DK3129374T3 - (5,6-dihydro) pyrimido [4,5-e] INDOLIZINER - Google Patents

Info

Publication number

DK3129374T3

DK3129374T3 DK15712912.3T DK15712912T DK3129374T3 DK 3129374 T3 DK3129374 T3 DK 3129374T3 DK 15712912 T DK15712912 T DK 15712912T DK 3129374 T3 DK3129374 T3 DK 3129374T3

Authority

DK

Denmark

Prior art keywords

carboxamide

indolizine

dihydropyrimido

anilino

alkyl

Prior art date

2014-04-07

Links

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• 150000001875 compounds Chemical class 0.000 claims description 549
• 125000000217 alkyl group Chemical group 0.000 claims description 160
• URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims description 93
• 125000003545 alkoxy group Chemical group 0.000 claims description 91
• -1 homopiperazinyl Chemical group 0.000 claims description 54
• 150000003839 salts Chemical class 0.000 claims description 54
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 49
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
• 229910052736 halogen Inorganic materials 0.000 claims description 32
• 150000002367 halogens Chemical class 0.000 claims description 32
• 206010028980 Neoplasm Diseases 0.000 claims description 31
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 23
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 19
• 201000011510 cancer Diseases 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 15
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 14
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 13
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000004043 oxo group Chemical group O=* 0.000 claims description 12
• 125000003282 alkyl amino group Chemical group 0.000 claims description 9
• 125000002393 azetidinyl group Chemical group 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 8
• 230000005764 inhibitory process Effects 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
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-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
• 206010027476 Metastases Diseases 0.000 claims description 5
• 229910052739 hydrogen Inorganic materials 0.000 claims description 5
• 230000003463 hyperproliferative effect Effects 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 239000001257 hydrogen Substances 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
• 208000026310 Breast neoplasm Diseases 0.000 claims description 3
• 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 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 3
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
• 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
• 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
• 206010025323 Lymphomas Diseases 0.000 claims description 2
• 206010059282 Metastases to central nervous system Diseases 0.000 claims description 2
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
• 206010029098 Neoplasm skin Diseases 0.000 claims description 2
• 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
• 230000033228 biological regulation Effects 0.000 claims description 2
• 210000000481 breast Anatomy 0.000 claims description 2
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 201000011523 endocrine gland cancer Diseases 0.000 claims description 2
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 208000037841 lung tumor Diseases 0.000 claims description 2
• 208000023958 prostate neoplasm Diseases 0.000 claims description 2
• 201000004477 skin sarcoma Diseases 0.000 claims description 2
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 3
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 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 2
• 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 2
• UFIJTGYZCFZMPA-UHFFFAOYSA-N N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethylpyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-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)N1CCN(CC1)C)OC)C UFIJTGYZCFZMPA-UHFFFAOYSA-N 0.000 claims 2
• PXOSVHWTKXCACO-UHFFFAOYSA-N N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound C(C)C1=NN(C(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC)CC)CCOCCOC PXOSVHWTKXCACO-UHFFFAOYSA-N 0.000 claims 2
• 201000005787 hematologic cancer Diseases 0.000 claims 2
• FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims 1
• 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 1
• 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 1
• 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 1
• OMCPUCQWFPVYAJ-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)OCCN(C)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)OCCN(C)C)OC OMCPUCQWFPVYAJ-UHFFFAOYSA-N 0.000 claims 1
• SKOVQURQPGBBNK-UHFFFAOYSA-N BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C Chemical compound BrC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C SKOVQURQPGBBNK-UHFFFAOYSA-N 0.000 claims 1
• LBDJJKHJZVLVBY-UHFFFAOYSA-N C(#N)C1(CCN(CC1)C(=O)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC)C Chemical compound C(#N)C1(CCN(CC1)C(=O)C1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC)C LBDJJKHJZVLVBY-UHFFFAOYSA-N 0.000 claims 1
• KKPQZYIFMSQJBT-UHFFFAOYSA-N C(#N)C1=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 C(#N)C1=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 KKPQZYIFMSQJBT-UHFFFAOYSA-N 0.000 claims 1
• QSHOMXOBJBDIRW-UHFFFAOYSA-N C(C)C1=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 C(C)C1=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 QSHOMXOBJBDIRW-UHFFFAOYSA-N 0.000 claims 1
• VEUSPUITHMWFJG-UHFFFAOYSA-N C(C)C1=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 C(C)C1=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 VEUSPUITHMWFJG-UHFFFAOYSA-N 0.000 claims 1
• WHLBQJTZROBCCV-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=CC=C(C=C1)N1CCN(CC1)C Chemical compound C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=CC=C(C=C1)N1CCN(CC1)C WHLBQJTZROBCCV-UHFFFAOYSA-N 0.000 claims 1
• DPRUUGIKMIGILV-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C Chemical compound C(C)C1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC=1C(=NC(=CC=1)N1CCOCC1)C DPRUUGIKMIGILV-UHFFFAOYSA-N 0.000 claims 1
• NJLCFSBWOBJLEP-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N(C)CCCN(C)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N(C)CCCN(C)C)OC NJLCFSBWOBJLEP-UHFFFAOYSA-N 0.000 claims 1
• ZBODMVDQKFDZCC-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CC(NCC1)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CC(NCC1)C)OC ZBODMVDQKFDZCC-UHFFFAOYSA-N 0.000 claims 1
• OGGAOOUUURDBQI-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C OGGAOOUUURDBQI-UHFFFAOYSA-N 0.000 claims 1
• HGEIUFJVGHMGRR-GKOSEXJESA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC([2H])([2H])[2H] Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC([2H])([2H])[2H] HGEIUFJVGHMGRR-GKOSEXJESA-N 0.000 claims 1
• VLWWXJPSQIIXON-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C VLWWXJPSQIIXON-UHFFFAOYSA-N 0.000 claims 1
• NBHJPPJQLVRDJM-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC NBHJPPJQLVRDJM-UHFFFAOYSA-N 0.000 claims 1
• SVXSPFBVTLNHQK-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCOCC1)C Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCOCC1)C SVXSPFBVTLNHQK-UHFFFAOYSA-N 0.000 claims 1
• KDRZMXUTFUZVIL-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CCN(CC1)C)OC KDRZMXUTFUZVIL-UHFFFAOYSA-N 0.000 claims 1
• AUVSGHNFQBUOTM-UHFFFAOYSA-N C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CN(CC1)C)OC Chemical compound C(C)C1=C(C(=CC=C1)CC)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)OC1CN(CC1)C)OC AUVSGHNFQBUOTM-UHFFFAOYSA-N 0.000 claims 1
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• UCQUZAVNHWQKQH-UHFFFAOYSA-N C(C)C1=NN(C(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(CNCC)=O)OC)CC)CCOCCOC Chemical compound C(C)C1=NN(C(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(CNCC)=O)OC)CC)CCOCCOC UCQUZAVNHWQKQH-UHFFFAOYSA-N 0.000 claims 1
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