RU2692479C2 - (5,6-дигидро)пиримидо[4,5-е]индолизины - Google Patents

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Publication number

RU2692479C2

RU2692479C2 RU2016141405A RU2016141405A RU2692479C2 RU 2692479 C2 RU2692479 C2 RU 2692479C2 RU 2016141405 A RU2016141405 A RU 2016141405A RU 2016141405 A RU2016141405 A RU 2016141405A RU 2692479 C2 RU2692479 C2 RU 2692479C2

Authority

RU

Russia

Prior art keywords

carboxamide

dihydropyrimido

anilino

methoxy

indolysin

Prior art date

2014-04-07

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• 150000001875 compounds Chemical class 0.000 claims abstract description 572
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 167
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 90
• 150000003839 salts Chemical class 0.000 claims abstract description 60
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 49
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 48
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 30
• 150000002367 halogens Chemical class 0.000 claims abstract description 30
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
• 125000002393 azetidinyl group Chemical group 0.000 claims abstract description 21
• 230000000694 effects Effects 0.000 claims abstract description 21
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 20
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 20
• 239000011737 fluorine Substances 0.000 claims abstract description 20
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 20
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims abstract description 17
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
• 125000003566 oxetanyl group Chemical group 0.000 claims abstract description 15
• 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 15
• 239000003112 inhibitor Substances 0.000 claims abstract description 13
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 12
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 12
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 12
• 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims abstract description 9
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 9
• 125000001424 substituent group Chemical group 0.000 claims abstract description 9
• 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 8
• 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 7
• 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
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract 12
• QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 claims abstract 4
• AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 claims abstract 4
• URUKMUHHWWCNKS-UHFFFAOYSA-N 2-cyclohexyloxane Chemical compound C1CCCCC1C1OCCCC1 URUKMUHHWWCNKS-UHFFFAOYSA-N 0.000 claims abstract 3
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims abstract 3
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims abstract 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract 3
• -1 amino, piperidinyl Chemical group 0.000 claims description 330
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 123
• 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 63
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
• 150000003857 carboxamides Chemical class 0.000 claims description 30
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
• 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 23
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 238000011282 treatment Methods 0.000 claims description 12
• 201000010099 disease Diseases 0.000 claims description 11
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 9
• FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims description 8
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
• 102000001253 Protein Kinase Human genes 0.000 claims description 6
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 6
• 108060006633 protein kinase Proteins 0.000 claims description 6
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
• 206010027476 Metastases Diseases 0.000 claims description 5
• URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 239000000460 chlorine Substances 0.000 claims description 4
• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 230000001404 mediated effect Effects 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 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
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
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• 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 description 2
• BOBDWLYTHZDBMJ-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)N1CCNCC1)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)N1CCNCC1)C BOBDWLYTHZDBMJ-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• 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 description 2
• 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 description 2
• NPECDAWOXFCMHL-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(COC)=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(COC)=O)OC)CC)CCOCCOC NPECDAWOXFCMHL-UHFFFAOYSA-N 0.000 claims description 2
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• WREYRYCBWFQCSO-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCOCC1)C 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)N1CCOCC1)C WREYRYCBWFQCSO-UHFFFAOYSA-N 0.000 claims description 2
• HHEZIJFTEXKGOB-UHFFFAOYSA-N CN(CCOC1=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 CN(CCOC1=CC(=C(NC=2N=CC3=C(N4C=CC(=C4CC3)C(=O)NC3=C(C=CC=C3C)C)N=2)C=C1)OC)C HHEZIJFTEXKGOB-UHFFFAOYSA-N 0.000 claims description 2
• PTKFYFCCZZHLLA-UHFFFAOYSA-N COCCN1N=C(C(=C1C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(=O)C1CN(C1)C)OC)C Chemical compound COCCN1N=C(C(=C1C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(=O)C1CN(C1)C)OC)C PTKFYFCCZZHLLA-UHFFFAOYSA-N 0.000 claims description 2
• MIFCWQHNAMSTAG-UHFFFAOYSA-N ClC1=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 ClC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)C MIFCWQHNAMSTAG-UHFFFAOYSA-N 0.000 claims description 2
• OOESAPRLEIQOOD-UHFFFAOYSA-N ClC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC Chemical compound ClC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC OOESAPRLEIQOOD-UHFFFAOYSA-N 0.000 claims description 2
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• WXXHRCLKKWMDIL-UHFFFAOYSA-N ClC1=C(C(=CC=C1)Cl)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C Chemical compound ClC1=C(C(=CC=C1)Cl)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C WXXHRCLKKWMDIL-UHFFFAOYSA-N 0.000 claims description 2
• FPIMPJBOKCFYNW-UHFFFAOYSA-N ClC1=C(C(=CC=C1)Cl)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC Chemical compound ClC1=C(C(=CC=C1)Cl)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)OC FPIMPJBOKCFYNW-UHFFFAOYSA-N 0.000 claims description 2
• 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
• 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
• 208000009849 Female Genital 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
• 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 description 2
• 206010029098 Neoplasm skin Diseases 0.000 claims description 2
• 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
• 210000000038 chest Anatomy 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
• 210000003734 kidney Anatomy 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 208000037841 lung tumor Diseases 0.000 claims description 2
• 230000009401 metastasis Effects 0.000 claims description 2
• 201000004477 skin sarcoma Diseases 0.000 claims description 2
• 210000003932 urinary bladder Anatomy 0.000 claims description 2
• 235000019000 fluorine Nutrition 0.000 claims 8
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 3
• 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
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• OKAONXZTHIKEGJ-UHFFFAOYSA-N C(C)C1=NNC(=C1NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C)C)CC 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)C)CC OKAONXZTHIKEGJ-UHFFFAOYSA-N 0.000 claims 1
• NLFIURXIRTXRJC-UHFFFAOYSA-N 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)CC 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)CC NLFIURXIRTXRJC-UHFFFAOYSA-N 0.000 claims 1
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