HRP20160243T1 - Pirazolo-kinazolini kao modulatori aktivnosti protein kinaze - Google Patents
Pirazolo-kinazolini kao modulatori aktivnosti protein kinaze Download PDFInfo
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- HRP20160243T1 HRP20160243T1 HRP20160243TT HRP20160243T HRP20160243T1 HR P20160243 T1 HRP20160243 T1 HR P20160243T1 HR P20160243T T HRP20160243T T HR P20160243TT HR P20160243 T HRP20160243 T HR P20160243T HR P20160243 T1 HRP20160243 T1 HR P20160243T1
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- Croatia
- Prior art keywords
- methyl
- amino
- dihydro
- pyrazolo
- carboxamide
- Prior art date
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- 102000001253 Protein Kinase Human genes 0.000 title claims 5
- 230000000694 effects Effects 0.000 title claims 5
- 108060006633 protein kinase Proteins 0.000 title claims 5
- GNOYRJIXSUNXIH-UHFFFAOYSA-N N1=CNC2=C3C=NN=C3C=CC2=C1 Chemical class N1=CNC2=C3C=NN=C3C=CC2=C1 GNOYRJIXSUNXIH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 13
- 125000003118 aryl group Chemical group 0.000 claims 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims 11
- -1 4-pentynyl Chemical group 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 10
- 125000000623 heterocyclic group Chemical group 0.000 claims 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 7
- 206010028980 Neoplasm Diseases 0.000 claims 6
- 125000003545 alkoxy group Chemical group 0.000 claims 6
- 229910052799 carbon Inorganic materials 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 5
- 125000004429 atom Chemical group 0.000 claims 5
- 125000004122 cyclic group Chemical group 0.000 claims 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 3
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims 3
- 125000004414 alkyl thio group Chemical group 0.000 claims 3
- 125000000304 alkynyl group Chemical group 0.000 claims 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims 3
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims 3
- 125000005110 aryl thio group Chemical group 0.000 claims 3
- 125000004104 aryloxy group Chemical group 0.000 claims 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims 3
- 125000003107 substituted aryl group Chemical group 0.000 claims 3
- DRETXDHLKHGSTB-UHFFFAOYSA-N 2h-pyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound C1=CC2=CN=CN=C2C2=C1C(C(=O)N)=NN2 DRETXDHLKHGSTB-UHFFFAOYSA-N 0.000 claims 2
- 102100022681 40S ribosomal protein S27 Human genes 0.000 claims 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims 2
- 101000678466 Homo sapiens 40S ribosomal protein S27 Proteins 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 2
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims 2
- 125000001769 aryl amino group Chemical group 0.000 claims 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims 2
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims 2
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims 2
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims 2
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims 2
- 125000004986 diarylamino group Chemical group 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 201000005787 hematologic cancer Diseases 0.000 claims 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims 1
- 125000006039 1-hexenyl group Chemical group 0.000 claims 1
- LTMPOWBIFCSVQK-UHFFFAOYSA-N 1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound C1CC2=CN=CN=C2C2=C1C(C(N)=O)=NN2C LTMPOWBIFCSVQK-UHFFFAOYSA-N 0.000 claims 1
- TUXLNRILIXNZHJ-UHFFFAOYSA-N 1-methyl-8-[4-[(1-methylpiperidin-4-yl)carbamoyl]-2-(trifluoromethoxy)anilino]-n-phenyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound C1CN(C)CCC1NC(=O)C(C=C1OC(F)(F)F)=CC=C1NC1=NC=C(CCC2=C3N(C)N=C2C(=O)NC=2C=CC=CC=2)C3=N1 TUXLNRILIXNZHJ-UHFFFAOYSA-N 0.000 claims 1
- 125000006017 1-propenyl group Chemical group 0.000 claims 1
- LIDYHWUOYHIKLN-UHFFFAOYSA-N 2,3-dihydroindol-1-yl-[8-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-3-yl]methanone Chemical compound C=1C=C(NC=2N=C3C=4N(C)N=C(C=4CCC3=CN=2)C(=O)N2C3=CC=CC=C3CC2)C(OC)=CC=1N1CCN(C)CC1 LIDYHWUOYHIKLN-UHFFFAOYSA-N 0.000 claims 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims 1
- 125000006024 2-pentenyl group Chemical group 0.000 claims 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims 1
- UCAVIZKQSBARGL-UHFFFAOYSA-N 2h-quinazoline-3-carboxamide Chemical compound C1=CC=CC2=CN(C(=O)N)CN=C21 UCAVIZKQSBARGL-UHFFFAOYSA-N 0.000 claims 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims 1
- MHXMTPXVFNKJGD-UHFFFAOYSA-N 4-[[3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-8-yl]amino]-3-methoxybenzoic acid Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(C(O)=O)C=C1OC MHXMTPXVFNKJGD-UHFFFAOYSA-N 0.000 claims 1
- XHDKKRKBUZEXHX-UHFFFAOYSA-N 4-[[3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-8-yl]amino]-3-methylbenzoic acid Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(C(O)=O)C=C1C XHDKKRKBUZEXHX-UHFFFAOYSA-N 0.000 claims 1
- JQDCUNPKNHPVJK-UHFFFAOYSA-N 8-(2-bromoanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=CC=C1Br JQDCUNPKNHPVJK-UHFFFAOYSA-N 0.000 claims 1
- DJAGHSLHIDDTBM-UHFFFAOYSA-N 8-(2-chloroanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=CC=C1Cl DJAGHSLHIDDTBM-UHFFFAOYSA-N 0.000 claims 1
- CQVMDHPOXBGLCR-UHFFFAOYSA-N 8-(4-amino-2-methoxyanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N)C=C1OC CQVMDHPOXBGLCR-UHFFFAOYSA-N 0.000 claims 1
- QUHNHGZXNAJXEQ-UHFFFAOYSA-N 8-(4-bromo-2-chloroanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(Br)C=C1Cl QUHNHGZXNAJXEQ-UHFFFAOYSA-N 0.000 claims 1
- SJXAEBKCGZRMCZ-UHFFFAOYSA-N 8-(4-bromo-2-methoxyanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(Br)C=C1OC SJXAEBKCGZRMCZ-UHFFFAOYSA-N 0.000 claims 1
- ZWRLLBAFCKACAL-UHFFFAOYSA-N 8-(4-carbamoyl-2-methoxyanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(C(N)=O)C=C1OC ZWRLLBAFCKACAL-UHFFFAOYSA-N 0.000 claims 1
- BJWZREISPNEEKH-UHFFFAOYSA-N 8-(4-carbamoyl-2-methylanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(C(N)=O)C=C1C BJWZREISPNEEKH-UHFFFAOYSA-N 0.000 claims 1
- YEFKJOAIOUCHQY-UHFFFAOYSA-N 8-(5-bromo-2-methoxyanilino)-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC(Br)=CC=C1OC YEFKJOAIOUCHQY-UHFFFAOYSA-N 0.000 claims 1
- CMNMKLDDGRMUTK-UHFFFAOYSA-N 8-[(1-acetylpiperidin-4-yl)amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(C(C)=O)CC1 CMNMKLDDGRMUTK-UHFFFAOYSA-N 0.000 claims 1
- DOMSXNQQNTURSJ-UHFFFAOYSA-N 8-[(1-benzoylpiperidin-4-yl)amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(C(=O)C=2C=CC=CC=2)CC1 DOMSXNQQNTURSJ-UHFFFAOYSA-N 0.000 claims 1
- ZBJKQQJEHYWWPQ-UHFFFAOYSA-N 8-[(1-benzylpiperidin-4-yl)amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(CC=2C=CC=CC=2)CC1 ZBJKQQJEHYWWPQ-UHFFFAOYSA-N 0.000 claims 1
- HWROKEWVUBMOHF-UHFFFAOYSA-N 8-[2-chloro-4-(4-methylpiperazin-1-yl)anilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1Cl HWROKEWVUBMOHF-UHFFFAOYSA-N 0.000 claims 1
- LWNHLIMFTSIYFI-UHFFFAOYSA-N 8-[2-chloro-4-[3-(dimethylamino)propyl-methylamino]anilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N(C)CCCN(C)C)C=C1Cl LWNHLIMFTSIYFI-UHFFFAOYSA-N 0.000 claims 1
- XPIPWHOSMHUBSV-UHFFFAOYSA-N 8-[2-chloro-4-[4-(dimethylamino)piperidin-1-yl]anilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCC(CC2)N(C)C)C=C1Cl XPIPWHOSMHUBSV-UHFFFAOYSA-N 0.000 claims 1
- GUKSNAJRVLPYFT-UHFFFAOYSA-N 8-[2-cyano-4-(4-methyl-1,4-diazepan-1-yl)anilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CCC2)C=C1C#N GUKSNAJRVLPYFT-UHFFFAOYSA-N 0.000 claims 1
- SHMCNEXTQLMDPT-UHFFFAOYSA-N 8-[2-cyano-4-(4-methylpiperazin-1-yl)anilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1C#N SHMCNEXTQLMDPT-UHFFFAOYSA-N 0.000 claims 1
- JBUQUKAGXUISRC-UHFFFAOYSA-N 8-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-1-methyl-n-(5,6,7,8-tetrahydronaphthalen-1-yl)-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound C=1C=C(NC=2N=C3C=4N(C)N=C(C=4CCC3=CN=2)C(=O)NC=2C=3CCCCC=3C=CC=2)C(OC)=CC=1N1CCN(C)CC1 JBUQUKAGXUISRC-UHFFFAOYSA-N 0.000 claims 1
- SRQDHNVEOBWEQV-UHFFFAOYSA-N 8-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-n-(2-methoxyphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound COC1=CC=CC=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(N2CCN(C)CC2)C=C1OC SRQDHNVEOBWEQV-UHFFFAOYSA-N 0.000 claims 1
- MXDQMWZWROWJDB-UHFFFAOYSA-N 8-[4-(1-azabicyclo[2.2.2]octan-3-ylamino)-2-methoxyanilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC(C(=C1)OC)=CC=C1NC1C(CC2)CCN2C1 MXDQMWZWROWJDB-UHFFFAOYSA-N 0.000 claims 1
- NXIXATQBIBYOMP-UHFFFAOYSA-N 8-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methoxyanilino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(CO[Si](C)(C)C(C)(C)C)C=C1OC NXIXATQBIBYOMP-UHFFFAOYSA-N 0.000 claims 1
- TVCGKXFDFYDXFD-UHFFFAOYSA-N 8-[[1-(2-aminoethylsulfonyl)piperidin-4-yl]amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(S(=O)(=O)CCN)CC1 TVCGKXFDFYDXFD-UHFFFAOYSA-N 0.000 claims 1
- KTDIJPDKVKJIGN-UHFFFAOYSA-N 8-[[1-(3-chloropropylsulfonyl)piperidin-4-yl]amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(S(=O)(=O)CCCCl)CC1 KTDIJPDKVKJIGN-UHFFFAOYSA-N 0.000 claims 1
- DTJAEIWDXGICLF-UHFFFAOYSA-N 8-[[1-(4-acetamidophenyl)sulfonylpiperidin-4-yl]amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(S(=O)(=O)C=2C=CC(NC(C)=O)=CC=2)CC1 DTJAEIWDXGICLF-UHFFFAOYSA-N 0.000 claims 1
- LDBVAJPXLPXCSJ-UHFFFAOYSA-N 8-[[1-(4-aminophenyl)sulfonylpiperidin-4-yl]amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide;hydrochloride Chemical compound Cl.CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(S(=O)(=O)C=2C=CC(N)=CC=2)CC1 LDBVAJPXLPXCSJ-UHFFFAOYSA-N 0.000 claims 1
- JUXWYNXJDXZVTL-UHFFFAOYSA-N 8-[[1-(benzenesulfonyl)piperidin-4-yl]amino]-n-(2,6-diethylphenyl)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(S(=O)(=O)C=2C=CC=CC=2)CC1 JUXWYNXJDXZVTL-UHFFFAOYSA-N 0.000 claims 1
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- MGFOVQHREHMLFU-MXVIHJGJSA-N CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3N[C@@H]1CC[C@@H](N)CC1 Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3N[C@@H]1CC[C@@H](N)CC1 MGFOVQHREHMLFU-MXVIHJGJSA-N 0.000 claims 1
- XKTXBNYDVXFTPA-YHBQERECSA-N CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3N[C@@H]1CC[C@@H](NS(=O)(=O)CCNC)CC1 Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3N[C@@H]1CC[C@@H](NS(=O)(=O)CCNC)CC1 XKTXBNYDVXFTPA-YHBQERECSA-N 0.000 claims 1
- 201000009030 Carcinoma Diseases 0.000 claims 1
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- 206010018338 Glioma Diseases 0.000 claims 1
- 208000017604 Hodgkin disease Diseases 0.000 claims 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims 1
- 101001019502 Homo sapiens Alpha-L-iduronidase Proteins 0.000 claims 1
- 101000659223 Homo sapiens Dual specificity protein kinase TTK Proteins 0.000 claims 1
- 101000962483 Homo sapiens Max dimerization protein 1 Proteins 0.000 claims 1
- 101001000302 Homo sapiens Max-interacting protein 1 Proteins 0.000 claims 1
- 101000896484 Homo sapiens Mitotic checkpoint protein BUB3 Proteins 0.000 claims 1
- 101000896657 Homo sapiens Mitotic checkpoint serine/threonine-protein kinase BUB1 Proteins 0.000 claims 1
- 101000794228 Homo sapiens Mitotic checkpoint serine/threonine-protein kinase BUB1 beta Proteins 0.000 claims 1
- 101000957106 Homo sapiens Mitotic spindle assembly checkpoint protein MAD1 Proteins 0.000 claims 1
- 101000957259 Homo sapiens Mitotic spindle assembly checkpoint protein MAD2A Proteins 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 1
- 102100039185 Max dimerization protein 1 Human genes 0.000 claims 1
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- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 102000020233 phosphotransferase Human genes 0.000 claims 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 206010039667 schwannoma Diseases 0.000 claims 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 210000003491 skin Anatomy 0.000 claims 1
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 229910052717 sulfur Chemical group 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- 208000001608 teratocarcinoma Diseases 0.000 claims 1
- JLOPGVIEILIHEW-UHFFFAOYSA-N tert-butyl 4-[[3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-8-yl]amino]-3,3-dimethylpiperidine-1-carboxylate Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1C(C)(C)CN(C(=O)OC(C)(C)C)CC1 JLOPGVIEILIHEW-UHFFFAOYSA-N 0.000 claims 1
- XTHFCLZGGOAZSH-UHFFFAOYSA-N tert-butyl 4-[[3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-8-yl]amino]-3-methoxybenzoate Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1=CC=C(C(=O)OC(C)(C)C)C=C1OC XTHFCLZGGOAZSH-UHFFFAOYSA-N 0.000 claims 1
- MKXGTQOGQWQZJT-UHFFFAOYSA-N tert-butyl 4-[[3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazolin-8-yl]amino]piperidine-1-carboxylate Chemical compound CCC1=CC=CC(CC)=C1NC(=O)C1=NN(C)C(C2=N3)=C1CCC2=CN=C3NC1CCN(C(=O)OC(C)(C)C)CC1 MKXGTQOGQWQZJT-UHFFFAOYSA-N 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Claims (15)
1. Spoj formule (I):
[image]
naznačen time, da:
R1 je orto-supstituirana-arilna skupina ili heterociklil ili C3-C7 cikloalkilna skupina;
R2 je vodikov atom ili ravna ili razgranana C1-C6 alkilna, C2-C6 alkenilna, C2-C6 alkinilna, C3-C7 cikloalkilna ili heterociklilna skupina;
R3 je aril;
R4 je atom vodika, hidroksil ili C1-C6 alkilna skupina, koja skupina može po izboru činiti prsten zajedno s jednim od atoma skupine koji R3 može predstavljati tako da tvori spojenu C4-C7 cikličku skupinu;
R5 i R6: su svaki neovisno atom vodika, C1-C6 alkil ili po izboru mogu činiti prsten zajedno s atomom ugljika za kojeg su vezani tako da tvore C3-C7 cikloalkilnu skupinu;
gdje je "aril" aromatska karbociklička ili heteroarilna skupina koja se sastoji od 1 do 2 prstenasta spoja, bilo spojenih ili vezanih jedan za drugi jednostrukom vezom, pri čemu barem jedan od prstenova je aromatski; ako je prisutan, bilo koji aromatski heteroarilni prsten (također poznat kao aromatska heterociklilna skupina) sadrži 5 do 6-eročlani prsten koji se sastoji od 1 do 3 heteroatoma odabrana između N, O ili S; "orto-supstituirani aril", je arilna skupina kako je gore definirana, vezana za -NH- polovicu, rečeni aril se uvijek supstituira u orto položaju, što je na prstenu susjedni atom onome koji je vezan za -NH- polovicu te također po izboru supstituiran na drugim slobodnim položajima;
"heterociklil" (također poznat kao "heterocikloalkil") je 3- do 7-eročlani zasićeni ili djelomično nezasićeni karbociklički prsten gdje jedan ili više ugljikovih atoma su zamijenjeni heteroatomima poput primjerice dušik, kisik i sumpor;
"C3-C7 cikloalkil", stoga sveobuhvatno od C4-C7 cikloalkila, je 3- do 7-eročlani sve-ugljik monociklički prsten, koji može imati jednu ili više dvostrukih veza ali nema potpuno sjedinjen sustav π-elektrona;
"ravni ili razgranani C1-C6 alkil", stoga sveobuhvatno od C1-C4 alkila, je bilo koja skupina kao takva, na primjer, metil, etil, n-propil, izopropil, n-butil, izobutil, terc-butil, sek-butil, n-pentil, n-heksil;
"ravni ili razgranani C2-C6 alkenil" je bilo koja od skupina poput primjerice, vinila, alila, 1-propenila, izopropenila, 1-butenila, 2-butenila, 3-butenila, 2-pentenila, 1-heksenila; i
"ravni ili razgranani C2-C6 alkinil" je bilo koja od skupina poput primjerice, etinila, 2- propinila, 4- pentinila; pri čemu skupine orto-supstituirani-aril, aril, heterociklil, C3-C7 cikloalkil, C4-C7 cikloalkil, C1-C6 alkil, C2-C6 alkenil i C2-C6 alkinil mogu po izboru biti (dalje) supstituirane s jednom ili više skupina, na primjer 1 do 6 skupina, neovisno odabranih od: atoma halogena, nitro, okso skupina (=O), cijano, C1-C6 alkila, polifluoriniranog alkila, polifluoriniranog alkoksi, alkenila, alkinila, hidroksialkila, arila, arilalkila, heterociklila, C3-C7 cikloalkila, hidroksi, alkoksi, ariloksi, heterocikliloksi, metilenedioksi, alkilkarboniloksi, arilkarboniloksi, cikloalkeniloksi, heterociklilkarboniloksi, alkilideneamino-oksi, karboksi, alkoksikarbonila, ariloksikarbonila, cikloalkiloksikarbonila, heterocikliloksikarbonila, amino, ureido, alkilamino, dialkilamino, arilamino, diarilamino, heterociklilamino, formilamino, alkilkarbonilamino, arilkarbonilamino, heterociklilkarbonilamino, aminokarbonila, alkilaminokarbonil, dialkilaminokarbonil, arilaminokarbonil, heterociklilaminokarbonil, alkoksikarbonilamino, hidroksiaminokarbonil alkoksiimino, alkilsulfonilamino, arilsulfonilamino, heterociklilsulfonilamino, formila, alkilkarbonila, arilkarbonila, cikloalkilkarbonila, heterociklilkarbonila, alkilsulfonila, arilsulfonila, aminosulfonila, alkilaminosulfonila, dialkilaminosulfonila, arilaminosulfonila, heterociklilaminosulfonila, ariltio, alkiltio, fosfonata i alkilfosfonata; i farmaceutski prihvatljive soli istog.
2. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je R1 orto-supstituirani aril formule A, B ili C:
[image]
pri čemu je R’4 atom halogena, nitro, cijano, C1-C6 alkil, polfluorinirani alkil, polifluorinirani alkoksi, alkenil, alkinil, hidroksialkil, aril, arilalkil, heterociklil, C3-C7 cikloalkil, hidroksi, alkoksi, ariloksi, heterocikliloksi, metilenedioksi, alkilkarboniloksi, arilkarboniloksi, cikloalkeniloksi, heterociklilkarboniloksi, alkilidenaminooksi, karboksi, alkoksikarbonil, ariloksikarbonil, cikloalkiloksikarbonil, heterocikliloksikarbonil, amino, ureido, alkilamino, dialkilamino, arilamino, diarilamino, heterocikliamino, formilamino, alkilkarbonilamino, arilkarbonilamino, heterociklilkarbonilamino, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, arilaminokarbonil, heterociklilaminokarbonil, alkoksikarbonilamino, hidroksiaminokarbonil, alkoksiimino, alkilsulfonilamino, arilsulfonilamino, heterociklilsulfonilamino, formil, alkilkarbonil, arilkarbonil, cikloalkilkarbonil, heterociklilkarbonil,alkilsulfonil, arilsulfonil, aminosulfonil, alkilaminosulfonil, dialkilaminosulfonil, arilaminosulfonil, heterociklilaminosulfonil, ariltio, alkiltio, fosfonat ili alkilfosfonat;
R"4 i R"’4 su neovisno vodik ili jedno od gore navedenih značenja za R’4; i farmaceutski prihvatljiva sol istog.
3. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da ima formulu (Ia):
[image]
pri čemu su R’4, R"4 i R"’4 definirani u patentnom zahtjevu 2;
R2 je po izboru supstituirana ravna ili razgranana C1-C6 alkilna ili C2-C6 alkenilna skupina;
R3 je po izboru supstituirana arilna skupina;
R4 je atom vodika ili C1-C6 alkilna skupina koja po izboru može činiti prsten zajedno s jednim od atoma skupine koji R3 predstavlja, tako da tvore spojenu C4-C7 cikličku skupinu i
R5 i R6 u kako je definirano u patentnom zahtjevu 1 ili farmaceutski prihvatljiva sol istog.
4. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da ima formulu (Ia’):
[image]
pri čemu su R’4, R"4 i R"’4 definirani u patentnom zahtjevu 2;
R2 je po izboru supstituirana ravna ili razgranana C1-C6 alkilna ili C2-C6 alkenilna skupina;
R3 je definiran u patentnom zahtjevu 1;
R4 je atom vodika ili C1-C6 alkilna skupina koja po izboru može činiti prsten zajedno s jednim od atoma skupine
koji R3 predstavlja tako da tvore spojenu C4-C7 cikličku skupinu i
R5 i R6 su atom vodika ili metilna skupina ili farmaceutski prihvatljiva sol istog.
5. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je R1 heterociklil ili C5-C7 cikloalkilna skupina formule D:
[image]
pri čemu je Z ugljikov ili dušikov atom, n is 1, 2 or 3; R’1 je atom vodika, C1-C6 alkil, polifluorinirani alkil, polifluorinirani alkoksi, alkenil, alkinil, hidroksialkil, aril, arilalkil, heterociklil, C3-C7 cikloalkil, hidroksi, alkoksi, ariloksi, heterocikliloksi, metilenedioksi, alkilkarboniloksi, arilkarboniloksi, cikloalkeniloksi, heterociklilkarboniloksi, alkilideneaminooksi, karboksi, alkoksikarbonil, ariloksikarbonil, cikloalkiloksikarbonil, heterocikliloksikarbonil, amino, ureido, alkilamino, dialkilamino, arilamino, diarilamino, heterocikliamino, formilamino, alkilkarbonilamino, arilkarbonilamino, heterociklilkarbonilamino, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, arilaminokarbonil, heterociklilaminokarbonil, alkoksikarbonilamino, hidroksiaminokarbonil, alkoksiimino,alkilsulfonilamino, arilsulfonilamino, heterociklilsulfonilamino, formil, alkilkarbonil, arilkarbonil, cikloalkilkarbonil, heterociklilkarbonil, alkilsulfonil, arilsulfonil, aminosulfonil, alkilaminosulfonil, dialkilaminosulfonil, arilaminosulfonil, heterociklilaminosulfonil, ariltio, alkiltio, fosfonat i alkilfosfonat; a R’2 i R’3 su svaki neovisno atom vodika ili C1-C3 alkil po izboru čine prsten zajedno s atomom ugljika za kojeg su vezani tako da tvore ciklopropilnu skupinu.
6. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da ima formulu (Ib):
[image]
pri čemu je Z ugljikov ili dušikov atom, n je 1 ili 2; R’1 je definiran u patentnom zahtjevu 5 i R’2 i R’3 su neovisno atom vodika ili C1-C2 alkilna skupina;
R2 je po izboru supstituirana ravna ili razgranana C1-C6 alkilna ili C2-C6 alkenilna skupina;
R3 je po izboru supstituirana arilna skupina;
R4 je vodikov atom ili C1-C6 alkilna skupina koja može po izboru činiti prsten zajedno s jednim od atoma arilne
skupine koji R3 predstavlja tako da tvori spojenu C4-C7 cikličku skupinu i
R5 i R6 su kako je definirano u patentnom zahtjevu 1 ili farmaceutski prihvatljiva sol istog.
7. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da ima formulu (Ib’):
[image]
pri čemu je Z ugljikov ili dušikov atom, n je 1ili 2, R’1 je kako definirano u patentnom zahtjevu 5, R’2 i R’3 su neovisno atom vodika ili C1-C2 alkilna skupina;
R2 je po izboru susptituirani ravni ili razgranani C1-C6 alkilna ili C2-C6 alkenilna skupina;
R3 je po izboru supstituirana arilna skupina;
R4 je atom vodika ili C1-C6 alkilna skupina koja po izboru može činiti prsten zajedno s jednim od atoma arilne skupine koji R3 predstavlja tako da tvori spojenu C4-C7 cikličku skupinu i R5 i R6 su atom vodika ili metilna skupina ili farmaceutski prihvatljiva sol istog.
8. Spoj formule (I) u skladu s patentnim zahtjevom 1 ili farmaceutski prihvatljiva sol istog, naznačen time, da je jedan od spojeva naveden u sljedećem popisu:
1) N-(2,6-dietilfenil)-1-metil-8-({4-[(1-metilpiperidin-4-il)karbamoil]-2-(trifluorometoksi)fenil}amino)-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
2) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(1-metilpiperidin-4-il)karbamoil]fenil}amino)-1-metil-4,5-dihidro-1H- pirazolo [4,3 -h]kinazolin-3 -karboksamid;
3) N-(2,6-dietilfenil)-1-metil-8-{[4-(4-metilpiperazin-1-il)-2-(trifluorometoksi)fenil]amino}-4,5-dihidro-1H- pirazolo [4,3 -h]kinazolin-3 -karboksamid;
4) 8-[(4-karbamoil-2-metilfenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
5) N-(2,6-dietilfenil)-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3 -karboksamid;
6) 8-[(4-bromo-2-metoksifenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
7) N-(2,6-dietilfenil)-8-[(4-{[3-(dimetilamino)propil](metil)amino}-2-metoksifenil)amino]-1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
8) N-(2,6-dietilfenil)-8-({4-[4-(dimetilamino)piperidin-1-il]-2-metoksifenil}amino)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
9) N-(2,6-dietilfenil)-8-{[2-metoksi-4-(4-metil-1,4-diazepan-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
10) terc-butil-4-({3-[(2,6-dietilfenil)karbamoil]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8-il}amino)-3- metoksibenzoat;
11) 4-({3-[(2,6-dietilfenil)karbamoil]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8-il}amino)-3-metoksibenzojeva kiselina;
12) N-(2,6-dietilfenil)-8-[(4-{[2-(dimetilamino)etil](metil)amino}-2-metoksifenil)amino]-1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
13) 8-[(4-karbamoil-2-metoksifenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
14) N-(2,6-dietilfenil)-8-[(4-{[2-(dimetilamino)etil]karbamoil}-2-metoksifenil)amino]-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
15) 1-metil-8-({4-[(1-metilpiperidin-4-il)karbamoil]-2-(trifluorometoksi)fenil}amino)-N-fenil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
16) N-(2-etilfenil)-1-metil-8-({4-[(1-metilpiperidin-4-il)karbamoil]-2-(trifluorometoksi)fenil}amino)-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
17) N-(2,6-dietilfenil)-8-[(2-metoksi-4-nitrofenil)amino]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
18) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(2-metoksietil)karbamoil]fenil}amino)-18) 1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
19) N-(2,6-dietilfenil)-8-[(4-{[4-(dimetilamino)piperidin-1-il]karbonil}-2-metoksifenil)amino]-1-metil-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
20) N-(2,6-dietilfenil)-8- [(2-metoksi-4- {[(2S)-2-(pirolidin- 1-ilmetil)pirolidin-1-il]karbonil}fenil)amino]-1 -metil-
4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
21) N-(2,6-dietilfenil)-8- [(2-metoksi-4- {[(2R)-2-(pirolidin-1-ilmetil)pirolidin-1 -il]karbonil}fenil)amino]-1-metil-
4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
22) N-(2-etilfenil)-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
23) N-(2,3-dihidro-1H-inden-5-il)-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
24) 8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-N-(5,6,7,8-tetrahidronaftalen-1-il)-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
25) 3-(2,3-dihidro-1H-indol-1-ilkarbonil)-N-[2-metoksi-4-(4-metilpiperazin-1-il)fenil]-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-8-amin;
26) N-(2,6-dimetilfenil)-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
27) N-(2-etil-6-metilfenil)-8- {[2-metoksi-4-(4-metilpiperazin- 1-il)fenil]amino}- 1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
28) 8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-N-(2-metoksifenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
29) N- 1,3-benzotiazol-5-il-8- {[2-metoksi-4-(4-metilpiperazin- 1-il)fenil]amino}- 1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
30) N-(2-kloro-6-metilfenil)-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
31) N-[2,6-bis(1-metiletil)fenil]-8-{[2-metoksi-4-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
32) N-(2,6-dietilfenil)-8-({4- [(2-hidroksietil)karbamoil]-2-metoksifenil }amino)- 1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
33) 8-{[2-cijano-4-(4-metilpiperazin-1-il)fenil]amino}-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
34) 8- {[2-cij ano-4-(4-metil- 1,4-diazepan-1 -il)fenil]amino}-N-(2,6-dietilfenil)- 1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
35) 8-[(2-klorofenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
36) 8-[(4-bromo-2-cijanofenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3h]kinazolin-3- karboksamid;
37) 8-[(2-bromofenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
38) N-(2,6-dietilfenil)-8-[(2-metoksifenil)amino]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
39) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(3-pirolidin-1-ilazetidin-1-il)karbonil]fenil}amino)-1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
40) N-(2,6-dietilfenil)-8-{[2-metoksi-4-(3-pirolidin-1-ilazetidin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
41) N-(2,6-dimetilfenil)-8- {[2-metoksi-4-(4-metilpiperazin-1 -il)fenil]amino}- 1,5,5-trimetil-4,5-dihidro- 1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
42) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(4-metil- 1,4-diazepan-1 -il)karbonil]fenil }amino)- 1-metil-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
43) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(2-metoksietil)amino]fenil}amino)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
44) 8-[(4-bromo-2-metoksifenil)amino]-N-(2,6-dimetilfenil)-1,5,5-trimetil-4,5-dihidro-1H- pirazolo[4,3h]kinazolin-3-karboksamid;
45) N-(2,6-dietilfenil)-8-[(2-jodofenil)amino]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
46) N-(2,6-dietilfenil)-8-({4- [(3S)-3-(dimetilamino)pirolidin-1 -il]-2-metoksifenil }amino)- 1-metil-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
47) N-(2,6-dietilfenil)-8-({4- [(3R)-3-(dimetilamino)pirolidin-1 -il]-2-metoksifenil }amino)-1-metil-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
48) 8-[(5-bromo-2-metoksifenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
49) N-(2,6-dietilfenil)-8-{[2-metoksi-5-(4-metilpiperazin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
50) N-(2,6-dietilfenil)-8-({4- [4-(2-hidroksietil)piperazin- 1-il]-2-metoksifenil}amino)-1 -metil-4,5-dihidro- 1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
51) N-(2,6-dietilfenil)-8- [(4- {[2-(dimetilamino)etil]amino}-2-metoksifenil)amino]-1 -metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
52) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(4-metilpiperazin-1-il)karbonil]fenil}amino)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
53) terc-butil-4-({3-[(2,6-dietilfenil)karbamoil]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8-il }amino)piperidin-1 -karboksilat;
54) N-(2,6-dietilfenil)-1-metil-8-(piperidin-4-ilamino)-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid, hidroklorid;
55) N-(2,6-dietilfenil)-8-{[1-(etenilsulfonil)piperidin-4-il]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3h]kinazolin- 3-karboksamid;
56) N-(2,6-dietilfenil)-1-metil-8-[(1-{[2-(metilamino)etil]sulfonil}piperidin-4-il)amino]-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
57) N-(2,6-dietilfenil)-1-metil-8-{[1-(metilsulfonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin- 3-karboksamid;
58) 8-[(1-acetilpiperidin-4-il)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
59) N-(2,6-dietilfenil)-1-metil-8-{[1-(fenilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin- 3-karboksamid;
60) N-(2,6-dietilfenil)-1-metil-8-({1-[(1-metilpiperidin-4-il)karbonil]piperidin-4-il}amino)-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
61) N-(2,6-dietilfenil)-1-metil-8-({1-[(4-metilpiperazin-1-il)karbonil]piperidin-4-il}amino)-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
62) N-(2,6-dietilfenil)-1-metil-8-{[1-(fenilsulfonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
63) 8-[(1-akriloilpiperidin-4-il)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
64) 8-[(1-benzilpiperidin-4-il)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
65) 8-({1-[(3-kloropropil)sulfonil]piperidin-4-il}amino)-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
66) N-(2,6-dietilfenil)-1-metil-8-{[1-(N-metil-beta-alanil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
67) N-(2,6-dietilfenil)-8-{[1-(N,N-dimetil-beta-alanil)piperidin-4-il]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
68) N-(2,6-dietilfenil)-8-[(1-etilpiperidin-4-il)amino]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3 karboksamid;
69) N-(2,6-dietilfenil)-1-metil-8-[(1-{[3-(metilamino)propil]sulfonil}piperidin-4-il)amino]-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid, hidroklorid;
70) N-(2,6-dietilfenil)-1-metil-8-[(1-{[2-(4-metilpiperazin-1-il)etil]sulfonil}piperidin-4-il)amino]-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
71) N-(2,6-dietilfenil)-8- [(1-{[2-(dimetilamino)etil]sulfonil }piperidin-4-il)amino]-1 -metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
72) N-(2,6-dietilfenil)-1-metil-8-({1-[(2-piperidin-1-iletil)sulfonil]piperidin-4-il}amino)-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
73) N-(2,6-dietilfenil)-1-metil-8-({1-[(2-morfolin-4-iletil)sulfonil]piperidin-4-il}amino)-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
74) N-(2,6-dietilfenil)-1-metil-8-({ 1-[(2-pirolidin-1 -iletil)sulfonil]piperidin-4-il }amino)-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
75) 8-({1-[(2-aminoetil)sulfonil]piperidin-4-il}amino)-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
76) N-(2,6-dietilfenil)-8-{[2-metoksi-4(4-pirolidin-1-ilpiperidin-1-il)fenil]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
77) N-(2,6-dietilfenil)-8-{[2-metoksi-4-(tetrahidro-2H-piran-4-ilamino)fenil]amino}-1-metil -4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
78) terc-butil4-({3-[(2,6-dietilfenil)karbamoil]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8-il}amino)-3- metil-benzoat;
79) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(1 -metilpiperidin-4-il)amino]fenil }amino)- 1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
80) 8-({ 1-[(3-klorometil)sulfonil]piperidin-4-il}amino)-N-(2,6-dietilfenil)-1 -metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
81) 8- [(4-amino-2-metoksifenil)amino]-N-(2,6-dietilfenil)-1 -metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
82) N-(2,6-dietilfenil)-8-[(2-metoksi-4-{[(1-metilpiperidin-4-il)karbonil]amino}fenil)amino]-1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
83) 4-({3-[(2,6-dietilfenil)karbamoil]-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8-il}amino)-3- metilbenzojeva kiselina;
84) N-(2,6-dietilfenil)-8-[(4-{[4-(dimetilamino)piperidin-1-il]karbonil}-2-metilfenil)amino]-1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
85) N-(2,6-dietilfenil)-8-[(4-{[2-(dimetilamino)etil]karbamoil}-2-metilfenil)amino]-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
86) N-(2,6-dietilfenil)-8-[(4-{[4-(dimetilamino)butanoil]amino}-2-metoksifenil)amino]-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid trifluoroacetat;
87) 8-[(4-bromo-2-klorofenil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
88) 8-{[2-kloro-4-(4-metilpiperazin-1 -il)fenil]amino} -N-(2,6-dietilfenil)-1 -metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
89) N-(2,6-dietilfenil)-1-metil-8-[(2-metil-4-{[(2R)-2-(pirolidin-1-ilmetil)pirolidin-1-il]karbonil}fenil)amino]-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
90) 8- [(2-kloro-4- {[3-(dimetilamino)propil](metil)amino}fenil)amino]-N-(2,6-dietilfenil)- 1-metil-4.5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
91) N-(2,6-dietilfenil)-1-metil-8-({2-metil-4-[(4-metil- 1,4-diazepan-1 -il)karbonil]fenil }amino)-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
92) 8-({2-kloro-4-[4-(dimetilamino)piperidin-1-il]fenil}amino)-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
93) N-(2,6-dietilfenil)-8-({4-[(4-hidroksicikloheksil)amino]-2-metoksifenil}amino)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
94) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(3-piperidin-1-ilpropanoil)amino]fenil}amino)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
95) N-(2,6-dietilfenil)-1-metil-8-({2-metil-4-[(4-pirolidin-1 -ilpiperidin-1 -il)karbonil]fenil }amino)-4,5-dihidro- 1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
96) 8-{[4-(1-azabiciklo[2.2.2]okt-3-ilamino)-2-metoksifenil]amino}-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
97) 8-{[4-({[terc-butil(dimetil)silil]oksi}metil)-2-metoksifenil]amino}-N-(2,6-dietilfenil)-1-metil-4,5- dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
98) N-(2,6-dietilfenil)-8-{[4-(hidroksimetil)-2-metoksifenil]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3h]kinazolin-3-karboksamid;
99) N-(2,6-dietilfenil)-8-({2-metoksi-4-[(4-metilpiperazin-1-il)metil]fenil}amino)-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
100) terc-butil4-({3-[(2,6-dietilfenil)karbamoil]-1 -metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-8- il}amino)-3,3-dimetilpiperidin-1-karboksilat;
101) N-(2,6-dietilfenil)-8- [(3,3-dimetil-1- {[2-(metilamino)etil] sulfonil}piperidin-4-il)amino]-1-metil-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
102) N-(2,6-dietilfenil)- 1-metil-8-({ 1-[(2,2,2-trifluoroetil)sulfonil]piperidin-4-il}amino)-4,5-dihidro 1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
103) N-(2,6-dietilfenil)- 1-metil-8-({ 1-[(trifluorometil)sulfonil]piperidin-4-il }amino)-4,5-dihidro- 1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
104) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(1H-pirazol-4-ilsulfonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
105) N-(2,6-dietilfenil)-8-{[1-(1H-imidazol-4-ilsulfonil)piperidin-4-il]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
106) N-(2,6-dietilfenil)- 1-metil-8-({ 1-[(4-metil-3,4-dihidro-2H- 1,4-benzoksazin-7-il)sulfonil]piperidin-4- il}amino)-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
107) N-(2,6-dietilfenil)-8-{[1-(dimetilsulfamoil)piperidin-4-il]amino}-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
108) N-(2,6-dietilfenil)-1-metil-8-({1-[(1-metil-1H-imidazol-4-il)sulfonil]piperidin-4-il}amino)-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
109) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(piridin-3-ilsulfonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
110) 8-[(1-{[4-(acetilamino)fenil]sulfonil}piperidin-4-il)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
111) 8-({1-[(4-aminofenil)sulfonil]piperidin-4-il}amino)-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid hidroklorid;
112) N-(2,6-dietilfenil)-8-({1-[(2-hidroksietil)sulfonil]piperidin-4-il}amino)-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
113) N-(2,6-dietilfenil)-8-({ 1-[(2-metoksietil)sulfonil]piperidin-4-il }amino)- 1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
114) 8-[(trans-4-aminocikloheksil)amino]-N-(2,6-dietilfenil)-1-metil-4,5-dihidro-1H-pirazolo[4,3-h]kinazolin-3- karboksamid;
115) N-(2,6-dietilfenil)-8-[(1-{[2-(etilamino)etil]sulfonil}piperidin-4-il)amino]-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
116) N-(2,6-dietilfenil)-1-metil-8-({1-[(5-metilisoksazol-4-il)karbonil]piperidin-4-il}amino)-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid;
117) N-(2,6-dietilfenil)- 1-metil-8-({ 1-[(1-metil-1H-imidazol-4-il)karbonil]piperidin-4-il} amino)-4,5-dihidro-1 H- pirazolo[4,3-h]kinazolin-3-karboksamid;
118) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(pirimidin-4-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
119) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(1H-pirol-2-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro- 1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
120) N-(2,6-dietilfenil)-8-{[1-(1H-imidazol-4-ilkarbonil)piperidin-4-il]amino}-1-metil-4,5-dihidro-1H- pirazolo[4,3-h]kinazolin-3-karboksamid;
121) N-(2,6-dietilfenil)-1-metil-8-{[1-(piridin-3-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
122) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(piridin-2-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
123) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(1H-pirazol-4-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
124) N-(2,6-dietilfenil)-1-metil-8-{[1-(tiofen-3-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
125) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(piridin-4-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
126) N-(2,6-dietilfenil)- 1-metil-8- {[ 1 -(1H-pirol-3-ilkarbonil)piperidin-4-il]amino}-4,5-dihidro- 1H-pirazolo[4,3- h]kinazolin-3-karboksamid;
127) N-(2,6-dietilfenil)- 1-metil-8- {[trans-4-({ [2-(metilamino)etil] sulfonil}amino)cikloheksil]amino}-4,5-dihidro- 1H-pirazolo[4,3-h]kinazolin-3-karboksamid i
128) N-(2,6-dietilfenil)-8-[(4-formil-2-metoksifenil)amino]-1-metil-4,5-dihidro-1H-pirazolo[4,3- h]kinazolin-3-karboksamid.
9. Farmaceutski pripravak, naznačen time, da kao djelatni sastojak sadrži, spoj formule (I) ili farmaceutski prihvatljivu sol istog, kako je definirano u bilo kojem od patentnih zahtjeva 1 do 8, u primjesi s prihvatljivim razblaživačem ili nosačem.
10. Spoj formule (I) ili farmaceutski prihvatljiva sol istog, kako je definiran u bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da je za terapijsku uporabu.
11. Spoj formule (I) ili farmaceutski prihvatljiva sol istog, kako je definirano u bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da je za liječenje bolesti uzrokovanih i/ili povezanih s izmijenjenom aktivnosti protein kinaze.
12. Spoj formule (I) u skladu s patentnim zahtjevom 11, naznačen time, da je izmijenjena aktivnost protein kinaze MPS-1.
13. Spoj formule (I) u skladu s patentnim zahtjevom 11 ili 12, naznačen time, da je bolest koja je uzrokovana i/ili povezana s izmijenjenom aktivnosti protein kinaze karcinom ili poremećaj stanične proliferacije.
14. Spoj formule (I) u skladu s patentnim zahtjevom 13, naznačen time, da je karicinom odabran od karcinoma mjehura, dojki, debelog crijeva, bubrega, jetara, pluća, uključujući karicom malih plućnih stanica, jednjaka, žučnog mjehura, jajnika, gušterače, želuca, vrata maternice, tiroidne žlijezde, prostate i kože, uključujući karcinom skvamoznih stanica; hematopoetske tumore limfoidne linije uključujući leukemiju, akutnu limfocitnu leukemiju, akutnu leukemiju limfoblasta, limfom B-stanica, limfom T-stanica, Hodgkinov limfom, ne-Hodgkinov limfom, limfom vlasastih stanica i Burkettov limfom; hematopoetske tumore mijeloidne linije, uključujući akutne i kronične mijelogene leukemije, mijelodisplastični sindrom i promijelocitnu leukemiju; tumore mezenhimalnog podrijetla, uključujući fibrosarkom i rabdomiosarkom; tumore središnjeg i perifernog živčanog sustava,
uključujući astrocitom, neuroblastom, gliom i schwannom; druge tumore, uključujući melanom, seminom, teratokarcinom, osteosarkom, xeseroderma pigmentosum, keratoksantom, folikularni karcinom štitnjače i Kaposijev sarkom, mezotelija, visoko aneuploidne tumore i tumore koji rade prekomjernu ekspresiju komponenti mitotičkih kontrolnih točaka kao što su MPS1, MAD2, MAD1, BUB1, BUBR1, BUB3 i drugi.
15. In vitro postupak za inhibiciju aktivnosti protein kinase, naznačen time, da se sastoji od dolaska u kontakt kinaze s učinkovitom količinom spoja formule (I) koji spoj je definiran u patentnom zahtjevu 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08159114 | 2008-06-26 | ||
| PCT/EP2009/057512 WO2009156315A1 (en) | 2008-06-26 | 2009-06-17 | Pyrazolo-quinazolines |
| EP09769164.6A EP2303891B1 (en) | 2008-06-26 | 2009-06-17 | Pyrazolo-quinazolines as protein kinase activity modulators |
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| HRP20160243T1 true HRP20160243T1 (hr) | 2016-04-08 |
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| HRP20160243TT HRP20160243T1 (hr) | 2008-06-26 | 2016-03-08 | Pirazolo-kinazolini kao modulatori aktivnosti protein kinaze |
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| Country | Link |
|---|---|
| US (1) | US8846701B2 (hr) |
| EP (1) | EP2303891B1 (hr) |
| JP (1) | JP5542133B2 (hr) |
| CN (1) | CN102076689B (hr) |
| AR (2) | AR072374A1 (hr) |
| AU (1) | AU2009264431B2 (hr) |
| BR (1) | BRPI0914649B1 (hr) |
| CA (1) | CA2729436C (hr) |
| CL (1) | CL2010001538A1 (hr) |
| CY (1) | CY1117595T1 (hr) |
| DK (1) | DK2303891T3 (hr) |
| EA (1) | EA020703B9 (hr) |
| ES (1) | ES2572360T3 (hr) |
| HK (1) | HK1154383A1 (hr) |
| HR (1) | HRP20160243T1 (hr) |
| HU (1) | HUE027527T2 (hr) |
| MX (1) | MX2010013843A (hr) |
| PL (1) | PL2303891T3 (hr) |
| SI (1) | SI2303891T1 (hr) |
| TW (1) | TWI464172B (hr) |
| WO (1) | WO2009156315A1 (hr) |
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| US8598172B2 (en) * | 2007-12-04 | 2013-12-03 | Nerviano Medical Sciences S.R.L. | Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors |
| WO2010108921A1 (en) | 2009-03-27 | 2010-09-30 | Nerviano Medical Sciences S.R.L. | N-aryl-2-(2-arylaminopyrimidin-4-yl)pyrrol-4-carboxamide derivatives as mps1 kinase inhibitors |
| JP5997143B2 (ja) * | 2010-07-30 | 2016-09-28 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | タンパク質キナーゼ活性の調整剤としてのイソオキサゾロ−キナゾリン |
| UA113280C2 (xx) | 2010-11-11 | 2017-01-10 | АМІНОСПИРТЗАМІЩЕНІ ПОХІДНІ 2,3-ДИГІДРОІМІДАЗО$1,2-c]ХІНАЗОЛІНУ, ПРИДАТНІ ДЛЯ ЛІКУВАННЯ ГІПЕРПРОЛІФЕРАТИВНИХ ПОРУШЕНЬ І ЗАХВОРЮВАНЬ, ПОВ'ЯЗАНИХ З АНГІОГЕНЕЗОМ | |
| CN103370322B (zh) * | 2010-12-17 | 2016-02-10 | 拜耳知识产权有限责任公司 | 在过度增殖性病症的治疗中用作mps-1和tkk抑制剂的2-取代的咪唑并吡嗪 |
| RU2652638C2 (ru) * | 2010-12-17 | 2018-04-28 | НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. | Замещенные пиразолхиназолиновые производные в качестве ингибиторов киназы |
| PL2666016T3 (pl) * | 2011-01-21 | 2017-07-31 | Basilea Pharmaceutica Ag | Zastosowanie BUBR1 jako biomarkera odpowiedzi lekowej |
| JP5925808B2 (ja) * | 2011-01-26 | 2016-05-25 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | 三環式誘導体、これらの調製方法およびこれらのキナーゼ阻害剤としての使用 |
| EP2668190B1 (en) | 2011-01-26 | 2016-08-17 | Nerviano Medical Sciences S.r.l. | Tricyclic pyrrolo derivatives, process for their preparation and their use as kinase inhibitors |
| US9284298B2 (en) | 2011-04-11 | 2016-03-15 | Nerviano Medical Sciences S.R.L. | Pyrazolyl-pyrimidine derivatives as kinase inhibitors |
| US20150087628A1 (en) * | 2012-04-10 | 2015-03-26 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| WO2014020041A1 (en) | 2012-08-02 | 2014-02-06 | Bayer Pharma Aktiengesellschaft | Combinations for the treatment of cancer |
| WO2014020043A1 (en) | 2012-08-02 | 2014-02-06 | Bayer Pharma Aktiengesellschaft | Combinations for the treatment of cancer |
| CN103130810B (zh) * | 2013-03-11 | 2015-02-25 | 河南师范大学 | 一种吡唑并[1,5-c]喹唑啉类化合物的合成方法 |
| US9856258B2 (en) | 2014-04-07 | 2018-01-02 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-E]indolizines |
| KR20180011089A (ko) | 2015-04-17 | 2018-01-31 | 네덜런즈 트랜슬레이셔널 리서치 센터 비.브이. | Ttk 억제제 화학요법을 위한 예후 바이오마커 |
| UY37778A (es) | 2017-06-29 | 2019-01-31 | Servier Lab | NUEVA SAL DE N-(2,6-DIETILFENIL)-8-({4-[4-(DIMETILAMINO)PIPERIDIN-1-IL]-2- METOXIFENIL}AMINO)-1-METIL-4,5-DIHIDRO- 1H-PIRAZOLO[4,3-h]QUINAZOLINA-3- CARBOXAMIDA, SU PREPARACIÓN, Y LAS FORMULACIONES QUE LA CONTIENEN |
| AR112217A1 (es) | 2017-06-30 | 2019-10-02 | Servier Lab | Una combinación de un inhibidor de mps1 y un compuesto taxano, usos y composiciones farmacéuticas de ésta |
| EP3652177A1 (en) * | 2017-07-11 | 2020-05-20 | Nerviano Medical Sciences S.r.l. | Pyrazolo-quinazoline derivatives as choline kinase inhibitors |
| JP7233743B2 (ja) * | 2017-08-11 | 2023-03-07 | 晟科薬業（江蘇）有限公司 | プロテインキナーゼ阻害剤としての１ｈ－ピラゾロ［４，３－ｈ］キナゾリン系化合物 |
| CN115485272A (zh) * | 2020-03-27 | 2022-12-16 | 朗多生物制药股份有限公司 | Plxdc2配体 |
| WO2022111634A1 (zh) * | 2020-11-26 | 2022-06-02 | 成都赛璟生物医药科技有限公司 | 杂芳基并喹唑啉类化合物作为蛋白激酶抑制剂 |
| CN114685520A (zh) * | 2020-12-25 | 2022-07-01 | 武汉誉祥医药科技有限公司 | 三并环化合物及其药物组合物和应用 |
| WO2022143576A1 (zh) * | 2020-12-31 | 2022-07-07 | 恒元生物医药科技(苏州)有限公司 | 一种吡唑并喹唑啉类化合物、其制备方法及应用 |
| WO2023113478A1 (en) * | 2021-12-15 | 2023-06-22 | Sillajen, Inc. | Methods of treating neoplastic diseases |
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| JP2005526730A (ja) * | 2002-02-19 | 2005-09-08 | ファルマシア・コーポレーション | 炎症の治療のための三環系ピラゾール誘導体 |
| RS20050944A (en) | 2003-05-22 | 2008-06-05 | Nerviano Medical Sciences S.R.L., | Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
| SG177911A1 (en) * | 2006-12-21 | 2012-02-28 | Nerviano Medical Sciences Srl | Substituted pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
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| Publication number | Publication date |
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| JP2011525516A (ja) | 2011-09-22 |
| CN102076689B (zh) | 2014-10-15 |
| CY1117595T1 (el) | 2017-04-26 |
| AU2009264431B2 (en) | 2013-11-07 |
| CA2729436C (en) | 2016-08-09 |
| AR072374A1 (es) | 2010-08-25 |
| EA020703B1 (ru) | 2015-01-30 |
| DK2303891T3 (en) | 2016-05-30 |
| CL2010001538A1 (es) | 2012-02-03 |
| CA2729436A1 (en) | 2009-12-30 |
| EP2303891A1 (en) | 2011-04-06 |
| CN102076689A (zh) | 2011-05-25 |
| SI2303891T1 (sl) | 2016-06-30 |
| EP2303891B1 (en) | 2016-02-17 |
| PL2303891T3 (pl) | 2016-08-31 |
| MX2010013843A (es) | 2011-01-21 |
| WO2009156315A1 (en) | 2009-12-30 |
| ES2572360T3 (es) | 2016-05-31 |
| JP5542133B2 (ja) | 2014-07-09 |
| US8846701B2 (en) | 2014-09-30 |
| EA201170090A1 (ru) | 2011-08-30 |
| AR113818A2 (es) | 2020-06-17 |
| TW201004960A (en) | 2010-02-01 |
| US20110105542A1 (en) | 2011-05-05 |
| BRPI0914649B1 (pt) | 2021-07-06 |
| EA020703B9 (ru) | 2015-12-30 |
| HUE027527T2 (en) | 2016-10-28 |
| TWI464172B (zh) | 2014-12-11 |
| AU2009264431A1 (en) | 2009-12-30 |
| HK1154383A1 (en) | 2012-04-20 |
| BRPI0914649A2 (pt) | 2015-07-07 |
| AU2009264431A2 (en) | 2011-02-17 |
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