ES2586588T3 - Derivados tricíclicos, procedimiento para su preparación y su uso como inhibidores de quinasa - Google Patents

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Publication number

ES2586588T3

ES2586588T3 ES12700566.8T ES12700566T ES2586588T3 ES 2586588 T3 ES2586588 T3 ES 2586588T3 ES 12700566 T ES12700566 T ES 12700566T ES 2586588 T3 ES2586588 T3 ES 2586588T3

Authority

ES

Spain

Prior art keywords

carboxamide

amino

cyclohepta

tetrahydropyrazolo

pyrimidine

Prior art date

2011-01-26

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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• 238000000034 method Methods 0.000 title description 70
• 238000002360 preparation method Methods 0.000 title description 23
• 229940043355 kinase inhibitor Drugs 0.000 title description 5
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 5
• -1 amino, ureido Chemical group 0.000 claims abstract description 215
• 150000001875 compounds Chemical class 0.000 claims abstract description 215
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 124
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 45
• 239000001257 hydrogen Substances 0.000 claims abstract description 44
• 125000003118 aryl group Chemical group 0.000 claims abstract description 39
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 32
• 150000003839 salts Chemical class 0.000 claims abstract description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 29
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 28
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 28
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 23
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 23
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 22
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
• 239000001301 oxygen Substances 0.000 claims abstract description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 9
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
• 150000002367 halogens Chemical group 0.000 claims abstract description 9
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims abstract description 5
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
• 125000001769 aryl amino group Chemical group 0.000 claims abstract description 5
• 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 5
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims abstract description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 4
• 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 4
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims abstract description 4
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims abstract description 4
• 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims abstract description 4
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims abstract description 4
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims abstract description 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 4
• 125000004986 diarylamino group Chemical group 0.000 claims abstract description 4
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims abstract description 4
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 4
• 125000001424 substituent group Chemical group 0.000 claims abstract description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims abstract description 3
• 125000004465 cycloalkenyloxy group Chemical group 0.000 claims abstract description 3
• 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims abstract description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract 2
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims abstract 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 101
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 44
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 40
• GMKKIKIHZNHRRW-UHFFFAOYSA-N cyclohepta[d]pyrimidine-3-carboxamide Chemical compound N1=CN(C=C2C1=CC=CC=C2)C(=O)N GMKKIKIHZNHRRW-UHFFFAOYSA-N 0.000 claims description 33
• 150000003857 carboxamides Chemical class 0.000 claims description 30
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 26
• LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 19
• RYTGHNMOSCSWJT-UHFFFAOYSA-N 6-imino-11-methyl-N-(3-morpholin-4-ylpropyl)-2-oxo-7-(2-phenylethyl)-1,7,9-triazatricyclo[8.4.0.03,8]tetradeca-3(8),4,9,11,13-pentaene-5-carboxamide Chemical compound Cc1cccn2c1nc1n(CCc3ccccc3)c(=N)c(cc1c2=O)C(=O)NCCCN1CCOCC1 RYTGHNMOSCSWJT-UHFFFAOYSA-N 0.000 claims description 13
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 13
• CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 claims description 12
• 241001024304 Mino Species 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 10
• 239000002253 acid Substances 0.000 claims description 9
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 8
• 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
• 150000001412 amines Chemical class 0.000 claims description 5
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
• YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 4
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 3
• 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 3
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 3
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 150000003254 radicals Chemical class 0.000 claims description 2
• YGNIQIAKEZGGNZ-UHFFFAOYSA-N 1,2,3,3a-tetrahydropyrazolo[4,5]cyclohepta[1,2-b]pyrimidine-3-carboxamide Chemical compound C1=CC2C(C(=O)N)NNC2=C2N=CN=CC2=C1 YGNIQIAKEZGGNZ-UHFFFAOYSA-N 0.000 claims 1
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
• NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 claims 1
• KSEBVSDOVDUCDD-UHFFFAOYSA-N 9-(benzylamino)-n-(2-methoxyethyl)-1-methyl-5,6-dihydro-4h-pyrazolo[4,5]cyclohepta[1,2-d]pyrimidine-3-carboxamide Chemical compound COCCNC(=O)C1=NN(C)C(C2=N3)=C1CCCC2=CN=C3NCC1=CC=CC=C1 KSEBVSDOVDUCDD-UHFFFAOYSA-N 0.000 claims 1
• VFGMCUZPRVYSDS-UHFFFAOYSA-N 9-anilino-1-methyl-5,6-dihydro-4h-pyrazolo[4,5]cyclohepta[1,2-d]pyrimidine-3-carboxamide Chemical compound N1=C2C=3N(C)N=C(C(N)=O)C=3CCCC2=CN=C1NC1=CC=CC=C1 VFGMCUZPRVYSDS-UHFFFAOYSA-N 0.000 claims 1
• VHTGQSNQMHYQQK-UHFFFAOYSA-N 9-anilino-n-(2-methoxyethyl)-1-methyl-5,6-dihydro-4h-pyrazolo[4,5]cyclohepta[1,2-d]pyrimidine-3-carboxamide Chemical compound COCCNC(=O)C1=NN(C)C(C2=N3)=C1CCCC2=CN=C3NC1=CC=CC=C1 VHTGQSNQMHYQQK-UHFFFAOYSA-N 0.000 claims 1
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 6
• 125000006517 heterocyclyl carbonyl group Chemical group 0.000 abstract description 4
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 abstract description 3
• 125000005600 alkyl phosphonate group Chemical group 0.000 abstract description 3
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• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 abstract description 3
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• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract description 3
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 abstract description 3
• 229910052717 sulfur Inorganic materials 0.000 abstract description 3
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 abstract description 2
• 125000005110 aryl thio group Chemical group 0.000 abstract description 2
• 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 abstract 1
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 134
• 238000005481 NMR spectroscopy Methods 0.000 description 89
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