ES2668479T3 - Compuestos de pirimidina sustituidos y su uso como inhibidores de SYK - Google Patents

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Publication number

ES2668479T3

ES2668479T3 ES13738382.4T ES13738382T ES2668479T3 ES 2668479 T3 ES2668479 T3 ES 2668479T3 ES 13738382 T ES13738382 T ES 13738382T ES 2668479 T3 ES2668479 T3 ES 2668479T3

Authority

ES

Spain

Prior art keywords

methyl

pyrimidin

ylamino

pyrazol

indole

Prior art date

2012-01-20

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.)

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• 239000003112 inhibitor Substances 0.000 title description 18
• 150000003230 pyrimidines Chemical class 0.000 title description 5
• -1 4- (4 - ((3-Hydroxyazetidin-1-yl) methyl) -3-methyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino Chemical group 0.000 claims abstract description 311
• 150000001875 compounds Chemical class 0.000 claims abstract description 295
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 99
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims abstract description 71
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims abstract description 30
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 28
• LVDAOOBTKGLDAK-UHFFFAOYSA-N 1-[5-[[4-[4-[(3-hydroxyazetidin-1-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound C1=C2C(C(=O)C)=CN(C)C2=CC=C1NC(N=1)=NC=CC=1N(N=C1C)C=C1CN1CC(O)C1 LVDAOOBTKGLDAK-UHFFFAOYSA-N 0.000 claims abstract description 6
• JHXAYGBXXCDEBZ-UHFFFAOYSA-N 1-[5-[[4-[4-[(3-hydroxyazetidin-1-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]ethanone Chemical compound C1=C2C(C(=O)C)=CNC2=CC=C1NC(N=1)=NC=CC=1N(N=C1C)C=C1CN1CC(O)C1 JHXAYGBXXCDEBZ-UHFFFAOYSA-N 0.000 claims abstract description 6
• FLGSFJVMDOPSIH-GOSISDBHSA-N 1-[5-[[4-[4-[[(3r)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]ethanone Chemical compound C1=C2C(C(=O)C)=CNC2=CC=C1NC(N=1)=NC=CC=1N(N=C1C)C=C1CN1CC[C@@H](O)C1 FLGSFJVMDOPSIH-GOSISDBHSA-N 0.000 claims abstract description 5
• NQRYGQAPAJNGLL-OYRHEFFESA-N 1-[5-[[4-[4-[[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]ethanone Chemical compound C1=C2C(C(=O)C)=CNC2=CC=C1NC(N=1)=NC=CC=1N(N=C1C)C=C1CN1C[C@H](O)[C@H](O)C1 NQRYGQAPAJNGLL-OYRHEFFESA-N 0.000 claims abstract description 5
• LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims abstract description 5
• KBAODVSDRBXPFB-BJKOFHAPSA-N 1-[5-[[4-[4-[[(3s,4r)-3-hydroxy-4-methoxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]-2-methylpropan-1-one Chemical compound C1[C@H](O)[C@H](OC)CN1CC1=CN(C=2N=C(NC=3C=C4C(C(=O)C(C)C)=CN(C)C4=CC=3)N=CC=2)N=C1C KBAODVSDRBXPFB-BJKOFHAPSA-N 0.000 claims abstract description 4
• FOMMYQUZCYYMNG-UHFFFAOYSA-N [5-[[4-[4-[(3-hydroxyazetidin-1-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1,2-dimethylindol-3-yl]-pyrrolidin-1-ylmethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)N5CCCC5)=C(C)N(C)C4=CC=3)N=CC=2)C=C1CN1CC(O)C1 FOMMYQUZCYYMNG-UHFFFAOYSA-N 0.000 claims abstract description 4
• AROPBXPDYKPBNJ-UHFFFAOYSA-N cyclopropyl-[5-[[4-[4-[(3-hydroxyazetidin-1-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indol-1-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C=CN(C4=CC=3)C(=O)C3CC3)N=CC=2)C=C1CN1CC(O)C1 AROPBXPDYKPBNJ-UHFFFAOYSA-N 0.000 claims abstract description 4
• ZRYVEASTNWHZKR-ZRZAMGCNSA-N cyclopropyl-[5-[[4-[4-[[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1,2-dimethylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=C(C)N(C)C4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 ZRYVEASTNWHZKR-ZRZAMGCNSA-N 0.000 claims abstract description 4
• RBKBIFWYNLXUJN-OALUTQOASA-N 1-[5-[[4-[4-[[(3s,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]-2,2-difluoroethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C(F)F)=CNC4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@@H](O)C1 RBKBIFWYNLXUJN-OALUTQOASA-N 0.000 claims abstract description 3
• VLSXAYNYBJKZAV-JOCHJYFZSA-N cyclopropyl-[1-cyclopropyl-5-[[4-[4-[[(3r)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C4=CC=3)C3CC3)N=CC=2)C=C1CN1CC[C@@H](O)C1 VLSXAYNYBJKZAV-JOCHJYFZSA-N 0.000 claims abstract description 3
• QSHBGWBTDPULOV-BGYRXZFFSA-N 1-[5-[[4-[4-[[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]-2,2,2-trifluoroethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C(F)(F)F)=CN(C)C4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 QSHBGWBTDPULOV-BGYRXZFFSA-N 0.000 claims abstract 2
• BOAWZTDHVMBMEN-KDURUIRLSA-N 1-[5-[[4-[4-[[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]-2,2,2-trifluoroethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C(F)(F)F)=CNC4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 BOAWZTDHVMBMEN-KDURUIRLSA-N 0.000 claims abstract 2
• RBKBIFWYNLXUJN-KDURUIRLSA-N 1-[5-[[4-[4-[[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]-2,2-difluoroethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C(F)F)=CNC4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 RBKBIFWYNLXUJN-KDURUIRLSA-N 0.000 claims abstract 2
• KQVUHDMIGFMKFO-UHFFFAOYSA-N [1-[2-[(1-cyclopropyl-3-methylindol-5-yl)amino]pyrimidin-4-yl]-3-methylpyrazol-4-yl]-(3-hydroxyazetidin-1-yl)methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C)=CN(C4=CC=3)C3CC3)N=CC=2)C=C1C(=O)N1CC(O)C1 KQVUHDMIGFMKFO-UHFFFAOYSA-N 0.000 claims abstract 2
• JSFJBYKBNANORA-OAQYLSRUSA-N cyclopropyl-[5-[[4-[4-[[(3r)-3-hydroxypiperidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C)C4=CC=3)N=CC=2)C=C1CN1CCC[C@@H](O)C1 JSFJBYKBNANORA-OAQYLSRUSA-N 0.000 claims abstract 2
• FNGJTJGYKVSXHA-HXUWFJFHSA-N cyclopropyl-[5-[[4-[4-[[(3r)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C)C4=CC=3)N=CC=2)C=C1CN1CC[C@@H](O)C1 FNGJTJGYKVSXHA-HXUWFJFHSA-N 0.000 claims abstract 2
• PHFOPTLWGQJGMW-SZPZYZBQSA-N cyclopropyl-[5-[[4-[4-[[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CNC4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 PHFOPTLWGQJGMW-SZPZYZBQSA-N 0.000 claims abstract 2
• 210000004027 cell Anatomy 0.000 claims description 26
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• 239000003085 diluting agent Substances 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 230000001684 chronic effect Effects 0.000 claims description 6
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 206010025135 lupus erythematosus Diseases 0.000 claims description 5
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 5
• 238000007918 intramuscular administration Methods 0.000 claims description 4
• 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 3
• 230000002500 effect on skin Effects 0.000 claims description 3
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• 238000007920 subcutaneous administration Methods 0.000 claims description 3
• 229940124597 therapeutic agent Drugs 0.000 claims description 3
• 238000011200 topical administration Methods 0.000 claims description 3
• 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 2
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
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• 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 2
• 238000007911 parenteral administration Methods 0.000 claims description 2
• WXWUQOPWCPNTJP-ZRZAMGCNSA-N 1-[5-[[4-[4-[[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]-2-methylpropan-1-one Chemical compound C1=C2C(C(=O)C(C)C)=CN(C)C2=CC=C1NC(N=1)=NC=CC=1N(N=C1C)C=C1CN1C[C@H](O)[C@H](O)C1 WXWUQOPWCPNTJP-ZRZAMGCNSA-N 0.000 claims 1
• HNSGGOLPCJWHBE-ZRZAMGCNSA-N cyclopropyl-[5-[[4-[4-[[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C)C4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@H](O)C1 HNSGGOLPCJWHBE-ZRZAMGCNSA-N 0.000 claims 1
• HNSGGOLPCJWHBE-GOTSBHOMSA-N cyclopropyl-[5-[[4-[4-[[(3s,4s)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C)C4=CC=3)N=CC=2)C=C1CN1C[C@H](O)[C@@H](O)C1 HNSGGOLPCJWHBE-GOTSBHOMSA-N 0.000 claims 1
• JCZPOYAMKJFOLA-ZXZARUISSA-N (3s,4r)-pyrrolidine-3,4-diol Chemical compound O[C@H]1CNC[C@H]1O JCZPOYAMKJFOLA-ZXZARUISSA-N 0.000 abstract description 8
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 abstract description 6
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• PQBYPDZGIKKGIO-MRXNPFEDSA-N 2,2,2-trifluoro-1-[5-[[4-[4-[[(3r)-3-hydroxypyrrolidin-1-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1h-indol-3-yl]ethanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C(F)(F)F)=CNC4=CC=3)N=CC=2)C=C1CN1CC[C@@H](O)C1 PQBYPDZGIKKGIO-MRXNPFEDSA-N 0.000 abstract description 2
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