ES2716165T3 - (5,6-Dihidro)pirimido[4,5-e]indolizinas - Google Patents

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Publication number

ES2716165T3

ES2716165T3 ES15712912T ES15712912T ES2716165T3 ES 2716165 T3 ES2716165 T3 ES 2716165T3 ES 15712912 T ES15712912 T ES 15712912T ES 15712912 T ES15712912 T ES 15712912T ES 2716165 T3 ES2716165 T3 ES 2716165T3

Authority

ES

Spain

Prior art keywords

indolizine

carboxamide

dihydropyrimido

anilino

methoxy

Prior art date

2014-04-07

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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• CTDDCCKSVYEWOC-UHFFFAOYSA-N N1=CN=CC2=C1N1C=CC=C1C=C2 Chemical class N1=CN=CC2=C1N1C=CC=C1C=C2 CTDDCCKSVYEWOC-UHFFFAOYSA-N 0.000 title description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 552
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 181
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 103
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 57
• 150000003839 salts Chemical class 0.000 claims abstract description 57
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 42
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 41
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 37
• 150000002367 halogens Chemical class 0.000 claims abstract description 35
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 28
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 19
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 18
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 18
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims abstract description 18
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 16
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 15
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 15
• 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 11
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims abstract description 10
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
• 125000003118 aryl group Chemical group 0.000 claims abstract description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
• 239000001257 hydrogen Substances 0.000 claims abstract description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims abstract description 4
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 4
• 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims abstract description 4
• 125000005843 halogen group Chemical group 0.000 claims abstract 2
• -1 piperidinylamino, azetidinylamino, tetrahydropyranylamino Chemical group 0.000 claims description 93
• 206010028980 Neoplasm Diseases 0.000 claims description 28
• 238000011282 treatment Methods 0.000 claims description 20
• URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims description 19
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
• 201000011510 cancer Diseases 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 125000002393 azetidinyl group Chemical group 0.000 claims description 9
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 125000003566 oxetanyl group Chemical group 0.000 claims description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 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 6
• UYPNZGVGCJECJV-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC UYPNZGVGCJECJV-UHFFFAOYSA-N 0.000 claims description 6
• 239000013543 active substance Substances 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 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 6
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
• 206010027476 Metastases Diseases 0.000 claims description 5
• 230000003463 hyperproliferative effect Effects 0.000 claims description 5
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
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• WRYZBCKSXQMHKO-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(oxan-4-ylcarbamoyl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C(NC1CCOCC1)=O)OC WRYZBCKSXQMHKO-UHFFFAOYSA-N 0.000 claims description 3
• XPORPDHLTHKBQR-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(COC)=O)OC XPORPDHLTHKBQR-UHFFFAOYSA-N 0.000 claims description 3
• CMSARXIYXRBTSN-UHFFFAOYSA-N N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)C1=NNC(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC(F)F)CC CMSARXIYXRBTSN-UHFFFAOYSA-N 0.000 claims description 3
• NIFYAXNEECFWPW-UHFFFAOYSA-N N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethylpyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxyanilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)OCCOCCN1N=C(C(=C1CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(CNCC)=O)OC)CC NIFYAXNEECFWPW-UHFFFAOYSA-N 0.000 claims description 3
• RWHBUXPJZMGWIZ-UHFFFAOYSA-N N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethylpyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound COCCOCCOCCN1N=C(C(=C1C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)C=1C(=NN(C=1C)C)C)OC)C RWHBUXPJZMGWIZ-UHFFFAOYSA-N 0.000 claims description 3
• 201000005787 hematologic cancer Diseases 0.000 claims description 3
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
• FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims description 2
• FEPTTWBIJAOREA-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C FEPTTWBIJAOREA-UHFFFAOYSA-N 0.000 claims description 2
• SCNJHTNENAOJON-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC SCNJHTNENAOJON-UHFFFAOYSA-N 0.000 claims description 2
• LNYQMDKVTIRBIZ-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C LNYQMDKVTIRBIZ-UHFFFAOYSA-N 0.000 claims description 2
• SMTVCUWSXLIKHQ-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC SMTVCUWSXLIKHQ-UHFFFAOYSA-N 0.000 claims description 2
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