KR20140114344A - 키나제 억제제로서의 피리미딘-2,4-디아민 유도체 - Google Patents

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Publication number

KR20140114344A

KR20140114344A KR1020147016971A KR20147016971A KR20140114344A KR 20140114344 A KR20140114344 A KR 20140114344A KR 1020147016971 A KR1020147016971 A KR 1020147016971A KR 20147016971 A KR20147016971 A KR 20147016971A KR 20140114344 A KR20140114344 A KR 20140114344A

Authority

KR

South Korea

Prior art keywords

methyl

amino

pyrazol

pyrimidin

pyrrolidin

Prior art date

2011-12-23

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.)

Withdrawn

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• YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 title claims description 26
• 229940043355 kinase inhibitor Drugs 0.000 title description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 125
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 72
• 201000010099 disease Diseases 0.000 claims abstract description 42
• 238000011282 treatment Methods 0.000 claims abstract description 29
• 239000003814 drug Substances 0.000 claims abstract description 25
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 15
• 230000001363 autoimmune Effects 0.000 claims abstract description 14
• 230000000172 allergic effect Effects 0.000 claims abstract description 13
• 208000010668 atopic eczema Diseases 0.000 claims abstract description 13
• 230000001900 immune effect Effects 0.000 claims abstract description 12
• 230000002265 prevention Effects 0.000 claims abstract description 12
• -1 (5-Chloro-2 - ((1 -methyl-1 H- pyrazol-4-yl) amino) pyrimidin- 1-yl) ethanone Chemical compound 0.000 claims description 335
• 238000000034 method Methods 0.000 claims description 264
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 240
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 200
• 125000000217 alkyl group Chemical group 0.000 claims description 81
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 71
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 67
• 150000003839 salts Chemical class 0.000 claims description 56
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 55
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 55
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 46
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 32
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 208000035475 disorder Diseases 0.000 claims description 29
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 24
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 24
• HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 22
• FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 21
• 125000001424 substituent group Chemical group 0.000 claims description 21
• ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 16
• 229920006395 saturated elastomer Polymers 0.000 claims description 16
• TYUIYYAELDDEKW-UHFFFAOYSA-N N-[1-(2,2-difluoroethyl)pyrazol-4-yl]-5-methylpyrimidin-2-amine Chemical compound FC(CN1N=CC(=C1)NC1=NC=C(C=N1)C)F TYUIYYAELDDEKW-UHFFFAOYSA-N 0.000 claims description 14
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• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
• YSPVHAUJXLGZHP-UHFFFAOYSA-N ethyl piperidine-1-carboxylate Chemical compound CCOC(=O)N1CCCCC1 YSPVHAUJXLGZHP-UHFFFAOYSA-N 0.000 claims description 10
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• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000002393 azetidinyl group Chemical group 0.000 claims description 6
• 125000003386 piperidinyl group Chemical group 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 5
• 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 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• ZLZPCDHVSMFGOH-UHFFFAOYSA-N 2-(1-methylpyrazol-4-yl)pyrimidine Chemical compound CN1N=CC(=C1)C1=NC=CC=N1 ZLZPCDHVSMFGOH-UHFFFAOYSA-N 0.000 claims description 4
• DAATVZRKBFLUHN-SBSPUUFOSA-N 5-fluoro-2-n-(1-methylpyrazol-4-yl)-4-n-[[(2r)-pyrrolidin-2-yl]methyl]pyrimidine-2,4-diamine;hydrochloride Chemical compound Cl.C1=NN(C)C=C1NC1=NC=C(F)C(NC[C@@H]2NCCC2)=N1 DAATVZRKBFLUHN-SBSPUUFOSA-N 0.000 claims description 4
• DAATVZRKBFLUHN-FVGYRXGTSA-N 5-fluoro-2-n-(1-methylpyrazol-4-yl)-4-n-[[(2s)-pyrrolidin-2-yl]methyl]pyrimidine-2,4-diamine;hydrochloride Chemical compound Cl.C1=NN(C)C=C1NC1=NC=C(F)C(NC[C@H]2NCCC2)=N1 DAATVZRKBFLUHN-FVGYRXGTSA-N 0.000 claims description 4
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• KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• NGRXFQJESUUKOY-UHFFFAOYSA-N 1-(2-methylsulfonylethyl)pyrrolidine Chemical compound CS(=O)(=O)CCN1CCCC1 NGRXFQJESUUKOY-UHFFFAOYSA-N 0.000 claims description 3
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• XSJQYKVQFGUVAS-HNNXBMFYSA-N 2-n-[1-(2,2-difluoroethyl)pyrazol-4-yl]-5-methyl-4-n-[[(2s)-1-(2-methylsulfonylethyl)pyrrolidin-2-yl]methyl]pyrimidine-2,4-diamine Chemical compound N1=C(NC[C@H]2N(CCC2)CCS(C)(=O)=O)C(C)=CN=C1NC=1C=NN(CC(F)F)C=1 XSJQYKVQFGUVAS-HNNXBMFYSA-N 0.000 claims description 3
• SQCGRQFNIAKQOV-GZJFXKPMSA-N 4-[[(2S,4S)-4-fluoro-1-(2-methylsulfonylethyl)pyrrolidin-2-yl]methyl]-5-methyl-2-N-(1-methylpyrazol-4-yl)-1H-pyrimidine-2,4-diamine Chemical compound F[C@H]1C[C@@H](N(C1)CCS(=O)(=O)C)CC1(NC(=NC=C1C)NC=1C=NN(C1)C)N SQCGRQFNIAKQOV-GZJFXKPMSA-N 0.000 claims description 3
• ZKVOZWYQEAXVMD-UHFFFAOYSA-N 5-chloro-2-n-(1-methylpyrazol-4-yl)-4-n-(oxan-4-ylmethyl)pyrimidine-2,4-diamine Chemical compound C1=NN(C)C=C1NC1=NC=C(Cl)C(NCC2CCOCC2)=N1 ZKVOZWYQEAXVMD-UHFFFAOYSA-N 0.000 claims description 3
• XSFJCGSXBDREEI-UHFFFAOYSA-N 5-chloro-2-n-(1-methylpyrazol-4-yl)-4-n-[(1-methylpyrrolidin-2-yl)methyl]pyrimidine-2,4-diamine Chemical compound CN1CCCC1CNC1=NC(NC2=CN(C)N=C2)=NC=C1Cl XSFJCGSXBDREEI-UHFFFAOYSA-N 0.000 claims description 3
• YVKFYNLRXUJIEG-OAHLLOKOSA-N 5-chloro-2-n-(1-methylpyrazol-4-yl)-4-n-[[(2r)-1-(2-propan-2-ylsulfonylethyl)pyrrolidin-2-yl]methyl]pyrimidine-2,4-diamine Chemical compound CC(C)S(=O)(=O)CCN1CCC[C@@H]1CNC1=NC(NC2=CN(C)N=C2)=NC=C1Cl YVKFYNLRXUJIEG-OAHLLOKOSA-N 0.000 claims description 3
• NAZVEDNLWCJNBR-LLVKDONJSA-N 5-chloro-2-n-(1-methylpyrazol-4-yl)-4-n-[[(2r)-1-methylsulfonylpyrrolidin-2-yl]methyl]pyrimidine-2,4-diamine Chemical compound C1=NN(C)C=C1NC1=NC=C(Cl)C(NC[C@@H]2N(CCC2)S(C)(=O)=O)=N1 NAZVEDNLWCJNBR-LLVKDONJSA-N 0.000 claims description 3
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• XWAIHPHTWPDHKD-AAEUAGOBSA-N Cn1cc(Nc2ncc(Cl)c(NC[C@@H]3C[C@H](F)CN3CCS(C)(=O)=O)n2)cn1 Chemical compound Cn1cc(Nc2ncc(Cl)c(NC[C@@H]3C[C@H](F)CN3CCS(C)(=O)=O)n2)cn1 XWAIHPHTWPDHKD-AAEUAGOBSA-N 0.000 claims description 3
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