MX2007006555A - N-substituted benzimidazolyl c-kit inhibitors and combinatorial benzimidazole library - Google Patents
N-substituted benzimidazolyl c-kit inhibitors and combinatorial benzimidazole libraryInfo
- Publication number
- MX2007006555A MX2007006555A MXMX/A/2007/006555A MX2007006555A MX2007006555A MX 2007006555 A MX2007006555 A MX 2007006555A MX 2007006555 A MX2007006555 A MX 2007006555A MX 2007006555 A MX2007006555 A MX 2007006555A
- Authority
- MX
- Mexico
- Prior art keywords
- benzimidazole
- alkyl
- carboxamide
- piperazine
- methyl
- Prior art date
Links
- -1 N-substituted benzimidazolyl Chemical group 0.000 title claims description 73
- 230000002401 inhibitory effect Effects 0.000 title abstract description 32
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title abstract description 26
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title abstract description 26
- 239000003112 inhibitor Substances 0.000 title abstract description 19
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 153
- 239000011780 sodium chloride Substances 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 62
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000004122 cyclic group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 210000004027 cells Anatomy 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 150000001412 amines Chemical class 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 201000011510 cancer Diseases 0.000 claims description 19
- 125000003107 substituted aryl group Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 11
- 229940113083 morpholine Drugs 0.000 claims description 11
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 claims description 11
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 claims description 10
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 claims description 10
- YZKSXUIOKWQABW-UHFFFAOYSA-N 4-piperazin-1-yl-1H-indole Chemical compound C1CNCCN1C1=CC=CC2=C1C=CN2 YZKSXUIOKWQABW-UHFFFAOYSA-N 0.000 claims description 10
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 125000005418 aryl aryl group Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
- RHXSYTACTOMVLJ-UHFFFAOYSA-N 1H-benzimidazole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=NC2=C1 RHXSYTACTOMVLJ-UHFFFAOYSA-N 0.000 claims description 8
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 claims description 8
- WJGBPNRJJBVFHH-UHFFFAOYSA-N N-methyl-1-(3-phenylphenyl)benzimidazole-5-carboxamide Chemical compound C1=NC2=CC(C(=O)NC)=CC=C2N1C(C=1)=CC=CC=1C1=CC=CC=C1 WJGBPNRJJBVFHH-UHFFFAOYSA-N 0.000 claims description 8
- ZADPBFCGQRWHPN-UHFFFAOYSA-N OBO Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 230000003463 hyperproliferative Effects 0.000 claims description 8
- 201000002674 obstructive nephropathy Diseases 0.000 claims description 8
- 206010024324 Leukaemias Diseases 0.000 claims description 7
- DILRJUIACXKSQE-UHFFFAOYSA-N N',N'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- DIIFZCPZIRQDIJ-UHFFFAOYSA-N (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid Chemical compound CC1=NOC(C)=C1B(O)O DIIFZCPZIRQDIJ-UHFFFAOYSA-N 0.000 claims description 6
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N Isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 6
- QHJABUZHRJTCAR-UHFFFAOYSA-N N'-methylpropane-1,3-diamine Chemical compound CNCCCN QHJABUZHRJTCAR-UHFFFAOYSA-N 0.000 claims description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 claims description 6
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 claims description 6
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 claims description 5
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 claims description 5
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 claims description 5
- YGZJTYCCONJJGZ-UHFFFAOYSA-N (3,5-dimethoxyphenyl)methanamine Chemical compound COC1=CC(CN)=CC(OC)=C1 YGZJTYCCONJJGZ-UHFFFAOYSA-N 0.000 claims description 5
- OJZQOQNSUZLSMV-UHFFFAOYSA-N (3-aminophenyl)methanol Chemical compound NC1=CC=CC(CO)=C1 OJZQOQNSUZLSMV-UHFFFAOYSA-N 0.000 claims description 5
- MXIGALIASISPNU-UHFFFAOYSA-N (3-chloro-4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1Cl MXIGALIASISPNU-UHFFFAOYSA-N 0.000 claims description 5
- KXFXHXPKGLLUGX-UHFFFAOYSA-N (3-fluorophenyl)-piperazin-1-ylmethanone Chemical compound FC1=CC=CC(C(=O)N2CCNCC2)=C1 KXFXHXPKGLLUGX-UHFFFAOYSA-N 0.000 claims description 5
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 claims description 5
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 claims description 5
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 claims description 5
- OITKVXMAEXNRRK-UHFFFAOYSA-N (4-fluorophenyl)-piperazin-1-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)N1CCNCC1 OITKVXMAEXNRRK-UHFFFAOYSA-N 0.000 claims description 5
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 5
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 claims description 5
- WXDWGQCDPGFBEN-UHFFFAOYSA-N (5-chloro-2-methylphenyl)methanamine Chemical compound CC1=CC=C(Cl)C=C1CN WXDWGQCDPGFBEN-UHFFFAOYSA-N 0.000 claims description 5
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 claims description 5
- XZXCBTBAADXWDD-UHFFFAOYSA-N 1-(2,4-dimethoxyphenyl)piperazine Chemical compound COC1=CC(OC)=CC=C1N1CCNCC1 XZXCBTBAADXWDD-UHFFFAOYSA-N 0.000 claims description 5
- TXQLUKMSYDOGDH-UHFFFAOYSA-N 1-(2-ethoxyethyl)piperazine Chemical compound CCOCCN1CCNCC1 TXQLUKMSYDOGDH-UHFFFAOYSA-N 0.000 claims description 5
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims description 5
- NWWINQCALMSSFD-UHFFFAOYSA-N 1-(2-piperidin-1-ylethyl)piperazine Chemical compound C1CCCCN1CCN1CCNCC1 NWWINQCALMSSFD-UHFFFAOYSA-N 0.000 claims description 5
- HJORCZCMNWLHMB-UHFFFAOYSA-N 1-(3-aminopropyl)pyrrolidin-2-one Chemical compound NCCCN1CCCC1=O HJORCZCMNWLHMB-UHFFFAOYSA-N 0.000 claims description 5
- JAXVYOQQRAMPQD-UHFFFAOYSA-N 1-(3-pyrrolidin-1-ylpropyl)piperazine Chemical compound C1CNCCN1CCCN1CCCC1 JAXVYOQQRAMPQD-UHFFFAOYSA-N 0.000 claims description 5
- HUVCCAJUSXXGFE-UHFFFAOYSA-N 1-(3-thiophen-3-ylphenyl)benzimidazole-5-carboxamide Chemical compound C1=NC2=CC(C(=O)N)=CC=C2N1C(C=1)=CC=CC=1C=1C=CSC=1 HUVCCAJUSXXGFE-UHFFFAOYSA-N 0.000 claims description 5
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims description 5
- KPXVKKBJROCIJB-UHFFFAOYSA-N 1-(4-piperazin-1-ylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CCNCC1 KPXVKKBJROCIJB-UHFFFAOYSA-N 0.000 claims description 5
- XZYLSJPLCLKCMR-UHFFFAOYSA-N 1-(pyridin-4-ylmethyl)piperazine Chemical compound C=1C=NC=CC=1CN1CCNCC1 XZYLSJPLCLKCMR-UHFFFAOYSA-N 0.000 claims description 5
- YLBWRMSQRFEIEB-UHFFFAOYSA-N 1-(pyrrolidin-2-ylmethyl)pyrrolidine Chemical compound C1CCCN1CC1CCCN1 YLBWRMSQRFEIEB-UHFFFAOYSA-N 0.000 claims description 5
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-Amino-2-propanol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 claims description 5
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- LISKJKUMLVQGKE-UHFFFAOYSA-N 1-morpholin-4-yl-2-piperazin-1-ylethanone Chemical compound C1COCCN1C(=O)CN1CCNCC1 LISKJKUMLVQGKE-UHFFFAOYSA-N 0.000 claims description 5
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 claims description 5
- OQZBAQXTXNIPRA-UHFFFAOYSA-N 1-pyridin-4-ylpiperazine Chemical compound C1CNCCN1C1=CC=NC=C1 OQZBAQXTXNIPRA-UHFFFAOYSA-N 0.000 claims description 5
- GEQNZVKIDIPGCO-UHFFFAOYSA-N 2,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C(OC)=C1 GEQNZVKIDIPGCO-UHFFFAOYSA-N 0.000 claims description 5
- HNVIQLPOGUDBSU-UHFFFAOYSA-N 2,6-dimethylmorpholine Chemical compound CC1CNCC(C)O1 HNVIQLPOGUDBSU-UHFFFAOYSA-N 0.000 claims description 5
- QXHDYMUPPXAMPQ-UHFFFAOYSA-N 2-(4-aminophenyl)ethanol Chemical compound NC1=CC=C(CCO)C=C1 QXHDYMUPPXAMPQ-UHFFFAOYSA-N 0.000 claims description 5
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 5
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-Pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 claims description 5
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 claims description 5
- FRICBZWJFIRJOB-UHFFFAOYSA-N 2-piperazin-1-ylbenzonitrile Chemical compound N#CC1=CC=CC=C1N1CCNCC1 FRICBZWJFIRJOB-UHFFFAOYSA-N 0.000 claims description 5
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 5
- UORNTHBBLYBAJJ-UHFFFAOYSA-N 2-piperazin-1-ylphenol Chemical compound OC1=CC=CC=C1N1CCNCC1 UORNTHBBLYBAJJ-UHFFFAOYSA-N 0.000 claims description 5
- HCGFLVDMFDHYJD-UHFFFAOYSA-N 2-piperazin-1-ylpyrazine Chemical compound C1CNCCN1C1=CN=CC=N1 HCGFLVDMFDHYJD-UHFFFAOYSA-N 0.000 claims description 5
- PTHDBHDZSMGHKF-UHFFFAOYSA-N 2-piperidin-2-ylethanol Chemical compound OCCC1CCCCN1 PTHDBHDZSMGHKF-UHFFFAOYSA-N 0.000 claims description 5
- NAHHNSMHYCLMON-UHFFFAOYSA-N 2-pyridin-3-ylethanamine Chemical compound NCCC1=CC=CN=C1 NAHHNSMHYCLMON-UHFFFAOYSA-N 0.000 claims description 5
- AXNUZKSSQHTNPZ-UHFFFAOYSA-N 3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1 AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 claims description 5
- IPBNQTRHMAXPRJ-UHFFFAOYSA-N 3-(2-aminoethyl)-1H-imidazol-2-one Chemical compound NCCN1C=CNC1=O IPBNQTRHMAXPRJ-UHFFFAOYSA-N 0.000 claims description 5
- FLROJJGKUKLCAE-UHFFFAOYSA-N 3-amino-2-methylphenol Chemical compound CC1=C(N)C=CC=C1O FLROJJGKUKLCAE-UHFFFAOYSA-N 0.000 claims description 5
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 claims description 5
- LJWAPDSCYTZUJU-UHFFFAOYSA-N 3-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C=C1F LJWAPDSCYTZUJU-UHFFFAOYSA-N 0.000 claims description 5
- MGRHBBRSAFPBIN-UHFFFAOYSA-N 3-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C=C1F MGRHBBRSAFPBIN-UHFFFAOYSA-N 0.000 claims description 5
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 claims description 5
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 claims description 5
- AYGYICRITMSJOC-UHFFFAOYSA-N 3-piperazin-1-ylphenol Chemical compound OC1=CC=CC(N2CCNCC2)=C1 AYGYICRITMSJOC-UHFFFAOYSA-N 0.000 claims description 5
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- 206010009944 Colon cancer Diseases 0.000 claims description 5
- IUNMPGNGSSIWFP-UHFFFAOYSA-N Dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 claims description 5
- VYFOAVADNIHPTR-UHFFFAOYSA-N Isatoic Anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 claims description 5
- NCBZRJODKRCREW-UHFFFAOYSA-N M-Anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 claims description 5
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- HVOYZOQVDYHUPF-UHFFFAOYSA-N N,N',N'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 claims description 5
- ZXQKYQVJDRTTLZ-UHFFFAOYSA-N N,N-diethylpiperidine-3-carboxamide Chemical compound CCN(CC)C(=O)C1CCCNC1 ZXQKYQVJDRTTLZ-UHFFFAOYSA-N 0.000 claims description 5
- JJEMPZXXGBIJIX-UHFFFAOYSA-N N,N-dimethyl-2-piperazin-1-ylacetamide Chemical compound CN(C)C(=O)CN1CCNCC1 JJEMPZXXGBIJIX-UHFFFAOYSA-N 0.000 claims description 5
- LGDNSGSJKBIVFG-UHFFFAOYSA-N N,N-dimethyl-2-piperazin-1-ylethanamine Chemical compound CN(C)CCN1CCNCC1 LGDNSGSJKBIVFG-UHFFFAOYSA-N 0.000 claims description 5
- YJRGRZJKGMBHIB-UHFFFAOYSA-N N,N-dimethyl-3-piperazin-1-ylpropan-1-amine Chemical compound CN(C)CCCN1CCNCC1 YJRGRZJKGMBHIB-UHFFFAOYSA-N 0.000 claims description 5
- GWFPMSIIVJMYRZ-UHFFFAOYSA-N N-(4-amino-2-methylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C=C1C GWFPMSIIVJMYRZ-UHFFFAOYSA-N 0.000 claims description 5
- QFELUFGHFLYZEZ-UHFFFAOYSA-N N-(4-aminophenyl)-N-methylacetamide Chemical compound CC(=O)N(C)C1=CC=C(N)C=C1 QFELUFGHFLYZEZ-UHFFFAOYSA-N 0.000 claims description 5
- BLMLGWLTQVSVKO-UHFFFAOYSA-N N-(pyridin-3-ylmethyl)-1-(3-thiophen-3-ylphenyl)benzimidazole-5-carboxamide Chemical compound C=1C=C2N(C=3C=C(C=CC=3)C3=CSC=C3)C=NC2=CC=1C(=O)NCC1=CC=CN=C1 BLMLGWLTQVSVKO-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
Compounds represented by Formula (I) or a pharmaceutically acceptable saltor N-oxide thereof act as c-kit inhibitors and are useful in the treatment of tumors.Combinatorial libraries composed of compounds represented by Formula (I) orbenzimidazole compounds represented by Formula (II) are useful in providingcompounds to assay for such therapeutically useful compounds.
Description
N-SUBSTITUTED BENZYMIDAZOLYL C-KIT INHIBITORS AND COMBINATORY BENZYMIDAZOLE GENOTECA
BACKGROUND OF THE INVENTION
The present invention relates to N-substituted benzimidazole compounds. In particular, the present invention relates to becimidazolyl N-substituted compounds that are inhibitors of proto-oncogene c-Kit (also known as KIT, CD-117, stem cell factor receptor, mast cell growth factor receptor). Also the present invention relates to benzimidazolyl compounds (N 1 -substituted) which are inhibitors of c-Kit. It is hypothesized that the c-Kit proto-oncogene is important in embryogenesis, melanogenesis, hematopoiesis, and the pathogenesis of mastocytosis, gastrointestinal tumors and other solid tumors, as well as certain leukemias, including AML. Accordingly, it is desirable to develop novel compounds that are inhibitors of the c-Kit receptor. Many of the current treatment regimens for hyperproliferative disorders (cancer) use compounds that inhibit DNA synthesis. Said mechanism of the operating compound is toxic to cells, particularly for rapidly dividing tumorous cells. In this way, its broad toxicity can be a problem for the patient in question. However, other methods for anti-aging agents
Carcinogens that act differently through the inhibition of DNA synthesis have been explored to try to increase the selectivity of the anti-carcinogenic action and thus reduce adverse side effects. It is known that a cell can become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (that is, a gene that, in activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinase proteins capable of causing cellular transformation. Through a different route, overexpression of a normal proto-oncogenic tyrosine kinase can also result in proliferative disorders, sometimes resulting in a malignant phenotype. Alternatively, the co-expression of a tyrosine kinase receptor and its cognate ligand within the same cell type can also lead to malignant transformation. Tyrosine kinase receptors are large enzymes that extend over the cell membrane and possess i) an extracellular binding domain for growth factors such as KIT ligand (also known as stem cell factor (SCF), Steel factor (SLF) or factor of mast cell growth (MGF)), ii) a transmembrane domain, and iii) an intracellular portion that functions as a kinase for specific tyrosine residues phosphorylated in proteins. The binding of KIT ligand to tyrosine kinase KIT results in the homodimerization of the receptor, the activation of KIT tyrosine kinase activity, and the subsequent phosphorylation of a variety of
protein substrates, many of which are intracellular signal transduction effectors. These cases can lead to increased cell proliferation or promote increased cell survival. With some receptor kinases, heterodimerization of the receptor may occur. It is known that said kinases are aberrantly expressed frequently in common human cancers such as breast cancer, head and neck cancers, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia and ovarian, bronchial cancer, Lung or pancreatic, KIT kinase expression has been documented in a wide variety of human malignancies such as mastocytosis / mast cell leukemia, gastrointestinal stomal tumors (GIST), small cell lung carcinoma (SCLC), natural killer cell lymphoma, sinonasal / T lymphocytes, testicular cancer (seminoma), thyroid carcinoma, malignant melamoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, acute lymphoblastic leukemia of prediátrica T lymphocyte, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma and prostate carcinoma. KIT kinase activity has been implicated in the pathophysiology of several of these tumors, and additional tumors, including breast carcinoma, SCLC, GIST, germ cell tumors, mast cell leukemia, neuroblastoma, AML, melanoma and ovarian carcinoma. Reference has been made to various mechanisms of KIT activation in tumor cells, including activation, activation mutations
autocrine and paracrine receptor kinase through its ligand, loss of protein-tyrosine phosphatase activity, and cross-activation by other kinases. The transformation mechanisms initiated by the activation mutations are thought to include dimer formation and intrinsic increased activity of the kinase domain, both of which result in kinase activation independent of the constitutive ligand, and possibly altered substrate specificity. More than thirty activating mutations of the KIT protein have been associated with highly malignant tumors in humans. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, Gleevec ™ (also known as imatinib mesylate, or ST1571), a 2-phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinase activity of the BCR-ABL fusion gene product, was recently approved for the administration of food and drugs. of the United States for the treatment of CML. Gleevec ™, in addition to the inhibition of BCR-ABL kinase, also inhibits KIT kinase and PDGF receptor kinase, although it is not effective against all mutant isoforms of KIT kinase. The growth stimulated by the ligand Kit of human leukemia cells MO7e is inhibited by Gleevec ™, which also induces apoptosis under these conditions. In contrast, growth stimulated by GM-CSF of human MO7e leukemia cells is not affected by Gleevec ™. In addition, in recent clinical studies using Gleevec ™ to treat patients with GIST, a disease where
involved KIT kinase in the transformation of cells, many of the patients show a marked improvement. These studies show how inhibitors of KIT kinase can treat tumors whose growth is dependent on the activity of KIT kinase. Other kinase inhibitors show even greater kinase selectivity. For example, the Tarceva ™ 4-anilinoquinazoline compound only inhibits EGF receptor kinase with high potency, although it can inhibit the signal transduction of other receptor kinases, probably by virtue of the fact that these receptors heterodimerize with the EGF receptor. Although anti-carcinogenic compounds such as those described above make a significant contribution to the art, there is a continuing need for anti-carcinogenic pharmaceutical compounds and it is desirable to develop new compounds with much better selectivity or potency or with reduced toxicity or side effects. The patent of E.U.A. Nos. 5,990,146 and 6,218,388 describe benzimidazoles to inhibit cell proliferation mediated by protein tyrosine kinase. The patent of E.U.A. No. 6,348,032 describes a method for inhibiting neoplastic cells with benzimidazole derivatives. International patent publication No. WO 01/21634 describes benzimidazole derivatives and combinatorial libraries thereof. International patent publication No. WO 01/57020 describes inhibitors of indole and benzimidazole of factor Xa. International Patent Publication No. WO 00/15222 describes fused pyridine inhibitors of cGMP phosphodiesterase. The
International patent publication describes No. WO 01/12600 describes factor Xa inhibitors. International patent publication No. WO 97/12613 describes a method for the treatment and prevention of inflammation and atherosclerosis. The patent of E.U.A. No 6,316,474 describe antagonists
NMDA / NR2b of 2-benzyl and 2-heteroaryl benzimidazole. The patent of E.U.A. No. 6,479,508 describes viral polymerase inhibitors. The patent of E.U.A. No. 6,444,617 describes diamide derivatives of fused heterocycle dicarboxylic acid or its salts, herbicides and use thereof. The patent of E.U.A. Nos. 6,087,380, 6,414,008 and 6,469,039 disclose disubstituted bicyclic heterocycles. The patent of E.U.A. No. 5,118, 688 describes tetrahydropyridonquinolone derivatives. The patent of E.U.A. No. 4,975,435 discloses certain 1 H-pyrrolo [3,4-b] quinolin-1-one-9-amino-2,3-dihydro derivatives useful for the treatment of anxiety. The patent of E.U.A. No. 6,548,524 discloses ortho-sulfonamido bicyclic heteroaryl hydroxamic acids. The patent of E.U.A. No. 6,348,474 discloses sulfonamide compounds. The patent of E.U.A. Nos. 5,972,980 and 6,001, 866 describe a method for the treatment and prevention of inflammation and atherosclerosis. The patent of E.U.A. No. 5,814,651 discloses catechol diethers as selective inhibitors of PDEIV. U.S. Patent No. 6,329,383 describes compounds 2-amino-5-pyrimidine acetic acid. U.S. Patent No. 5,688,809 describes 5-heteroarylindole derivatives. European patent application No. EP 0 846 689 describes benzimidazole compounds. The patent publication
No. WO 00/59888 describes N-becimidazolylmethyl- and N-indolylmethyl-benzamides and their use as modulators of CRF. International patent publication No. WO 02/069965 describes benzimidazole derivatives as therapeutic agents. International Patent Publication No. WO 02/30886 describes heterocyclic angiogenesis inhibitors. The patent of E.U.A. No. 6,162,804 discloses tyrosine kinase inhibitors. U.S. Patent No. 6,465,484 describes inhibitors of angiogenesis. International patent publication No. WO 00/12089 discloses novel angiogenesis inhibitors. German Patent Publication No. DE 2244908 describes selectively permeable polymer membranes. European Patent Application No. EP 0 706 795 describes catechol ether compounds as inhibitors of TNF release. International patent publication No. WO 02/076960 describes processes mediated by transition metal. International Patent Publication No. WO 02/059118 describes methods for N-oxyalkating carboxamides. International patent publication No. WO 02/04425 describes viral polymerase inhibitors. International patent publication No. WO 02/083143 discloses CXCR3 antagonists. International patent publication No. WO 01/57019 describes inhibitors of indolone and benzimidazolone of factor Xa. European Patent Application No. EP 1 085 372 describes photographic material having improved color reproduction. International patent publication No. WO 01/14342 describes benzimidazole derivatives
aminocarbonyl-substituted. International Patent Publication No. WO 00/76501 discloses IL-8 receptor antagonists. Thus, it is desirable to develop compounds that exhibit inhibition of Kit in order to treat oncology. In addition, said compounds can be active in other kinases such as, for example, GIST, FLT3, hematopoietic R-PTKs, PDGFR-beta or KDR to add efficacy in mast cell leukemias, small cell lung cancer (SCLC), mastocytosis, leukemia, myelodysplastic disorders, or angiogenic dependent diseases.
BRIEF DESCRIPTION OF THE INVENTION
Compounds represented by the formula (I):
(D) its pharmaceutically acceptable salt or N-oxide or its N-oxide are useful in the treatment of tumors Combinatorial libraries composed of compounds represented by the formula (I) or benzimidazole compounds represented by the formula (II):
(p) are useful for providing compounds for analyzing said therapeutically useful compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a compound represented by the formula (I):
O) or its pharmaceutically acceptable salt or N-oxide, wherein R1 and R2 are independently
I U-li.llUk.Ji.lll
C0-8 alkyl optionally substituted with a heterocyclyl substituent, C0-8 alkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11, -S (O) 0-2NR11R12, -NR11S (O) 0-2R12, CN, OH or optionally substituted aryl; -C 8 alkyl-C 3-8 cycloalkyl, -C 0-8 -O-alkyl-Co-β alkyl, -CO 8 -N alkyl (Co-β-alkyl-Co-β alkyl), -C 0-8-S alkyl (O ) o-2-alkyl Co-β; or heterocyclyl optionally substituted with 1-4 independent substituents of C0-8 alkyl > cyclyl or cyclyl substituted; or R1 and R2, taken together with the nitrogen to which they are attached, form a heterocyclic group, optionally substituted with 1-4 independent substituents C0-β alkyl, -C0-8-O-alkyl-C0-β alkyl, -alkyl Co -β-aryl, or groups-Co-β-heteroaryl alkyl, with the proviso that the heterocyclic group formed is not piperazine; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of C0-8 alkyl, alkyl Co-a-cyclyl, halo, OH, -NR31s (O) 0-2R32, -S (O) 0-2NR31R32 , -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R13, R31, R32, and R33 are each independently C0-βalkyl optionally substituted with a heterocyclyl substituent,
C0-β alkyl optionally substituted with 1-6 halo-independent substituents, -CON (Co-βXalkyl alkyl Co-β), -N (C0- alkyl)
8) CON (C0-8 Co-βXalkyl alkyl), -N (C0-8 alkyl) CO2 (C0-8 alkyl), S (O) 0-
2N (C0-alquilo alkyl) (C0-alquilo alkyl), -NR11S (O) or-2 (Co-8 alkyl), CN, OH, or optionally substituted aryl; -alkyl Co-β-cycloalkyl C3-8, -alkyl C0-ß-O-alkyl Co-ß, -alkyl C0-8-N (alkyl Co-ßXalkyl Co-ß), -alkyl C0-ß-S (O ) o-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 independent C0-8 alkyl > cyclyl, or cyclyl substituted; and with the proviso that R3 is not a tetrazolyl, 5-pyrimidinyl, or 4-biphenyl group. In one aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted aryl group, and the other variables are as described above for the formula (I). In one embodiment of this aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted aryl group, R1 is heterocyclyl optionally substituted with 1 - C0-β, cyclic, or substituted cyclic alkyl independent substituents, and the other variables are as described above for formula (I).
In another embodiment of this aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted aryl group, R1 is C0-βalkyl optionally substituted with a heterocyclyl substituent, or R1 is C0-βalkyl optionally substituted with 1-6 halo-independent substituents, -CONR11R12, -NR 3CONR11R12, -NR13CO2R11, -S (O) 0-2NR11R12, -NR11S (O) 0 -2R12, CN, OH or aryl optionally substituted, and other variables are as defined above for formula (I). In still another embodiment of this aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted aryl group, R1 is -C0-alkyl β-N (Co-βXalkyl alkyl C 0 - β); and the other variables are as described above for formula (I). In a second aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted hetaryl group, and the other variables are as described above for the formula (I). In an embodiment of this second aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted hetaryl group, R1 is heterocyclyl optionally substituted with 1-4
alkyl substituents of Co-β, cyclyl, or cyclyl substituted, and the other variables are as described above for formula (I). In another embodiment of this second aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted hetaryl group, R1 is C0- alkyl ß optionally substituted with a heterocyclyl substituent, or R1 is C0-ß alkyl optionally substituted with 1-6 halo-independent substituents, -CONR11R12, -NR 3CONR11R12, -NR13C02R11, -S (O) or-2NR11R12, -NR11S (O) 0-2R12, CN, OH or optionally substituted aryl; and the other variables are as described above for formula (I). In yet another embodiment of this second aspect, the present invention relates to a compound represented by the formula (I), or its pharmaceutically acceptable salt or N-oxide, wherein R3 is an optionally substituted hetaryl group, R1 is Co-alkyl, 8-N (C0-alkyl-X-alkyl Co-β); and the other variables are as described above for formula (I). The compounds of the present invention include 1- (4, -cyano-1,1'-biphenyl-3-yl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide, N- (pyridine-3 -ylmethyl) -1 - (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1-S'-chloro-1-fiuoro-1 .r-biphenyl-Si-N-Ípyridin-S- ilmeti - H-benzimidazole-5-carboxamide,
1- (3'-cyano-1, 1'-biphenyl-3-yl) -N- (pipclin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1-S'-nitro-1-biphenyl- Si-N-Ípyridin-S-ilmeti-IH-benzimidazol-d-carboxamide, 1- (2, -nitro-1,1'-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1H- benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. The compounds of the present invention also include 1- [3-acetylamino) -1,1-D-phenyl-3-yl] -N-methyl-1H-benzyldazole-5-carboxamide, - (3'-chloro-4'-fluoro-1, 1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, 1- (1,1'-biphenyl-3-yl) -N-methyl-1H-benzimidazole-5-carboxamide, N-methyl-1 - (2"-phenoxy-1,1-biphenyl-3-yl) -1 H-benzimidazole-5-carboxamide, N-methyl- 1 -. { 3 '- [(methylsulfonyl) amino] -1,1' -biphenyl-3-yl-1-H-benzimidazole-5-carboxamide, 1- (1,1'-biphenol-3-yl) -N-methyl -1H-benzimidazole-5-carboxamide, N-methyl-1- (4'-methyl-1,1'-biphenyl-3-yl) -1H-benzimidazole-5-carboxamide, 1- (3'-fluoro) -1, r-biphenyl-3-yl) -N-methyl-1H-benzimidazole-5-carboxamide, N-methyl-l- -methyl-sulphonyl-l-biphenyl-S-ylj-IH-benzimidazole-d-
carboxamide, or its pharmaceutically acceptable salt or N-oxide. In addition, the compounds of the present invention include: N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- ( pyridin-3-methyl] -1- (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- [3- (1-benzyl-1 H -pyrazol-4-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-3-yl) phenyl] - 1 H-benzimidazole-5-carboxamide, 1 - [3- (1-methyl-1 H-pyrrol-2-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - [3- (1, 3-thiazol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, 1- [3- (3,5-dimethylisoxazole- 4-yl) phenyl] -N-tetrahydro-2H-pyran-4-yl-1 H-benzimidazole-5-carboxamide, N-tetrahydro-2H-pyran-4-yl-1- (3-thien-3 ilphenyl) -1 H-benzimidazole-5-carboxamide, N-tetrahydro-2 H -pyran-4-yl-1- (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (1, 3-benzodioxol-5-ylmethyl) -1 - [3- (1 H -pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide,
0 its pharmaceutically acceptable salt or N-oxide. In addition, the compounds of the present invention also include N-methyl-1- (3-thien-3-phenyl) -1 H -benzimidazole-5-carboxamide, N-methyl-1 - [3- (1 H -pyrrol- 2-yl) phenyl] -1 H-benzimidazole-5-carboxamide,
N-ethyl-1- (3-thien-3-ylphenyl) -1 H-benzimidazole-5-carboxamide, N-ethyl-1 - [3- (1 H -pyrrol-2-yl) phenyl] -1 H- benzimidazole-5-carboxamide, N-methyl-1- (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- [3- (1,3-benzodioxol-5-yl) phenyl] - N-methyl-1 H-benzimidazole-5-carboxamide, 1 - [3- (2,3-dihydro-1-benzofuran-5-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, - [3- (5-chlorothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1- (3-thien-2-ylphenyl) -1 H -benzimidazole- 5-carboxamide, 1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (tert-butyl) -1- (3-thien-3-ylphenyl) -1 H -benzimidazole- 5-carboxamide, 1 - [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, 1 - [3- (3,5-dimethylisoxazole-4- il) phenyl] -N-ethyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - [3- (2-naphthyl) phenyl] -1 H -benzimidazole-5-carboxamide, 1 - [3- ( 1-benzothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-
carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. The compounds of the present invention also include N- [2- (dimethylamino) ethyl] -1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- [3- (3,5-Dimethyl-oxazol-4-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- (3-pyrrole-2) -ylphenyl) -1 H-benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. In this manner, the compounds of the present invention include 1- (4'-cyano-1,1'-biphenyl-3-yl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - [3- (1 H -pyrrol- 2-yl) phenyl] -1H-benzimidazole-5-carboxamide, l-S'-chloro ^ '-fluoro-l.-biphenyl-Si-N-Ípyridin-S-ilmeti-I H-benzimidazole-5- carboxamide, l-S'-cyano-l .l'-biphenyl-Si-N-Ípyridin-S-ilmeti-I H-benzimidazole-
-carboxamide, l-ÍS'-nitro-l.r-biphenyl-Si-N-Ípyridin-S-ilmeti-I H-benzimidazole-d-carboxamide, N- (pyridin-3-ylmethyl) -1- (3 -pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- [3- (1-benzyl-1 H -pyrazol-4-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H-benzimidazole-5-carboxamide, N- (pyridin-3-methylmethyl) -1 - [3- (1 H -pyrrol-3-yl) phenyl] -1H-benzimidazole-5-carboxamide, 1- [3- (1-methyl-1 H -pyrrol-2-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1- (2'-nitro-1, 1 '-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1H-benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1, 3-thiazole- 2-yl) phenyl] -1H-benzimidazole-5-carboxamide, N-methyl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-methyl-1- [3- (1 H-pyrrol-2-yl) phenyl] -1 H-benzimidazole-5-carboxamide,
N-ethyl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-ethyl-1- [3- (1 H -pyrrol-2-yl) phenyl] -1 H- benzimidazole-5-carboxamide, N-methyl-1- (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- (3-thien-3) -ylphenyl) -1H-benzimidazole-5-carboxamide, 1- [3 '- (acetylamino) -1, 1'-biphenyl-3-yl] -N-methyl-1 H-benzimidazole-5-
carboxamide, 1- (3'-chloro-4'-fluoro-1, 1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, 1 - [3- (1, 3- benzodioxol-5-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, 1- (1,1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1- (2, -phenoxy-1, 1'-biphenyl-3-yl) -1 H -benzimidazole-5-carboxamide, 1- [3- (2,3-dihydro-1-benzofuran-5 -yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1-. { 3 '- [(methylsulfonyl) amino] -1, r-biphenyl-3-yl} -1 H-benzimidazole-5-carboxamide, 1 - [3- (5-chlorothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1- (3-thien) -2-ylphenyl) -1 H-benzimidazole-5-carboxamide, l-l, 1'-biphenyl-Si-N-methyl-1 H-benzimidazole-d-carboxamide, N-methyl-1 - (4'-methyl) -1, 1'-biphenyl-3-yl) -1 H-benzimidazole-5-carboxamide, 1 - (3'-fluoro-1, 1'-biphenyl-Si-N-methyl-1 H-benzimidazole-5 carboxamide, 1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (tert-butyl) -1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5- carboxamide,
1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-methyl-1 H-benzimidazole-5-
carboxamide, 1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-ethyl-1 H-benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -1 H -benzimidazole-5-carboxamide, 1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-tetrahydro-2H-pyran 4-yl-1 H-benzimidazole-5-carboxamide, N-tetrahydro-2H-pyran-4-yl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-tetrahydro- 2 H -pyran-4-yl-1 - (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-methyl-1 - [3- (2-naphthyl) phenyl] -1 H -benzimidazole -5-carboxamide, N-methyl-1 - [4 '- (methylsulfonyl) -1, 1'-biphenyl-3-yl] -1 H -benzimidazole-5-carboxamide, 1- [3- (1-benzothien- 2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- (3-pyrrol-2-ylphenyl) -1 H-benzimidazole-5- carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- (1,3-benzodioxol-5-) ilmethyl) -1 - [3- (1 H -pyrrol-1 -yl) phenyl] -1 H -benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide.
The present invention also relates to a combinatorial library comprising at least three compounds represented by the formula (II):
or its pharmaceutically acceptable salt or N-oxide, wherein R1 and R2 are independently C0-8 alkyl optionally substituted with a heterocyclyl substituent, Co-β alkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13C02R11, -S (O) 0-2NR11R12, -NR11S (O) 0-2R12, CN, OH or optionally substituted aryl; -C0-8-C3-8-C3-8alkyl, -C0-8 -O-C0-8alkyl, -C0-8-Nalkyl (C0-ß-C0-alkyl-C0-alkyl), -C0-8-S-alkyl (O ) 0-2-C0-β alkyl; or heterocyclyl optionally substituted with 1-4 alkyl substituents of Co-β, cyclyl or cyclic substituted; or R1 and R2 taken together with the nitrogen to which they are attached form a heterocyclic group, optionally substituted with 1-4 substituents
l UJJiii.illk-iiii-l
C0-β alkyl, -C0-β-O-alkyl-C0-β alkyl, -C1-aryl alkyl, or -C0-β-heteroaryl alkyl groups; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of C0-β, -C1-cyclyl alkyl, halo, OH, -NR31S (O) 0-2R32, -S (O) 0-2NR31R32 , -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R13, R31, R32, and R33 are each independently C0-β alkyl optionally substituted with a heterocyclyl substituent, C0-βalkyl optionally substituted with 1-6 halo-independent substituents, -CON (C0-βXalkyl) Co-ß), -N (C0-ß-alkyl) CON (C0-βX-C0-8 alkyl), -N (C0-8 alkyl) CO2 (C0-8 alkyl), S (O) 0-2N ( optionally substituted Co-βXalkyl C0-ß), -NR11S (O) 0.2 (C0-8 alkyl), CN, OH, or aryl; -C0-8-C3-8-C3-8alkyl, -C0-8 -O-C0-βalkyl, -C0-8-Nalkyl (Co-β-Alkyl-Co-βalkyl), -C0-8-Salkyl (O ) 0-2-C0-alqu alkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-β, cyclyl, or cyclyl substituted. The present invention also relates to a method for forming a combinatorial library comprising at least three compounds represented by the formula (II):
(ID or its pharmaceutically acceptable salt or N-oxide, wherein R1 and R2 are independently C0-8 alkyl optionally substituted with a heterocyclyl substituent, C0-β alkyl optionally substituted with 1-6 halo-independent substituents, -CONR11R12, - NR13CONR11R12, -NR13CO2R11, -S (O) 0-2NR11R12, -NR11S (O) 0-2R12, CN, OH or optionally substituted aryl; -C0-8 alkyl-C3-8 cycloalkyl) -C0-β-O- alkyl- C0-β alkyl, -C0-8-N-alkyl (Co-β-alkyl-Co-β alkyl), -Co-β-S (O) 0-2-alkyl Co-β alkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents C0-8 alkyl, cyclic or cyclic substituted; or R1 and R2, taken together with the nitrogen to which they are attached, form a heterocyclic group, optionally substituted by 1-4 independent substituents C0-β alkyl, -C0-β-O-alkyl-C0-βalkyl, -alkylCo -ß-aryl, or
groups -C0-β-heteroaryl alkyl; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of Co-β alkyl, Co-β-cyclyl alkyl, halo, OH, -NR 31 S (O) 0.2 R 32, -S (O) 0.2 NR 31 R 32, - NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R13, R31, R32, and R33 are each independently C0-β alkyl optionally substituted with a heterocyclyl substituent, C0-βalkyl optionally substituted with 1-6 halo-independent substituents, -CON (Co-βXalkyl alkyl) Co-β), -N (C 0 alkyl.
8) CON (C0-βXalkyl C0-β alkyl), -N (Co-8 alkyl) CO2 (C0-β alkyl), S (O) 0-2N (C0-β alkyl) (C0-8 alkyl), - NR11S (O) 0-2 (C0-8 alkyl), CN, OH, or optionally substituted aryl; -C0-β-cycloalkyl C3-8 alkyl, -Co-β-O-alkyl Co-β alkyl, -Co-β-N alkyl (Co-βXalkyl alkyl C0-β), -C 8 -SO alkyl (O ) o-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-β, cyclyl, or cyclyl substituted. As used herein, unless otherwise indicated,
"alkyl" as well as other groups having the prefix "alq" such as, for example, alkoxy, alkanyl, alkenyl, alkynyl, and the like, means carbon chains which may be linear or branched or combinations thereof.
Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tere-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other similar terms include carbon chains having at least one unsaturated carbon-carbon bond. As used herein, "C0- alkyl" is used to refer to an alkyl having 0-4 carbons - that is, 0, 1, 2, 3 or 4 carbons in a straight or branched configuration. An alkyl that has no carbon is hydrogen when the alkyl is a terminal group. An alkyl that has no carbon is a direct bond when the alkyl is a bridged (connecting) group. The terms "cycloalkyl", "carbocyclic ring", "cyclic", or
"cyclyl" means 3-10 mono or polycyclic aromatic, partially aromatic or non-aromatic ring carbocycles containing no heteroatoms, and include saturated mono-, bi-, and tricyclic carbocycles, as well as fused or bridged systems. Such fused ring systems can include a ring that is partially or totally unsaturated, such as a benzene ring, to form fused ring systems, such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl and carbocyclic rings include C3.8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthalene, adamantane, indanyl, 1,2,3,4-tetrahydronaphthalene, and the like. The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
The term "carbamoyl" unless otherwise specified means -C (O) -NH- or -NH-C (O) -. The term "aryl" is well known to chemists. Preferred aryl groups are phenyl and naphthyl. The term "hetaryl" is well known to chemists. The term includes 5- or 6- membered heteroaryl rings containing 1-4 heteroatoms chosen from oxygen, sulfur, and nitrogen wherein the oxygen and sulfur are not one after the other. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term "hetaryl" includes hetaryl rings with fused carbocyclic ring systems that are partially or totally unsaturated, such as a benzene ring, to form a benzofused hetaryl. For example, benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, and the like. Unless stated otherwise, the terms "heterocyclic ring", "heterocycle", "heterocyclic" and "heterocyclyl" are equivalent, and are defined as for cyclic but also contain one or more atoms independently chosen from N, O, and S (and oxides of N and S), as long as said derivatives exhibit appropriate and stable valencies and exclude radicals containing OO, S (O) nS (O) n, S (O) nO bonds where n = 0-2 . Terms include saturated 4-8 member rings that contain one or
two heteroatoms chosen from oxygen, sulfur, and nitrogen. Examples of heterocyclic rings include azetidine, oxetane, tetrahydrofuran, tetrahydrofuran, oxepane, oxocane, thietane, thiazolidine, oxazolidine, oxazetidine, pyrazolidine, isoxazolidine, isothiazolidine, tetrahydrothiophene, tetrahydrothiopyran, tiepane, thiokane, azetidine, pyrrolidine, piperidine, azepane, azocan, [1, 3] dioxane, oxazolidine, piperazine, homopiperazine, morpholine, thiomorpholine, and the like. Other examples of heterocyclic rings include the oxidized forms of rings containing sulfur. Thus, tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, and thiazolidine-1,1-dioxide are also considered to be heterocyclic rings. The term "heterocyclic" also includes fused ring systems, which include het-het fused systems, and may include a carbocyclic ring that is partially or totally unsaturated, such as a benzene ring, to form benzofused heterocycles. For example, 3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline, tetrahydroisoquinoline and the like. The compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers as well as their racemic mixtures, their substantially resolved enantiomers substantially, all possible geometric isomers, and their pharmaceutically acceptable salts. Formula I above is shown without a
definitive stereochemistry in certain positions. The present invention includes all stereoisomers of formula I and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereosomers are also included. During the course of the synthetic procedures used to prepare said compounds, or used in the racemization or epimerization procedures known to those skilled in the art, the products of said processes may be a mixture of stereoisomers. The invention also includes a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier. Preferably, the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of the formula I as described above (or a pharmaceutically acceptable salt or N-oxide). Furthermore, within this preferred embodiment, the invention includes a pharmaceutical composition for the treatment of diseases by inhibiting a c-Kit kinase, which may be a wild-type or mutant form of the protein, comprising a pharmaceutically acceptable carrier and a therapeutically non-toxic effective amount of the compound of the formula I as described above (or its pharmaceutically effective salt or N-oxide). The compounds and compositions of the present invention are
effective for the treatment of mammals such as, for example, humans. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acid, its corresponding salt can be conveniently prepared from non-toxic pharmaceutically acceptable bases, including inorganic bases and organic bases. Salts derived from said inorganic bases include aluminum, calcium, copper (ico and bear), ferric, ferrous, lithium, magnesium, manganese (ico and bear), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from non-toxic pharmaceutically acceptable bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines such as substituted amines of natural origin and synthesized. Other non-toxic, pharmaceutically acceptable organic bases from which the salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N'.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosaline, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, its salt
corresponding can be conveniently prepared from said pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pam, pentothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particularly preferred are citric, hydrochloric, maleic, phosphoric, sulfuric, methanesulfonic, and tartaric acids. The pharmaceutical compositions of the present invention comprise a compound represented by formula I (or its pharmaceutically acceptable salt or N-oxide) as an active ingredient, a pharmaceutically acceptable carrier and optionally other ingredients or therapeutic adjuvants. The compositions include compositions suitable for oral administration, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous), although the most appropriate route in any given case will depend on the particular host, and the nature and severity of the conditions for which the active ingredient will be administered. The pharmaceutical compositions can conveniently be presented in unit dosage form and are prepared by any of the methods well known in the pharmacy art. In practice, the compounds represented by formula I, or their pharmaceutically acceptable salts or N-oxides, of this invention are
they can combine as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. For example, oral or parenteral (including intravenous). In this manner, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, wafers or tablets each containing a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set forth above, the compound represented by formula I, or its pharmaceutically acceptable salt or N-oxide, may also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the pharmacy methods. In general, said methods include a step that consists of bringing in association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
In this manner, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a pharmaceutically acceptable salt or N-oxide compound or formula I. The compounds of formula I, or their pharmaceutically acceptable salts or N-oxides, are also they may include in pharmaceutical compositions in combination with one or more other therapeutically active compounds. The pharmaceutical compositions of this invention include a pharmaceutically acceptable liposomal formulation containing a compound of formula I or its pharmaceutically acceptable salt or N-oxide. The pharmaceutical carrier used can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In the preparation of compositions for oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions, although carriers such as starches, sugars, microcrystalline cellulose, diluents , granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form solid preparations
oral products such as powders, capsules and tablets. Due to their easy administration, tablets and capsules are preferred for oral dosage units with which pharmaceutical carriers are employed. Optionally, the tablets can be coated by standard aqueous or non-aqueous techniques. A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more additional ingredients or adjuvants. Compressed tablets can be prepared by compression, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent, or dispersing agent and others. excipients These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, corn starch, or alginic acid, binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action for a long time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. In hard gelatin capsules, the active ingredient is mixed with
an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. The molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each wafer or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a proposed formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg . The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may also be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and their mixtures in oils. In addition, a preservative can be included to prevent the harmful growth of microorganisms. The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of said sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy injection capacity. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; in this way, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils and their suitable mixtures. The pharmaceutical compositions of the present invention may be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, powder thin layer, or the like. In addition, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared, using a compound represented by formula I of this invention, or its pharmaceutically acceptable salt or N-oxide, via processing methods
conventional As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5% by weight to about 10% by weight of the compound, to produce a cream or ointment having a desired consistency. The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter, and other materials commonly used in the art. Suppositories can be conveniently formed first by mixing the composition with softened carrier (s) or melt (s) followed by cooling and forming into molds. In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, pH regulators, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. In addition, other adjuvants may be included to produce the isotonic formulation with the blood of the proposed recipient. Compositions containing a compound described by formula I, or their pharmaceutically acceptable salts or N-oxides, can also be prepared in powder or liquid concentrate form. In general, dosage levels in the order of
about 0.01 mg / kg to about 750 mg / kg of body weight per day are useful in the treatment of the conditions indicated above, or alternatively from about 0.5 mg to about 75 g per patient per day. For example, breast cancer, head and neck cancers, and gastrointestinal cancer such as colon, rectal or stomach cancer can effectively be treated by administering from about 0.01 to 500 mg of the compound per kilogram of body weight per day. , or alternatively about 0.5 mg to about 50 g per patient per day. Similarly, leukemia, ovarian, bronchial, lung and pancreatic cancer can effectively be treated by administration of about 0.01 to 500 mg of the compound per kilogram of body weight per day, or alternatively from about 0.5 mg to about 50 g per patient per day. Mastocytosis / stem cell leukemia, gastrointestinal stromal tumors (GIST), small cell lung carcinoma (SCLC), colon cancer, T cell lymphoma / natural killer sinonasal cell, testicular cancer (seminoma), thyroid carcinoma, melanoma malignancy, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T lymphoblastic acute lymphocytic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma can all be effectively treated by administration of about 0.01 to 500 mg of the compound per
kilogram of body weight per day, or alternatively from about 0.5 mg to about 50 g per patient per day. It is understood, however, that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drug and the severity of the particular disease undergoing therapy. The compounds of the present invention, or their pharmaceutically acceptable salts or N-oxides, can also be effectively administered together with other cancer therapeutic compounds. For example, cytotoxic agents and angiogenesis inhibiting agents can be advantageous coagents with the compounds of the present invention. Accordingly, the present invention includes compositions comprising the compounds represented by formula I, or its pharmaceutically acceptable salt or N-oxide, and a cytotoxic agent or an angiogenesis inhibiting agent. The amounts of each can be therapeutically effective individually - in which case the additive effects can overcome treatment-resistant cancers by mono-therapy. The amounts of either can also be sub-therapeutic - to minimize adverse effects, particularly in sensitive patients. It is understood that the treatment of cancer depends on the type of cancer. For example, lung cancer is treated differently as a first-line therapy as opposed to colon cancer treatment or
breast cancer Even within lung cancer, for example, first-line therapy is different from second-line therapy, which in turn is different from third-line therapy. Patients newly diagnosed can be treated with regimens containing cisplatin. When they fail, they move to a second-line therapy such as a taxane. Finally, if this fails, they can obtain an EGFR tyrosine kinase inhibitor as a third-line therapy. In addition, the regulatory approval procedure differs from country to country. As a result, accepted treatment regimens may differ from country to country. However, the compounds of the present invention, or their pharmaceutically acceptable salts or N-oxides, can be co-administered beneficially together with or in combination with other cancer therapeutic compounds. The other compounds mentioned include, for example, a variety of cytotoxic agents (alkylating agents, DNA topoisomerase inhibitors, antimetabolites, tubulin binders); inhibitors of angiogenesis, and other different forms of therapies including kinase inhibitors such as Tarceva, monoclonal antibodies, and vaccines for cancer. Other mentioned compounds that can be beneficially co-administered with the compounds of the present invention include doxorubicin, vincristine, cisplatin, carboplatin, gemcitabine and the taxanes. In this manner, the compositions of the present invention include a compound according to formula I, or its pharmaceutically acceptable salt or N-oxide, and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeutic agent.
The compounds of the present invention, or their pharmaceutically acceptable salts or N-oxides, can also be effectively administered together with other therapeutic compounds, in addition to cancer therapy. For example, effective therapeutic agents for alleviating adverse side effects may be convenient co-agents with the compounds of the present invention.
I. Assay for the inhibition of c-Kit in intact cells The ability of the compounds to inhibit the tyrosine kinase activity of c-Kit is determined in a cell-based ELISA using the H526 cell line (ATCC # CRL-5811) , which is originally derived from a human small cell lung cancer. The assay determines the ability of the compounds to block tyrosine phosphorylation stimulated by the ligand of the wild-type c-Kit receptor protein that is endogenously expressed in H526 cells. The cells are pre-incubated with compounds in various concentrations prior to the addition of the stem cell factor (SCF), the ligand for the tyrosine kinase of the c-Kit receptor. The cellular ones are then prepared and the c-Kit protein is captured in a 96-well ELISA plate coated with c-Kit antibody. The phosphotyrosine content of the receptor protein is then monitored by quantifying the degree of binding of an antibody that recognizes only the phosphorylated tyrosine residues within the captured protein. The antibody used has a reporter enzyme (for example, peroxidase
horseradish, HPR) covalently linked, such that binding of the antibody to phosphorylated c-Kit can be determined quantitatively by incubation with an appropriate HRP substrate. The storage reagents used are the following:
50 μM Tris-HCl cell lysis pH regulator, pH 7.4 150 mM NaCl 10% glycerol 1% Triton X-100 0.5 mM EDTA leupeptin 1 μg / ml aprotinin 1 μg / ml sodium orthovanadate 1 mM
Antibody anti c-Kit Ab-3 anti c-Kit 0.5 μg / ml (Lab Vision, catalog # MS289P1) in 50 mM sodium bicarbonate, pH 9.
ELISA assay plates ELISA assay plates are prepared by adding 100 μl of anti-c-Kit antibody to each well of a 96-well Microlite-2 plate (Dynex, catalog # 7417), followed by incubation at 37 ° C for 2h. The
I HJ I .U,
wells are then washed twice with 300 μl of wash buffer.
PBS plate washing pH regulator containing 0.5% Tween-20 (PBST)
RPMI cellular assay medium with 0.1% BSA
PY20-HRP pY20-HRP 25 ng / ml (Calbiochem, catalog # 525320) in PBS, containing 0.5% Tween-20, 5% BSA, 1 mM sodium orthovanadate.
HRP Substrate Chemiluminescent detection reagent (Pierce, catalog # 37075)
Test protocol Cultures of H526 cells, grown in RPMI with 10% fetal goat serum, are collected by centrifugation, washed twice with PBS, and suspended in cell assay medium. The cells are then distributed in a 96-well bottom V plate at 7.5 x 10 4 cells per well in 100 μl of cell assay medium. The dilutions of the compound are prepared from stocks of
100 mM DMSO by dilution in the cell assay medium, the final concentration of DMSO in the assay is 0.1%. To incubation wells of the compound, 50 μl of the test compound is added (the compounds are analyzed in concentrations between 0.1 nM and 100 μM); to control wells 5 positive and negative, 50 μl of cell assay medium containing 0.1% DMSO is added. The cells are then incubated with compound at 37 ° C for 3 h. Then SCF (R & D Systems, catalog # 255-SC-010) is added in order to stimulate the Kit receptor and induce its tyrosine phosphorylation. Then, 10 μl of a 1.6 μg / ml solution of SCF is added in a cell assay medium to
all wells aside from the negative control wells, and the cells are incubated for an additional 15 minutes at 37 ° C. After the addition of ice-cold PBS, the plate is set at 1000 rpm for 5 minutes, the medium is removed by aspiration, and the cell pellets are used by the addition of 120 μl of ice-cold cell lysis pH regulator. by15 well. The plate is kept on ice for 20 minutes and 100 μl of cellular samples from each well are then transferred to the wells of an ELISA assay plate and incubated at 4 ° C for 16 h. After incubation of the cellular ones in the ELISA plate, the wells are washed 4 times with 300 μl of washing pH regulator,
Then, 100 μl of the phosphotyrosine detection antibody pY20-HRP is added to each well and the plate is incubated at room temperature for 2 h. The wells are then washed 4 times with 300 μl of wash buffer. Then, 50 μl of the chemiluminescent HRP substrate is added to
each well for luminometric quantification of the amount of HRP-antiphosphotyrosine conjugate to the plate. The comparison of the test signals obtained in the presence of the compound with those of the positive and negative controls (the cells are incubated in the presence or absence of SCF, without addition of compound), allows the degree of inhibition of tyrosine phosphorylation of the c-Kit receptor is determined over a range of compound concentrations. These inhibition values are adjusted to a sigmoidal dose-response inhibition curve to determine the IC 50 values (ie, the concentration of the compound that inhibits the tyrosine phosphorylation induced by SCF of the c-Kit protein by 50%).
II. Activated kinase bank assay c-Kit The cDNA encoding the tyrosine kinase c-Kit domain is isolated from K562 cells and cloned into a baculovirus expression vector for protein expression in insect cells as a fusion protein with
GST (Glutathione S-Tranferase). After purification, the enzyme is incubated with ATP to generate a phosphorylated tyrosine, an activated form of the enzyme, which is used in kinase assays to determine the ability of the compounds to inhibit the phosphorylation of an exogenous substrate by the domain of tyrosine kinase c-Kit.
Protein phosphorylation c-Kit The reagents used are the following:
Column pH regulator HEPES 50 mM pH 7.4 NaCl 125 mM glycerol 10% BSA 1 mg / ml DTT 2mm NaVO3 200 μM
Phosphorylation pH buffer HEPES 50mM pH 7.4 NaCl 125mM 24mM MgCl 2 1 mM MnCl 2 glycerol 1% NavO3 200 μM 2 mM DTT 2 mM ATP 75 μl of purified GST-Kit tyrosine kinase protein (approximately 150 μg) is incubated with 225 μl of Phosphorylation pH regulator for 1 h at 30 ° C. In a cold room, a desalination column (for example,
PD-10 Pharmacia column) is equilibrated using 25 ml of column pH regulator. The phosphorylated protein is applied to the column followed by sufficient column pH regulator to equal 2.5 ml total (in this case 2.2 ml). The phosphorylated Kit protein is then eluted with 3.5 ml of column pH regulator, and collected in a tube containing 3.5 ml of glycerol (final concentration of 50% glycerol). After mixing, the aliquots are stored at -20 ° C or -70 ° C. The kinase activity is determined in an ELISA-based assay that measures the ability of c-Kit to phosphorylate an exogenous substrate (poly Glu: Tyr) in tyrosine residues in the presence of ATP. The phosphorylation of the substrate is monitored by quantifying the degree of binding of an antibody that recognizes only the phosphorylated tyrosine residues within the substrate after incubation with c-Kit. The antibody used has a reporter enzyme (eg, horseradish peroxidase, HRP) covalently linked, such that binding of the antibody to the phosphorylated substrate can be determined quantitatively by incubation with an appropriate HRP substrate (eg, ABTS).
The sample reagents used are as follows PGT stock solution 13.3 μg / ml: 66.7 μl of 10 mg / ml PGT is added to 50 ml PBS. Wash pH regulator 1X: wash pH regulator 20X diluted (KPL # 50-63-00) to 1X with H2O.
Test pH regulator: 50 mM Hepes, pH 4 125 mM NaCI MgCI2 24 mM 1 mM MnCl2 1% glycerol Vanadate 200 μM - 2 mM DTT is added immediately before use - it is added immediately before use Test pH regulator + ATP: 5.8 μl of 75 mM ATP is added to 12 ml of assay pH buffer. Activated GST-c-Kit (TK): diluted 1: 500 in assay pH regulator.
Block pH regulator: PBS containing 0.5% Tween-20, 3% BSA Vanadate 200 μM - added immediately before use
PY20-HRP: 6.2 μl of a 100 μg / ml pY20-HRP stock solution is added to 10 ml of ABTS Substrate block buffer: KPL 3 50-66-06, used as provided.
Test protocol Each well of a 94-well immulon-4 micro-titration plate is coated with 75 μl of 13.3 μg / ml PGT stock solution, incubated overnight at 37 ° C and washed once with a pH regulator. 1X wash 250 μl. To the negative control wells, 50 μl of assay pH buffer (without ATP) is added, all other wells contain 50 μl assay buffer + ATP. To negative and positive control wells, 10 μl of 5% DMSO are added, the other wells contain 10 μl of test compounds (in concentrations between 10 nM and 100 μm) dissolved in 5% DMSO. 30 μl of activated GST-c-Kit is added to start the assay, which is incubated at room temperature for 30 minutes, and then stopped by the addition of 50 μl / well of EDTA 0.5M. The plate is washed 3X with 1X wash pH buffer, and then 75 μl of a phospho-tyrosine-specific antibody-HRP conjugate (eg, pY20-HRP, Calbiochem) in block pH buffer are added. The plate is incubated at room temperature for 2 h, and then washed 3X with 1X wash buffer. After 100 μl of ABTS substrate is added, the plate is incubated at room temperature for 30 minutes, and the reaction is stopped by the addition of 100 μl of 1% SDS. The reaction is quantified by the measurement of OD at 405/490 nM in a micro-titration plate reader. The comparison of the test signals obtained in the presence of the compound with those of the controls (in the presence and absence of ATP, without the addition of compound), allows the degree of
inhibition of kinase activity is determined over a range of compound concentrations. These inhibition values are adjusted to a sigmoidal dose-response inhibition curve to determine the IC50 values (ie, the concentration of compound that inhibits the tyrosine kinase protein activity c-Kit by 50%). Examples of this invention or reduce the level of tyrosine phosphorylation induced by Kit SCF in intact H526 cells as determined in assay I with IC 50 values between 10 μM and 0.4 nM, or reduce Kit's ability to phosphorylate poly (Glu) : Tyr) in assay II for at least 50% in compound concentrations of 10 μM.
Experimental part The examples of the present invention are prepared according to the following procedures by the methods illustrated in the following schemes. The solvents, temperatures, pressure and other appropriate reaction conditions can be easily selected by one skilled in the art. Similarly, suitable starting materials can be obtained commercially or are readily prepared by one skilled in the art.
SCHEME 1
IV
In scheme 1, diarylamines (III) can be produced from the condensation of nitrobenzenes (I, X = F, OMs, OTs) with substituted anilines (II). The coupling of the anilines (II) can also be achieved where X = l, Br, Cl, OTf by using conditions of Buchwald-Hartwig type mediated by Pd (0) (such as those conditions described in J. Organic Chem. ., (1996), 61 (21), 7740) or with Cu (l) catalysts and the base (for example, K2CO3). The reduction of lll to provide the phenylenediamines (IV) can be achieved using for example, hydrogen in the presence of a suitable transition metal catalyst (palladium, platinum, ruthenium, nickel), iron, zinc or tin under acidic conditions, with hydrosulfite of sodium or with tin (II) chloride dihydrate. The cyclisation of IV to the benzimidazoles (V) can be carried out by reaction with a corresponding carboxylic acid, acid halide, acid anhydride or an orthoformate (e.g., (MeO) 3CH)) and an acid such as formic acid or p- toluenesulfonic Under certain conditions used
to reduce lll, for example, iron powder in formic acid, the conversion to benzimidazoles V can be achieved in a container. Also, by including trimethyl orthoformate in a hydrogenation mixture with III, it allows direct conversion to V. Scheme 2 shows that the formation of N-arylbenzimidazoles (V) can also be carried out via the procedure summarized, with which benzimidazoles N1 H (VIII) can be arylated under conditions mediated by Pd (0) media as described in J. Am. Chem. Sic, (2000), 122, 7600. The separation of the resulting regioisomers can be performed by a number of means known to those skilled in the art including, but not limited to, chromatographic media or through crystallization of a suitable solvent. The benzimidazoles (VIII) can be produced from the crystallization of the anuides (VII) with acids such as, but not limited to, acetic, p-toluenesulfonic, hydrochloric, sulfuric or phosphoric acid. The anuides (VII) can in turn be prepared by reaction or o-phenylenediamines with acid halides or anhydrides or with carboxylic acids in the presence of appropriate coupling reagents known to those skilled in the art such as, but not limited to, EDC , DCC, HOAt, HOBt, HATU, TBTU or CDI including supported versions with solids of these solution phase reagents. Where R3 = H, compounds such as Vil can be prepared by the formylation of VI with alkyl formates (e.g., methyl formate). In the procedure described, the conversion from VI to VII can also lead to partial conversion or
complete to VIII.
SCHEME 2
Vile
The functionalities R1 and R2 can be included in the target molecules through the appropriate choice of starting materials, for example, of type I, II, VI and IX. When the final functionality is not available directly through this procedure, or when such functionality can be compromised during the subsequent chemistry to build the final molecule, the alternate functionalities can be used and subsequently transformed into the final desired functionality by the methods, and at points in the sequence, easily determined by a person skilled in the art. For example, a non-exhaustive list of such transformation includes OMe conversions? OH (BBr3), NH2? CI (NaNO2, CuCI), Br? CN
(Pd2 (dba) 3, Zn (CN) 2, DPPF), Me? CO2H (KMnO4), CO2H? CO2Me (MeOH, H2SO4), OH? Oalkyl (alkyl halide, base), CO2H? CONR'R "(EDC, HOAt, DIPEA, HNR'R"), Br? CO2Me (Pd2 ( dba) 3, DPPF, CO (g), MeOH), Br? CO2H (tBuLi, CO2), Ar-H? Ar-Br (NBS), CN? CO2H (H2SO4 conc.), Br? NR'R "( Pd2 (dba) 3, DPPF, HNR'R "). Examples of the preparation of the claimed target molecules are shown below in Schemes 3 and 4.
SCHEME 3
XI
The condensation of 3-benzyloxyaniline with 4-fluoro-3-nitrobenzoic acid occurs through heating in ethanol to provide X which can be reduced via catalytic hydrogenation over 10% Pd / C in ethanol to provide the phenylenediamine (XI). The cyclization of XI to bezimidazole (XII) is carried out by heating with an excess of trimethylortoformate. Coupling mediated by 1,1 '-carbonyldiimidazole with 3-pyridinylmethylamine provides amide XIII which can be converted to its triflate with triflic anhydride in the presence of a base. This triflate is then subjected to coupling mediated by Pd (0) with 4-cyanophenylboronic acid to provide XV.
SCHEME 4
In scheme 4 benzimidazole XIX is formed by a reduction-cyclisation process in a single vessel using iron in
formic acid in the presence of trimethylortoformate. This bromine derivative can then be coupled with arylboronic acids in the presence of Pd (0) catalysts as described above to generate intermediate biaryl molecules such as XX which in turn can be coupled with amines such as 2- (N, N -dimethylamino) ethylamine in the presence of reagents such as EDC and HOBt to provide the claimed target molecules such as a XXI.
Definitions EDC = ethyl dimethylaminopropylcarbodiimide hydrochloride,
HOAt = 1-hydroxyazabenzotriazole, HOBt = 1-hydroxybenzotriazole, CDI = 1,1 '-carbonyldiimidazole, TBTU = O-benzotriazole-N, N, N', N'-tetramethyl uronium tetrafluoroborate, HATU = azabenzotriazolyl-NNN hexafluorophosphate '.N'-tetramethyluronium, DIPEA = diisopropylethylamine, TEA = triethylamine, DMF = N, N-dimethylformamide, NMP = N-methylpyrrolidinone, DCM = dichloromethane, DMAP = 4-dimethylaminopyridine, TFA = trifluoroacetic acid, Boc = t-butoxycarbonyl, Fmoc = fluorenylmethyloxycarbonyl, DMSO = dimethylsulfoxide, AcOH = acetic acid, OMs = OSO2Me, OTs = OSO2- (4-Me) Ph, OTf = OSO2CF3, DPPF = Pd2 (dba) 3, NBS = N-bromosuccinimide, HCl (ac) = aqueous hydrochloric acid, DMA = N, N-dimethylacetamide, MeOH = methanol, EtOH = ethanol, HOAC = acetic acid, EtOAc = ethyl acetate, THF = tetrahydrofuran, hplc = high performance liquid chromatography, PS-TFP = resin tetrafluorophenol supported with polystyrene, PS-HOBt = 1-hydroxybenzotriazole resin supported with
polystyrene, DIC = 1,3-diisopropylcarbodiimide, IMS = industrial methyl alcohol, NMM = N-methyl morpholine, Pd / C = palladium on carbon, Pd (PPh3) 4 = tetrakis (triphenylphosphine) palladium (0), Cs2CO3 = carbonate of cesium, Pd2 (dba) 3 = tris (dibenzylideneacetone) dipalladium (0), BINAP = 1, 1'-biphenyl, Pd (OAc) 2 = palladium (II) acetate, K2CO3 = potassium carbonate, MeCN = acetonitrile, DCC = 1, 3-dicyclohexylcarbodiimide, HPLC = high performance liquid chromatography, rt or rt = ambient temperature, MTP = micro-titration plate, min = minute (s), h = time (s), d = day (s).
General procedures for the preparation of benzimidazoles
N-substituted a) 4-Fluoro-3-nitrobenzoic acid (25.58 g, 138 mmol) and an aniline (138 mmol) are dissolved in ethanol (400 ml) and the mixture is refluxed under N2 atmosphere for 16 h. On cooling to room temperature the resulting yellow / orange precipitate is isolated by filtration and washed with methanol to provide the 4-anilino-3-nitrobenzoic acid, for example 4- acid. { [3-bromophenyl] amino} -3-nitrobenzoic acid. b) This crude intermediate is then dissolved in acetic acid (366 ml) and trimethyl orthoformate (232 ml) and iron powder (< 10 microns, 21.5 g, 384 mmol) are added causing a modest exotherm. The resulting mixture is stirred at room temperature under an N2 atmosphere for 16 h, after which the excess iron and the associated oxides are removed by filtration and washed with CH2Cl2. The filtrate is concentrated and the material
The resulting mixture is triturated with methanol to give the N-arylbenzimidazole carboxylic acid, for example, 1- (3-bromophenyl) -1 H -benzimidazole-5-carboxylic acid. 1 H NMR (DMSO-d 6, 400 MHz): d 7.61 (dd, 1 H, J = 8.4, 8.4 Hz), 7.71 (dd, 1 H, J = 8.4, 8.4 Hz), 7.73-7.78 (m, 2H) , 7.96 (dd, 1 H, J = 8.8, 1.6
Hz), 8.00 (dd, 1 H, J = 1.6, 1.6 Hz), 8.33 (d, 1 H, J = 0.8 Hz) and 8.74 (s, 1 H); MS (ES +): m / z 317 [Br79MH +], 319 [Br81 MH +]. c) A mixture of N-arylbenzimidazole carboxylic acid (19.7 mmol), EDC (5.64 g, 29.5 mmol) and DMAP (0.24 g, 1.97 mmol) in DMF (100 mL) is treated with 3-aminomethylpyridine (3.19 g, 29.5 mmol). ) and the mixture is stirred at room temperature for 16 h. The DMF is then removed in vacuo and the residue is dissolved in DCM (150 ml) and the resulting solution is washed with water (3 x 50 ml). The organic phase is dried (MgSO4) and concentrated in vacuo and the crude product is analyzed by chromatography on silica gel eluting with 1-10% MeOH / DCM. The material then so isolated is further purified by crystallization to provide the N-arylbenzimidazole carboxamide, for example 1- (3-bromophenyl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide. 1 H NMR (1: 1 DMSO-d 6: CDCl 3, 400 MHz): d 4.64 (d, 2 H, J = 5.9 Hz), 7.29 (dd, 1 H, J = 7.8, 4.8 Hz), 7.51-7.60 (m, 3H), 7.65 (ddd, 1 H, J = 7.5,
1. 7.7, 1.7 Hz), 7.75 (dd, 1 H, J = 1.7, 1.7 Hz), 7.78 (ddd, 1 H, J = 7.9, 1.8, 1.8
Hz), 7.99 (dd, 1 H, J = 8.6, 1.5 Hz), 8.29 (s, 1 H), 8.46 (d, 1 H, J = 1.2 Hz), 8.49
(dd, 1 H, J = 4.8, 1.4 Hz), 8.65 (d, 1H, J = 1.7 Hz), 8.85 (t, 1 H, J = 5.8 Hz);
MS (ES +): m / z 407 [Br79MH +], 409 [Br81 MH +]. Alternatively: a) 4-Fluoro-3-nitrobenzoic acid (21.6 mmol) and an aniline (43.2 mmol) in 15 ml of ethanol are stirred under reflux under argon for 5h resulting in the formation of an orange precipitate. After 12 h the heterogeneous reaction mixture is poured into 50 ml of 1 N HCl (aq) and diluted with 100 ml of water. The solution is stirred for 20 minutes and then the precipitate is filtered to yield 4-anilino-3-nitrobenzoic acid, for example 4- acid. { [3- (benzyloxy) phenyl] amino} -3-nitrobenzoic acid. b) A solution of 4-anilino-3-nitrobenzoic acid (20.1 mmol) in THF (100 ml) is charged with 10% Pd / C (500 mg) and the reaction flask is evacuated and subsequently charged with H2 (g. ) three times. The mixture is stirred vigorously for 12 h after which it is filtered through diatomaceous earth and the filtrate is concentrated in vacuo to provide the desired 3-amino-4-anilinobenzoic acid: for example, 3-amino-4 - [( 3-hydroxyphenyl) amino] benzoic acid. c) A solution of 3-amino-4-anilinobenzoic acid (20.1 mmol) in formic acid (40 ml) is charged with trimethylortoformate (2.4 ml, 22.0 mmol) and heated to reflux for 3 h after which it is left to cool at room temperature and stir for 12 h. The reaction mixture is then poured into 150 ml of H 2 O and stirred for 20 min to produce a precipitate which is isolated by filtration to provide 1-aryl-1 H-benzimidazole-5-carboxylic acid: for example, 1- ( 3-hydroxyphenyl) -1 H-
benzimidazole-5-carboxylic acid. d) A solution of 1-aryl-1 H-bezimidazole-5-carboxylic acid (0.39 mmol) in DMF (5 ml) is treated with DCI (95 mg, 0.58 mmol) and stirred for 15 minutes resulting in the formation of a white precipitate. A primary or secondary amine (0.78 mmol) is then added and the mixture is stirred overnight before being poured into 75 ml of H2O and any subsequently formed solid is isolated by filtration to provide 1-aryl-N- (substituted) - 1 H-becimidazole-5-carboxamide. When the desired product does not precipitate from the reaction solution or during the treatment, it is isolated by the addition of water, extraction in the organic solvent (typically EtOAc), drying and concentration of the extracts, and the residue is then purified by Preparative HPLC or by normal phase chromatography on silica gel.
EXAMPLE R1 l- ^ '- cyano-l .l'-biphenyl-S-iiyN-pyridin-S-ilmetiHH-benzimidazole-S-carboxamide
A flask containing a mixture of 1- (3-bromophenyl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide (prepared according to the general procedures described above, 80 mg, 0.20 mmol) and acid
4-cyanophenylboronic acid (57 mg, 0.39 mmol) is evacuated and refilled with N2 (2x).
To this is added Pd (PPh3) (34 mg, 0.029 mmol) in one portion with
minimal exposure to air. The flask is evacuated again and filled with N2 (3x). The degassed solutions of DME: EtOH (4: 1 v / v, 2 ml) and Na2CO3 ac (2M, 0.6 ml) are added via syringe and the solution is stirred under N2 for 10 min at room temperature and then at 85 °. C for 19h. The reaction is then cooled to room temperature, filtered and purified using the Waters mass-directed HPLC purification system. Further recrystallization of acetonitrile yields 1- (4'-cyano-1,1-biphenyl-3-yl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide as a white solid (18.5 mg, 22% yield). MS (ES +): m / z 430 (100) [H +]. 1 H NMR (400 MHz, CD 3 OD): d 8.66 (s, 1 H), 8.61 (d, J = 2.4 Hz, 1 H), 8.45 (dd, J = 4.8 Hz, 1.2 Hz, 1 H), 8.34 (dd) , J = 1.0 Hz, 0.4 Hz, 1 H), 7.99 (t, J = 1.6 Hz, 1 H), 7.88-7.86 (m, 3H), 7.86-7.82 (m, 4H), 7.80 (t, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 2H), 7.43 (dd, J = 8.4 Hz, 5.2 Hz, 1 H), 7.67 (s, 2H). The following compounds are prepared according to the procedure described above for example R1 using the appropriate boronic acid derivatives.
EXAMPLE R2 N- (pyridin-3-ylmethyl) -1- (3-thien-3-ylphenyl) -1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 411 [MH +].
EXAMPLE R3 N- (pyridin-3-ylmethyl) -1-r3- (1 H -pyrrol-2-yl) phenyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 394 (100) [MH +].
EXAMPLE R4 I ^ S'-chloro ^ '- fluoro-l .l'-biphenyl-S-i-N-tpiridin-S-ilmetiQ-IH-benzimidazol-5-carboxamide
MS (ES +): m / z 457 (100) [MH +].
EXAMPLE R5 l-tS'-cyano-l .l'-biphenyl-S-il N-tpiridin-S-ilmetiQ-IH-benzimidazole-d-carboxamide
MS (ES +): m / z 430 (100) [MH +].
EXAMPLE R6 l-O'-Nitro-l.r-biphenyl-S-iD-N-fpyridm-S-ilmetiD-IH-benzimidazole-S-carboxamide
MS (ES +): m / z 449 (100) [MH +].
EXAMPLE R7 N- (pyridin-3-ylmethyl) -1- (3-pyridin-3-ylphenyl) -1H-benzyldazole-5-carboxamide
MS (ES +): m / z 406 (100) [MH +].
EXAMPLE R8 1- [3- (1-Benzyl-1H-pyrazol-4-yl) phenyl-N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 485 (100) [MH +].
EXAMPLE R9 N- (pyridin-3-ylmethyl) -1 -f3- (1 H -pyrrol-3-infenyl-1 H-benzimidazole-5-carboxamide
T-BuLi (1.7M, 0.60 mL, 1.0 mmol) is added dropwise to a solution of 3-bromo-1 -triisopropylsilanyl-1 H-pyrrole (144 mg, 0.476 mmol) in THF (2 mL) at -78 ° C. The reaction mixture is stirred for 40 minutes at that temperature before B (OMe) 3 (0.27 ml, 2.38 mmol) is rapidly added thereto. The reaction is stirred for 19 minutes at -78 ° C and then the cooling bath is removed. After reaching room temperature the reaction mixture is concentrated under reduced pressure to provide the crude boron intermediate as a white solid which is
add 1- (3-bromophenyl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide (86 mg), DME (3.5 ml), aq Na2CO3. 2M (1.0 ml). The mixture is purged by passing a slow stream of N2. Pd (PPh3) 4 (56 mg, 0.048 mmol) is added rapidly with minimal exposure to air. The mixture is again purged by passing a slow stream of N2 before it is heated to reflux for 18 h under N2 and then cooled to room temperature, filtered through Celite, concentrated under reduced pressure and purified by column chromatography. (SiO2, 0 to 9% MeOH in CH2Cl2). The material is recrystallized (CH3CN) to provide the title compound as a white solid. MS (ES +): m / z 394.44 (100) [MH +].
EXAMPLE R10 1-r3- (1-Methyl-1H-pyrrol-2-yl) phenyl-N- (pyridin-3-methyl) -1H-benzimidazole-5-carboxamide
A mixture of 1- (3-bromophenyl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide (85 mg, 0.209 mmol), Pd (PPh3) 2 Cl2 (28 mg, 0.040 mmol) and Ag2O ( 45 mg, 0.196 mmol) is added in one portion to a flask loaded with 1-methyl-2-tributylstannyl-1 H-pyrrole (0.391 g, 1.06 mmol). The flask is evacuated and refilled with N2 (2x) and then charged with anhydrous DMF (3.0 ml). After stirring at room temperature for 5 minutes the reaction mixture is heated at 90 ° C under N2 for 2 days. Then, the reaction is cooled to room temperature and treated with KF aq.
1 M (3 ml) and stirring overnight at room temperature. It is then filtered through Celite (using MeOH to rinse the Celite) and purified by MDPS to provide the product as a white solid. MS (ES +): m / z 408.46 (100) [MH +].
EXAMPLE R11 1- (2, -nitro-1, 1, -biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1H-benzimidazole-5-carboxamide
It is prepared according to the procedure described above for example R1 using 2-nitrophenylboronic acid MS (ES +): m / z 450 (100) [MH +].
EXAMPLE R12 N- (pyridin-3-ylmethyl) -1-r3- (1,3-thiazol-2-yl) phenin-1 H-benzimidazole-5-carboxamide
A flask containing a mixture of 1- (3-bromophenyl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide (80 mg, 0.196 mmol, 4049-79-2), Pd (PPh3) 2CI2 (16 mg, 0.0196 mmol) and Ag2O (45 mg, 0.196 mmol) is evacuated and refilled with N2 (2x) and loaded with anhydrous DMF (0.5 ml). 2-Tributylstananthiazole (367 mg, 0.306 mmol) is added via a syringe from a container that is later rinsed with two portions of DMF
(2x0.75 ml), each portion is added to the reaction mixture. After stirring at room temperature for 5 minutes the reaction mixture is heated at 100 ° C under N2 for 12 h. Later, the reaction is cooled to room temperature, diluted with MeOH to -50 ml, treated with KF aq. 1 M (4 ml) and stirring overnight at room temperature. It is then filtered through Celite (using MeOH to rinse the Celite) and purified by preparative TLC (DCM: MeOH 9: 1) to obtain the crude material which is purified by MDPS to provide the product as a white solid. MS (ES +): m / z 412.31 (100) [MH +].
EXAMPLE R13 N-methyl-1- (3-thien-3-ylphenyl) -1H-benzimidazole-5-carboxamide
MS (ES +): m / z 334.1 (100%) [MH +].
EXAMPLE R14 N-methyl-1-f3- (1 H-pyrrol-2-yl) phen-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 317.2 (100%) [MH +].
EXAMPLE R15 N-ethyl-1- (3-thien-3-ylphenyl) -1H-benzimidazole-5 carboxamide
MS (ES +): m / z 348.1 (100%) [MH +].
EXAMPLE R16 N-ethyl-1-f3- (1H-pyrrol-2-yl) phen-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 331.2 (100%) [MH +].
EXAMPLE R17 N-methyl-1- (3-pyridin-3-ylphenyl) -1H-benzimidazole-5 carboxamide
MS (ES +): m / z 329.2 (100%) [MH +].
EXAMPLE R18 N-r2- (dimethylamino) etn-1- (3-thien-3-ylphenyl) -1H-benzimidazole-5-carboxamide
MS (ES +): m / z 391.2 (100%) [MH +].
EXAMPLE R19 1-f3 '- (acetylamino) -1, 1'-biphenyl-3-in-N-methyl-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 385.1 (100%) [MH +].
EXAMPLE R20 1-r 3'-Chloro-4'-fluoro-1,1'-biphenyl-3-n-N-methyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 380.1 (100%) [MH +].
EXAMPLE R21-r3- (1,3-benzodioxol-5-yl) phen.p-N-methyl-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 372.1 (100%) [MH +].
EXAMPLE R22 1- (1,1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 404.2 (100%) [MH +].
EXAMPLE R23 N-methyl-1- (2'-phenoxy-1,1'-biphenyl-3-yl) -1H-benzimidazole-5-carboxamide
MS (ES +): m / z 420.1 (100%) [MH +].
EXAMPLE R24 1-f3- (2,3-dihydro-1-benzofuran-5-yl) phenin-N-methyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 370.1 (100%) [MH +].
EXAMPLE R25 N-methyl-1 ^ 3W (methylsulfonyl) amino1-1 '-biphenyl-3-yl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 421.1 (100%) [MH +].
EXAMPLE R26 1-í3- (5-chlorothien-2-yl) phenan-N-methyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 367.9 (100%) [MH +].
EXAMPLE R27 N-methyl-1- (3-thien-2-ylphenyl) -1H-benzimidazole-5-carboxamide
To a solution of 1- (3-bromophenyl) -N-methyl-1 H-benzimidazole-5-carboxamide (20 mg, 0.06 mmol) and thiophene-2-boronic acid (9.0 mg, 0.073 mmol) in anhydrous DMF (0.6 ml) was added Pd (PPh3) 4 (3.5 mg, 0.003 mmol) followed by a solution of Na2CO3 (19 mg, 0.18 mmol) in water (0.16 ml).
The reaction is irradiated in the microwave for 10 minutes (200W, 150 ° C).
After cooling, the reaction mixture is filtered through Celite and washed with EtOAc (15 ml). The combined organic layer is washed with saturated aqueous NaHCO3 solution (10 ml) followed by saturated aqueous saline (3 x 10 ml), dried (MgSO4) and evaporated to dryness. The crude product is purified by solid phase extraction (Isolute SAX, followed by
Isolute SCX), providing N-methyl-1- (3-thien-2-ylphenyl) -1H-benzimidazole-5-carboxamide as an off-white solid; 1 H NMR (400 MHz, MeOH-d 4): d 8.57 (s, 1 H), 8.27 (d, J = 2 Hz, 1 H), 7.89-7.86 (m, 2 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.66-7.62 (m, 2H), 7.52-7.54 (m, 2H), 7.45 (d, J = 5.1 Hz, 1 H), 7.12 (dd, J = 3.5Hz, 1.5Hz, 1 H) 2.97 (s, 3H); MS (ES +): m / z 333.9 (100%) [MH +].
EXAMPLE R28 1- (1,1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 327.9 (100%) [MH +].
EXAMPLE R29 N-methyl-1- (4'-methyl-1,1'-biphenyl-3-yl) -1H-benzimidazole-5-carboxamide
MS (ES +): m / z 342.0 (100%) [MH +].
EXAMPLE R30 - (3'-fluoro-1, 1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 345.9 (100%) [MH +].
EXAMPLE R31 1- (3-thien-3-ylphenyl) -1H-benzimidazole-5-carboxamide
MS (ES +): m / z 320.0 (100%) [MH +].
uniiiiii.! !! L.i.
EXAMPLE R32 N- (tert-butyl) -1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 376.1 (100%) [MH +].
EXAMPLE R33 1-f3- (3,5-dithmethaloxazol-4-yl) phenyl-1-N-methyl-1H-benzamidazole-5-carboxamide
MS (ES +): m / z 347.2 (100%) [MH +].
EXAMPLE R34 - [3- (3,5-dimethylisoxazol-4-yl) phenin-N-ethyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 361.2 (100%) [MH +].
EXAMPLE R35 N-r2- (dimethylammono) ethyl-1-r3- (3,5-dimethylisoxazol-4-yl) phenan-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 404.2 (100%) [MH +].
EXAMPLE R36 1-r3- (3,5-D-methylisoxazol-4-yl) phenyl-N-tetrahydro-2H-pyran-4-yl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 417.2 (100%) [MH +].
EXAMPLE R37 N-Tetrahydro-2 H -pyran-4-yl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 404.1 (100%) [MH +].
EXAMPLE R38 N-Tetrahydro-2 H -pyran-4-yl-1- (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 387.2 (100%) [MH +].
EXAMPLE R39 N-methyl-1-r3- (2-naphthyl) phen-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 378.1 (100%) [MH +].
EXAMPLE R40 N-methyl-1-r4 '- (methylsulfonyl) -1, 1-biphenyl-3-yn-1 H-benzimidazole-5-carboxamide
MS (ES +): m / z 406.1 (100%) [MH +].
EXAMPLE R41 -f3- (1-benzothien-2-yl) phenin-N-methyl-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 383.9 (100%) [MH +].
EXAMPLE R42 N- [2- (dimethylamino) ethyll-1- (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 374.2 (100%) [MH +].
EXAMPLE R43 N- (pyridin-3-ylmethyl) -1-r3- (1 H -pyrrol-1-yl) phen'n-1H-benzimidazole-5-carboxamide
MS (ES +): m / z 394.4 (100%) [MH +].
EXAMPLE R44 N- (1,3-Benzodioxol-5-ylmethyl) -1-f3- (1 H -pyrrol-1-yl) phenin-1 H -benzimidazole-5-carboxamide
MS (ES +): m / z 437.4 (100%) [MH +].
Combinatorial library and method The examples of the combinatorial library of the present invention are prepared according to the phase-assisted methods of polymer-assisted solution ("capture and release" resin) illustrated in the following schemes. Solvents, temperatures, pressures and other appropriate reaction conditions can be easily selected by one of ordinary skill in the art. Similarly, suitable starting materials can be obtained commercially or easily prepared by one skilled in the art.
SCHEME C1
IIIIIIIII;, h. i
In Scheme C1, N-substituted (IV) benzimidazole-5-carboxamides can be produced from the binding of N1-substituted (II) benzimidazole-5-carboxylic acids to tetrafluorophenol resins supported by commercially available polystyrene (PS-TFP ) (Salvino, JW et al., J. Comb. Chem. 2000, 2, 691-697) by the use of conventional condensation reagents. DIC with DMAP is the preferred coupling reagent combination. Other polymer-supported reagents that provide stable active esters, such as polymer-supported 1-hydroxybenzotriazole (PS-HOBt) and polymer-supported nitrophenols, are alternative resins that could be used in place of PS-TFP. Resin loading is typically estimated by the weight increase, although 19F NMR can also be used to provide a more accurate determination of loading efficiency. The charges typically of > 80% can be achieved. These activated esters attached to resin are relatively stable and can be stored in the refrigerator under an inert atmosphere. The reaction of the benzimidazole carboxylic acid supported by polymer (II) with limiting amounts of primary and secondary amines typically ensures a single clean reaction product, the desired benzimidazoles (IV). The release effectiveness of the product is dependent on the nucleophilicity of the amine and as a result of the division reactions can be run over extended reaction times. The benzimidazole acids (II) required as blocks of
Construction for the process can be prepared by a number of methods, including but not limited to those described above in schemes 1, 2 and 3, as well as the schemes described below. Examples of the preparation of representative members of the target libraries using the described procedure are shown below in schemes C4 to C7.
SCHEME C4
4-pyrazolyl-aniline can be heated with 4-fluoro-3-nitrobenzoic acid in 2-methoxyethanol to provide (XIII) which is subjected to reductive cyclization using 10% Pd / C in triethylamine with formic acid to provide the benzimidazole (XIV) . The DIC / CMAP mediated loading of the resulting benzimidazole carboxylic acid (XIV) in PS-TFP provides the supported benzimidazole acid, which is divided with a range of amines for
provide the corresponding benzimidazole carboxamides. The example shown provides benzimidazole (XV) by the use of N, N-dimethylethylenediamine as the dividing amine.
SCHEME C5
The condensation of 3-bromoaniline with 4-fluoro-3-nitrobenzoic acid occurs through heating with NMM in 2-methoxyethanol to provide (XVI) which can be reacted by a reduction-cyclization process in a single vessel, using iron / acid acetic acid in IMS followed by formic acid, to give the benzimidazole (XVII). The DIC / DMAP mediated loading of the resulting benzimidazole carboxylic acid (XVII) in PS-TFP provides the supported benzimidazole acid, which can be divided with a range of amines to provide the corresponding benzimidazole carboxamides. The example shown provides benzimidazole (XVIII) by the use of isonipecotamide as the dividing amine.
The intermediate bromine benzimidazoles such as (XVII) can be further transformed by a variety of metal catalyzed coupling methods to provide for example biaryl, aryl-heteroaryl or arylamine benzimidazole carboxylic acids, examples of which are shown in the 6 & 7. While the metal-catalyzed arylations proceed effectively in the benzimidazole acids, the corresponding benzimidazole methyl esters are preferred for metal-catalyzed aminations. The benzimidazole carboxylic acid derivatives can be loaded into PS-TFP and subsequently partitioned with a range of amines to provide the corresponding benzimidazole carboxamides. In the examples shown, cleavage of the acids bound to respective resins with 4-aminotetrahydropyran provides benzimidazole (XX) or with ethylamine providing benzimidazoles (XXIV) and (XXVI).
SCHEME C6
SCHEME C7
General procedures for the preparation of N1-substituted benzimidazole-5-carboxylic acids a) 4-Fluoro-3-nitrobenzoic acid (0.27 mol), an aniline (0.32 mol) and NMM (32.5 ml) in 2-methoxyethanol (750 ml) they are stirred at reflux under argon for 24 h. The suspension is concentrated under reduced pressure and the
'v IGFI? W'
The residue is sonicated with 1 M HCl (aq) for 1.5 h. The resulting orange solid is isolated by filtration, washed with water, dried, then sonicated with t-butyl methyl ether, isolated by filtration and dried. When necessary, the product is further purified by recrystallization to produce 4-anilino-3-nitrobenzoic acid: for example, 4- (3-bromophenyl-amino) -3-nitrobenzoic acid. (In some cases, for example with heteroaromatic anilines, the NMM can be omitted from the reaction mixture). b) To a stirred solution of 4-anilino-3-nitrobenzoic acid (0.099 mol) in IMS (or ethanol) (300 ml) is added iron powder (33.2 g, 0.594 mol) and glacial acetic acid (300 ml). The resulting mixture is refluxed for 3 h, then concentrated to dryness under reduced pressure. Formic acid (300 ml) is added and the reaction mixture is heated to reflux overnight. The reaction mixture is poured into ice and diluted with water (up to 2000 ml) and stirred for 30 minutes. The resulting gelatinous mixture is filtered and the residue is washed with water. The crude product is suspended in water and basified with 2M aqueous sodium hydroxide (to pH 10-12) and then MeOH (500 ml) and DMF (100 ml) are added. The suspension is filtered through Celite and decolorizing charcoal is added to the solution and the suspension is filtered again through Celite. The filtrate is concentrated in vacuo and the resulting solid residue is suspended in water and acidified with 2M aqueous hydrochloric acid (to pH 2-3). The mixture is sonicated for 1.5 hours. The resulting precipitate is removed by filtration, washed with water and
dried to give the desired 1-aryl-1H-benzimidazole-5-carboxylic acid: for example, 1- (3-bromophenyl) -1H-benzimidazole-5-carboxylic acid; 1 H NMR (DMSO-d 6, 400 MHz): d 12.9 (br. S), 8.74 (s, 1 H), 8.33 (d, 1 H, J = 0.8 Hz), 8.00 (dd, 1 H, J = 1.6 , 1.6 Hz), 7.96 (dd, 1 H, J = 8.8, 1.6 Hz), 7.78-7.73 (m, 2H), 7.71 (dd, 1 H, J = 8.4, 8.4 Hz) and 7.61 (dd, IH, J = 8.4, 8.4 Hz); MS (ES +): m / z 317.1 / 319.1 [MH +; Br79 / 81] to R, 3.22 min; p.f. 289-290 ° C. Alternatively, a stirred solution of 4-anilino-3-nitrobenzoic acid (5.5 g, 0.017 mol), triethylamine (16 ml) and 10% Pd in carbon (0.2 g) is heated to 60 ° C before adding drop to formic acid drop (10 ml). The resulting solution is stirred at reflux for 20 hours under nitrogen. The hot mixture is filtered through a pad of Celite, and the cake is washed with hot DMF and EtOH. The filtrate is concentrated under reduced pressure, the residue is triturated with water, isolated by filtration, sonicated with MeCN, washed with t-butyl methyl ether and dried to provide 1-aryl-1 H-benzimidazole-5 acid. desired carboxylic acid (in some cases, the column chromatographic purification of the desired product is required): for example, 1- (4-pyrazol-1-yl-phenyl) -1H-benzoimidazole-5-carboxylic acid; 1 H NMR (DMSO-d 6, 400 MHz): d 12.80 (br.s, 1 H), 8.72 (s, 1 H),
8. 62 (d, J = 2.3 Hz, 1 H), 8.34 (s, 1 H), 8.10 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1 H), 7.84 (d, J = 8.7 Hz, 2H), 7.81 (m, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 6.60 (m, IH);
MS (ES +): m / z 305.2 [MH +] to R, 2.89 min; p.f. 278-279 ° C.
c) 1 - (Aryl / heteroaryl-phenyl) -1H-benzimidazole-5-carboxylic acids A 250-ml Schlen-type flask is charged with 1-bromophenyl-1H-benzimidazole-5-carboxylic acid (3.0 g, 9.45 mmol), an aryl / heteroaryl boronic acid (1.5 g, 11.71 mmol), Pd (PPh3) (0.55 g, 5 mol%) and
DMF (90 ml). The mixture is stirred at room temperature for 15 minutes under nitrogen, before a sodium carbonate solution is added.
(4.8 g) in water (12 ml) under nitrogen. The mixture is refluxed for 24 hours and filtered while still hot through Celite. After the Celite is washed twice with hot DMF, the combined filtrate is concentrated in vacuo. The resulting residue is dissolved in water and acidified (to pH 4) with
1 M HCl (ac). The resulting precipitate is removed by filtration, washed with water and dried. This crude product is sonicated with acetonitrile, filtered, washed with t-butyl methyl ether and dried to give the desired 1-aryl / heteroaryl-phenyl-1H-benzimidazole-5-carboxylic acid: for example, (3-thiophen-3-yl-phenyl) -1H-benzimidazole-5-carboxylic acid: 1 H NMR 400 MHz, d6-DMSO): d 12.84 (br. S, 1 H), 8.78 (s, 1 H), 8.37 (s, 1 H), 8.08 (s, 1 H), 8.05 (s, 1 H), 7.98 (d, J = 9 Hz, 1 H), 7.88 (d, J = 9 Hz, 1 H), 7.78-7.60 (m, 5H); MS (ES +): m / z 321.2 (100%) [MH +] to R, 3.31 min; p.f. 274-275 ° C.
d) 1- (Amin-il-phenyl) -1 H-benzimidazole-5-carboxylic acids a. Thionyl chloride (10 ml, 0.137 mol) is added dropwise to a stirred suspension of 1-bromophenyl-1H-benzimidazole-5-carboxylic acid (20 g, 0.063 mol) in MeOH (200 ml) at 0-5. ° C. The reaction is stirred at reflux for 18 h and then concentrated under reduced pressure. The solid residue is triturated with cold water, basified with aqueous ammonium hydroxide solution and extracted with DCM. The extract is washed with water, aqueous saline, dried over MgSO and concentrated in vacuo to give the corresponding methyl ester of 1-bromophenyl-1H-benzimidazole-5-carboxylic acid: for example, methyl ester of acid 1 (4-bromophenyl) -1 H-benzimidazole carboxylic acid. b. Palladium-catalyzed amination: A mixture of 1-bromophenyl-1H-benzimidazole-5-carboxylic acid methyl ester (5.0 g, 0.0151 mol), the amine (2.0 g, 0.0227 mol), Cs2CO3 (8.6 g, 0.0264 mol) , Pd2 (dba) 3 (0.28 g, 0.3 mmol, 2 mol%) and BINAP (0.56 g, 0.91 mmol, 6 mol%) in dioxane (100 ml) is stirred at 90 ° C for 64 h. The reaction mixture is poured into water and extracted several times with EtOAc. The combined extracts are washed with water, aqueous saline, dried over MgSO and concentrated in vacuo to give crude l- (amino-yl-phenyl) -1H-benzimidazole-5-carboxylic acid methyl ester product, which is purify by flash chromatography: for example, 1- (4-morpholin-4-yl-phenyl) -1H-benzimidazole-5-carboxylic acid methyl ester. (Pd (OAc) 2 (2 mol%) and toluene, instead of
Pd2 (dba) 3 and dioxane, respectively, can also be used for this reaction). c. o Copper-catalyzed amination: A mixture of 1-bromophenyl-1H-benzimidazole-5-carboxylic acid methyl ester (3.0 g, 9.0 mmol), amine (1.63 g, 13.5 mmol), K2CO3 (2.49 g, 18.0 mmol) ), copper iodide (I) (0.171 g, 0.9 mmol) and L-proline (0.21 g, 1.8 mmol) in DMSO (40 mL) is stirred at 90 ° C for 63 hours. The cooled mixture is partitioned between 5% aqueous ammonium chloride solution and EtOAc. The organic layer is separated, and the aqueous phase is back extracted with EtOAc. The combined organic extracts are washed with aqueous saline, dried over MgSO4 and concentrated in vacuo to give the product 1- (amino-1-phenyl) -1H-benzimidazole-5-carboxylic acid methyl ester, which is purified by means of flash chromatography, for example, 1- [4- (3-methyl-benzylamino) -phenyl] methyl ester} -1H-benzimidazole-5-carboxylic acid. d. A mixture of 1- (amin-1-phenyl) -1H-benzimidazole-5-carboxylic acid methyl ester (3.0 g, 8.9 mmol) and lithium hydroxide (0.64 g, 26.7 mmol) in THF / water 2: 1 (30 ml) is stirred at 60 ° C for 5 h and then concentrated under reduced pressure. The residue is diluted with water and acidified with 5% aqueous hydrochloric acid. The resulting solid is removed by filtration, washed with water and dried to yield l- (amino-yl-phenyl) -1H-benzimidazole-5-carboxylic acid: for example, 1- (4-morpholin-4) acid. -yl-phenyl) -1 H-benzimidazole-5-carboxylic acid;
1 H NMR (DMSO-d 6, 250 MHz): d 12.85 (br.s, IH), 8.58 (s, 1 H), 8.32 (s, 1 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 3.74 (t, J = 4.6 Hz, 4H) , 3.37 (t, J = 4.3 Hz, 4H); MS (ES +): m / z 322.2 [MH +] (100%) at Rt 2.86 min; p.f. 269-270 ° C. And for example, 1- [4- (3-methyl-benzylamino) -phenyl] -1 H -benzoimidazole-5-carboxylic acid; 1 H NMR (DMSO-d 6, 400 MHz): d 12.80 (br.s, 1 H), 8.48 (s, 1 H), 8.30 (s, 1 H), 7.90 (d, J = 8.5 Hz, 1 H) , 7.50 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.27-7.17 (m, 3H), 7.06 (d, J = 6.9 Hz, 1 H), 6.76 (d , J = 8.7 Hz, 2H), 6.67 (br.t, NH), 4.30 (d, J = 4.4 Hz, 2H), 2.30 (s, 3H); MS (ES +): m / z 357.2 [MH +] (100%) at Rt 3.69 min; p.f. 217-218 ° C. and. Alternatively, for the preparation of water-soluble acids the following modified procedure is preferred: after removal of the organic solvent from the reaction mixture, ion exchange resin Amberlyst IR 120 (excess) is added in portions to an aqueous solution stirring of the residue until the solution reaches a pH of 6. The mixture is filtered and the resin is washed with MeOH. The combined filtrates are concentrated to dryness under reduced pressure and the residual water is removed by co-distillation with toluene. The crude oily residue is sonicated and then stirred in MeCN overnight to typically provide a
crystalline material which is removed by filtration, washed with MeCN and dried in vacuo to yield the desired 1- (amino-yl-phenyl) -1H-benzimidazole-5-carboxylic acid. The foregoing describes the various procedures for forming the building blocks for use in the general procedure for making a combinatorial library of benzimidazoles from the building blocks.
General procedures for the preparation of N1-substituted benzimidazole-5-carboxamides A flask containing a mixture of PS-TFP (1.32 mmol / g, 350 mg, 0.462 mmol), substituted N-1-H-benzimidazole-5-carboxylic acid (222 mg, 0.693 mmol) and DMAP (33 mg, 0.277 mmol) are charged with DMF (ca. 10 ml) and stirred at room temperature for 10 minutes. DIC (262 mg, 2079 mmol) is added and the reaction is stirred at room temperature for 3 days. The filter reaction and the resin are washed with DMF (35 ml), THF (15 ml) and DCM (15 ml) before it is dried in a vacuum oven overnight. A portion of the polymer-bound 1H-benzimidazole-5-carboxylic acid N1 (86 mg, 0.075 mmol) is treated with a solution of the amine (300 μl, 0.2 mol / ml, ca 0.9 eq.) In DMF ( 1 ml) for days at room temperature. The reaction is filtered, the resin is washed with DMF (0.9 ml). The filtrate is concentrated in vacuo to yield benzimidazole-5-
N1-substituted substituted carboxamide: for example, N-methyl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide; 1 H NMR (500 MHz, d 6 -DMSO): d 8.75 (s, 1 H), 8.50 (d, 1 H), 8.30 (s, 1 H), 8.10 (s, 1 H), 8.05 (s, 1 H). ), 7.85 (m, 2H), 7.7 (m, 5H), 2.85 (d, 3H); MS (ES +): m / z 334.1 (100%) [MH < + > ]; Rt 3.40 min. When the splitting of the resin fails to provide the desired amide product with purity > 85% required (as determined by UV detection at 220 nm), the compound is purified either by UV or mass-directed HPLC.
Automated Synthesis Details The resin (0.075 mmol) is supplied to the required number of wells of a 96-well MPT using either a Titan ™ resin dispenser or an Argoscoop ™, and DMF (0.7 ml) is added to each well using a liquid manipulator (for example, Tecan Genesis ™). Then, 300 μl of each amine (from amine stock solutions at 0.2 mmol / ml) are added to the appropriate wells using a liquid manipulator (e.g., Tecan Genesis ™). The 96-well MTP is sealed hot and stirred at room temperature for 3 days. The liquid is then aspirated from the resin using a liquid manipulator equipped with filter probes (eg, Zinser Analytic LISSY ™) and the resin washed with DMF (900 μl). For LC / MS analysis, 20 μl of this solution is taken and diluted with MeOH (80 μl). Finally, the volume of the reaction solutions is dried using Genevac ™. One portion (15-20%)
of the library is analyzed by 1 H NMR, using either a conventional probe (Varian Mercury 400 spectrometer operating at 400 MHz or a Bruker AMX2 spectrometer operating at 500 MHz) or a flow probe (flow injection samples run in a Bruker BEST system comprising the Bruker AMX2 500 spectrometer, a Gilson 215 autosampler, a heated transfer line and a Bruker F1-SEI NMR 4 mm probe The BEST system is controlled by software XWINNMR V2.6).
Purification details
Mass directed purification The mass directed purification system consists of a LC Micromass PlatForm mass spectrometer, a Waters 600 HPLC pump, a Waters reagent manager, a Waters 2700 autosampler, a Waters 996 PDA detector, a Waters fraction collector II and Waters Xterra Prep MS C18 columns (19 x 50 mm). The compounds are eluted with varying gradients water / acetonitrile + 0.1% formic acid which are run over a period of 8 minutes. The flow rate is 20 ml / min. The system is controlled by a MassLynx and FractionLynx V3.5 software.
UV-directed purification UV-directed purification is carried out in a 4-channel Parallex Flex Biotage system equipped with 4 columns Waters Xterra
Prep MS C18 (19 x 50 mm). The compounds are eluted using a gradient water / acetonitrile + 0.1% formic acid with a cycle time of 10 min and a flow rate of 20 ml / min. UV detection is at 220 nm and 254 nm. The system is controlled by Biotage parallex Flex V2.9 software.
Library monomers
The amines (R1 R2NH) used for all subsets of the library are: 1. (aminomethyl) cyclopropane 2. 2- (2-aminoethyl) pyridine 3. 2- (aminomethyl) pyridine 4. 4- (2-aminoethyl) morpholine 5. tetrahydrofurfurylamine 6. veratrilamine 7. 1- (2-aminoethyl) -2-imidazolone 8. 5-amino-2-methoxyphenol 9. 3-aminobenzyl alcohol 10. 4-amino-m-cresol 11. 5-chloro-2 -methylbenzylamine
12. 2- (aminomethyl) -5-methylpyrazine 13. 3- (2-aminoethyl) pyridine 14. 4- (Trifluoromethyl) piperidine hydrochloride
. 3-picolylmethylamine 16. 1- (3-aminopropyl) imidazole 17. 1 - (3-aminopropyl) -2-pyrrolidinone 18. isopropylamine 19. 2-methylbenzylamine 20. 3-methylbenzylamine 21. 3-fluorobenzylamine 22. 4-fluorobenzylamine 23 N, N-dimethyl-1,3-propanediamine 24. 4- (3-aminopropyl) morpholine 25. DL-1-amino-2-propanol 26. cyclopropylamine 27. 2-methoxyethylamine 28. histamine 29. piperonylamine 30. 1 phenylpiperazine 31. 4-piperazineacetophenone 32. 1- (2-pyridyl) piperazine 33. 4-hydroxy-4-phenylpiperidine 34. 4-acetyl-4-phenylpiperidine hydrochloride
. 1- (3-methoxyphenyl) piperazine 36. 1- (4-methoxyphenyl) piperazine 37. 1-methylpiperazine 38. 1- (2-methoxyphenyl) piperazine 39. 1- (2-hydroxyethyl) piperazine 40. 1 - (2, 4-dimethoxyphenyl) piperazine 41. 1-piperazinepropanol 42. 1- (2-morpholinoethyl) piperazine 43. 1- (4-hydroxyphenyl) piperazine 44. 1- (2-furoyl) piperiazine 45. 1-ethylpiperazine 46. 1-acetylpiperazine 47. 2-Piperazin-1-yl-1-pyrrolidin-1-ethanone 48. N, N-dimethylethylenediamine 49. 4-benzylpiperidine 50. 4-Cyano-phenylpiperidine hydrochloride 51. 1- (2-dimethylaminoethyl) piperazine 52. 4-benzyl-4-hydroxypiperidine 53. 1- (4-pyridyl) piperazine 54. N- (3-hydroxyphenyl) piperazine 55. N- (2-hydroxyphenyl) piperazine 56. 1- (2-cyanophenyl) piperazine 57 4- (hydroxymethyl) piperidine
tmpntGiü & i¡
58. 4-hydroxypiperidine 59. 4-piperidinopiperidine 60. 4- (1-pyrrolidino) piperidine 61. isonipecotamide 62. piperidine 63. N, N-diethylnipecotamide 64. 3-piperidinemethanol 65. 3-hydroxypiperidine 66. 4-piperazinoindole 67. 1- (2-pyrazinyl) piperazine 68. 4- (aminomethyl) pyridine 69. 4- (trifluoromethoxy) benzylamine 70. 4-methoxybenzylamine 71. 4-chlorobenzylamine 72. 1- (tetrahydro-2-furoyl) piperazine 73. 1 - (2 - (6-methylpyridyl) piperazine 74. 1- (4-cyanophenyl) piperazine 75. 3-chloro-4-methylbenzylamine 76. pyrrolidine 77. diethylamine 78. 4-piperazinoindole 79.1, 2,3,6-tetrahydropyridine 80. 2- (2-methylaminoethyl) pyridine
tlHU Uill i l II, iilc
81. 1-methyl-4- (methylamino) piperidine 82. 1- (2-pyrrolidinylmethyl) pyrrolidine 83. N, N, N'-trimethylethylenediamine 84. 2,6-dimethylmorpholine 85. 8-aza-1,4-dioxaspiro [4.5 ] decane (4-piperidone ethylene ketal) 86. N- (4-aminophenyl) -N-methylacetamide 87. 2- (4-aminophenyl) ethanol 88. 3-fluoro-P-anisidine 89. p-toluidine 90. 3, 4-ethylenedioxianiline 91. 1-acetyl-6-aminoindole 92. 4-fluoroaniline 93. 3-fluoro-4-methylaniline 94. p-anisidine 95. 3-chloro-4-fluoroaniline 96. m-anisidine 97. 3,4 -difluoroaniline 98. 3-methoxybenzylamine 99. 4-methylbenzylamine 100. 3-chloro-4-methylaniline 101. 3- (trifluoromethyl) benzylamine 102. 2-chlorobenzylamine 103. 3,5-dimethoxybenzylamine
HlllliUll tltli
104. 2-fluorobenzylamine 105. 3- (trifluoromethoxy) benzylamine 106. 4-aminoacetanilide 107. 3-amino-o-cresol 108. N1- (4-amino-2-methylphenyl) acetamide
109. 1- (2-piperidinoethyl) piperazine 110. 1-morpholin-4-yl-2-piperazin-1-yl-ethanone 111. 1- (4-pyridylmethyl) piperazine 112. N, N-dimethyl-2-piperazin-1 -yl-acetamide 113. 1- (3-dimethylaminopropyl) piperazine
114. 1- (3-morpholinopropyl) piperazine 115. 1- (3-pyrrolidinopropyl) piperazine 116. 1- (2-ethoxyethyl) piperazine 117. 1-pyridin-2-ylmethylpiperazine 118. (4-fluorophenyl) piperazin-1-ylmethanone
119. (3-fluorophenyl) piperazin-1-ylmethanone
120. 2-aminobenzyl alcohol 121. 4-aminotetrahydropyran 122. ethylamine 123. methylamine 124. benzylamine 125. cyclohexanomethylamine 126. 3- (aminomethyl) pyridine
127. butylamine 128. 2-piperidineethanol 129. morpholine 130. 1- (3-methoxyphenyl) piperazine 131. n-methylcyclohexylamine 132. 2,4-dimethoxyaniline
Subset of library A: simple functionalized phenyls in
R3
Benzimidazole-5-carboxylic acid building blocks
The anilines (R3NH2) used to install R3: A. aniline B. 3-bromoaniline C. 4-bromoaniline D. 3'-aminoacetophenone E. 3'-aminoacetanilide F. 4'-Aminoacetanilide
G. Methyl 3-aminobenzoate H. Methyl 4-aminobenzoate
TABLE 1
A combinatorial library is tabulated in Table 1 below -subset A, formed by the method of the present invention. The data is prese in a [M + H] + (Rt) format.
BI TÍ? TTT
ll.littl_H.IU
iiUiíiatMii. ii
Total = # of compounds prepared from each benzimidazole-5-carboxylic acid building block
lü i ll < l? i I,
Subset of library B: commercially available aniline biaryls Becimidazole-5-carboxylic acid building blocks
Anilines (R3NH2) used to install R3: I. 5- (3-aminophenyl) tetrazole J. 3- (1 H-pyrazol-1 -yl) aniline K. 4- (1 H -pyrazol-1-yl) aniline L 4- (1, 2,3-thiadiazol-4-yl) aniline
TABLE 2
A combiatorial library is tabulated in Table 2 below - subset B, formed by the method of the present invention. The data is prese in a [M + H] + (Rt) format.
lUlUilll.UtlI
Total = # of compounds prepared from each benzimidazole-5-carboxylic acid building block
Subset of library B1: biaryls of the Suzuki reaction of boronic acids with benzimidazole carboxylic acids derived from bromoaniline. Benzimidazole-5-carboxylic acid building blocks
The boronic acids R3 used with 3-bromophenyl benzimidazole-5-carboxylic acid include: M. Thiophene-3-boronic acid O. 1- (tert-butoxycarbonyl) -2-pyrrole boronic acid *
P. 4,4,5,5, -tetramethyl-2- (1 H -pyrazol-4-yl) -1, 3,2-dioxoborlane Q. 3,5-Dimethyl-isoxazole-4-boronic acid R. pyridine-acid 3-boronic The boronic acids R3 used with 4-bromophenyl benzimidazole-5-carboxylic acid include: N '. Thiophen-2-boronic acid O '. 1- (t-Butoxycarbonyl) -2-pyrrole boronic acid * P '. 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborlane Q '. 3,5-dimethylisoxazole-4-boronic acid R '. Pyridine-3-boronic acid. * With 1- (t-butoxycarbonyl) -2-pyrroleboronic acid, the protected group Boc in the pyrrolo nitrogen is removed during the reaction and procedure to provide the desired benzimidazole-5-carboxylic acid. The resulting unprotected benzimidazole-5-carboxylic acid building blocks are subsequently charged to PS-TFP and used for the summarized procedure, with no further need for N-protection of the pyrrolo.
TABLE 3
A combinatorial library is tabulated in Table 3 below - subset B1, formed by the method of the present invention. The data is presented in a [M + H] + (Rt) format.
Total = # of prepared compounds of each benzimidazole-5-carboxylic acid building block
Subset of qenotheque C: arylamines of amine reactions of amines R4R5NH listed with benzimidazole carboxylic acids derived from bromoaniline.
Benzimidazole-5-carboxylic acid building blocks
llli i llá,]! , !! . i;
Amines R4R5NH used with 3-bromophenyl benzimidazole-5-carboxylic acid include: S. Morpholine U. 3-chlorobenzylamine - there are no examples V. 3- (aminomethyl) pyridine W. 2,6-dimethylaniline - there are no examples Amines R4R5NH used with 3-Bromophenyl benzimidazole-5-carboxylic acid include: S '. Morpholine T. 3-methylbenzylamine U '. 3-chlorobenzylamine - there are no examples V. 3- (aminomethyl) pyridine W. 2,6-dimethylaniline - there are no examples
TABLE 4
A combinatorial library is tabulated in Table 4 below -subset C, formed by the method of the present invention. The data is presented in a [M + H] + (Rt) format.
Total = # of prepared compounds of each benzimidazole-5-carboxylic acid building block
Accordingly, the present invention includes a combinatorial library comprising at least three benzimidazoles formed by the reaction:
wherein: wherein R1 and R2 are independently C0-8 alkyl optionally substituted with a heterocyclyl substituent, C0-8 alkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11, -S (O ) 0- 2 NR 11 R 12, -NR 11 S (O) 0-2 R 12, CN, OH or optionally substituted aryl; -C 8 alkyl-C 3-8 cycloalkyl, -C 0-8 -O-C 0-8 alkyl, -C 0-8-N alkyl (Co-β-alkyl-Co-β alkyl). -C0-8-S (O) o-2-C0-8 alkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents C0-8 alkyl, cyclic or cyclic substituted; or R1 and R2, taken together with the nitrogen to which they are attached, form a heterocyclic group, optionally substituted with 1-4 independent substituents of C0-8 alkyl, -C0-8 -O-alkyl-C0-8 alkyl, -alkyl Co -β-aryl, or groups-C0-8-heteroaryl alkyl; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of Co-β alkyl, Co-β-cyclyl alkyl, halo, OH, -NR31s (O) 0-2R32, -S (O) o-2NR31R32 , -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R3, R31, R32, and R33 are each independently C0-8 alkyl optionally substituted with a substituent
heterocyclyl, C0-β alkyl optionally substituted with 1-6 halo-independent substituents, -CON (C 1-8 alkyl) (Co-β alkyl), -N (C 0- alkyl)
8) CON (Co-8 alkyl) (C 1-8 alkyl), -N (C 1-8 alkyl) CO 2 (C 0-8 alkyl), S (O) 0-2 N (C 1-8 alkyl) (C 1-8 alkyl) ), -NR11S (O) 0-2 (C0-8 alkyl), CN, OH, or optionally substituted aryl; -C0-8-C3-8-C3-8alkyl, -C0-8 -O-C0-8 alkyl, -C0-8-Nalkyl (C0-8 alkyl) (-C1-alkyl), -C0-8alkyl- S (O) 0-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-8 alkyl, cyclic, or cyclic substituted. The present invention includes a combinatorial library comprising at least three bezimidazoles formed from the reaction of a benzimidazole carboxylic acid supported with polymer with an amine selected from (aminomethyl) cyclopropane; 2- (2-aminoethyl) pyridine; 2- (aminomethyl) pyridine; 4- (2-aminoethyl) morpholine; tetrahydrofurfurylamine; veratrylamine; 1- (2-aminoethyl) -2-imidazolone; 5-amino-2-methoxyphenol; 3-aminobenzyl alcohol; 4-amino-m-cresol; 5-chloro-2-methylbenzylamine; 2- (aminoethyl) -5-methylpyrazine; 3- (2-aminoethyl) pyridine; 4- (trifluoromethyl) piperidine; 3-picolylmethylamine; 1- (3-aminopropyl) imidazole; 1- (3-aminopropyl) -2-pyrrolidinone; isopropylamine; 2-methylbenzylamine; 3-methylbenzylamine; 3-fluorobenzylamine; 4-fluorobenzylamine; N, N-dimethyl-1,3-propanediamine; 4- (3-
aminopropyl) morpholine; DL-1-amino-2-propanol; cyclopropylamine; 2-methoxyethylamine; histamine; piperonylamine; 1-phenylpiperazine; 4-piperazinoacetophenone; 1- (2-pyridyl) piperazine; 4-hydroxy-4-phenylpiperidine; 4-acetyl-4-phenylpiperidine; 1- (3-methoxyphenyl) piperazine; 1- (4-methoxyphenyl) piperazine; 1-methylpiperazine; 1- (2-methoxyphenyl) piperazine; 1- (2-hydroxyethyl) piperazine; 1- (2,4-dimethoxyphenyl) piperazine; 1-piperazinepropanol; 1- (2-morpholinoethyl) piperazine; 1- (4-hydroxyphenyl) piperazine; 1- (2-furoyl) piperazine; 1-ethylpiperazine; 1-acetylpiperazine; 2-piperazin-1-yl-1-pyrrolidin-1-ylethanone; N, N-dimethylethylenediamine; 4-benzylpiperidine; 4-cyano-4-phenylpiperidine hydrochloride; 1- (2-dimethylaminoethyl) piperazine; 4-benzyl-4-hydroxypiperidine; 1- (4-pyridyl) piperazine; N- (3-hydroxyphenyl) piperazine; N- (2-hydroxyphenyl) piperazine; 1- (2-cyanophenyl) piperazine; 4- (hydroxymethyl) piperidine; 4-hydroxypiperidine; 4-piperidinopiperidine; 4- (1-pyrolidino) piperidine; isonipecotamide; piperidine; N, N-diethylnipecotamide; 3-piperidinemethanol; 3-hydroxypiperidine; 4-piperazinoindole; 1- (2-pyrazinyl) piperazine; 4- (aminomethyl) pyridine; 4- (trifluoromethoxy) benzylamine; 4-methoxybenzylamine; 4-chlorobenzylamine; 1- (tetrahydro-2-furoyl) piperazine; 1- (2- (6-methylpyridyl)) piperazine; 1- (4-cyanophenyl) piperazine; 3-chloro-4-methylbenzylamine; pyrrolidine; diethylamine; 4-piperazinoindole; 1, 2,3,6-tetrahydropyridine; 2- (2-methylaminoethyl) pyridine; 1-methyl-4- (methylamino) piperidine; 1- (2-pyrrolidinylmethyl) pyrrolidine; N, N, N'-trimethylethylenediamine; 2,6-dimethylmorpholine; 8-aza-1, 4-dioxaspiro [4.5] decane (4-piperidone ethylene ketal); N- (4-aminophenyl) -N-methylacetamide; 2- (4-aminophenyl) ethanol; 3-fluoro-P-anisidine; p-toluidine; 3,4-ethylenedioxianiline; 1-
acetyl-6-aminoindoline; 4-fluoroaniline; 3-fluoro-4-methylaniline; p-anisidine; 3-chloro-4-fluoroaniline; m-anisidine; 3,4-difluoroaniline; 3-methoxybenzylamine; 4-methylbenzylamine; 3-chloro-4-methylaniline; 3- (trifluoromethyl) benzylamine; 2-chlorobenzylamine; 3,5-dimethoxybenzylamine; 2-fluorobenzylamine; 3- (trifluoromethoxy) benzylamine; 4-aminoacetanilide; 3-amino-o-cresol; N1- (4-amino-2-methylphenyl) acetamide; 1- (2-piperidinoethyl) piperazine; 1-morpholin-4-yl-2-piperazin-1-yl-ethanone; 1- (4-pyridylmethyl) piperazine; N, N-dimethyl-2-piperazin-1-yl-acetamide; 1- (3-dimethylaminopropyl) piperazine; 1- (3-morpholinopropyl) piperazine; 1- (3-pyrrolidinopropyl) piperazine; 1 - (2-ethoxyethyl) piperazine; 1-pyridin-2-ylmethylpiperazine; (4-fluorophenyl) piperazin-1-ylmethanone; (3-fluorophenyl) piperazin-1-ylmethanone; 2-aminobenzyl alcohol; 4-aminotetrahydropyran; ethylamine; methylamine; benzylamine; cyclohexanomethylamine; 3- (aminomethyl) pyridine; Butylamine; 2-piperidineethanol; morpholine; 1- (3-methoxyphenyl) piperazine; n-methylcyclohexylamine; or 2,4-dimethoxyaniline. The present invention includes a combinatorial library comprising at least three benzimidazoles formed from the Suzuki reaction of a boronic acid with an N-bromophenyl benzimidazole carboxylic acid:
to form a substituted N-phenylbenzimidazole carboxylic acid
R3, wherein R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of C0-8 alkyl, C0-8 alkyl-cyclyl, halo, OH, -NR31s (O) 0-2R32, -S (O ) 0-2NR31R32, -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R31, R32, and R33 are each independently C0-8 alkyl optionally substituted with a heterocyclyl substituent, Co-β alkyl optionally substituted with 1-6 halo-independent substituents, -CON (C0-β alkyl) (Co-β alkyl ). -N (C0- alkyl)
8) CON (C0-8 alkyl) (C0-8 alkyl), -N (C0-8 alkyl) CO2 (C0-8 alkyl), S (O) 0.
2N (C0-8 alkyl) (C0-β alkyl), -NR11S (O) 0-2 (Co-8 alkyl), CN, OH, or optionally substituted aryl; -alkyl Co-β-cycloalkyl C3-8, -alkyl Co-β-O-alkyl C0-8, -alkyl C0-ß-N (alkyl Co-ßKalkyl Co-ß), -alkyl C0-ß-S (O ) o-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-β, cyclic, or cyclic substituted; followed by the reaction of N-phenylbenzimidazole carboxylic acid
R 3 substituted with an amine selected from (aminomethyl) cyclopropane; 2- (2-aminoethyl) pyridine; 2- (aminomethyl) pyridine; 4- (2-aminoethyl) morpholine; tetrahydrofurfurylamine; veratrylamine; 1- (2-aminoethyl) -2-imidazolone; 5-amino-
2-methoxyphenol; 3-aminobenzyl alcohol; 4-amino-m-cresol; 5-chloro-2-methylbenzylamine; 2- (aminoethyl) -5-methylpyrazine; 3- (2-aminoethyl) pyridine; 4- (trifluoromethyl) piperidine; 3-picolylmethylamine; 1- (3-aminopropyl) imidazole; 1- (3-aminopropyl) -2-pyrrolidinone; isopropylamine; 2-methylbenzylamine; 3-methylbenzylamine; 3-fluorobenzylamine; 4-fluorobenzylamine; N, N-dimethyl-1,3-propanediamine; 4- (3-aminopropyl) morpholine; DL-1-amino-2-propanol; cyclopropylamine; 2-methoxyethylamine; histamine; piperonilamin; 1-phenylpiperazine; 4-piperazinoacetophenone; 1- (2-pyridyl) p -perazine; 4-hydroxy-4-phenylpiperidine; 4-acetyl-4-phenylpiperidine; 1- (3-methoxyphenyl) piperazine; 1- (4-methoxyphenyl) piperazine; 1-methylpiperazine; 1- (2-methoxyphenyl) piperazine; 1- (2-hydroxyethyl) piperazine; 1- (2,4-dimethoxyphenyl) piperazine; 1-piperazinepropanol; 1- (2-morpholinoethyl) piperazine; 1- (4-hydroxyphenyl) piperazine; 1- (2-furoyl) piperazine; 1-ethylpiperazine; 1-acetylpiperazine; 2-piperazin-1-yl-1-pyrrolidin-1-ylethanone; N, N-dimethylethylenediamine; 4-benzylpiperidine; 4-cyano-4-phenylpiperidine hydrochloride; 1- (2-dimethylaminoethyl) piperazine; 4-benzyl-4-hydroxypiperidine; 1- (4-pyridyl) piperazine; N- (3-hydroxyphenyl) piperazine; N- (2-hydroxy-phenyl) piperazine; 1- (2-cyanophenyl) piperazine; 4- (hydroxymethyl) piperidine; 4-hydroxypiperidine; 4-piperidinopiperidine; 4- (1-pyrrolidino) piperidine; isonipecotamide; piperidine; N, N-diethylnipecotamide; 3-piperidinemethanol; 3-hydroxypiperidine; 4-piperazinoindole; 1- (2-pyrazinyl) piperazine; 4- (aminomethyl) pyridine; 4- (trifluoromethoxy) benzylamine; 4-methoxybenzylamine; 4-chlorobenzylamine; 1- (tetrahydro-2-furoyl) piperazine; 1- (2- (6-methylpyridyl)) piperazine; 1- (4-cyanophenyl) piperazine; 3-chloro-4-methylbenzylamine; pyrrolidine; diethylamine; 4-
piperazinoindole; 1, 2,3,6-tetrahydropyridine; 2- (2-methylaminoethyl) pyridine; 1-methyl-4- (methylamino) piperidine; 1- (2-pyrrolidinylmethyl) pyrrolidine; N, N, N'-trimethylethylenediamine; 2,6-dimethylmorpholine; 8-aza-1, 4-dioxaspiro [4.5] decane (4-piperidone ethylene ketal); N- (4-aminophenyl) -N-methylacetamide; 2- (4-aminophenyl) ethanol; 3-fluoro-P-anisidine; p-toluidine; 3,4-ethylenedioxianiline; 1-acetyl-6-aminoindoline; 4-fluoroaniline; 3-fluoro-4-methylaniline; p-anisidine; 3-chloro-4-fluoroaniline; m-anisidine; 3,4-difluoroaniline; 3-methoxybenzylamine; 4-methylbenzylamine; 3-chloro-4-methylaniline; 3- (trifluoromethyl) benzylamine; 2-chlorobenzylamine; 3,5-dimethoxybenzylamine; 2-fluorobenzylamine; 3- (trifluoromethoxy) benzylamine; 4-aminoacetanilide; 3-amino-o-cresol; N 1 - (4-amino-2-methylphenyl) acetamide; 1- (2-piperidinoethyl) piperazine; 1-morpholin-4-yl-2-piperazin-1-yl-ethanone; 1- (4-pyridylmethyl) piperazine; N, N-dimethyl-2-piperazin-1-yl-acetamide; 1- (3-dimethylaminopropyl) piperazine; 1- (3-morpholinopropyl) piperazine; 1- (3-pyrrolidinopropyl) piperazine; 1 - (2-ethoxyethyl) piperazine; 1-pyridin-2-ylmethylpiperazine; (4-fluorophenyl) piperazin-1-ylmethanone; (3-fluorophenyl) piperazin-1-ylmethanone; 2-aminobenzyl alcohol; 4-aminotetrahydropyran; ethylamine; methylamine; benzylamine; cyclohexanomethylamine; 3- (aminomethyl) pyridine; Butylamine; 2-piperidineethanol; morpholine; 1- (3-methoxyphenyl) piperazine; n-methylcyclohexylamine; or 2,4-dimethoxyaniline. The boronic acid used in the present invention includes thiophene-3-boronic acid; 1- (t-butoxycarbonyl) -2-pyrrole boronic acid; 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborolane; 3,5-dimethylisoxazole-4-boronic acid; pyridine-3-boronic acid, thiophen-2-boronic acid; acid 1- (t-
butoxycarbonyl) -2-pyrrole boronic; 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborolane; 3,5-dimethylisoxazole-4-boronic acid; and pyridine-3-boronic acid. The present invention includes a combinatorial library comprising at least three benzimidazoles formed from the amination of an N-bromophenyl benzimidazole carboxylic acid, thereby replacing the bromine with an amine, wherein the amine includes morpholine, 3-chlorobenzylamine, 3- (aminomethyl) pyridine, and 2,6-dimethylaniline.
M._UU.lUi_Jl.! U
Claims (32)
1. - A compound represented by the formula (I)
(i) or its pharmaceutically acceptable salt or N-oxide, characterized in that R1 and R2 are independently Co-β alkyl optionally substituted with a heterocyclyl substituent, C0-β alkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11, -S (O) 0-2NR11R12, -NR11S (O) 0.2R12, CN, OH or optionally substituted aryl; -C3-C3-cycloalkyl-alkyl, -C0-β-O-alkyl-C0-βalkyl, -C0.8-Nalkyl (C0-βalkyl) (C0-βalkyl), -C0-8alkyl- S (O) 0-2-C0-alqu alkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-β, cyclic or substituted cyclyl; or R1 and R2, taken together with the nitrogen to which they are attached, form a heterocyclic group, optionally substituted with 1-4 independent substituents of C0-β, -C0-β-O-alkyl-C0-βalkyl,
-Co-β-aryl alkyl, or -C0-β-heteroaryl alkyl groups, with the proviso that the heterocyclic group formed is not piperazine; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of C0-8 alkyl, alkyl Co-β-cyclyl, halo, OH, -NR31s (O) 0-2R32, -S (O) or- NR31R32 , -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R13, R31, R32, and R33 are each independently C0-β alkyl optionally substituted with a heterocyclyl substituent, C0-βalkyl optionally substituted with 1-6 halo-independent substituents, -CON (Co-βXalkyl alkyl) Co-ß), -N (Co-ß alkyl) CON (C0-ß alkyl) (C 1-8 alkyl), -N (C 1-8 alkyl) CO 2 (C 1-8 alkyl), S (O) 0-2 N (C0-8 Co-βXalkyl alkyl), optionally substituted -NR 1S (O) 0-2 (Co-β alkyl), CN, OH, or aryl; -alkyl Co-8-cycloalkyl C3-8, -alkyl C0-ß-O-alkyl C0-8, -alkyl Co-ß-N (alkyl Co-ß) (alkyl Co-ß), -alkyl C0-ß- S (O) o-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-β, cyclic, or cyclic substituted; and with the proviso that R3 is not a tetrazolyl, 5-pyrimidinyl, or 4-biphenyl group. 2. The compound according to claim 1, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R3 is an aryl group optionally substituted with 1-4 independent substituents of C0-β alkyl, Co-β-cyclyl alkyl , halo, OH, -NR31s (O) 0.2R32, -S (O) 0.
2 NR31R32, -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0.2R31, -O-aryl, -O-hetaryl, NO2, CN , CF3, OCF3, or OCHF2.
3. The compound according to claim 2, or its salt
or pharmaceutically acceptable N-oxide, further characterized in that R1 is a heterocyclyl optionally substituted with 1-4 independent substituents of C0-8 alkyl, cyclic, or substituted cyclylyl.
4. The compound according to claim 2, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R1 is C0-βalkyl optionally substituted with a heterocyclyl substituent, or R1 is C0-βalkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11, -S (O) 0. 2NR 11 R 12, -NR 11 S (O) 0.2 R 12, CN, OH or optionally substituted aryl.
5. The compound according to claim 2, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R1 is -alkyl Co-β-N (C0-βalkyl-C0-βalkyl) - 6.- The compound of according to claim 1, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R3 is hetaryl, optionally substituted with 1-4 independent substituents of Co-β alkyl, C-β-cyclyl alkyl, halo, OH, -NR31S (O) 0- R32, -S (O) 0-2NR31R32, -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) or-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3 , or OCHF2. 7. The compound according to claim 6, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R1 is heterocyclyl optionally substituted with 1-4 alkyl substituents of Co-β, cyclyl, or substituted cyclylyl. 8. The compound according to claim 6, or its salt
or pharmaceutically acceptable N-oxide, further characterized in that R1 is C0-βalkyl optionally substituted with a heterocyclyl substituent, or R1 is C0-βalkyl optionally substituted with 1-6 halo-independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11 , -S (O) 0-2NR11R12, -NR11S (O) 0-2R12, CN, OH or optionally substituted aryl. 9. The compound according to claim 6, or its pharmaceutically acceptable salt or N-oxide, further characterized in that R1 is -C0-β-N (C0-8 alkyl) alkyl (C0-β alkyl). 10. A composition, characterized in that it comprises a compound according to claim 1, or its pharmaceutically acceptable salt or N-oxide, and a pharmaceutically acceptable carrier. 11. A composition, characterized in that it comprises a compound according to claim 1, or its pharmaceutically acceptable salt or N-oxide, and an anti-neoplastic, anti-tumor, anti-angiogenic or chemotherapeutic agent. 12. A composition, characterized in that it comprises a compound according to claim 1, or its pharmaceutically acceptable salt or N-oxide, and a therapeutic, carcinogenic, cytotoxic agent. 13. A composition, characterized in that it comprises a compound according to claim 1, or its pharmaceutically acceptable salt or N-oxide, and a carcinogenic therapeutic agent that inhibits angiogenesis.
14. - A compound, characterized in that it consists of 1- (4'-cyano-1, 1 '-biphenyl-3-yl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide, N- (pyridine- 3-ylmethyl) -1 - (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-2-yl ) ilphenyl] -1 H-benzimidazole-5-carboxamide, 1- (3'-chloro-4'-f? uoro-1, 1'-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) - 1 H-benzimidazole-5-carboxamide, 1- (3'-cyano-1,1 '-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1- (3'-nitro-1, 1 '-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - ( 3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- [3- (1-benzyl-1 H -pyrazol-4-yl) phenyl] -N- (pyridin-3-ylmethyl) - 1 H-benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - [3- (1 H -pyrrol-3-yl) phenyl] -1 H -benzimidazole-5-carboxamide, 1- [3 - (1-methyl-1 H -pyrrol-2-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1- (2'n-tro-1, 1 ' biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1 - [3- (1, 3-thiazol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N-methyl-1- (3-thien-3-phenyl) ) -1 H-benzimidazole-5-carboxamide, N-methyl-1- [3- (1 H -pyrrol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N-ethyl-1 - (3 -thien-3-ylphenyl) -1 H-benzimidazole-5-carboxamide, N-ethyl-1- [3- (1 H -pyrrol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- methyl-1 - (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1 - (3-thien-3-ylphenyl) -1 H -benzimidazole -5-carboxamide, 1 - [3 '- (acetylamino) -1, 1'-biphenyl-3-yl] -N-methyl-1 H-benzimidazole-5-carboxamide, 1- (3'-chloro-4' -fluoro-1, 1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, 1- [3- (1,3-benzodioxol-5-yl) phenyl] -N -methyl-1 H-benzimidazole-5-carboxamide, 1- (1,1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - (2'- phenoxy-1, 1 '-
biphenyl-3-yl) -1 H-benzimidazole-5-carboxamide, 1 - [3- (2,3-dihydro-1-benzofuran-5-yl) phenyl] -N-methyl-1 H-benzimidazole-5- carboxamide, N-methyl-1 -. { 3'- [(methylsulfonyl) amino] -1,1'-biphenyl-3-yl} -1 H-benzimidazole-5-carboxamide, 1 - [3- (5-chlorothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - (3-thien) -2-ylphenyl) -1 H-benzimidazole-5-carboxamide, 1- (1,1 '-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1- ( 4'-methyl-1, 1 '-biphenyl-3-yl) -1H-benzimidazole-5-carboxamide, 1- (3'-fluoro-1, 1'-biphenyl-3-yl) -N-methyl- 1 H-benzimidazole-5-carboxamide, 1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (tert-butyl) -1 - (3-thien-3-ylphenyl) - 1 H-benzimidazole-5-carboxamide, 1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, 1- [3- (3, 5-dimethylisoxazol-4-yl) phenyl] -N-ethyl-1 H-benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1- [3- (3,5-dimethylisoxazole-4- il) phenyl] -1H-benzimidazole-5-carboxamide, 1 - [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-tetrahydro-2H-pyran-4-yl-1 H-benzimidazole- 5-carboxamide, N-tetrahydro-2H-pyran-4-yl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-tetrahydro-2H-pyran-4-yl-1 - (3-pyrrol-2-ylphenyl) -1 H-benzimidazole-5-carboxamide, N-methyl-1 - [3- (2-naphthyl) phenyl] -1 H -benzimidazole-5-carboxamide, N-methyl- 1 - [4 '- (methylsulfonyl) -1,1' -biphenyl-3-yl] -1 H -benzimidazole-5-carboxamide, 1 - [3- (1-benzothien-2-yl) phenyl] -N- methyl-1 H-benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1 - (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3) ilmethyl) -1- [3- (1 H -pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- (1,3-benzodioxol-5-ylmethyl) -1- [3- ( 1 H-pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide.
15. - A compound, characterized in that it consists of 1- (4'-cyano-1, 1 '-biphenyl-3-yl) -N-pyridin-3-ylmethyl-1 H-benzimidazole-5-carboxamide, N- (pyridin- 3-ylmethyl) -1 - (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- (3'-chloro-4'-phloro-1,1'-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1- (3'-cyano-1, 1'-biphenyl-3-yl) -N- (pyridin-3-methyl) -1 H-benzimidazole-5-carboxamide, 1- (3'-nitro-1, 1'-biphenyl-3-yl) -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, 1 - (2'-nitro-1, 1 '-biphenyl-Si-N-Ípyridin-S-ilmethyl) -! H-benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. 16. A compound, characterized in that it consists of 1- [3 '- (acetylamino) -l, 1'-biphenyl-3-ylj-N-methyl-1H-benzimidazole-5-carboxamide, 1- (3'- chloro-4'-fluoro-1, 1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, 1- (1,1'-biphenyl-3-yl) -N-methyl -1H-benzimidazole-5-carboxamide, N-methyl-1- (2'-phenoxy-1,1'-biphenyl-3-yl) -1H-benzimidazole-5-carboxamide, N-methyl-1-. { 3'- [(methylsulfonyl) amino] -1,1'-biphenyl-3-yl} -1 H-benzimidazole-5-carboxamide, 1- (1, 1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - (4'-methyl- 1,1 '-biphenyl-3-yl) -1 H-benzimidazole-5-carboxamide, 1- (3'-fluoro-1, 1'-biphenyl-3-yl) -N-methyl-1 H-benzimidazole- 5-carboxamide, N-methyl-1- [4 '- (methylsulfonyl) -1, 1'-biphenyl-3-yl] -1H-benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. 17. A compound, characterized in that it consists of N- (pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N- ( pyridin-3-methylmethyl) -1 - (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1 - [3- (1-benzyl-1 H -pyrazol-4-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N-
(pyridin-3-ylmethyl) -1- [3- (1 H -pyrrol-3-yl) phenyl] -1 H -benzimidazole-5-carboxamide, 1- [3- (1-methyl-1 H -pyrrol- 2-yl) phenyl] -N- (pyridin-3-ylmethyl) -1 H -benzimidazole-5-carboxamide, N- (pyridin-3-ylmethyl) -1- [3- (1,3-tiazole- 2-yl) pheny] -1 H-benzimidazole-5-carboxamide, 1 - [3- (3,5-dimethylisoxazole-4-yl) pheny] -N-tetrahydro-2H-pyran-4- il-1 H-benzimidazole-5-carboxamide, N-tetrahydro-2H-pyran-4-yl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-tetrahydro-2H- piran-4-yl-1 - (3-pyrrol-2-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (1,3-benzodioxol-5-ylmethyl) -1- [3- (1 H- pyrrol-1-yl) phenyl] -1H-benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. 18. A compound, characterized in that it consists of N-methyl-1- (3-thien-3-phenyl) -1 H -benzimidazole-5-carboxamide, N-methyl-1- [3- (1 H-pyrrol- 2-yl) phenyl] -1H-benzimidazole-5-carboxamide, N-ethyl-1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N-ethyl-1- [3- (1 H-pyrrol-2-yl) phenyl] -1 H -benzimidazole-5-carboxamide, N-methyl-1- (3-pyridin-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, 1- [ 3- (1, 3-benzodioxol-5-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, 1- [3- (2,3-dihydro-1-benzofuran-5-yl) phenyl ] -N-methyl-1 H-benzimidazole-5-carboxamide, 1 - [3- (5-chlorothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - (3-thien-2-ylphenyl) -1 H-benzimidazole-5-carboxamide, 1- (3-thien-3-ylphenyl) -1 H -benzimidazole-5-carboxamide, N- (tert-butyl) -1 - (3-thien-3-ylphenyl) -1 H-benzimidazole-5-carboxamide, 1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-methyl-1 H-benzimidazole-5- carboxamide, 1 - [3- (3,5-dimethylisoxazol-4-yl) phenyl] -N-ethyl-1 H-benzimidazole-5-carboxamide, N-methyl-1 - [3- (2-naphthyl) phenyl] -1 H-benzimidazole-5-car boxamide, 1 - [3- (1-benzothien-2-yl) phenyl] -N-methyl-1 H-benzimidazole-5-carboxamide, N- (pyridin-3-
ilmethyl) -1- [3- (1 H -pyrrol-1-yl) phenyl] -1 H -benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. 19. A compound, further characterized in that it consists of N- [2- (dimethylamino) ethyl] -1- (3-thien-3-ylphenyl) -1 H-benzimidazole-5-carboxamide, N- [2- (dimethylamino ) ethyl] -1- [3- (3,5-dimethylisoxazol-4-yl) phenyl] -1H-benzimidazole-5-carboxamide, N- [2- (dimethylamino) ethyl] -1 - (3-pyrrol- 2-ylphenyl) -1 H-benzimidazole-5-carboxamide, or its pharmaceutically acceptable salt or N-oxide. 20. The use of a compound as claimed in claim 1, in the preparation of a drug useful for the treatment of hyperproliferative disorder. 21. The use as claimed in claim 20, wherein the medicament is further adapted to be administrable with an anti-neoplastic, anti-tumor, anti-angiogenic or chemotherapeutic agent. 22. The use as claimed in claim 20, wherein the hyperproliferative disorder is breast cancer, head cancer, or neck cancer. 23. The use as claimed in claim 20, wherein the hyperproliferative disorder is gastrointestinal cancer. 24. The use as claimed in claim 20, wherein the hyperproliferative disorder is leukemia. 25. The use as claimed in claim 20, wherein the hyperproliferative disorder is cancer of the ovary, bronchus, lung or pancreas.
26. - The use as claimed in claim 20, wherein the hyperproliferative disorder is small cell lung or colon cancer. 27. The use as claimed in claim 20, wherein the hyperproliferative disorder is natural killer sinonasal cells / T lymphocytes, testicular cancer (seminoma), thyroid carcinoma, malignant melamoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, acute lymphoblastic leukemia of prediátrica T lymphocyte, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma and prostate carcinoma. 28.- A combinatorial gentoteca, characterized because it comprises at least three benzimidazoles formed by the reaction:
wherein: R1 and R2 are independently C0-8 alkyl optionally
substituted with a heterocyclyl substituent, C0-β alkyl optionally substituted with 1-6 halo independent substituents, -CONR11R12, -NR13CONR11R12, -NR13CO2R11, -S (O) 0. NR 11 R 12, -NR 11 S (O) or-2 R 12, CN, OH or optionally substituted aryl; -C0-8-C3-cycloalkyl-C3-alkyl, -C0.8-O-alkyl -C1-, -C0-8-N-alkyl (C0-βC1-alkyl-alkyl), -C0-β-S-alkyl (O ) 0-2-C0.8 alkyl; or heterocyclyl optionally substituted with 1-4 unsubstituted substituents of C0-8 alkyl, cyclic or substituted cyclyl; or R1 and R2, taken together with the nitrogen to which they are attached, form a heterocyclic group, optionally substituted with 1-4 independent substituents of Co-β, -alkyl Co-β-O-C0-βalkyl, -alkyl Co -β-aryl, or groups-Co-β-heteroaryl alkyl; R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of C0-β, -C1-cyclyl alkyl, halo, OH, -NR31s (O) 0-2R32, -S (O) 0-2NR3 R32, -NR3 COR32, -NR31CONR32R33, -CONR31R32, S (O) 0-2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R11, R12, R13, R31, R32, and R33 are each independently C0-β alkyl optionally substituted with a heterocyclyl substituent, C0-8 alkyl optionally substituted with 1-6 halo-independent substituents, -CON (C0-8 alkyl) ) (Co-ß alkyl), -N (C0-ß alkyl) CON (Co-ßXalkyl C0-ß alkyl), -N (C0-8 alkyl) CO2 (Co-ß alkyl), S (O) 0.2N ( C0-8 alkylC0-8 alkyl), -NR11S (O) 0.2 (C0-8 alkyl), CN, OH, or optionally substituted aryl; -alkyl Co-β-cycloalkyl C3.8, -alkyl Co-ß-O-alkyl Co-ß, -alkyl C0.8-N (C0-8 alkyl) (C0.8 alkyl), -C0.8 alkyl- S (O) 0-2-C0-βalkyl; or heterocyclyl optionally substituted with 1-4 alkyl substituents of Co-β, cyclyl, or cyclyl substituted.
29. - A combinatorial library, characterized in that it comprises at least three becimidazoles formed from the reaction of a benzimidazole carboxylic acid supported with polymer with an amine selected from (aminomethyl) cyclopropane; 2- (2-aminoethyl) pyridine; 2- (aminomethyl) pyridine; 4- (2-aminoethyl) morpholine; tetrahydrofurfurylamine; veratrylamine; 1- (2-aminoethyl) -2-imidazolone; 5-amino-2-methoxyphenol; 3-aminobenzyl alcohol; 4-amino-m-cresol; 5-chloro-2-methylbenzylamine; 2- (aminoethyl) -5-methylpyrazine; 3- (2-aminoethyl) pyridine; 4- (trifluoromethyl) piperidine; 3-picolylmethylamine; 1- (3-aminopropyl) imidazole; 1- (3-aminopropyl) -2-pyrrolidinone; isopropylamine; 2-methylbenzylamine; 3-methylbenzylamine; 3-fluorobenzylamine; 4-fluorobenzylamine; N, N-dimethyl-1,3-propanediamine; 4- (3-aminopropyl) morpholine; DL-1-amino-2-propanol; cyclopropylamine; 2-methoxyethylamine; histamine; piperonylamine; 1-phenylpiperazine; 4-piperazinoacetophenone; 1- (2-pyridyl) piperazine; 4-hydroxy-4-phenylpiperidine; 4-acetyl-4-phenylpiperidine; 1- (3-methoxyphenyl) piperazine; 1- (4-methoxyphenyl) piperazine; 1-methylpiperazine; 1- (2-methoxyphenyl) piperazine; 1- (2-hydroxyethyl) piperazine; 1- (2,4-dimethoxyphenyl) piperazine; 1-piperazinepropanol; 1- (2-morpholinoethyl) piperazine; 1- (4-hydroxyphenyl) piperazine; 1- (2-furoyl) piperazine; 1-ethylpiperazine; 1-acetylpiperazine; 2-piperazin-1-yl-1-pyrrolidin-1-ylethanone; N, N-dimethylethylenediamine; 4-benzylpiperidine; 4-cyano-4-phenylpiperidine hydrochloride; 1- (2-dimethylaminoethyl) piperazine; 4-benzyl-4-hydroxypiperidine; 1- (4-pyridyl) piperazine; N- (3-hydroxyphenyl) piperazine; N- (2-hydroxyphenyl) piperazine; 1- (2-cyanophenyl) piperazine; 4- (hydroxymethyl) piperidine; 4-hydroxypiperidine; 4-
piperidinopiperidine; 4- (1-pyrolidino) piperidine; isonipecotamide; piperidine; N, N-diethylnipecotamide; 3-piperidynametanol; 3-hydroxypiperidine; 4-piperazinoindole; 1- (2-pyrazinyl) piperazine; 4- (aminomethyl) pyridine; 4- (trifluoromethoxy) benzylamine; 4-methoxybenzylamine; 4-chlorobenzylamine; 1- (tetrahydro-2-furoyl) piperazine; 1- (2- (6-methylpyridyl)) piperazine; 1- (4-cyanophenyl) piperazine; 3-chloro-4-methylbenzylamine; pyrrolidine; diethylamine; 4-piperazinoindole; 1, 2,3,6-tetrahydropyridine; 2- (2-methylaminoethyl) pyridine; 1-methyl-4- (methylamino) piperidine; 1- (2-pyrrolidinylmethyl) pyrrolidine; N, N, N'-trimethylethylenediamine; 2,6-dimethylmorpholine; 8-aza-1, 4-dioxaspiro [4.5] decane (4-piperidone ethylene ketal); N- (4-aminophenyl) -N-methylacetamide; 2- (4-aminophenyl) ethanol; 3-fluoro-P-anisidine; p-toluidine; 3,4-ethylenedioxianiline; 1-acetyl-6-aminoindoline; 4-fluoroaniline; 3-fluoro-4-methylaniline; p-anisidine; 3-chloro-4-fluoroaniline; m-anisidine; 3,4-difluoroaniline; 3-methoxybenzylamine; 4-methylbenzylamine; 3-chloro-4-methylaniline; 3- (trifluoromethyl) benzylamine; 2-chlorobenzylamine; 3,5-dimethoxybenzylamine; 2-fluorobenzylamine; 3- (trifluoromethoxy) benzylamine; 4-aminoacetanilide; 3-amino-o-cresol; N1- (4-amino-2-methylphenyl) acetamide; 1- (2-piperidinoethyl) piperazine; 1-morpholin-4-yl-2-piperazin-1-yl-ethanone; 1- (4-pyridylmethyl) piperazine; N, N-dimethyl-2-piperazin-1-yl-acetamide; 1- (3-dimethylaminopropyl) piperazine; 1- (3-morpholinopropyl) piperazine; 1- (3-pyrrolidinopropyl) piperazine; 1- (2-ethoxyethyl) piperazine; 1-pyridin-2-ylmethylpiperazine; (4-fluorophenyl) piperazin-1-ylmethanone; (3-fluorophenyl) piperazin-1-ylmethanone; 2-aminobenzyl alcohol; 4-aminotetrahydropyran; ethylamine; methylamine; benzylamine; cyclohexanomethylamine; 3- (aminomethyl) pyridine;
Butylamine; 2-piperidineethanol; morpholine; 1- (3-methoxyphenyl) piperazine; n-methylcyclohexylamine; or 2,4-dimethoxyaniline. 30.- A combinatorial library, characterized in that it comprises at least three benzimidazoles formed from the Suzuki reaction of a boronic acid with an N-bromophenyl benzimidazole carboxylic acid:
to form a substituted N-phenylbenzimidazole carboxylic acid R3, wherein R3 is an aryl or hetaryl group, optionally substituted with 1-4 independent substituents of Co-β alkyl, Co-β-cyclyl alkyl, halo, OH, -NR31s ( O) 0-2R32, -S (O) 0-2NR31R32, -NR31COR32, -NR31CONR32R33, -CONR31R32, S (O) 0.2R31, -O-aryl, -O-hetaryl, NO2, CN, CF3, OCF3, OCHF2; R31, R32, and R33 are each independently C0.8 alkyl optionally substituted with a heterocyclyl substituent, C0-8 alkyl optionally substituted with 1-6 halo-independent substituents, -CON (C0-βXalkyl Co-β alkyl), - N (C0-β alkyl) CON (C0-8 alkyl) (C 1-8 alkyl), -N (C0-ß alkyl) CO2 (C0.8 alkyl), S (O) 0-2N (C0-β alkyl) (C0-8 alkyl), -NR 1S (O) 0.2 (C0.8 alkyl), CN, OH, or optionally substituted aryl; -alkyl Co-β-cycloalkyl C3-8, -alkyl C0-8-O-alkyl Co-8, -alkyl C0.8-N (alkyl Co-β) (C0-β alkyl), -alkyl C0- 8-S (O) 0-2-C0-8 alkyl;
Or heterocyclyl optionally substituted with 1-4 alkyl substituents of Co-β, cyclic, or cyclic substituted; followed by the reaction of the N-phenylbenzimidazole carboxylic acid R3 substituted with an amine selected from (aminomethyl) cyclopropane; 2- (2-aminoethyl) pyridine; 2- (aminomethyl) pyridine; 4- (2-aminoethyl) morpholine; tetrahydrofurfurylamine; veratrylamine; 1- (2-aminoethyl) -2-imidazolone; 5-amino-2-methoxyphenol; 3-aminobenzyl alcohol; 4-amino-m-cresol; 5-chloro-2-methylbenzyl amine; 2- (aminoethyl) -5-methylpyrazine; 3- (2-aminoethyl) pyridine; 4- (trifluoromethyl) piperidine; 3-picolylmethylamine; 1- (3-aminopropyl) imidazole; 1- (3-aminopropyl) -2-pyrrolidinone; isopropylamine; 2-methylbenzylamine; 3-methylbenzylamine; 3-fluorobenzylamine; 4-fluorobenzylamine; N, N-dimethyl-1,3-propanediamine; 4- (3-aminopropyl) morpholine; DL-1-amino-2-propanol; cyclopropylamine; 2-methoxyethylamine; histamine; piperonylamine; 1-phenylpiperazine; 4-piperazinoacetophenone; 1- (2-pyridyl) piperazine; 4-hydroxy-4-phenylpiperidine; 4-acetyl-4-phenylpiperidine; 1- (3-methoxyphenyl) piperazine; 1- (4-methoxyphenyl) piperazine; 1-methylpiperazine; 1- (2-methoxyphenyl) piperazine; 1- (2-hydroxyethyl) piperazine; 1- (2,4-dimethoxyphenyl) piperazine; 1-piperazinepropanol; 1- (2-morpholinoethyl) piperazine; 1- (4-hydroxyphenyl) piperazine; 1- (2-furoyl) piperazine;
1 - . 1-ethylpiperazine; 1-acetylpiperazine; 2-piperazin-1-yl-1-pyrrolidin-1-yletanone; N, N-dimethylethylenediamine; 4-benzylpiperidine; 4-cyano-4-phenylpiperidine hydrochloride; 1- (2-dimethylaminoethyl) piperazine; 4-benzyl-4-hydroxypiperidine; 1- (4-pyridyl) piperazine; N- (3-hydroxyphenyl) piperazine; N- (2-hydroxyphenyl) piperazine; 1- (2-cyanophenyl) piperazine; 4- (hydroxymethyl) piperidine; 4-hydroxypiperidine; 4-
piperidinopiperidine; 4- (1-pyrrolidino) piperidine; isonipecotamide; piperidine; N, N-diethylnipecotamide; 3-piperidinemethanol; 3-hydroxypiperidine; 4-piperazinoindole; 1- (2-pyrazinyl) piperazine; 4- (amimethyl) pyridine; 4- (trifluoromethoxy) benzylamine; 4-methoxybenzylamine; 4-chlorobenzylamine; 1- (tetrahydro-2-furoyl) piperazine; 1- (2- (6-methylpyridyl)) piperazine; 1- (4-cyanophenyl) piperazine; 3-chloro-4-methylbenzylamine; pyrrolidine; diethylamine; 4-piperazinoindole; 1, 2,3,6-tetrahydropyridine; 2- (2-methylaminoethyl) pyridine; 1-methyl-4- (methylamino) piperidine; 1- (2-pyrrolidinylmethyl) pyrrolidine; N, N, N'-trimethylethylenediamine; 2,6-dimethylmorpholine; 8-aza-1, 4-dioxaspiro [4.5] decane (4-piperidone ethylene ketal); N- (4-aminophenyl) -N-methylacetamide; 2- (4-aminophenyl) ethanol; 3-fluoro-P-anisidine; p-toluidine; 3,4-ethylenedioxianiline; 1-acetyl-6-aminoindoline; 4-fluoroaniline; 3-fluoro-4-methylaniline; p-anisidine; 3-chloro-4-fluoroaniline; m-anisidine; 3,4-difluoroaniline; 3-methoxybenzylamine; 4-methylbenzylamine; 3-chloro-4-methylaniline; 3- (trifluoromethyl) benzylamine; 2-chlorobenzylamine; 3,5-dimethoxybenzylamine; 2-fluorobenzylamine; 3- (trifluoromethoxy) benzylamine; 4-aminoacetanilide; 3-amino-o-cresol; N1- (4-amino-2-methylphenyl) acetamide; 1- (2-piperidinoethyl) piperazine; 1-morpholin-4-yl-2-piperazin-1-yl-ethanone; 1- (4-pyridylmethyl) piperazine; N, N-dimethyl-2-piperazin-1-yl-acetamide; 1- (3-dimethylaminopropyl) piperazine; 1- (3-morpholinopropyl) piperazine; 1- (3-pyrrolidinopropyl) piperazine; 1- (2-ethoxyethyl) piperazine; 1-pihdin-2-ylmethylpiperazine; (4-fluorophenyl) piperazin-1-ylmethanone; (3-fluorophenyl) piperazin-1-ylmethanone; 2-aminobenzyl alcohol; 4-aminotetrahydropyran; ethylamine; methylamine; benzylamine; cyclohexanomethylamine; 3- (aminomethyl) pyridine;
Butylamine; 2-piperidineethanol; morpholine; 1- (3-methoxyphenyl) piperazine; n-methylcyclohexylamine; or 2,4-dimethoxyaniline. 31. The library according to claim 30, further characterized in that the boronic acid is thiophene-3-boronic acid; 1- (t-butoxycarbonyl) -2-pyrrole boronic acid; 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborolane; 3,5-dimethylisoxazole-4-boronic acid; pyridine-3-boronic acid, thiophen-2-boronic acid; 1- (t-butoxycarbonyl) -2-pyrrole boronic acid; 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborolane; 3,5-dimethylisoxazole-4-boronic acid; or pyridine-3-boronic acid. 32. A combinatorial library, characterized in that it comprises at least three benzimidazoles formed from the amination of an N-bromophenyl benzimidazole carboxylic acid, thus replacing the bromine with an amine, wherein the amine includes morpholine, 3-chlorobenzylamine , 3- (aminomethyl) pyridine, and 2,6-dimethylaniline.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/632,432 | 2004-12-01 |
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