
- 239000001257 hydrogen Substances 0.000 claims description 231
- 125000001072 heteroaryl group Chemical group 0.000 claims description 211
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 195
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 175
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 149
- 125000003118 aryl group Chemical group 0.000 claims description 121
- 125000002252 acyl group Chemical group 0.000 claims description 118
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- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 90
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 90
- 150000003839 salts Chemical class 0.000 claims description 84
- 229910052736 halogen Inorganic materials 0.000 claims description 82
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 78
- 125000000304 alkynyl group Chemical group 0.000 claims description 75
- 150000002367 halogens Chemical group 0.000 claims description 75
- 125000003342 alkenyl group Chemical group 0.000 claims description 74
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 71
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 71
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 66
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 61
- 125000003107 substituted aryl group Chemical group 0.000 claims description 58
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
- 125000004442 acylamino group Chemical group 0.000 claims description 50
- 208000035475 disorder Diseases 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 38
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 32
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 31
- 239000012453 solvate Substances 0.000 claims description 31
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 30
- 125000001153 fluoro group Chemical group F* 0.000 claims description 25
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 19
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- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 14
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- 230000004913 activation Effects 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000003725 azepanyl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
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- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 7
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
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- 208000003747 lymphoid leukemia Diseases 0.000 claims description 6
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
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- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 6
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- SYYSBZOSEAUMEY-UHFFFAOYSA-N 1,1,1-trifluoro-2-$l^{1}-sulfanylethane Chemical group FC(F)(F)C[S] SYYSBZOSEAUMEY-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 4
- 206010023332 keratitis Diseases 0.000 claims description 4
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 3
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- QELZCXZWTOYAND-UHFFFAOYSA-N 4-[2-(difluoromethoxy)-4-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenoxy]-n-ethylazepane-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCCC1OC(C(=C1)OC(F)F)=CC=C1NC1=NC=C(F)C(NC2CC(C)(C)NC(C)(C)C2)=N1 QELZCXZWTOYAND-UHFFFAOYSA-N 0.000 claims description 2
- 208000032843 Hemorrhage Diseases 0.000 claims description 2
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- 150000002431 hydrogen Chemical group 0.000 claims 11
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- FHPOARWPEVYWGX-UHFFFAOYSA-N 2-[4-fluoro-3-(5-methyltetrazol-1-yl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound CC1=NN=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C#N)=CN=2)=CC=C1F FHPOARWPEVYWGX-UHFFFAOYSA-N 0.000 claims 1
- GDYDHLRWGXMBEG-UHFFFAOYSA-N 2-n-[3,4-difluoro-5-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(F)=C(F)C=2)C=2N(N=NN=2)C)=NC=C1F GDYDHLRWGXMBEG-UHFFFAOYSA-N 0.000 claims 1
- PFBFIHMAUYXBBT-UHFFFAOYSA-N 2-n-[3,4-difluoro-5-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound CN1N=NN=C1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(F)=C1F PFBFIHMAUYXBBT-UHFFFAOYSA-N 0.000 claims 1
- GWFZJRLEUAMBJA-UHFFFAOYSA-N 2-n-[3-(1-cyclopropyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=CC=2)C=2N(N=NN=2)C2CC2)=NC=C1F GWFZJRLEUAMBJA-UHFFFAOYSA-N 0.000 claims 1
- VFWMSNXVWUFXQG-UHFFFAOYSA-N 2-n-[3-(1-cyclopropyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=NC(NC=2C=C(C=CC=2)C=2N(N=NN=2)C2CC2)=NC=C1F VFWMSNXVWUFXQG-UHFFFAOYSA-N 0.000 claims 1
- HOJSSXNCMRIXHD-UHFFFAOYSA-N 2-n-[3-chloro-5-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(Cl)C=2)C=2N(N=NN=2)C)=NC=C1F HOJSSXNCMRIXHD-UHFFFAOYSA-N 0.000 claims 1
- YNLSCEYLGAUVAT-UHFFFAOYSA-N 2-n-[3-chloro-5-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound CN1N=NN=C1C1=CC(Cl)=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C1 YNLSCEYLGAUVAT-UHFFFAOYSA-N 0.000 claims 1
- UOWWJSZPWAQBQK-UHFFFAOYSA-N 2-n-[3-cyclopropyl-5-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound CN1N=NN=C1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C2CC2)=C1 UOWWJSZPWAQBQK-UHFFFAOYSA-N 0.000 claims 1
- VLSWEHCWDXFTNV-UHFFFAOYSA-N 2-n-[3-cyclopropyl-5-(tetrazol-1-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)C2CC2)N2N=NN=C2)=NC=C1F VLSWEHCWDXFTNV-UHFFFAOYSA-N 0.000 claims 1
- DFYIBNINAOPFOZ-UHFFFAOYSA-N 2-n-[3-cyclopropyl-5-(tetrazol-1-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)C2CC2)N2N=NN=C2)=NC=C1F DFYIBNINAOPFOZ-UHFFFAOYSA-N 0.000 claims 1
- WZGSSEBZFIRTTD-UHFFFAOYSA-N 2-n-[4-chloro-3-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(Cl)=CC=2)C=2N(N=NN=2)C)=NC=C1F WZGSSEBZFIRTTD-UHFFFAOYSA-N 0.000 claims 1
- OCQGDWMILSFCEE-UHFFFAOYSA-N 2-n-[4-chloro-3-(1-methyltetrazol-5-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound CN1N=NN=C1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1Cl OCQGDWMILSFCEE-UHFFFAOYSA-N 0.000 claims 1
- QLUBKRYLFMXJNY-UHFFFAOYSA-N 2-n-[4-cyclopropyl-3-(tetrazol-1-yl)phenyl]-5-fluoro-4-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C3CC3)=CC=2)N2N=NN=C2)=NC=C1F QLUBKRYLFMXJNY-UHFFFAOYSA-N 0.000 claims 1
- MQQIZFQCEPINDF-UHFFFAOYSA-N 2-n-[4-cyclopropyl-3-(tetrazol-1-yl)phenyl]-5-fluoro-4-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=NC(NC=2C=C(C(C3CC3)=CC=2)N2N=NN=C2)=NC=C1F MQQIZFQCEPINDF-UHFFFAOYSA-N 0.000 claims 1
- PEIZWDDUHJKWEC-UHFFFAOYSA-N 3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(1-methyltetrazol-5-yl)benzonitrile Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)C#N)C=2N(N=NN=2)C)=NC=C1F PEIZWDDUHJKWEC-UHFFFAOYSA-N 0.000 claims 1
- RICOONOXQYXDSZ-UHFFFAOYSA-N 3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(1-methyltetrazol-5-yl)benzonitrile Chemical compound CN1N=NN=C1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C#N)=C1 RICOONOXQYXDSZ-UHFFFAOYSA-N 0.000 claims 1
- RJITYGCHTQNQJX-UHFFFAOYSA-N 4-n-(1-cyclopropyl-2,6-dimethylpiperidin-4-yl)-5-fluoro-2-n-[3-(5-methylsulfanyltetrazol-1-yl)phenyl]pyrimidine-2,4-diamine Chemical compound CSC1=NN=NN1C1=CC=CC(NC=2N=C(NC3CC(C)N(C4CC4)C(C)C3)C(F)=CN=2)=C1 RJITYGCHTQNQJX-UHFFFAOYSA-N 0.000 claims 1
- JSMQWKGCPPHLGS-UHFFFAOYSA-N 4-n-(1-cyclopropyl-2,6-dimethylpiperidin-4-yl)-5-fluoro-2-n-[3-(5-methyltetrazol-1-yl)phenyl]pyrimidine-2,4-diamine Chemical compound CC1CC(NC=2C(=CN=C(NC=3C=C(C=CC=3)N3C(=NN=N3)C)N=2)F)CC(C)N1C1CC1 JSMQWKGCPPHLGS-UHFFFAOYSA-N 0.000 claims 1
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- YTUKHABUYPSSGE-UHFFFAOYSA-N 4-n-(1-cyclopropyl-2,6-dimethylpiperidin-4-yl)-5-fluoro-2-n-[3-[5-(2,2,2-trifluoroethylsulfanyl)tetrazol-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound CC1CC(NC=2C(=CN=C(NC=3C=C(C=CC=3)N3C(=NN=N3)SCC(F)(F)F)N=2)F)CC(C)N1C1CC1 YTUKHABUYPSSGE-UHFFFAOYSA-N 0.000 claims 1
- JEFAEOFWEBTYPD-UHFFFAOYSA-N 4-n-(1-cyclopropyl-2,6-dimethylpiperidin-4-yl)-5-fluoro-2-n-[3-methoxy-5-(tetrazol-1-yl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C(N2N=NN=C2)=CC(OC)=CC=1NC(N=1)=NC=C(F)C=1NC(CC1C)CC(C)N1C1CC1 JEFAEOFWEBTYPD-UHFFFAOYSA-N 0.000 claims 1
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US14627309P | 2009-01-21 | 2009-01-21 | |
| US61/146,273 | 2009-01-21 | ||
| US26416509P | 2009-11-24 | 2009-11-24 | |
| US61/264,165 | 2009-11-24 | ||
| PCT/US2010/021662 WO2010090875A1 (en) | 2009-01-21 | 2010-01-21 | Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases |
Publications (2)
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| CA2749837A1 CA2749837A1 (en) | 2010-08-12 |
| CA2749837C true CA2749837C (en) | 2017-07-11 |
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| CA2749837A Active CA2749837C (en) | 2009-01-21 | 2010-01-21 | Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases |
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| Country | Link |
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| US (2) | US8377924B2 (enExample) |
| EP (1) | EP2389373B1 (enExample) |
| JP (2) | JP5781943B2 (enExample) |
| CA (1) | CA2749837C (enExample) |
| ES (1) | ES2635504T3 (enExample) |
| WO (1) | WO2010090875A1 (enExample) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1663242T1 (sl) * | 2003-08-07 | 2011-09-30 | Rigel Pharmaceuticals Inc | 2,4-pirimidindiaminske spojine in uporabe kot antiproliferativna sredstva |
| JP5802677B2 (ja) * | 2009-12-01 | 2015-10-28 | ライジェル ファーマシューティカルズ， インコーポレイテッド | プロテインキナーゼｃ阻害剤およびその使用 |
| JP6035238B2 (ja) | 2010-07-21 | 2016-11-30 | ライジェル ファーマシューティカルズ， インコーポレイテッド | プロテインキナーゼｃ阻害剤およびその使用 |
| KR101643721B1 (ko) * | 2010-11-09 | 2016-07-28 | 후지안 하이시 파머수티클스, 인코포레이티드 | 키나아제 활성을 증진시키기 위한 화합물 및 이의 응용 |
| CN111471021B (zh) * | 2011-04-22 | 2024-04-02 | 西格诺药品有限公司 | 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法 |
| US9321763B2 (en) | 2012-04-04 | 2016-04-26 | Rigel Pharmaceuticals, Inc. | Protein kinase C inhibitors and uses thereof |
| CA2892677A1 (en) | 2012-12-04 | 2014-06-12 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
| CA2904610A1 (en) | 2013-03-14 | 2014-09-25 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
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| EP2389373A1 (en) | 2011-11-30 |
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