ZA200103610B - Tricyclic pyrazole derivatives. - Google Patents
Tricyclic pyrazole derivatives. Download PDFInfo
- Publication number
- ZA200103610B ZA200103610B ZA200103610A ZA200103610A ZA200103610B ZA 200103610 B ZA200103610 B ZA 200103610B ZA 200103610 A ZA200103610 A ZA 200103610A ZA 200103610 A ZA200103610 A ZA 200103610A ZA 200103610 B ZA200103610 B ZA 200103610B
- Authority
- ZA
- South Africa
- Prior art keywords
- phenyl
- group
- optionally substituted
- alkyl
- dihydroindeno
- Prior art date
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- 150000003217 pyrazoles Chemical class 0.000 title description 3
- -1 tri-substituted phenyl Chemical group 0.000 claims description 512
- 125000000217 alkyl group Chemical group 0.000 claims description 320
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 316
- 229910052799 carbon Inorganic materials 0.000 claims description 180
- 125000003545 alkoxy group Chemical group 0.000 claims description 163
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 150
- 229910052739 hydrogen Inorganic materials 0.000 claims description 133
- 125000005843 halogen group Chemical group 0.000 claims description 121
- 239000001257 hydrogen Substances 0.000 claims description 119
- 150000001875 compounds Chemical class 0.000 claims description 95
- 150000002431 hydrogen Chemical class 0.000 claims description 83
- 125000003277 amino group Chemical group 0.000 claims description 78
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 70
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 57
- 229910052760 oxygen Inorganic materials 0.000 claims description 57
- 125000004076 pyridyl group Chemical group 0.000 claims description 54
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 125000001544 thienyl group Chemical group 0.000 claims description 36
- 125000002541 furyl group Chemical group 0.000 claims description 32
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 25
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 25
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 239000001301 oxygen Substances 0.000 claims description 25
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 21
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 102000001253 Protein Kinase Human genes 0.000 claims description 13
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 13
- 108060006633 protein kinase Proteins 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 102000004190 Enzymes Human genes 0.000 claims description 11
- 108090000790 Enzymes Proteins 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 230000033115 angiogenesis Effects 0.000 claims description 9
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 claims description 9
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 claims description 7
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 108091000080 Phosphotransferase Proteins 0.000 claims description 5
- 102000020233 phosphotransferase Human genes 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 3
- 206010030113 Oedema Diseases 0.000 claims description 3
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 3
- 208000002780 macular degeneration Diseases 0.000 claims description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 3
- 206010003445 Ascites Diseases 0.000 claims description 2
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 206010063045 Effusion Diseases 0.000 claims description 2
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims 45
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 28
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 21
- 125000003342 alkenyl group Chemical group 0.000 claims 20
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 20
- 125000003282 alkyl amino group Chemical group 0.000 claims 19
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 17
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 15
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 14
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 14
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 14
- 125000003368 amide group Chemical group 0.000 claims 14
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 14
- 125000001153 fluoro group Chemical group F* 0.000 claims 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 14
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 13
- 125000001624 naphthyl group Chemical group 0.000 claims 13
- 125000005554 pyridyloxy group Chemical group 0.000 claims 13
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims 13
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical group CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 claims 12
- 125000000304 alkynyl group Chemical group 0.000 claims 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 10
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 9
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims 9
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 9
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 9
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 8
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 8
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 8
- 239000004202 carbamide Substances 0.000 claims 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 8
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims 7
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 7
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 7
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 7
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 7
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 7
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 7
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 7
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 7
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims 7
- 150000001408 amides Chemical class 0.000 claims 7
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 7
- 125000004104 aryloxy group Chemical group 0.000 claims 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 7
- 229910052794 bromium Inorganic materials 0.000 claims 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims 7
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 7
- 229910052731 fluorine Inorganic materials 0.000 claims 7
- 229910052740 iodine Inorganic materials 0.000 claims 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 7
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 7
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 7
- 150000003536 tetrazoles Chemical class 0.000 claims 7
- 150000003852 triazoles Chemical class 0.000 claims 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 6
- 230000005764 inhibitory process Effects 0.000 claims 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 5
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 5
- 241000689227 Cora <basidiomycete fungus> Species 0.000 claims 5
- 229910052801 chlorine Inorganic materials 0.000 claims 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 5
- 239000000203 mixture Substances 0.000 claims 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
- AOPRXJXHLWYPQR-UHFFFAOYSA-N 2-phenoxyacetamide Chemical compound NC(=O)COC1=CC=CC=C1 AOPRXJXHLWYPQR-UHFFFAOYSA-N 0.000 claims 3
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- ZJZNZNMPNRNCLA-UHFFFAOYSA-N 2-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]ethanol Chemical compound OCCOC1=CC=CC(C=2C3=C(C4=CC=CC=C4C3)NN=2)=C1 ZJZNZNMPNRNCLA-UHFFFAOYSA-N 0.000 claims 2
- BWRNWWSQZROEOA-UHFFFAOYSA-N 2-morpholin-4-ylacetamide Chemical compound NC(=O)CN1CCOCC1 BWRNWWSQZROEOA-UHFFFAOYSA-N 0.000 claims 2
- DEQJKZRYMLWJBH-UHFFFAOYSA-N 3-phenyl-1h-[1]benzothiolo[3,2-c]pyrazole Chemical compound C1=CC=CC=C1C1=NNC2=C1SC1=CC=CC=C12 DEQJKZRYMLWJBH-UHFFFAOYSA-N 0.000 claims 2
- JONNOQBWAKYHJE-UHFFFAOYSA-N 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)-n-(2-morpholin-4-ylethyl)benzamide Chemical compound C=1C=C(C=2C3=C(C4=CC=CC=C4C3)NN=2)C=CC=1C(=O)NCCN1CCOCC1 JONNOQBWAKYHJE-UHFFFAOYSA-N 0.000 claims 2
- MRDKBCGWHNPOFW-UHFFFAOYSA-N 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)-n-methylbenzamide Chemical compound C1=CC(C(=O)NC)=CC=C1C1=NNC2=C1CC1=CC=CC=C21 MRDKBCGWHNPOFW-UHFFFAOYSA-N 0.000 claims 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 2
- 206010016654 Fibrosis Diseases 0.000 claims 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 claims 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- WTNAMXIGHPHQLL-UHFFFAOYSA-N n-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)acetamide Chemical compound C=1C(NC(=O)C)=CC=C2C=1CC1=C2NN=C1C1=CC=CC=C1 WTNAMXIGHPHQLL-UHFFFAOYSA-N 0.000 claims 2
- OLBCBJLTUPNFPS-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide Chemical compound C1=CC(C(=O)NCCN(CC)CC)=CC=C1C1=NNC2=C1CC1=CC=CC=C21 OLBCBJLTUPNFPS-UHFFFAOYSA-N 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- RHWVVGJOLLGHPM-UHFFFAOYSA-N 1-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-1-(2-morpholin-4-ylethyl)urea Chemical compound C=1C=C(C=2C3=C(C4=CC=CC=C4C3)NN=2)C=CC=1N(C(=O)N)CCN1CCOCC1 RHWVVGJOLLGHPM-UHFFFAOYSA-N 0.000 claims 1
- IFPJOYYOWRGVSW-UHFFFAOYSA-N 1-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-3-(2-piperidin-1-ylethyl)urea;urea Chemical compound NC(N)=O.C=1C=C(C=2C3=C(C4=CC=CC=C4C3)NN=2)C=CC=1NC(=O)NCCN1CCCCC1 IFPJOYYOWRGVSW-UHFFFAOYSA-N 0.000 claims 1
- CICIXNWIIGJYFK-UHFFFAOYSA-N 1-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-3-(pyridin-4-ylmethyl)urea Chemical compound C=1C=C(C=2C3=C(C4=CC=CC=C4C3)NN=2)C=CC=1NC(=O)NCC1=CC=NC=C1 CICIXNWIIGJYFK-UHFFFAOYSA-N 0.000 claims 1
- KAUABWYBFARJAF-UHFFFAOYSA-N 1h-pyrazol-4-ol Chemical compound OC=1C=NNC=1 KAUABWYBFARJAF-UHFFFAOYSA-N 0.000 claims 1
- NEYLQPUBSGXTBO-UHFFFAOYSA-N 2-(1,4-diazepan-1-yl)-n-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]acetamide Chemical compound C=1C=C(C=2C3=C(C4=CC=CC=C4C3)NN=2)C=CC=1NC(=O)CN1CCCNCC1 NEYLQPUBSGXTBO-UHFFFAOYSA-N 0.000 claims 1
- PIPBEWHETLVUCG-UHFFFAOYSA-N 2-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]-n-(2-morpholin-4-ylethyl)acetamide Chemical compound C=1C=CC(C=2C3=C(C4=CC=CC=C4C3)NN=2)=CC=1OCC(=O)NCCN1CCOCC1 PIPBEWHETLVUCG-UHFFFAOYSA-N 0.000 claims 1
- WOWVOEVNUNJEHD-UHFFFAOYSA-N 2-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(C=2C3=C(C4=CC=CC=C4C3)NN=2)=C1 WOWVOEVNUNJEHD-UHFFFAOYSA-N 0.000 claims 1
- JPULUQHTUYCRCO-UHFFFAOYSA-N 2-amino-2-ethyl-n-phenylbutanamide Chemical compound CCC(N)(CC)C(=O)NC1=CC=CC=C1 JPULUQHTUYCRCO-UHFFFAOYSA-N 0.000 claims 1
- XZUCBHPUPYFPNV-UHFFFAOYSA-N 2-chloro-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol Chemical compound C1=C(Cl)C(O)=CC=C1C1=NNC2=C1CC1=CC=CC=C21 XZUCBHPUPYFPNV-UHFFFAOYSA-N 0.000 claims 1
- GVQMFFMYOWZTFS-UHFFFAOYSA-N 2-ethyl-n-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)butanamide Chemical compound C=1C(NC(=O)C(CC)CC)=CC=C(C=2NN=3)C=1CC=2C=3C1=CC=CC=C1 GVQMFFMYOWZTFS-UHFFFAOYSA-N 0.000 claims 1
- FKVIYERFOLSTTM-UHFFFAOYSA-N 2-fluoro-n-phenylacetamide Chemical compound FCC(=O)NC1=CC=CC=C1 FKVIYERFOLSTTM-UHFFFAOYSA-N 0.000 claims 1
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Description
TRICYCLIC PYRAZOLE DERIVATIVES
This invention relates to certain 3-aryl or 3-heteroaryl pyrazoles with 4,5(3,4)-bicyclic ring fusion which are inhibitors of protein kinases, particularly tyrosine kinases and serine/threonine kinases, of which some are novel compounds, to pharmaceutical compositions containing these pyrazoles and to processes for preparing these pyrazoles.
There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate.
The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.
The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or .25 localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.
Protein Tyrosine Kinases. Protein tyrosine kinases (PTKs) are enzymes which catalyse the phosphorylation of specific tyrosine residues in cellular proteins.
This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ulrich, 1992, Neuron 9:383-391),
Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders),
S allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKSs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving : inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas).
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular),
Receptor Tyrosine Kinases (RTKs). The RTKs comprise a large family of transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, receptor . tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans- phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment); see Schlessinger and Ullrich, 1992, Neuron 9:1-20.
Proteins with SH2 (src homology -2) or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals into cells. Both of the domains recognize phosphotyrosine (Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol.
Cell. Biol. 14:2777-2785; Songyang et al., 1993, Cell 72:767-778; and Koch et al., 1991, Science 252:668-678; Shoelson, Curr. Opin. Chem. Biol. (1997), 1(2), 227- 234; Cowbum, Curr. Opin. Struct. Biol. (1997), 7(6), 835-838). Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Cell 72:767-778). The specificity of the interactions between receptors or proteins and SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors correlate with the observed differences in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72:767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor as well as the timing and duration of those stimuli. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Several receptor tyrosine kinases, and growth factors that bind thereto, have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. Cell Biol. 129:895-898, 1995).
One such receptor tyrosine kinase, known as “fetal liver kinase 1” (FLK-1), is a member of the type III subclass of RTKs. An alternative designation for human
FLK-1 is “kinase insert domain-containing receptor” (KDR) (Terman er al,
Oncogene 6:1677-83, 1991). Another alternative designation for FLK-1/KDR is “vascular endothelial cell growth factor receptor 2” (VEGFR-2) since it binds VEGF with high affinity. The murine version of FLK-1/VEGFR-2 has also been called
NYXK (Oelrichs et al, Oncogene 8(1):11-15, 1993). DNAs encoding mouse, rat and human FLK-1 have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews er al., Proc. Natl. Acad. Sci. USA, 88:9026-30, 1991;
Terman et al., 1991, supra; Terman et al., Biochem. Biophys. Res. Comm. 187:1579- 86, 1992; Sarzani et al., supra; and Millauer et al., Cell 72:835-846, 1993).
Numerous studies such as those reported in Millauer et al., supra, suggest that
VEGF and FLK-1/KDR/VEGFR-2 are a ligand-receptor pair that play an important role in the proliferation of vascular endothelial cells, and formation and sprouting of blood vessels, termed vasculogenesis and angiogenesis, respectively.
Another type 11 subclass RTK designated “fims-like tyrosine kinase-1" (F1t- 1) is related to FLK-1/KDR (DeVries et al. Science 255;989-991, 1992; Shibuya et al., Oncogene 5:519-524, 1990). An alternative designation for Flt-1 is “vascular endothelial cell growth factor receptor 1” (VEGFR-1). To date, members of the
FLK-1/ KDR/VEGFR-2 and Flt-1/ VEGFR-1 subfamilies have been found expressed primarily on endothelial cells. These subclass members are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) family of ligands (Klagsburn and D’ Amore, Cytokine & Growth Factor Reviews 7: 259- 270, 1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with higher affinity than to FLK-1/KDR and is mitogenic toward vascular endothelial cells (Terman et al., 1992, supra; Mustonen et al. supra; DeVries et al., supra). Flt- 1 isbelieved to be essential for endothelial organization during vascular development. Flt-1 expression is associated with early vascular development in mouse embryos, and with neovascularization during wound healing (Mustonen and
Alitalo, supra). Expression of Fit-1 in adult organs such as kidney glomeruli suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra).
As previously stated, recent evidence suggests that VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al.,
Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and
Treatment 36: 139-155, 1995; Ferrara et al., Endocrine Reviews 18(1); 4-25, 1997;
Ferrara et al., Regulation of Angiogenesis (ed. L. D. Goldberg and E.M. Rosen), 209-232, 1997). In addition, VEGF has been implicated in the control and enhancement of vascular permeability (Connolly, et al., J. Biol. Chem. 264: 20017-
20024, 1989; Brown et al., Regulation of Angiogenesis (ed. L.D. Goldberg and E.M.
Rosen), 233-269, 1997).
Different forms of VEGF arising from altemative splicing of mRNA have been reported, including the four species described by Ferrara et al. (J. Cell. 5S Biochem. 47:211-218, 1991). Both secreted and predominantly cell-associated species of VEGF have been identified by Ferrara et al. supra, and the protein is known to exist in the form of disulfide linked dimers.
Several related homologs of VEGF have recently been identified. However, their roles in normal physiological and disease processes have not yet been elucidated. In addition, the members of the VEGF family are often coexpressed with
VEGF in a number of tissues and are, in general, capable of forming heterodimers with VEGF. This property likely alters the receptor specificity and biological effects of the heterodimers and further complicates the elucidation of their specific functions as illustrated below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159- 164, 1998 and references cited therein).
Placenta growth factor (PIGF) has an amino acid sequence that exhibits significant homology to the VEGF sequence (Park et al., J. Biol. Chem. 269:25646- 54, 1994; Maglione et al. Oncogene 8:925-31, 1993). As with VEGF, different species of PIGF arise from altemative splicing of mRNA, and the protein exists in dimeric form (Park et al., supra). PIGF-1 and PIGF-2 bind to Flt-1 with high affinity, and PIGF-2 also avidly binds to neuropilin-1 (Migdal et al, J. Biol. Chem. 273 (35): 22272-22278), but neither binds to FLK-1/KDR (Park et al., supra). PIGF has been reported to potentiate both the vascular permeability and mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (purportedly due to heterodimer formation) (Park ef al., supra).
VEGF-B is produced as two isoforms (167 and 185 residues) that also appear to bind Fit-1/VEGFR-1. It may play a role in the regulation of extracellular matrix degradation, cell adhesion, and migration through modulation of the expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1 (Pepperetal, Proc. Natl. Acad. Sci. U S. A. (1998), 95(20): 11709-11714).
VEGF-C was originally cloned as a ligand for VEGFR-3/Flt-4 which is primarily expressed by lymphatic endothelial cells. In its fully processed form,
A
VEGF-C can also bind KDR/VEGFR-2 and stimulate proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models ( Lymboussaki et al,
Am. J. Pathol. (1998), 153(2): 395-403; Witzenbichler ef al, Am. J. Pathol. (1998), 153(2), 381-394). The transgenic overexpression of VEGF-C causes proliferation and enlargement of only lymphatic vessels, while blood vessels are unaffected.
Unlike VEGF, the expression of VEGF-C is not induced by hypoxia (Ristimaki ez al, J. Biol. Chem. (1998), 273(14),8413-8418).
The most recently discovered VEGF-D is structurally very similar to VEGF-
C. VEGF-D is reported to bind and activate at least two VEGFRs, VEGFR-3/Flt-4 and KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominently expressed in the mesenchymal cells of the lung and skin (Achen et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(2), 548-553 and references therein).
VEGF-C and VEGF-D have been claimed to induce increases in vascular permeability in vivo in a Miles assay when injected into cutaneous tissue (PCT/US97/14696; WO98/07832, Witzenbichler et al., supra). The physiological role and significance of these ligands in modulating vascular hyperpermeability and endothelial responses in tissues where they are expressed remains uncertain.
Based upon emerging discoveries of other homologs of VEGF and VEGFRs and the precedents for ligand and receptor heterodimerization, the actions of such
VEGF homologs may involve formation of VEGF ligand heterodimers, and/or heterodimerization of receptors, or binding to a yet undiscovered VEGFR (Witzenbichler et al., supra). Also, recent reports suggest neuropilin-1 (Migdal et al, supra) or VEGFR-3/Flt-4 (Witzenbichler et al., supra), or receptors other than
KDR/VEGFR-2 may be responsible for the induction of vascular permeability (Stacker, S.A, Vitali, A, Domagala, T., Nice, E., and Wilks, A.F., “Angiogenesis and Cancer” Conference, Amer. Assoc. Cancer Res., Jan. 1998, Orlando, FL;
Williams, Diabetelogia 40: S118-120 (1997)). Until now, no direct evidence for the essential role of KDR in VEGF-mediated vascular hyperpermeability has been disclosed.
The Non-Receptor Tyrosine Kinases. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, :
Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of
PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogene 8:2025-2031, which is incorporated herein by reference.
Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyper-immune responses.
Development of Compounds to Modulate the PTKs. In view of the surmised importance of PTKs to the control, regulation, and modulation of cell proliferation, the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase "inhibitors" using a variety of approaches, including the use of mutant ligands (U.S.
Application No. 4,966,849), soluble receptors and antibodies (Application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Natl. Acad. Sci 90:10705-09; Kim et al., 1993, Nature 362:841-844), RNA ligands (Jellinek, et al., Biochemistry 33:10450- 56; Takano, et al., 1993, Mol. Bio. Cell 4:358A; Kinsella, er al. 1992, Exp. Cell Res. 199:56-62; Wright, et al., 1992, J. Cellular Phys. 152:448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Patent
No. 5,330,992; Mariani, et al., 1994, Proc. Am. Assoc. Cancer Res. 35.2268).
More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,3 02,606), certain quinazoline derivatives (EP
Application No. 0 566 266 Al; Expert Opin. Ther. Pat. (1998), 8(4): 475-478), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. Anilinocinnolines (PCT W(097/34876) and quinazoline derivative compounds (PCT W097/22596; PCT W(Q97/42187) have 5S been described as inhibitors of angiogenesis and vascular permeability.
In addition, attempts have been made to identify small molecules which act as serine/threonine kinase inhibitors. In particular, bis(indolylmaleimide) compounds have been described as inhibiting particular PKC serine/threonine kinase isoforms whose dysfunction is associated with altered vascular permeability in
VEGF-related diseases (PCT W097/40830; PCT W097/40831).
The 1dentification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders would be beneficial. : 20
The present invention provides a method of inhibiting the kinase activity of tyrosine kinases and serine/threonine kinases comprising the administration of a compound represented by formula I:
Rs
R, X R,
CLT
RS vo
Rs R,
and pharmaceutically acceptable salts thereof in which X represents a) substituted methylene ,b) carbonyl, c) oxygen, d) a group of formula -C=NOR?7 in which Ry represents H or a C1-4 alkyl group, e) a group of formula NRg in which Rg represents H, an optionally substituted C]-4 alkyl group or optionally substituted phenyl, f)a group of formula (CH, ), in which nis 1,2 or 3, or g) a group of formula S(O)p in which pis 0, 1 or 2;
R, represents H ;
R, represents aryl, pyridyl, thienyl, fury! or pyrrolyl each of which is optionally substituted;
R3,R4, Rs and Rg independently represent a) H, b) halo, ¢) a C]-4 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRpR; wherein Rp and Rj are as defined below, d) a C, ; alkoxy group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRyRj wherein Rp and R; are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula
CORg in which Rg represents hydroxy, a Cj.¢ alkoxy group or Rj represents a group of formula NRp Rc in which Rp and Rc independently represent hydrogen, a
C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula
NRhR; wherein Rp and Rj independently represent hydrogen or a Cj.¢ alkyl group or wherein Rp and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Cj.¢ alkyl group, h) a group of formula NR{ Re in which Rg and
Re are independently selected from hydrogen, a C1-12 alkyl group, a C3.12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C1.12 alkyl group, a C3.12 cycloalkyl group , a phenyl C1.g alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy , nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above 1) a group of formula O(CH2)m Rg in which ms 2, 3, 4 or § and Rg represents hydroxy or a group of formula NR4Re in which Rq and Re are as defined above; or
Rg represents a group of formula COR, wherein Rj, is as defined above and m is 1, 2,3, 4 or 5, j) nitro, k) optionally substituted phenyl C|-¢ alkyl, 1) optionally substituted phenyl! C}.¢ alkoxy m) cyano or 0) a C24 alkenyl group or a C24 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1-6 alkyl group, a C1.¢ alkoxy group or halo, with the provisos that 1) when X represents carbonyl or a substituted methylene, R is hydrogen and
R3, R4, Rs and Rg each represent hydrogen, then R2 is not pyridyl, phenyl or phenyl substituted by C1-2 alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; and 2) when X is a group of formula (CH, ), in which nis 1,2 or 3, Rj is hydrogen and two of R3, R4, R5 and Rg independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C]-4 alkyl, C]-4 alkoxy or trifluoromethyl! and the other two represent hydrogen, then R? is not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C1-4 alkyl, C1.4 alkoxy or trifluoromethyl; to said kinase in sufficient concentration to inhibit the enzyme activity of said kinase.
In further embodiments, R3, R4 , R5 and Rg independently represent a) H, b) halo, ¢) a Cy.6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, d) a C, (alkoxy group optionally substituted by one or more of the
S following: hydroxy, a C, salkoxy, halo or an amino group of formula NRpR; wherein
Rh and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula COR3 in which Rj represents hydroxy, a
C1-6 alkoxy group or Ry represents a group of formula NRp Re in which Rp and Re independently represent hydrogen, a C1-g alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a Cj-¢ alkyl group, (C;-C)heterocycloalkyl-(C,-Cy)alkyl (heterocycloalkyl = pyridine, morpoline, piperazine, and N-methylpiperazine) or wherein Rp and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a C1. alkyl group, h) a group of formula NR{ Re in which Rg and
Re are independently selected from hydrogen, a C-12 alkyl group, a C3-12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C1-12 alkyl group, a C3-12 cycloalkyl group, a phenyl Cj.¢ alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above i) a group of formula O(CH2)m Rg in whichm is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or
Rg represents a group of formula CORg wherein Rj is as defined above and m is 1, 2,3,40r5, j)nitro, k) optionally substituted phenyl Ci_¢ alkyl, 1) optionally substituted phenyl C1.¢ alkoxy m) cyano or 0) a C4 alkenyl group ora C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally
Claims (1)
- AMENDED SHEET ® WO 00/27822 oo PCT/US99/26105 CLAIMS1. A compound of formula I or its pharmaceutically acceptable salts for use in inhibiting protein kinase activity by a method which comprises the administration of the compound of formula I in sufficient concentration to inhibit the enzyme activity of said kinase. R, R, X\ ‘Ry . LKRe. Ri in which X represents a) substituted methylene ,b) carbonyl, ¢) oxygen, d) a group of formula -C=NOR?7 in which R7 represents H or a C14 alkyl group, e) a group of ) formula NR§g in which Rg represents H, an optionally substituted C}-4 alkyl group or optionally substituted phenyl, f) a group of formula (CH, ), in whichnis 1,2 or 3, or g) a group of formula S(O)p in whichp is 0,1 0r2; 18 R, represents H ; R, represents aryl, pyridyl, thienyl, fury! or pyrrolyl each of which is optionally substituted; R3,R4, Rs and Rg independently represent a) H, b) halo, c) a C1.¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhRj wherein Rp and Rj are as defined below, d) a C, jalkoxy group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula CORja in which Rj represents hydroxy; a Cj.6 alkoxy group or Ra represents a group of formula NR} Re in which Rp and Rc independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a C1.6 alkyl group or wherein Rp, and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Cj. alkyl group, h) a group of formula NRq Re in which R4 and Re are independently selected from hydrogen, a C]-12 alkyl group , a C3.12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C112 alkyl group, a C3-12 cycloalkyl group , a phenyl Cj-6 alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above 1) a group of formula O(CH2)m Rg in whichm is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NR4Re in which Rg and Re are as defined above; or Rgrepresents a group of formula COR, wherein Rj is as defined above and m is 1, 2,3, 4 or5, )) nitro, k) optionally substituted phenyl C1-¢ alkyl, 1) optionally substituted phenyl Cj. alkoxy m) cyano or 0) a C2-4 alkenyl group or a C24 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C]-¢ alkyl group, a C1-¢ alkoxy group or halo, with the provisos that 1) when X represents carbonyl or a substituted methylene, R| is hydrogen and . R3,R4, R5 and Rg each represent hydrogen, then R2 is not pyridyl, phenyl or phenyl substituted by C1. alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; and 2) when X is a group of formula (CH, ), in which nis 1, 2 or 3, Ry is hydrogen and two of R3, R4, R5 and Rg independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C-4 alkyl, C4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R2 is not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl! having twoAMENDED SHEET ® | WO 00127822 ) PCT/US99/26105 ~~ or less substituents wherein the substituents are halogen having an atomic - weight of about 19 to 36, C1.4 alkyl, C1-4 alkoxy or trifluoromethyl. . 5 . . , T2. Compound of Claim 1 wherein said protein kinase is tyrosine kinase.3. . Compound of Claim 2 wherein said tyrosine kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase.4. Compound of Claim 3 wherein said tyrosine kinase is selected from the group consisting of KDR, flt-1, TIE-2, Lck, Src, fyn and yes.5. Compound of Claim 1 wherein the activity of said tyrosine kinase affects angiogenesis. : .6. Compound of Claim 5 wherein the inhibition of said tyrosine kinase is anti- angiogenic. ’ 7 Compound of Claim 6 wherein said inhibition of said tyrosine kinase inhibits the progression of a disease state selected from the group consisting of cancer, arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collateral vascularization, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, retinopathy of prematurity, wound healing, ulcers, Helicobacter related diseases, fractures, endometriosis, diabetic retinopathy, cat scratch fever, and thyroid hyperplasia.8. Compound of Claim 2 wherein the activity of said tyrosine kinase affects vascular hyperpermeability or the production of edema.AMENDED SHEET : ® WO 0027822 : PCT/US99/26105 i oo 138 : Co oo9. Compound of Claim 8, wherein the inhibition of said tyrosine kinase is antiedematous.10. © Compound of Claim 9, wherein the inhibition of said tyrosine kinase inhibits the progression of a disease state selected from the group consisting of burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis, psoriasis, chronic and allergic inflammation, macular degeneration, diabetic retinopathy, retinopathy of prematurity, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, adult respiratory distress syndrome, ascites and tumor-associated effusions and edema. oo 11. Compound of Claim 2 wherein the inhibition of said tyrosine kinase has an anti-tumor effect. . oo12. Compound of Claim 2 wherein the inhibition of said tyrosine activity is associated with anti-fertility or abortifacient effects.13. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents a group of formula 5(0), in which p represents 0,1 or 2; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted; and R3, R4, Rs, and Rg are as previously defined; with the provisos that 1) when Ry, R3, R4, R5 and Rg each represent hydrogen and X represents SO,, then R, does not represent phenyl and 2) when X represents S and Ry, R3, R4, R5 and Rg each represent hydrogen, then R, does not represent 2,4-dichlorophenyl .14. Compounds according to Claim 13 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.15. Compounds according Claim 13 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4- pyridyl each of which is optionally substituted, naphthy! and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- 1yl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alky! (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.16. Compounds according to Claim 13 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, S-methyl-2-furyl, 5-(2-nitro-4- trifluoromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl,2-methoxyphenyl, 3,4-dimethoxypheny!, 3,4,5-tnmethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5- di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chiorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro- S-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoyl) propoxy phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)pheny!, 4- [3-(N-(2-diethylaminoethyl)-carbamoyl)propoxylphenyl, 2-furyl, 5-(3,5- bis(trifluoromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl) carbamoyl)propoxy-phenyl], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)pheny! , 4-(morpholinacetamido)phenyl and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.17. Compounds according to Claim 13 in which R,, R,, R; and R, independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1-yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pymolidin-1-yl)propoxy, 3- 5) dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino.18. Compounds according to Claim 13 in which R;, R,, R; and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.19. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents oxygen, R, represents H ; R, represents aryl, pyridyl, thienyl, fury! or pyrrolyl each of which is optionally substituted; and R3, R4, R5 and Rg are as previously defined; with the proviso that when Ri, R3, Rg, R5 and Rg each represent hydrogen, then R, does not represent phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl.20. Compounds according to Claim 19 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.21. Compounds according Claim 19 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridy! or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yDethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- lyl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.22. Compounds according to Claim 19 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, S-methyl-2-furyl, 5-(2-nitro-4- trifluoromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4-carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5- S di-tert-butyl-4-hydroxyphenyl, 4-methylpheny], 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chloropheny!, 2,4-dichlorophenyl, 2-chloro- 5-mitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminopheny], 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)pheny], 3-[3-(N-(2-diethylamino-ethyl)carbamoyl) propoxy]phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)phenyl, 4- [3-(N-(2-diethylaminoethyl)-carbamoy!)propoxy]phenyl, 2-furyl, 5-[3,5- bis(trifluoromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl) carbamoyl)propoxy-phenyl], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl , 4-(morpholinacetamido)phenyl and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.23. Compounds according to Claim 19 in which R;, R,, R; and R; independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3- carboxypropoxy, carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3- carbamoylpropoxy, 2-piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylaminoethoxy, 2-(perhydrothiazin-1- yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-1- yl)propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoyl! and N-phenylcarbamoyl), carboxy, nitro and amino.24. Compounds according to Claim 19 in which R;, R,, R; and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.25. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents a group of formula NR, ; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted; and R3, R4, R5 and Rg are as previously defined.26. Compounds according to Claim 25 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.27. Compounds according Claim 25 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- : morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4-yDethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- 1yl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.28. Compounds according to Claim 25 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5-(2-nitro-4- trifluoromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxypheny], 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5- di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichloropheny!, 2-chloro- 5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl,4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]pheny!, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoyl) propoxy]phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)pheny!, 4- (3-(N-(2-diethylaminoethyl)-carbamoyl)propoxy]phenyl, 2-furyl, 5-[3,5- bis(trifluoromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl) carbamoyl)propoxy-phenyl], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl , 4-(morpholinacetamido)pheny! and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy phenyl.29. Compounds according to Claim 25 in which R;, R,, Rs and R, independently represent hydrogen, halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy- methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1 -yDethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- 1 -yl)propoxy, 3- dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl! (particularly carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino.30. Compounds according to Claim 25 in which R;, R,, Ry and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.31. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents a group of formula -C=NOR?7 in which R7 represents H or a C1-4 alkyl group; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted; and R;, Ri, Rs, and R, are as previously defined; with the proviso that when R], R3, R4, Rs and Rg each represent hydrogen, and X represents C=NOH then R2 does not represent 4-methylphenyl or 3,4-dimethoxyphenyl.32. Compounds according to Claim 31 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.33. Compounds according Claim 31 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pynidyl, 3-pyridyl or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yDethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-lyl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), 5) polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.34. Compounds according to Claim 31 in which R, represents 4-pyndyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyndyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5-(2-nitro-4- trifluoromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-tnmethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoyimethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5- di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro- 5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenyly], 3-phenoxyphenyl, 4-phenoxyphenyl], 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethy1)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoyl) propoxy]phenyl, 4-(N-(2-diethylaminoethyl)carbamoy!l-methoxy)phenyl, 4- [3-(N-(2-diethylaminoethyl)-carbamoyl)propoxy]phenyl, 2-furyl, 5-[3,5- bis(trifluoromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-triflucromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl) carbamoyl)propoxy-phenyl], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl , 4-(morpholinacetamido)phenyl and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.35. Compounds according to Claim 31 in which R;, R,, Rs and R; independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy- methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1-yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy, 3- dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino.36. Compounds according to Claim 31 in which R;, R,, Ry and Rg represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.37. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents substituted methylene or a carbonyl group; R, represents H ;R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is . optionally substituted; and R3, R4, Rs, and Rg are as previously defined, with the provisos that1) when X represents carbonyl or a substituted methylene, Rj is hydrogen and R3, R4, R5 and Rg each represent hydrogen, then R) is not pyridyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted by C2 alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group;2) when X represents methylene, R1 is hydrogen and two of R3, Ra, Rs and Re independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C|_4 alkyl, C1.4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R? is not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C14 alkyl, C1-4 alkoxy or trifluoromethyl; and3) when X represents a carbonyl group, R) represents phenyl, 4-chlorophenyl or 4-methoxyphenyl, then R3, R4, R5 and Rg are not trifluoromethyl; and4) when X represents a carbonyl group, R) represents phenyl, R3 represents bromo, R4 represents hydroxy and R$ represents methoxy,then Rg is not hydrogen and5) when X represents carbonyl and R3, R4, R5 and Rg represent hydrogen, then Rg is not aryl.38. Compounds according to Claim 37 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.39. Compounds according Claim 37 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridy! or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tni-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- 1yl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoy!l, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.40. Compounds according to Claim 37 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, S-methyl-2-furyl, 5-(2-nitro-4-trifluoromethylpheny!)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinocthoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2-morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro- 5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl,4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoy!)propoxy phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)phenyl, 4- [3-(N-(2-diethylaminoethyl)-carbamoyl)propoxy]phenyl, 2-furyl, 5-(3,5- bis(trifluoromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl)carbamoy!l)propoxy-phenyl], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl , 4-(morpholinacetamido)pheny! and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.41. Compounds according to Claim 37 in which R;, R,, Ry and R, independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy- methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1-yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-1 -yl)propoxy, 3- dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino.42. Compounds according to Claim 37 in which R;, R,, R; and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoy], 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.43. Compounds of formula I and pharmaceutically acceptable salts thereof in which X represents a group of formula (CH2)p, in which nis 1, 2 or 3 R, represents H; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted; and Rj, Ri, Rand R; are as previously defined with the proviso that when X is a group of formula (CH, ), in which n is 1, 2 or 3, R, is hydrogen and two of R3, Rg, R5 and Rg independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R is not thienyl,furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl, and with the proviso that when n is 2 and R3, R4, R5 and Rg each represent hydrogen or methoxy, then R) does not represent 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2- yl or 2-carboxyphenyl44. Compounds according to Claim 43 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.45. Compounds according Claim 43 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyndyl, 3-pyridyl or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- lyl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyndylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.46. Compounds according to Claim 43 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5-(2-nitro-4- trifluoromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitropheny!, 4-nitrophenyl, 3,5- di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro- 5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoy!l) propoxy]phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)phenyl, 4- [3-(N-(2-diethylaminoethyl)-carbamoyl)propoxy phenyl, 2-furyl, 5-[3,5- bis(triflucromethyl)phenyl]-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl)carbamoyl)propoxy-phenyl}], 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)pheny! , 4-(morpholinacetamido)phenyl and 4-[3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.47. Compounds according to Claim 43 in which R;, R,, Ry and R, independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy- methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- pipenidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1-yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy, 3- dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino.48. Compounds according to Claim 43 in which R;, R,, Rs and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyl), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.49. Compounds of formula I and pharmaceutically acceptable salts thereof in which : X represents a) substituted methylene b) carbonyl , ¢) oxygen, d) a group of formula -C=NOR?7 in which R7 represents H or a C1.4 alkyl group, €) a group of formula NRg in which Rg represents H, an optionally substituted C1-4 alkyl group or optionally substituted phenyl, f) a group of formula (CH, ), in whichnis 1,2 or 3, or g) a group of formula S(O)p in which p is 0, lor2;R, representsH; R, represents aryl, pyridyl, thienyl, fury! or pyrrolyl each of which is optionally substituted; R3,R4, Rs and Rg independently represent a) H, b) halo, c) a C}-g alkyl S group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, d) a C, alkoxy group optionally substituted by one or more of the following: hydroxy, or an amino group of formula NRhR; wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo €) optionally substituted phenoxy, f) hydroxy, g) a group formula COR; in which Rj represents hydroxy, a Cj-6 alkoxy group or Rj represents a group of formula NRp Rc in which Rp and R¢ independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a C1-6 alkyl group or wherein Rj, and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a C1. alkyl group, h) a group of formula NRg Re in which Rg and Re are independently selected from hydrogen, a C1-¢ alkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a Ci-g alkyl group, a C3-8 cycloalkyl group or phenyl, wherein in each case the alky! group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj are as defined above, 1) a group of formula O(CH2)m Rg in whichm is 2, 3,4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or Rg represents a group of formula CORy wherein Rp1s as defined above and mis 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl C1-¢ alkyl, I) optionally substituted phenyl C1.¢ alkoxy or 0) a C2-4 alkenyl group or a C7-4 alkynyl group each of which 1s optionally substituted by phenyl which is optionally substituted by one or more of the following : a C, ¢alkyl group, a C, 4 alkoxy group or halo, providing that at least one of R3 S , R4, Rs and R; or a substituent on R, represents one of the following: a) a group of formula O(CH2)m Rg in which mis 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRgRe in which Rd and Re are as defined above; or Rg represents a group of formula CORa wherein Rj is as defined above and mis 1, 2, 3, 4 or 5, b) a C1. alkyl group substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj are as defined above, ¢) a C, ; alkoxy group optionally substituted by one or more of the following: hydroxy, or an amino group of formula NRhR;j wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) a group formula COR; in which Rj represents hydroxy, a C1.¢ alkoxy group or Rj represents a group of formula NRp Re wherein Rp and Rc are as defined above, €) a group of formula NRdRe in which Rd and Rg are as defined above.50. Compounds according to Claim 49 in which R, represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.S51. Compounds according Claim 49 in which R, represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyndyl, 3-pyridyl or 4- pyridyl each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy,3-carbamoylpropoxy, 2-piperidino-ethoxy, 2-(piperazin-1-yl)ethoxy, 2- (pyrrolidin-1-yl)ethoxy, 2-dimethylamino-ethoxy, 2-(perhydro-thiazin-4- yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin- 1yl)-propoxy, 3-dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), lower alkyl! (particularly methyl), halo (particularly fluoro and chloro), aryl (particularly phenyl), hydroxy, aryloxy (particularly phenoxy), arylalkoxy (particularly benzyloxy), di-lower-alkylamino (particularly dimethylamino), v polyhalo-lower-alkyl, polyhalo-lower-alkoxy (particularly difluoromethoxy), nitro, cyano, lower-alkylthio (particularly methylthio), carboxy, lower- alkoxycarbonyl (particularly methoxycarbonyl), amido (particularly acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following: trifluoromethyl or nitro.52. Compounds according to Claim 49 in which R, represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2-(hydroxyamidino)-4-pyridyl, 2-carbamoy!-4-pyridyl, 4-pyridyl-N- oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, S-methyl-2-furyl, 5-(2-nitro-4- triflucromethylphenyl)fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(3- morpholinopropoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, 4-(3-carboxy:- propoxy)phenyl, 4-carboxymethoxyphenyl, 4-(3-carbamoylpropoxy)phenyl, 4-carbamoylmethoxyphenyl, 3-(3-morpholino-propoxy)phenyl, 3-(2- morpholino-ethoxy)phenyl, 3-(3-carboxy-propoxy)phenyl, 4- carboxymethoxyphenyl, 3-(3-carbamoylpropoxy)phenyl, 3- carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3- methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5- di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichiorophenyl, 2-chloro- 5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methyithiophenyl, 4-biphenylyl,3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N- phenylcarbamoylphenyl, 4-acetamido-phenyl, 4-benzamidophenyl , 4- carboxyphenyl, 4-[N-(2-diethylaminoethyl)-carbamoyl]phenyl, 4-(prop-1- enyloxy)phenyl, 3-(2-hydroxyethoxy)phenyl, 3-(N-(2-diethyl aminoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-diethylamino-ethyl)carbamoyl) propoxy phenyl, 4-(N-(2-diethylaminoethyl)carbamoyl-methoxy)phenyl, 4- [3-(N-(2-diethylaminoethyl)-carbamoyl)propoxy]phenyl, 2-furyl, 5-3,5- bis(trifluoromethyl)phenyl}-2-furyl, 3-bromo-2-thienyl, 5S-methoxy-2-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 3-N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl, 3-[3-(N-(2-morpholinoethyl) carbamoyl)propoxy-phenyl}, 4-(N-(2-morpholinoethyl)- carbamoylmethoxy)phenyl , 4-(morpholinacetamido)phenyl and 4-{3-(N-(2- morpholinoethyl)carbamoyl)propoxy]phenyl.53. Compounds according to Claim 49 in which R,;, Ry, Rand R; independently represent hydrogen , halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3- morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxy- methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2- piperidinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 2- dimethylaminoethoxy, 2-(perhydrothiazin-1-yl)ethoxy, 3-piperidinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy, 3- dimethylaminopropoxy, 3-(perhydrothiazin-4-yl)propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3- morpholino)propoxy and (2-morpholino)ethoxy), amido (particularly acetamido and benzamido), optionally substituted carbamoyl (particularly carbamoyl, N-methyl-carbamoy! and N-phenylcarbamoyl), carboxy, nitro and amino.54. Compounds according to Claim 49 in which R,, R,, R; and R, represent the following 6,7-dimethoxy, 6,7,8-trimethoxy, 6- fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6-(N-methylcarbamoyt), 6-(N- phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy.55. A compound selected from: 3-(3,4,5-trimethoxyphenyl)-1,4-dihydroindeno(1,2-c]pyrazole, 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol, 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole, 3-(2-thienyl)-1H-[1]benzothieno[3,2-c]pyrazole, 3-phenyl-1H-[1]benzothieno(3,2-c]pyrazole 4-oxide, 3-phenyl-1H-[1]benzothieno{3,2-c]pyrazole 4,4-dioxide, 3-(2-thienyl)-1H-[1]benzothieno[3,2-c]pyrazole, 3-phenylindeno[1,2-c]pyrazol-4(1H)-one oxime, 3-(3,4-dimethoxyphenyl)indeno[1,2-c]pyrazol-4(1H)-one oxime, 3-(4-methylphenyl)indeno(1,2-c]pyrazol-4(1H)-one oxime, 3-(2-thienyl)indeno[1,2-c]pyrazol-4(1H)-one, 3-phenyl-1H-benzofuro[3,2-c]pyrazole, 1,4-dihydro-3-phenylpyrazolo[4,3-b]indole, 1,4-dihydro-4-methyl-3-phenylpyrazolo[4,3-bjindole, 4 4-dimethyl-3-phenyl-1,4-dihydroindeno(1,2-c]pyrazole, 4-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)benzoic acid, methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate, 4'-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)acetanilide, 4’-(1,4-dihydroindeno(l,2-c]pyrazol-3-yl)-3-morpholinopropionanilide, 4'-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)morpholinoacetanilide, 4'-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzanilide, N-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)acetamide, 3-morpholino-N-(3-pheny!-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)propionamide, N-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzanilide, 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-methyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzanilide,N -(2-diethylaminoethyl)-4-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)benzamide,N-(2-morpholinoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenol,3-[3-(2-morpholinoethoxy)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole, 3-(2-thienyl)-1,4-dihydroindeno[ 1,2-c}pyrazol-6-ol, 6-(2-morpholinoethoxy)-3-(2-thienyl)-1,4-dihydroindeno[1,2-c]pyrazole, 3-[3-(2-hydroxyethoxy)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole, 3-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenoxyacetic acid,ethyl 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetate, 3-(1,4-dihydroindenof1,2-cJpyrazol-3-yl)phenoxyacetamide, N-(2-diethylaminoethyl)-3-(1,4-dihydroindeno[1,2-c}pyrazol-3- yl)phenoxyacetamide, N-(2-morpholinoethyl)-3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetamide,4-{3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy} butyric acid, ethyl 4-{3-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)phenoxy} butyrate, 4-{3-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenoxy} butyramide, N-(2-diethylaminoethyl)-4-{3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy}- butyramide,N-(2-morpholinoethyl)-4- {3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy}- butyramide, 3-(2-thienyl)-1,4-dihydroindeno[1,2-c]pyrazole-6-carboxamide, N-methyl-3-(2-thienyl)-1,4-dihydroindeno(1,2-c]pyrazole-6-carboxamide, N-(2-morpholinoethyl)-3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-6-carboxamide,3-(2-thienyl)-1,4-dihydroindeno[1,2-c]pyrazole-6-carboxanilide; N-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)acetamide, 3-phenyl-1,4-dihydroindeno| 1,2-c]pyrazol-6-ylamine, 3-(4-nitrophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)aniline,4-(4,5-dihydro-1H-benzo[g]indazol-3-yl)pyridine 1-oxide, 3-(2-chloro-4-pyridyl)-4,5-dihydro-1H-benzo[g]indazole, 4-(4,5-dihydro- 1H-benzo[glindazol-3-yl)-2-pyridinecarbonitrile,4-(4,5-dihydro-1H-benzo[g)indazol-3-yl)-2-pyridinecarboxamide oxime, 4-(4,5-dihydro-1H-benzo[g)indazol-3-yl)-2-pyridinecarboxamide, {{4-(4,5-dihydro-1H-benzo[g]indazol-3-yl)-2-pyridyljmethyl} ammonium chloride, N-{[4-(4,5-dihydro-1H-benzo[g]-indazol-3-yl)-2-pyridyl methyl} formamide,S 2-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]ethanol, 2-morpholinoethyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate, 3-(3-nitrophenyl)-1,4-dithydroindeno[1,2-c]pyrazole, 3-(4-thiomethoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 3-(2-naphthyl)-1,4-dihydroindeno{1,2-c]pyrazole,3-(4-difluoromethoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 3-(4-acetamidophenyl)-4,5-dihydro-2H-benz[gJindazole, 3-(4-bromo-2-thienyl)-4,5-dihydroindeno(1,2-c]pyrazole, 3-(4-benzyloxyphenyl)-4,5-dihydro-2H-benz[g]indazole, 6,7-dimethoxy-3-(3-phenoxyphenyl)-1,4-dihydroindeno-{1,2-c]pyrazole,16 3-[4-(5-trifluoromethyl-2-pyridyloxy)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole, 6,7,8-trimethoxy-3-(2,3,4-trimethoxyphenyl)-1,4-dihydroindeno[ 1,2-c]pyrazole, 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)-2-hydroxymethyl)phenol, 2-methoxy-5-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol, 2-chloro-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenol,2-methoxy-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol, 3-chloro-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenol, 2-{4-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)phenoxy acetamide, 4’-(1,4-dihydroindeno[ 1,2-c}pyrazol-3-yl)diethylamino-acetanilide, 4-(1H-[1]benzothieno[3,2-c]pyrazol-3-yl)benzamide,3-(4-aminophenyl)-1H-[1]benzothieno [3,2-c]pyrazole, 3-(4-methoxyphenyl!)-1H-benzothieno[3,2-c]pyrazole, 3-(4-hydroxyphenyl)-1H-[1]benzothieno[3,2-c]pyrazole, N-(3-phenyl-1,4-dihydroindeno( 1,2-c]pyrazol-6-yl)benzamide, N-(2-morpholinoethyl)-4-(1,4-dihydroindeno[ 1,2-c]pyrazol-3-yl)benzamide,4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile, 7-methoxy-3-(4-methylsulphonylphenyl)-4,5-dihydro-2H-benz[ g]indazole, 4-methyl-3-phenyl-1,4-dihydroindenof[1,2-c]pyrazol-4-ol,N-[2-(N,N-diethylamino)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,N-[2-(N,N-dimethylamino)ethyl]-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-ylbenzamide,N-[2-(N,N-dipropylamino)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-[2-(N,N-di-isopropylamino)ethyl]-4-(1,4-dihydroindeno([1,2-c]pyrazol-3- yl)benzamide, N-[3-(N,N-diethylamino)propyl}-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yhbenzamide,N-[3-(N,N-dimethylamino)propyl]-4-(1,4-dihydroindeno(1,2-c]pyrazol-3- yDbenzamide, N-[3-(N,N-dipropylamino)propyl}-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yDbenzamide, N-[3-(N,N-di-isopropylamino)propyi]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-(2-Piperidinoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-(2-Piperidinopropy1)-4-(1,4-dihydroindeno 1,2-c]pyrazol-3-yl)benzamide, N-(2-Morpholinoethyl)-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-(2-Morpholinopropyl)-4-(1,4-dihydroindeno[1,2-c]jpyrazol-3-yl)benzamide,N-[2-(Piperazin-1-yl)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-[3-(Piperazin-1-yl)propyl]-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-[2-(Pyrrolidin-1-yl)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-[3-(Pyrrolidin-1-yl)propyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-[2-(4-Methylpiperazin-1-yl)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-[3-(4-Methylpiperazin-1-yl)propyl}-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide,N-[2-(Thiomorpholin-1-yl)ethyl]-4-(1,4-dihydroindeno[ 1,2-c]pyrazol-3- yhbenzamide, :N-[3-(Thiomorpholin-1-yl)propyl}-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yhbenzamide,N-[2-(Homopiperazin-1-yl)ethyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, N-(3-(Homopiperazin-1-yl)propyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide,S N-[2-(Perhydroazepin-1-yl)ethyl]-4-(1,4-dihydroindeno(1,2-c]pyrazol-3- yDbenzamide, N-[3-(Perhydroazepin-1-yl)propyl]-4-(1,4-dihydroindeno(1,2-c]pyrazol-3- yl)benzamide,N-Isopropyl-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide,N-But-2-yl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-Methyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-Ethyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-Pentyl-4-(1,4-dihydroindeno| 1,2-c]pyrazol-3-yl)benzamide, N-(2-Bromoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,N-(3,3,3-trifluoroprop-1-yl-4-(1,4-dihydroindenof 1,2-c]pyrazol-3-yl)benzamide, N-(Cyclopropylmethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yi)benzamide, N-Cyclopentyl-4-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)benzamide, N-(Cyclohexylmethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-(2-Chlorocyclopentyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,N-[3-(N,N-dimethylamino)-2,2-dimethylpropyl}-4-(1,4-dihydroindeno[1,2- c]pyrazol-3-yl)benzamide, N-[3-(2-Methylpiperidin-1-yl)propyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, N-(3-Methylbut-2-yl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,N-[2-(Pyrrolidin-1-yl)ethyl]-4-(1,4-dihydroindeno[ 1,2-c]pyrazol-3-yl)benzamide, N-[3-(N,N-Dimethylamino)prop-2-yl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, N-(2-Hexyl)-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-tert-Butyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,N-[7-(N,N-Dimethylamino)heptyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, N-(2-Methylbut-2-yl)-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide,N-(2-Pentyl)-4-(1,4-dihydroindeno[1,2-c}pyrazol-3-yl)benzamide, N-sec-Butyl-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-(3,3-Dimethylbutyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, N-(2,2,3,3,3-Pentafluoropropyl)-4-(1,4-dihydroindeno{1,2-c}pyrazol-3- yl)benzamide, N-(2,5-Dichloropentyl)-4-(1,4-dihydroindeno[ 1,2-c]pyrazol-3-yl)benzamide, N-(2,2-Difluoroethyl)-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-(2-Chloroethyl)-4-(1,4-dihydroindeno( 1,2-c]pyrazol-3-yl)benzamide, N-[2-(N,N-dimethylamino)propyl]-4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yDbenzamide, N-(3-Morpholinopropyl)-4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)benzamide, N-[3-(Pyrrolidin-1-yl)propyl}-4-(1,4-dihydroindeno( | ,2-c]pyrazol-3-yl)benzamide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)piperidinoacetanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-4-methylpiperazin-1-ylacetanilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)-4-methylhomopiperazin-1-ylacetanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)piperazin-1-ylacetanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)homopiperazin-1-ylacetanilide,4’. (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)dipropylaminoacetanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)dimethylaminoacetanilide, 4’- (1,4-Dihydroindeno[1,2-clpyrazol-3-yl)fluoroacetanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-3,5-difluorobenzylanilide, 4’- (1,4-Dihydroindeno[1,2-c])pyrazol-3-yl)-4-fluorobenzylanilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-2-fluorobenzylanilide, 4’- (1,4-Dihydroindeno[ 1,2-c]pyrazol-3-yl)-3-fluorobenzylanilide, 4’-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)-2,4-difluorobenzylanilide, 4’- (1,4-Dihydroindeno[1,2-c)pyrazol-3-yl)-2,5-difluorobenzylanilide, 4’- (1,4-Dihydroindeno{1,2-c]pyrazol-3-yl)-2,3-difluorobenzylanilide, 4’- (1,4-Dihydroindeno[1,2-c]}pyrazol-3-yl)-4-nitrobenzylanilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)-3-nitrobenzylanilide, 4’-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-3,3,3-triflucropropananilide, 4’- (1,4-Dihydroindeno[1,2-c)pyrazol-3-yl)isobutananilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)isopentananilide,4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)-2-methylbutananilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-2-methylpentananilide, 4’- (1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-2-ethylbutananilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)neopentylanilide, 4’-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-4,4-dimethylpentananilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)cyclohexananilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-ytrifluoroacetanilide, 4’- (1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)pentafluoropropananilide, Fluoro-N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)acetamide,3,5-Difluoro-N-(3-Phenyl-1,4-dihydroindenof1,2-c]pyrazol-6-yl)benzylamide, 4-Fluoro-N-(3-Pheny!l-1,4-dihydroindeno[ 1,2-c]pyrazol-6-yl)benzylamide, 2-Fluoro-N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzylamide, 3-Fluoro-N-(3-Phenyl-1,4-dihydroindeno{ 1,2-c]pyrazol-6-yl)benzylamide, 2,4-Difluoro-N-(3-Phenyl-1 ,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzylamide,2,3-Difluoro-N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzylamide, 2,5-Difluoro-N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzylamide, 4-Nitro-N-(3-Phenyl-1,4-dihydroindeno[ 1,2-c]pyrazol-6-yl)benzylamide, 3-Nitro-N-(3-Phenyl-1,4-dihydroindeno[ 1,2-c]pyrazol-6-yl)benzylamide, 3,3,3-Trifluoro-N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)propanamide,N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)isobutanamide, N-(3-Phenyl-1,4-dihydroindeno[ 1,2-c]pyrazol-6-yl)isopentanamide, 2-Methyl-N-(3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)butanamide, 2-Methyl-N-(3-phenyl-1,4-dihydroindeno(1,2-c]pyrazol-6-yl)pentanamide, 2-Ethyl-N-(3-phenyl-1,4-dihydroindeno[ 1,2-c]pyrazol-6-yl)butanamide,N-(3-Phenyl-1,4-dihydroindeno[1,2-c}pyrazol-6-yl)neopentanamide, 4,4-Dimethyl-N-(3-phenyl-1,4-dihydroindeno(1,2-c]pyrazol-6-yl)pentanamide, N-(3-Phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)cyclohexanecarboxamide, Trifluoro-N-(3-Phenyl-1,4-dihydroindeno(1,2-c]pyrazol-6-yl)acetamide, Pentafluoro-N-(3-Phenyl-1,4-dihydroindeno( 1 ,2-c]pyrazol-6-yl)propanamide,4’-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)acetanilide, 2-Hydroxy-N-(2-morpholinoethyl)-5-(1,4-dihydroindeno(1,2-c]pyrazol-3- yl)benzamide,2-Hydroxy-N-(2-morpholinopropyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-ylhbenzamide,2-Hydroxy-N-[2-(pyrrolidin-1-yl)ethyl}-5-(1,4-dihydroindeno[ 1,2-c]pyrazol-3-y)benzamide,2-Hydroxy-N-[3-(pyrrolidin-1-yl)propyl]-5-(1,4-dihydroindeno(1,2-c]pyrazol-3- yl)benzamide, N-[2-(N,N-Diethylamino)ethyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)-2- hydroxybenzamide, N-[3-(N,N-Diethylamino)propyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)-2-hydroxybenzamide, 2-Hydroxy-N-[2-(N,N-dimethylamino)ethyl]-5-(1,4-dihydroindeno[ 1,2-c]pyrazol-3- yhbenzamide, 2-Hydroxy-N-[3-(N,N-dimethylamino)propyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol- 3-yl)benzamide,2-Hydroxy-N-[2-(N,N-dipropylamino)ethyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, 2-Hydroxy-N-[2-(N,N-di-isopropylamino)ethyl]-5-(1,4-dihydroindeno[1,2- c]pyrazol-3-yl)benzamide, 2-Hydroxy-N-[3-(N,N-dipropylamino)propyl]-5-(1,4-dihydroindeno([ 1,2-c]pyrazol-3-ylbenzamide, 2-Hydroxy-N-[3-(N,N-di-isopropylamino)propyl]-5-(1,4-dihydroindeno(1,2- c¢]pyrazol-3-yl)benzamide, 2-Hydroxy-N-(2-piperidinoethyl)-5-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide,2-Hydroxy-N-(2-piperidinopropy!l)-5-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, 2-Hydroxy-N-[2-(piperazin-1-yl)ethyl]-5-(1,4-dihydroindeno[ 1,2-c]pyrazo}-3- yl)benzamide, 2-Hydroxy-N-[3-(piperazin-1-y})propyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide,2-Hydroxy-N-[2-(4-methylpiperazin-1-yl)ethyl]-5-(1,4-dihydroindeno[ 1,2- c]pyrazol-3-yl)benzamide,2-Hydroxy-N-[3-(4-methylpiperazin-1-yl)propyl]-5-(1 ,4-dihydroindeno[1,2- c]pyrazol-3-yl)benzamide, 2-Hydroxy-N-[2-(thiomorpholin-1-yl)ethyl]-5-(1 ,4-dihydroindeno(1,2-c]pyrazol-3- yl)benzamide,2-Hydroxy-N-[3-(thiomorpholin-1-yl)propy1]-5-(1,4-dihydroindeno[ 1,2-c)pyrazol-3- yl)benzamide, 2-Hydroxy-N-[2-(Homopiperazin-1-yl)ethyl]-5-(1 ,4-dihydroindeno[1,2-c]pyrazol-3- ylbenzamide, 2-Hydroxy-N-[3-(Homopiperazin-1-yl)propyl]-5-(1 ,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, 2-Hydroxy-N-[2-(Perhydroazepin-1 -yDethyl]-5-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)benzamide, 2-Hydroxy-N-[3-(Perhydroazepin-1-yl)propyl}-5-(1,4-dihydroindeno{ 1,2-c]pyrazol- 3-yl)benzamide,4-(1,4-Dihydroindeno(1 ,2-¢]pyrazol-3-yl1)-N-(2-morphilinoethyl)aniline, 4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-N-(2-morphilinopropyl)aniline, 4-(1,4-Dihydroindenof1 ,2-C]pyrazol-3-yl)-N-(2-piperidinoethyl)aniline, 4-(1,4-Dihydroindenof 1 ,2-c]pyrazol-3-yl)-N-(2-piperidinopropyl)aniline, 4-(1,4-Dihydroindeno[1,2-¢]pyrazol-3-yl)-N-[2-(thiomorphilin] -yl)ethyl]aniline,4-(1,4-Dihydroindeno[ 1,2-c]pyrazol-3-y1)-N-[2-(thiomorphilin1-yl)propyl]aniline, 4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)-N-[2-(piperazin-1 -ybethyl]aniline, 4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-y!)-N-[2-(piperazin-1 -yl)propyl]aniline, 4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-y1)-N-[2-(4-methylpiperazin-1- )ethyl]aniline,4-(1,4-Dihydroindeno[ 1,2-c]pyrazol-3-yl)-N-[2-(4-methylpiperazin-1- yl)propyl]aniline,N-[2-(N,N-Diethylamino)ethyl}-4-(1,4-Dihydroindeno[ ,2-C]pyrazol-3-yl)aniline, N-[3-(N,N-Diethylamino)propyl]-4-(1,4-Dihydroindeno[1,2-c]pyrazol-3 -yl)aniline, 4-(1,4-Dihydroindenol[ 1,2-c}pyrazol-3-yl)-N-[2-(N ,N-dipropylamino)ethyl]aniline,4-(1,4-Dihydroindeno[1 2-c]pyrazol-3-yl)-N-[3-(N ,N-dipropylamino)propyl}aniline, 4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)-N-[2-(N ,N-dimethyllamino)ethyl]aniline, 4-(1,4-Dihydroindeno[ 1,2-c]pyrazol-3-y1)-N-[3-(N ;N-dimethylamino)propyl]aniline,Methyl 4-(6-Acetamido- 1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)benzoate, N-(3-Methoxypropyl)-4-(1 »4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, 4-(1,4-Dihydroindeno|1 ,2-c]pyrazol-3-yl)-N-(4-Nitrophenyl)benzamide, N-(3-Phenyl-1 ,4-dihydroindenof[1 »2-C|pyrazol-6-yl)morpholinoacetamide, N-(3-Phenyl-1 ;4-dihydroindeno(1 ,2-c]pyrazol-6-yl)morpholinoacetamide, N-(3-Phenyl-1 ,4-dihydroindeno([1 ,2-c]pyrazol-6-yl)piperidinoacetamide, N-(3-Phenyl-1 y4-dihydroindeno[1 »2-c]pyrazol-6-yl)thiomorpholinoacetamide, N-(3-Phenyl-1 »4-dihydroindeno[1 ,2-c]pyrazol-6-yl)-4-methylpiperazin-1- ylacetamide,N-(3-Phenyl-1 s4-dihydroindeno[1 »2-c]pyrazol-6-yl)piperazin-1-ylacetamide,N-(3-Phenyl-1 ;4-dihydroindeno[1 ,2-c]pyrazol-6-yl)pyrrolidin-1 -ylacetamide, 2-(N,N-Diethylamino)-N-(3-phenyi- 1,4-dihydroindeno(1,2-c]pyrazol-6- ylacetamide,N-(3-Phenyl-1 +4-dihydroindeno(1,2-c]pyrazol-6-yl)-2-(dimethylamino)acetamide,N-(3-Phenyl-1 ;4-dihydroindeno(1 ,2-¢]pyrazol-6-yl)-2-(dipropylamino)acetamide, 4-(6-Amino-1,4-dihydroindeno( 1 ,2-c]pyrazol-3 -y1)-N-[2-(N,N-diethylamino)ethyl]- benzamide, 3-[3-(2-Morpholinoethoxy)phenyl]-1 ,4-dihydroindeno(1,2c]pyrazole, 3-[3-(2-Morpholinoethoxy)phenyl]- 1,4-dihydroindeno[1,2¢]pyrazole,3-[3-(3-Morpholinopropoxy)phenyl]-1,4-dihydroindenof 1,2¢pyrazole, 3-[3-(2-Piperidinoethoxy)phenyl]-1 ,4-dihydroindeno[1,2¢]pyrazole, 3-[3-(3-Piperidinopropoxy)phenyl]-1,4-dihydroindeno{ 1,2c]pyrazole, 3-{3-[2-(Piperazin-1 -YD)ethoxy]phenyl}-1,4-dihydroindeno( 1 ,2c]pyrazole, 3-{3-[3-(Piperazin-1 -yDpropoxy]phenyl}-1 ,4-dihydroindeno[1,2c]pyrazole,3-{3-[2-(4-Methylpiperazin-1 -yDethoxy]phenyl}-1 ,4-dihydroindeno(1,2c]pyrazole, 3-{3-[3-(4-Methylpiperazin-1 -yl)propoxy]phenyl}-1,4-dihydroindeno( 1 ,2c]pyrazole, 3-{3-[2-(Homopiperazin-1 -yhethoxy]phenyl} -1,4-dihydroindeno[1,2¢]pyrazole, 3-{3-[3-(Homopiperazin-1 -yDpropoxy]phenyl}-1 ,4-dihydroindeno(1,2¢c]pyrazole,3- {3-[2-(4-Methylhomopiperazin-1-yl)ethoxy]pheny!} -1,4-dihydroindeno[1,2c]pyrazole, 3-{3-[3-(4-Methylhomopiperazin-1 -yl)propoxy]phenyl}-1,4-dihydroindeno[1,2c]pyrazole,3- {3-[2-(N,N-Diethylamino)ethoxy Jphenyl} -1,4-dihydroindeno[1,2c]pyrazole, 3-{3-[3-(N ,N-Diethylamino)propoxy]phenyl}-1,4-dihydroindeno( 1 ,2c]pyrazole, 3-{3-[2-(N ,N-Dimethylamino)ethoxy]pheny!}-1,4-dihydroindenof[ 1 ,2¢]pyrazole, 3-{3-[3-(N ,N-Dimethylamino)propoxy)phenyl}-1 ,4-dihydroindeno[1,2c]pyrazole, 3-{3-[2-(N,N-Dipropylamino)ethoxy]phenyl} -1,4-dihydroindeno[ 1,2c]pyrazole, and 3-{3-[3-(N ,N-Dipropylamino)propoxy]phenyl}-1,4-dihydroindeno[1,2¢]pyrazole, and pharmaceutically acceptable salts thereof and tautomers thereof,56. A compound selected from: R; R, X R, BE 5 il Rs R, R, X=(CH2)n TABLE 1 R3 Ry Rs Re H 1 N a NO,6.7-(OMe)) 3-0Ph H 1 MN Ceo 3-0H,4-0Me4.0H,3-OMe6.7-(0Me)R3 Re Rs Rg H 1 1 6,78-(0Mo)3 2,34-0Me)3 OCH LOH, 35Bul) 4:0CH) CH=CH NO; 4-0CHgPh2.CL 5-N0) and pharmaceutically acceptable salts thereof and tautomers thereof.57. A compound selected from: R, R X R, ! ; \ Re R, X=(CH2)n TABLE 2 Rs Ra Rs Re 6-AcNH 1 7 OoR3 Ra Rs Rs H 1 CF, ~~ CF, H 1 Br S 7-OMe 2 BR @) Me } AL I E- and pharmaceutically acceptable salts thereof and tautomers thereof.358. A compound selected from: R, R X R, 1 : \ Rg R, TABLE 3 R3 Ra Rs Re H C=0 NO, ~Q CF, and pharmaceutically acceptable salts thereof and tautomers thereof.AMENDED SHEET ® WO 00/27822 Co PCT/US99/26105 - | RB . BERET ZR59. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 in conjunction with a pharmaceutically acceptable diluent or carrier.60. A compound of formulal as defined in claim 1 for use as a medicament.61. A compound of formula I as defined in claim 1 for use as a medicament for h : inhibiting protein kinase activity.62. The use of a compound of formula I as defined in claim 1 in the manufacture of a medicament for use in inhibiting protein kinase activity.63. ‘Compound of Claim 1 wherein said compound is in an enantiomeric form, is in a mixture with one or more other said compounds, or is both in an . enantiomeric form and in a mixture with one or more other said compounds.64. Compound of Claim 1 wherein said protein kinase is a serine kinase.65. Compound of Claim 1 wherein said protein kinase is a threonine kinase. © 66. Compound of Claim 2 wherein said tyrosine kinase is KDR.67. A compound selected from: Dihydroxy 4-(4H-indeno-{1,2-c]-pyrazol-3-yl)phenylborane 4-(1H-[1]Benzothieno[3,2-c]pyrazol-3-yl)benzaldehyde : 4-(1H-[1]Benzothieno(3,2-c]pyrazol-3-yl)-N-[3-(imidazol-1- yDpropyllbenzylamine trihydrochloride Methyl 4-(4-oxo0-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide oxime 3-{4-{(2-diethylaminoethyl)aminomethylJphenyl}-1,4-dihydroindeno[ 1,2 - c}pyrazole trihydrochloride N-[4-(1 ,4-Dihydroindeno[1,2-¢]pyrazol-3-yl)phenyl]benzenesulphonamideN-(2-Morpholinoethyl)-4’-dihydroindeno[ 1,2-c}pyrazol-3-ylaniline dihydrochloride N-(1,4-Dihydroindeno[1,2-c]pyrazol-6-yl)-2-morpholinoacetamide N-(2-Morpholinoethyl)-3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-ylamine trihydrochloride 4’-(1-Acetyl-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)acetanilide 3-[4-(2-morpholinoethoxy)phenyl]-1,4-dihydroindeno{1,2-c]pyrazole 3-[2-(2H-1,2,3,4-Tetraazol-5-yl)-4-pyridyl}-4,5-dihydro-2H- benzo[glindazole 3-(4-Isocyanatophenyl)-1,4-dihydroindeno[1,2-c]pyrazole, 2-(Diethylamino)ethyl N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)phenyljcarbamate 2-Morpholinoethyl N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yDphenyl]carbamate 3-(Dibenzylamino)propy! N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- ylphenyljcarbamate 2-[Ethyl(2-hydroxyethyl)amino]ethyl N-{4-(1,4-dihydroindeno[1,2-c]pyrazol- 3-yDphenyl]carbamate 2-[[2-(Dimethylamino)ethyl](methyl)amino]ethyl N-[4-(1,4- dihydroindeno[1,2-c]pyrazol-3-yl)phenyljcarbamate 1-Methyl-2-propoxyethyl N-[4-(1,4-dihydroindeno[1,2-¢]pyrazol-3- ylphenyl]jcarbamate 2-(1-Methyltetrahydro-1H-2-pyrrolyl)ethyl N-[4-(1,4-dihydroindeno[1,2- c]pyrazol-3-yl)phenyl]carbamate 2-[2-(Dimethylamino)ethoxy]ethyl N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)phenyl]carbamate 2-(Diethylamino)-1-methylethyl N-[4-(1,4-dihydroindenof1,2-c]pyrazol-3- yl)phenyl]carbamate N-[2-(Diethylamino)ethyl]-N'-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yDphenyljurea N-[4-(1,4-Dihydroindeno[ 1,2-c]pyrazol-3-yl)phenyl]-N-(2- morpholinoethyl)ureaN1-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-1- piperidinecarboxamide N-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-N'-[2-(dimethylamino)- l-methylethyljurea N-{4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)phenyl)-N-tetrahydro-2- furanylmethylurea N-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-V-(2-furylmethyl)urea N-(1,3-Benzodioxol-5-ylmethyl)-N'-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- ylphenylJurea N-Cyclobutyl-N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl] N-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-N'-(2- piperidinoethyl)urea urea N-Benzyl-N'-[4-(1,4-dihydroindeno(1,2-c]pyrazol-3-yl)phenyljurea N-[4-(Diethylamino)butyl]-N'-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)phenyl)urea N-{4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-N-[2-(2- thienyl)ethyl]urea N-[3-(Diethylamino)propyl]-N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3- yl)phenyljurea N-{4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-NV-[(1-ethyltetrahydro- 1H-2-pyrrolyl)methyljurea N-(2,5-Difluorobenzyl)-N'-[4-(1,4-dihydroindeno[ 1,2-c]pyrazol-3- yDphenyl]urea N-[4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)phenyl}-N'-[2-(2- hydroxyethoxy)ethyljurea N-(4-(1,4-Dihydroindeno] 1,2-c]pyrazol-3-yl)phenyl]-N-[2-hydroxy-1- (hydroxymethyl)ethyljurea N-[4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)phenyl]-N-(2,3- dihydroxypropyl)urea N1-[4-(1,4-Dihydroindeno[1 2-clpyrazol-3-ylphenyl]-4-(2-pyridy])- 1- piperazinecarboxamideN'-[4-(1,4-Dihydroindeno[ ,2-c]pyrazol-3-yl)phenyl]-N-[3- (dimethylamino)propyl]-N-methylurea N1-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-1-azetanecarboxamide N1-[4-(1,4-Dihydroindeno[ 1,2-c]pyrazol-3-yl)phenyl}-4-(4-fluorophenyl)-1- piperazinecarboxamide N-Benzyl-N'-[4-(1,4-dihydroindeno{1,2-c]pyrazol-3-yl)phenyl}-N- methylurea N'-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-N-ethyl-N-(2- hydroxyethyl)urea N1-[4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)phenyl]-4-(2-methoxyphenyl)- [-piperazinecarboxamide N'-[4-(1,4-Dihydroindeno{1,2-c]pyrazol-3-yl)phenyl]-N-[2- (dimethylamino)ethyl]-N-methylurea N1-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-4-methyl-1- piperazinecarboxamide N1-[4-(1,4-Dihydroindeno[,2-c]pyrazol-3-yl)phenyl}-4-(4-hydroxyphenyl)- 1 -piperazinecarboxamide N1-[4-(1,4-Dihydroindeno(1,2-c}pyrazol-3-yl)phenyl}-4-[(E)-3-phenyl-2- propenyl}-1-piperazinecarboxamide N1-[4-(1,4-Dihydroindeno{1,2-c]}pyrazol-3-yl)phenyl]-4-phenyl-1- piperazinecarboxamide N'-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]}-N,N-di(2- methoxyethyl)urea N'-(4-(1,4-Dihydroindeno(1,2-c]pyrazol-3-yl)phenyl]-N-(2,3- dihydroxypropyl)-N-methylurea N,N-di[2-(Diethylamino)ethyl]-NV'-[4-(1,4-dihydroindeno(1,2-c]pyrazol-3- yl)phenyl]urea N-{4-(1,4-Dihydroindeno(1 2-c]pyrazol-3-yl)phenyl]-N'-(2- pyridylmethyl)urea N-[4-(1 4-Dihydroindenof1,2-c]pyrazol-3-yl)phenyl]-N-(3- pyridylmethyl)ureaN-[4-(1,4-Dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]-N'-(4- pyridylmethyl)urea N-{4-(1,4-Dihydroindeno([1,2-c]pyrazol-3-yl)phenyl]-N-(2- hydroxyethyl)urea N-[4-(1,4-Dihydroindeno([1,2-c]pyrazol-3-yl)phenyl]-V-[7- (dimethylamino)heptyl]urea.68. A compound selected from: R, R, X R, 1 R: We Rs Ry R,=H 3-(CO,H).4-(OH)PHENYL 3-(NO,).4-(OH)PHENYL 4-(OCH;Ph)PHENYL 3-(CONH(CH,),MOR)4- oH H OH))PHENYL 2 3-(CONH(CH,),NEY,).4- 4-(CONH(CH,),NEt,) 4-(CONH(CH,),OMe) 4-(CONH(4-NO,Ph)) 4-(OH)PHENYL £-(CONH(CH,),NET)PHENYL I 4-(BPHENYL H 4-(OH)PHENYL R3 = O(CH,),0Me 4-(SO,NH(CH,),MOR) PHENYL CH, H 4-(SO,NH(CH,),0Me) PHENYL CHa H PHENYL CH, H 4-(OH)PHENYL R3=0(CH,),MOR PHENYL CH, H 4-(OCH,CONH,) _ PHENYL CH, R3=0(CH,),0Me R4=(OH), 4-(OH)PHENYL CH, R4=0Q(CH,),0Me 4-(CONH(CH,),NHEY) PHENYL CH, H 4-(CONHCH,-2-PYRR)PHENYL 4-(OCH,CONH,)PHENYL R3 = OH 4-(OCH,CO,H)PHENYL69. A compound selected from: H N-n \ x 7N. R ee |ePCT/US99/26105 or 0 HNN ue HN HN, H N o ~N N ~, HN, H ) 1 N CH2 iN) N CH2 | rd Co | eee VA Co | Om N EE N en EEE Hh, NH (HEY EE ON N- yy ee n_/ " :s n> as," oe | (Ow CH2 N NMe__/CH2 N 6) nnN N HN —HN N CH2 hi “NH N=/HN SCH2 NJCOHN O ~""NMe, HN ~N b (2HCL) N—/70. A compound selected from: H N-< N R' 4 \_ ew DO] CH2 Ne N N N71. Compounds of formula [ and pharmaceutically acceptable salts thereof in which: X represents a group of formula S(O), in which p represents 0,1 or 2 ; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo, ’b) a Cj.¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, c) a C, alkoxy group optionally substituted by one or more of the following: 5S hydroxy, COOH, an amino group of formula NRhR;j, or an amide of the formula CONRR,, wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula COR or SO,R, wherein Rj is hydroxy, (C,-Cy)alkyl, (C, Cyalkoxy or Ry represents a group of formula NR,R_; where Rp and R¢ independently represent hydrogen, a C1-12 alkyl group, aC3.12 cycloalkyl group, phenyl(C,-C;)alkyl or heterocyclyl-(C,-Cq)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (Co-Cy)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-Cy)-hyrdroxy, halo, nitro, (C,-Cyalkyl, (C,-C¢)alkoxy, -O-(C,-C¢)alkyl-hydroxy a C3.12 cycloalkyl group or an amino group of formula NR;R;; where Rp and Rj independently represent hydrogen, (C,-C,,)alkyl, (C,- Ce)eycloalkyl, (C,-Cy)heterocycloalkyl-(C,-Cy)alkyl (heterocycloalkyl = tetrazole, pyndine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-C;)alkenyl, (C,-Cyalkynyl, (C,-C,)cycloalkenyl-(C,- Cyalkyl, hydroxy(C,-Cy)alkyl, amino(C,-C)alkyl, (C,-C,)alkoxy(C,- Cy)alkyl, mono- or di-(C,-C)alkylamino(C,-Cg)alkyl, morpholinyl-(C,- Celalkyl, pyrrolidinyl-(C,-Cy)alkyl, pyridinyl, phenyl(C,-C¢)alky! where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,- Cg)alkylamino, (C,-C,)alkyl and (C,-Ce)alkoxy; or Rp and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and 1s optionally substituted by a Cj-¢ alkyl group or a heterocycle, or R; and R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ringS optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-C,)alkyl, pyridinyl, phenyl(C,-C)alkyl, phenyl(C,-C,)alkenyl, where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di-(C,-C)alkylamino, (C,-Cs)alkyl and (C,-Cj)alkoxy;g) a group of formula NRdRe in which Rd and Re are independently selected from hydrogen, a C1-12 alkyl group, a C312 cycloalkyl group, S(O),-phenyl, phenyl, a heterocycloalkyl-(C,-Cy)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected16 from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR R,, (C,-C¢)alkoxy, amino-(C,- Ce)alkoxy-(C,-Cq)alkoxy, mono-(C,-C,)alkyl-amino-(C,-C)alkoxy-(C,-C)alkoxy, N,N-di-(C,-C¢)alkyl-amino-(C,-C¢)alkoxy-(C,-Cy)alkoxy, a C1-12 alkyl group, a C3.12 cycloalkyl group, a phenyl Cj.g alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-Cy)alkyl, (C,-C,)alkoxy, di-(C,-Cy)alkyl-amino-(C,-C4)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cg)alkyl, or an amino group of formula NRhRj wherein Rh and Rj are as defined above,h) a group of formula O(CH2)m Rg in which m is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NR4qRe in which Rq and Re are as defined above; or Rg represents a group of formula COR3 wherein Rj is as defined above andmis 1, 2,3, 40r5,1) nitro,J) optionally substituted phenyl Cj.¢ alkyl,k) optionally substituted phenyl Cj-6 alkoxy 1) cyano, m) a C, calkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) a C1-¢ alkythio group s) phenyl t) a C2-4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1-6 alkyl group, a C}-6 alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyl; and R3, R4, R5 and Rg independently represent a) H, b) halo, c) a C]-¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRpR;j wherein Rp and Rj are as defined below, d) a C, ¢alkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRhR; wherein Rp, and R; are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula CORg in which Rj represents hydroxy, a C1-6 alkoxy group or Ra represents a group of formula NRp Re in which Rp and R¢ independently represent hydrogen, a C]-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rh and Rj independently represent hydrogen or a Ci-6 alkyl group, (C,-Cy)heterocycloalkyl-(C,-Calkyl (heterocycloalkyl = pyridine, morpoline, piperazine, and N-methylpiperazine) or wherein Rp and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a C}-6 alkyl group, h) a group of formula NR Re in which Rd and Re are independently selected from hydrogen, a C-12 alkyl group , a C3-12 cycloalkyl group or phenyl or a group of formula COR f wherein Rf represents hydrogen, a C1-12 alkyl group, a C3.12 cycloalkyl group , a phenyl C}-6 alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRyR; wherein Rp and Rj are as defined above i) a group of formula O(CH2)m Rg in which mis 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or Rg represents a group of formula COR; wherein R, is as defined above and mis 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl C16 alkyl, 1) optionally substituted phenyl Cj-¢ alkoxy m) cyano or 0)aCp- 4 alkenyl group or a C).4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1-g alkyl group, a C1-6 alkoxy group or halo; with the provisos that 1) when R1, R3, R4, Rs and Rg each represent hydrogen and X represents SO,, then R, does not represent phenyl and 2) when X represents S and Ri, R3, R4, R5 and Rg each represent hydrogen, then R, does not represent 2,4-dichlorophenyl.72. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents oxygen; R, represents H; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo,b) a C1.6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, c) a C, ,alkoxy group optionally substituted by one or more of the following: hydroxy, COOH, an amino group of formula NRhR;, or an amide of the formula CONRR;, wherein Ry and R; are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula COR; or SO,R, wherein Rj is hydroxy, (C,-C)alkyl,(C,.Cyalkoxy or Rj represents a group of formula NR R; where Rp and Rc independently represent hydrogen, a C1-12 alkyl group, a C3-12 cycloalkyl group, phenyl(C,-Cy)alkyl or heterocyclyl-(C,-Cq)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (C,-Cyalkyl are optionally substituted by one or more of the following: hydroxy, (C,-C,)-hyrdroxy, halo, nitro, (C,-C¢)alkyl, (C,-Cs)alkoxy, -O-(C,-Cy)alkyl-hydroxy a C312 cycloalkyl group or an amino group of formula NR,R;; where Rp and Rj independently represent hydrogen, (C,-C),)alkyl, (C;- C,)cycloalkyl, (C;-Co)heterocycloalkyl-(Co-Cg)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-C¢)alkenyl, (C,-Cy alkynyl, (C,-C4)cycloalkenyl-(C,- Cyalkyl, hydroxy(C,-C/)alkyl, amino(C,-Cg)akkyl, (C,-Cs)alkoxy(C,- C,alkyl, mono- or di-(C,-C4)alkylamino(C,-C¢)alkyl, morpholinyl-(C,- Cyalkyl, pyrrolidinyl-(C,-Cy)alkyl, pyridinyl, phenyl(C,-Cs)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,- C,)alkylamino, (C,-Cy)alkyl and (C,-C¢)alkoxy; or Rp and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a C1.¢ alkyl group or a heterocycle, or R, and R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ring optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-Cy)alkyl, pyridinyl, phenyl(C,-C,)alkyl, phenyl(C,-C)alkenyl, where the phenyl portion 1s optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di-(C,-C¢)alkylamino, (C,-Cs)alkyl and (C,-Cg)alkoxy;g) a group of formula NRdRe in which Rq and Re are independently selected. from hydrogen, a C1-12 alkyl! group, a C3.12 cycloalkyl group, S(O),-phenyl, phenyl, a heterocycloalkyl-(C,-Cy)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR,R,, (C,-Cy)alkoxy, amino-(C,- C,alkoxy-(C,-C4)alkoxy, mono-(C,-C,)alkyl-amino-(C,-C/alkoxy-(C,-C¢)alkoxy, N,N-di-(C,-C,)alkyl-amino-(C,-C,)alkoxy-(C,-C,)alkoxy, a C}-12 alkyl group, a C3.12 cycloalkyl group, a phenyl C1-6 alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-Cy)alky}, (C,-Cs)alkoxy, di-(C,-C,)alkyl-amino-(C,-C4)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cy)alkyl, or an amino group of formula NRhR;j wherein Rp and Rj are as defined above,h) a group of formula O(CH2)m Rg in which mis 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rg and Re are as defined above; or Rg represents a group of formula CORa wherein Rj 1s as defined above andmis1,2,3,4o0r5,1) nitro,j) optionally substituted phenyl Cj.6 alkyl,k) optionally substituted phenyl Cj. alkoxy 1) cyano, m) a C, calkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl, 1) a C1-6 alkythio group s) phenyl t) a C2.4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1 -g alkyl group, a C1-¢ alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyl; and R3, R4, Rs and Rg independently represent a) H, b) halo, ¢) a C1.¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRRR; wherein Rp and R; are as defined below, d) a C, alkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRhR; wherein Rh and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxy, g) a group formula COR; in which Rj represents hydroxy, a Cj-6 alkoxy group or Ra represents a group of formula NRp R¢ in which Rp and R¢ independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a Cj.g alkyl group, (C,-Cy)heterocycloalkyl-(C,-Cy)alkyl(heterocycloalkyl = pyridine, morpoline, piperazine, and N- methylpiperazine) or wherein Ry and R; together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a C1.¢ alkyl group, h) a group of formula NRd Re in which Rg and Re are independently selected from hydrogen, a C1-12 alkyl group , a C3.12 cycloalkyl group or phenyl or a group of formula COR f wherein Rf represents hydrogen, a C1.12 alkyl group , a C3-172 cycloalkyl group , a phenyl Cj.¢ alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl! are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above i) a group of formula O(CH2)m Rg in whichm is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NR4Re in which Rd and Re are as defined above; or Rg represents a group of formula CORa wherein Ra is as defined above and mis 1, 2, 3, 4 or 5, )) nitro, k) optionally substituted phenyl C1-¢ alkyl, 1) optionally substituted phenyl C1.¢ alkoxy m) cyano or 0) a C2-4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1.-6 alkyl group, a C1-¢ alkoxy group or halo. with the proviso that when Ri, R3, R4, Rs and Rg each represent hydrogen, then R, does not represent phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl.73. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents a group of formula NR; ; R, represents H ; . R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo,b) a C1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, c) a C,, alkoxy group optionally substituted by one or more of the following: $5 hydroxy, COOH, an amino group of formula NRhR;j, or an amide of the formula CONR,R,, wherein Rh and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula COR; or SO,R, wherein Ry is hydroxy, (C,-Cy)alkyl,(C,.Cyalkoxy or Ry represents a group of formula NR,R; where Rp and Rc independently represent hydrogen, a C1.12 alkyl group, a C3-12 cycloalkyl group, phenyl(C,-Cy)alkyl or heterocyclyl-(C,-C)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (C,-C4)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-C¢)-hyrdroxy, halo, nitro, (C,-Cg)alkyl, (C,-C¢)alkoxy, -O-(C,-C)alkyl-hydroxy a C3-12 cycloalkyl group or an amino group of formula NR;R;; where Rp and Rj independently represent hydrogen, (C,-C,)alkyl, (C,- Co)cycloalkyl, (C,-C)heterocycloalkyl-(C,-Cg)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-C,)alkenyl, (C,-C¢)alkynyl, (C,-Cq)cycloalkenyl-(C,- Coalkyl, hydroxy(C,-C)alkyl, amino(C,-Cs)alkyl, (C,-Cy)alkoxy(C,- Cy)alkyl, mono- or di-(C,-C¢)alkylamino(C,-C)alkyl, morpholinyl-(C,- C,)alkyl, pyrrolidinyl-(C,-Cy)alkyl, pyridinyl, phenyl(C,-C,)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,- C¢)alkylamino, (C,-C;)alkyl and (C,-Cy)alkoxy; or Rp and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a Cj-¢ alkyl group or a heterocycle, or R,and R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ring optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-Cy)alkyl], pyridinyl, phenyl(C,-C,)alkyl, phenyl(C,-C)alkenyl, where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di-(C,-C¢)alkylamino, (C,-C,)alkyl and (C,-Cy)alkoxy;g) a group of formula NRdRe in which Rg and Re are independently selected from hydrogen, a C1-12 alkyl group, a C3-12 cycloalkyl group, S(O),-phenyl, phenyl, a heterocycloalkyl-(C,-C,)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR,R,, (C,-C;)alkoxy, amino-(C,- C¢)alkoxy-(C,-Cy)alkoxy, mono-(C,-C)alkyl-amino-(C,-Cy)alkoxy-(C,-Cy)alkoxy, N,N-di-(C,-C,)alkyl-amino-(C,-Cy)alkoxy-(C,-C)alkoxy, a C1-12 alkyl group, a C3-12 cycloalkyl group, a phenyl C1.6 alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-C,)alkyl, (C,-Cy)alkoxy, di-(C,-C¢)alkyl-amino-(C,-C;)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cy)alkyl, or an amino group of formula NRpRj wherein Rh and Rj are as defined above,h) a group of formula O(CH2)m Rg in whichm is 2,3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rq and Re are as defined above; or Rg represents a group of formula COR 3 wherein Rj is as defined above andmis 1,2,3,4o0r5,i) nitro,j) optionally substituted phenyl C1.¢ alkyl,k) optionally substituted phenyl C}.6 alkoxy 1) cyano, m) a C, calkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl, 1) a C1-6 alkythio group s) phenyl t) a C2-4 alkenyl group or a C2.4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1-6 alkyl group, a C1-6 alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyl; and R3, R4, Rs and Rg independently represent a) H, b) halo, ¢) a C1 .6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR;j wherein Rp and Rj are as defined below, d) a C, calkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRhR; wherein Rp and R; are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula CORj in which Rj represents hydroxy, a C1-6 alkoxy group or Ra represents a group of formula NRp Rc in which Rp and R¢ independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a Cj.¢ alkyl group, (C,-C,)heterocycloalkyl-(C,-Cy)alkyl(heterocycloalkyl = pyridine, morpoline, piperazine, and N- methylpiperazine) or wherein Rp and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Cj-6 alkyl group, h) a group of formula NR{ Re in which Rg and Re are independently selected from hydrogen, a C1-12 alkyl group , a C3-12 cycloalkyl group or phenyl or a group of formula COR f wherein Rf represents hydrogen, a C1.12 alkyl group , a C3.12 cycloalkyl group , a phenyl C1.¢ alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR;j wherein Rp and Rj are as defined above i) a group of formula O(CH2)m Rg in whichm is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or Rg represents a group of formula COR, wherein Rj is as defined above and mis 1, 2, 3,4 or 5, j) nitro, k) optionally substituted phenyl C1.¢ alkyl, I) optionally substituted phenyl C16 alkoxy m) cyano or 0) a C2-4 alkenyl group or a C2.4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1.¢ alkyl group, a C1-6 alkoxy group or halo.74. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents a group of formula -C=NOR7 in which R7 represents H or a C1-4 alkyl group; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo,b) a C1.6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rh and Rj are as defined below, ¢) a C, alkoxy group optionally substituted by one or more of the following: hydroxy, COOH, an amino group of formula NRhR;, or an amide of the formula CONR,R,, wherein Rj and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula CORa or SO;R, wherein Rj is hydroxy, (C,-Cy)alkyl,(C,.C,)alkoxy or Ry represents a group of formula NR R_; where Rp and Rc independently represent hydrogen, a C1-12 alkyl group, a C3-12 cycloalkyl group, phenyl(C,-Cyalkyl or heterocyclyl-(Cy-Cg)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (C,-Cg)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-C,)-hyrdroxy, halo, nitro, (C,-Cy)alkyl, (C,-Cyalkoxy, -O-(C,-Cg)alkyl-hydroxy a C3.12 cycloalkyl group or an amino group of formula NR,R;; where Rh and Rj independently represent hydrogen, (C,-C),)alkyl, (Cs- C cycloalkyl, (C,-Co)heteracycloalkyl-(C,-Ce)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-Coalkenyl, (C,-Cgalkynyl, (C,-Co)cycloalkenyl-(C,- Coalkyl, hydroxy(C,-Cjalkyl, amino(C,-C,)alkyl, (C,-Cy)alkoxy(C,- C,)alkyl, mono- or di-(C,-C¢)alkylamino(C,-C)alkyl, morpholinyl-(C,- C,)alkyl, pyrrolidinyl-(C,-Cy)alkyl, pyridinyl, phenyl(C,-C,)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C;- C,)alkylamino, (C,-Cy)alkyl and (C,-Cy)alkoxy; or Rp and R; together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a C1-¢ alkyl group or a heterocycle, or R,and R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said nng optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-Cyalkyl, pyridinyl, phenyl(C,-C¢)alkyl, phenyl(C,-Cy)alkenyl, where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di-(C,-C,)alkylamino, (C,-Cyalkyl and (C,-C¢)alkoxy;g) a group of formula NRdRe in which Rd and Re are independently selected from hydrogen, a C1.12 alkyl group, a C3.12 cycloalkyl group, S(O),-phenyl, phenyl, a heterocycloalkyl-(C,-Cy)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR, R, (C;-C¢)alkoxy, amino-(C,- C,)alkoxy-(C,-Cy)alkoxy, mono-(C,-C,)alkyl-amino-(C,-Cs)alkoxy-(C,-Cq)alkoxy, N,N-di-(C,-C,)alkyl-amino-(C,-C4)alkoxy-(C,-Cs)alkoxy, a C1-12 alkyl group, a C3.12 cycloalkyl group, a phenyl C1.6 alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-Cealkyl, (C,-Cy)alkoxy, di-(C,-C4)alkyl-amino-(C,-C4)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cy)alkyl, or an amino group of formula NRhR; wherein Rp and Rj are as defined above,h) a group of formula O(CH2)m Rg in which m is 2, 3, 4or5and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or Rg represents a group of formula COR; wherein Rj is as defined above andmis1,2,3,4o0r5,1) nitro,j) optionally substituted phenyl C1.6 alkyl,k) optionally substituted phenyl C1-6 alkoxy 1) cyano, m) a C, calkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) a C1-6 alkythio group s) phenyl t) a C7-4 alkenyl group or a C2.4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1.6 alkyl group, a C-6 alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyi; and R3, R4, Rs and Rg independently represent a) H, b) halo, ¢) a C1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below, d) a C, alkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula COR; in which Rj represents hydroxy, a C1-6 alkoxy group or Ra represents a group of formula NRp R¢ in which Rp and Rg independently represent hydrogen, a C1-¢ alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhRj wherein Rp, and Ry independently represent hydrogen or a C16 alkyl group, (C,-Cyheterocycloalkyl-(C,-Colalkyl(heterocycloalkyl = pyridine, morpoline, piperazine, and N- methylpiperazine) or wherein Rh and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Cj. alkyl group, h) a group of formula NR( Re in which R( and Re are independently selected from hydrogen, a C1-12 alkyl group , a C3-12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C1.12 alkyl group , a C3.12 cycloalkyl group , a phenyl Cj.¢ alkyl group or phenyl wherein in each case the alkyl! group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above 1) a group of formula O(CH2)m Rg in which m is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which R4 and Re are as defined above; or Rg represents a group of formula COR, wherein Ra is as defined above and mis 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl Cj .¢ alkyl, 1) optionally substituted phenyl Cj.g alkoxy m) cyano or 0) a C2-4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1.¢ alkyl group, a C1.¢ alkoxy group or halo; with the proviso that when R1, R3, Rg, R5 and Rg each represent hydrogen, and X represents C=NOH then R} does not represent 4-methylphenyl or 3,4-dimethoxyphenyl.75. Compounds of formula I and pharmaceutically acceptable salts thereof in which: X represents substituted methylene or a carbonyl group; R, represents H ; - R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo,b) a C1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRnR;j wherein Rp and Rj are as defined below, c) a C, calkoxy group optionally substituted by one or more of the following: hydroxy, COOH, an amino group of formula NRhR;j, or an amide of the formula CONR,R;, wherein Rj and R; are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula CORj or SO,R, wherein Rj 1s hydroxy, (C,-C,)alkyl,(C,.Cealkoxy or Rj represents a group of formula NR,R; where Rp and Rc independently represent hydrogen, a C1.12 alkyl group, a C3-12 cycloalkyl group, phenyl(C,-C¢)alkyl or heterocyclyl-(C,-C,)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (C,-Cy)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-C,)-hyrdroxy, halo, nitro, (C,-C,)alkyl, (C,-C¢)alkoxy, -O-(C,-C)alkyl-hydroxy a C3-12 cycloalkyl group or an amino group of formula NR,R;; where Rp and Rj independently represent hydrogen, (C,-C),)alkyl, (C;- C,)cycloalkyl, (C,-C¢)heterocycloalkyl-(C,-C)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-Cy)alkenyl, (C,-C¢alkynyl, (C,-Cq)cycloalkenyl-(C,- Cyalkyl, hydroxy(C,-C,)alkyl, amino(C,-C¢)alkyl, (C,-C)alkoxy(C,- C,)alkyl, mono- or di-(C,-Cy)alkylamino(C,-C,)alkyl, morpholinyl-(C,- Cyalkyl, pyrrolidinyl-(C,-Cyalkyl, pyndinyl, phenyl(C,-C¢)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,- Ce)alkylamino, (C,-C)alkyl and (C,-Cs)alkoxy; or Rp and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a Cg alkyl group or a heterocycle, or Ryand R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ringS optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-C,)alkyl, pyridinyl, phenyl(C,-C)alkyl, phenyl(C,-C,)alkenyl, where the phenyl! portion is optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di-(C,-C)alkylamino, (C,-C,)alkyl and (C,-Cy)alkoxy;g) a group of formula NR4Re in which Rd and Re are independently selected from hydrogen, a C)-12 alkyl group, a C3-12 cycloalkyl group, S(O),-phenyl, phenyl, a heterocycloalkyl-(C,-C,)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR R., (C,-Cy)alkoxy, amino-(C,- Cealkoxy-(C,-Cy)alkoxy, mono-(C,-Cy)alkyl-amino-(C,-C4)alkoxy-(C,-C,)alkoxy, N,N-di~(C,-Cy)alkyl-amino-(C,-C¢)alkoxy-(C,-C¢)alkoxy, a C}-12 alkyl group, a C3.12 cycloalkyl group, a phenyl C6 alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-C4)alkyl, (C,-C,)alkoxy, di-(C,-Cy)alkyl-amino-(C,-C)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cs)alkyl, or an amino group of formula NRHR; wherein Rh and Rj are as defined above,h) a group of formula O(CH?2)m Rg inwhichmis2,3,40r5and Rg represents hydroxy or a group of formula NR4Re in which Rg and Re are as defined above; or Rg represents a group of formula COR, wherein Rj is as defined above andmis 1,2,3,4o0r5,1) nitro,J) optionally substituted phenyl Cj.¢ alkyl,k) optionally substituted phenyl C1-¢ alkoxy 1) cyano, m) a C, calkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally S substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) a C1.6 alkythio group s) phenyl t) a C2_4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1.6 alkyl group, a C]-¢ alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyl; and R3,R4, R5 and Rg independently represent a) H, b) halo, ¢) a C-¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRpR; wherein Rp, and R; are as defined below, d) a C, 4 alkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRhR; wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxy, g) a group formula COR; in which Rj represents hydroxy, a C}-¢ alkoxy group or Rj represents a group of formula NRp Rc in which Rp and R¢ independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp, and Rj independently represent hydrogen or a Cj. alkyl group, (C,-C,)heterocycloalkyl-(C,-C alkyl(heterocycloalkyl = pyridine, morpoline, piperazine, and N- methylpiperazine) or wherein Rp, and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom S selected from O, S or N and is optionally substituted by a C1. alkyl group, h) a group of formula NR4 Re in which Rg and Re are independently selected from hydrogen, a C1-12 alkyl group , a C3.12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C1-12 alkyl group , a C3.12 cycloalkyl group , a phenyl Cj. alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl! are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhRj wherein Rp and R; are as defined above i) a group of formula O(CH2)m Rg in which mis 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRdRe in which Rd and Re are as defined above; or Rg represents a group of formula CORa wherein Ra is as defined above and mis 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl C1.¢ alkyl, 1) optionally substituted phenyl Cj.¢ alkoxy m) cyano or 0) a C).4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1.¢ alkyl group, a Cj-¢ alkoxy group or halo;with the provisos that1) when X represents carbonyl or a substituted methylene, R1 is hydrogen and R3, R4, R5 and Rg each represent hydrogen, then R2 is not pyridyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted by C}.2 alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group;2) when X represents methylene, R] is hydrogen and two of R3, R4, Rs and Rg independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C1-4 alkyl, C}.-4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R2 is not thienyl, furyl,pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C}-4 alkyl, C1.4 alkoxy or trifluoromethyl; and 3) when X represents a carbonyl group, R) represents phenyl, 4- chlorophenyl or 4-methoxyphenyl, then R3, R4, R5 and Rg are not trifluoromethyl; and 4) when X represents a carbonyl group, R) represents phenyl, R3 represents bromo, R4 represents hydroxy and Rs represents methoxy, then Rg is not hydrogen and 5) when X represents carbonyl and R3, R4, R5 and Rg represent hydrogen, then Rg is not aryl.76. Compounds of formula I and pharmaceutically acceptable salts thereof in which X represents a group of formula (CH2)p in whichnis 1,2 or3 R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo, b) a C1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRyR; wherein Rp and R; are as defined below, ¢) a C, calkoxy group optionally substituted by one or more of the following: hydroxy, COOH, an amino group of formula NRhR;, or an amide of the formula CONR,R,, wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula COR, or SO,R, wherein Rj is hydroxy, (C,-Cyalkyl,(C,.Cyalkoxy or Rj represents a group of formula NR,R ; where Rp and Re independently represent hydrogen, a C1.12 alkyl group, aC3.12 cycloalkyl group, phenyl(C,-C)alkyl or heterocyclyl-(C,-Cy)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl group, phenyl or heterocyclyl- (C,-C,)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-C,)-hyrdroxy, halo, nitro, (C,-C,)alkyl}, (C,-C¢)alkoxy, -O-(C,-C)alkyl-hydroxy a C3-12 cycloalkyl group or an amino group of formula NR,R; where Rp and Rj independently represent hydrogen, (C,-C, alkyl, (C;- Cy)cycloalkyl, (C,-Cy)heterocycloalkyl-(C,-Cg)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-Cy)alkenyl, (C,-Cy)alkynyl, (C,-C¢)cycloalkenyl-(Cy- Cy)alkyl, hydroxy(C,-Cy)alkyl, amino(C,-C¢)alkyl, (C,-C¢)alkoxy(C,- C,)alkyl, mono- or di-(C,-C¢)alkylamino(C,-C,)alkyl, morpholinyl-(C,- C,)alkyl, pyrrolidinyl-(C,-C)alkyl, pyridinyl, phenyl(C,-C¢)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,- Cy)alkylamino, (C,-C¢)alkyl and (C,-C4)alkoxy; or Rp and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a C1. alkyl group or a heterocycle, or R, and R_ are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ring optionally contains one or more additional heteroatoms selected from the group consisting of O, N and §, and said ring is optionally substituted by (C,-Cy)alkyl, pyridinyl, phenyl(C,-C,)alkyl, phenyl(C,-Cs)alkenyl, where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting ofBr, C}, F, I, hydroxy, nitro, amino, mono- or di-(C,-C¢)atkylamino, (C,-C)alkyl and (C,-Cyalkoxy; g) a group of formula NRgRe in which Rd and Re are independently selected from hydrogen, a C1-17 alkyl group, a C3-12 cycloalkyl group, S(O),-phenyl,S phenyl, a heterocycloalkyl-(C,-C)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR,R, (C,-C,)alkoxy, amino-(C,- Cyalkoxy-(C,-Ce)alkoxy, mono-(C,-C,)alkyl-amino-(C,-Cyalkoxy-(C,-Cy)alkoxy, N,N-di-(C,-C,)alkyl-amino-(C,-C,)alkoxy-(C,-Cy)alkoxy, a C1-12 alkyl group, a C3. 12 cycloalkyl! group, a phenyl C1. alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-Cyalkyl, (C,-C/)alkoxy, di-(C,-Cyalkyl-amino-(C,-C alkoxy, pyrrolidine which is optionally substituted with a (C,-Cg)alkyl, or an amino group of formula NRhR;j wherein Rh and Rj are as defined above, h) a group of formula O(CH2)m Rg in which mis 2,3, 4 or 5 and Rg represents hydroxy or a group of formula NR3Re in which Rd and Re are as defined above; or Rg represents a group of formula CORp wherein Rj is as defined above andmis 1,2,3,4o0r5, 1) nitro, }) optionally substituted phenyl C1.¢g alkyl, k) optionally substituted phenyl Cj.g alkoxy 1) cyano, m) a C, ;alkenyloxy group, n) a pynidyloxy or pyridylthio group in which the pyndine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro, 0) hydroxyamidino, p) aminomethyl, q) formamidomethyl,r) a C1_¢ alkythio group s) phenyl t) a C2.4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C}.g alkyl group, a C].6 alkoxy group or halo,u) CHO, v) dithydroxyborane w) tetrazolyl; and R3, R4, Rs and Rg independently represent a) H, b) halo, ¢) a C1-¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rh and Rj are as defined below, d) a C, calkoxy group optionally substituted by one or more of the following: hydroxy, a C, salkoxy, halo or an amino group of formula NRpR; wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula CORj; in which Rg represents hydroxy, a C1-g alkoxy group or Ra represents a group of formula NRp R¢ in which Rp and Rc independently represent hydrogen, a C1-6 alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen or a Cj. alkyl group, (C,-C¢)heterocycloalkyl-(C,-C¢)alkyl (heterocycloalkyl = pyridine, morpoline, piperazine, and N- methylpiperazine) or wherein Rj and R; together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic ring which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Cj.¢ alkyl group, h) a group of formula NRd Re in which Rd and Re are independently selected from hydrogen, a Cy.12 alkyl group, a C3.12 cycloalkyl group or phenyl or a group of formula COR f wherein Rf represents hydrogen, a C1.12 alkyl group , a C3.12 cycloalkyl group , a phenyl C1.6 alkyl group or phenyl wherein in each case the alky! group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rh and R; are as defined above i) a group of formula O(CH2)m Rg in which m is 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NRgRe in which Rg and Re are as defined above; or Rg represents a group of formula COR, wherein Ry is as defined above and mis 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl C1.¢ alkyl, 1) optionally substituted phenyl C1.g alkoxy m) cyano or 0) a C2-4 alkenyl group or a C24 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a Cj.g alkyl group, a C]-¢ alkoxy group or halo. with the proviso that when X is a group of formula (CH, ), in which nis 1, 2 or 3, R, is hydrogen and two of R3, R4, R5 and Rg independently represent hydrogen, halogen having an atomic weight of about 19 to 36, C1-4 alkyl, C1.4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R2 is not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C|-4 alkyl, C1-4 alkoxy or trifluoromethyl, and with the proviso that when nis 2 and R3, R4, R35 and Rg each represent hydrogen or methoxy, then R) does not represent 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2- yl or 2-carboxyphenyl77. Compounds of formula I and pharmaceutically acceptable salts thereof in which : X represents a) substituted methylene b) carbonyl, c) oxygen, d) a group of formula -C=NOR?7 in which R7 represents H or a C]-4 alkyl group, €) a group of formula NRg in which Rg represents H, an optionally substitutedC1-4 alkyl group or optionally substituted phenyl, f) a group of formula (CH,), in which nis 1, 2 or 3, or g) a group of formula S(O)p in which p is 0,1o0r2; R, represents H ; R, represents aryl, pyridyl, thienyl, furyl or pyrrolyl each of which is optionally substituted by one or more of the following: a) halo, b) a C-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR; wherein Rh and Rj are as defined below, ¢) a C, 4alkoxy group optionally substituted by one or more of the following: hydroxy, COOH, an amino group of formula NRhR;, or an amide of the formula CONR,R;, wherein Rh and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group; or halo d) optionally substituted phenoxy, e) hydroxy, f) a group of formula COR4 or SO,R, wherein Ry is hydroxy, (C,-C¢)alkyl,(C,.Cyalkoxy or Rj represents a group of formula NR,R ; where Rp and R¢ independently represent hydrogen, a C1-12 alkyl group, a C3-12 cycloalkyl group, phenyl(C,-C)alkyl or heterocyclyl-(C,-C,)alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl, and thiophenyl) wherein the alkyl group, the cycloalkyl! group, phenyl or heterocyclyl- (C,-Cy)alkyl are optionally substituted by one or more of the following: hydroxy, (C,-C¢)-hyrdroxy, halo, nitro, (C,-Cyalkyl, (C,-C,)alkoxy, -O-(C,-C¢)alkyl-hydroxy a C3-12 cycloalkyl group or an amino group of formula NR,R; where Rp, and R; independently represent hydrogen, (C,-C,,)alkyl, (C;- Ce)cycloalkyl, (C,-Cgheterocycloalkyl-(C,-Ce)alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpoline, and piperazine), (C,-C¢)alkenyl, (C,-C,)alkynyl, (C,-C¢)cycloalkenyl-(C,- Ce)alkyl, hydroxy(C,-Cyalkyl, amino(C,-C,)alkyl, (C,-Cy)alkoxy(C,-Cyalkyl, mono- or di-(C,-C¢)alkylamino(C,-Cy)alkyl, morpholinyl-(C,- Cyalkyl, pyrrolidinyl-(C,-C)alkyl, pyridinyl, phenyl(C,-C,)alkyl where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of halo, hydroxy, nitro, amino, mono- or di-(C,-S Cyalkylamino, (C,-C)alkyl and (C,-C,)alkoxy; or Ry; and Rj together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional hetero atoms selected from O, S and N and is optionally substituted by a Cj-¢ alkyl group or a heterocycle,or Rand R, are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-, 5-, 6- or 7-membered ring where said ring optionally contains one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted by (C,-C,)alkyl, pyridinyl, phenyl(C,-Cy)alkyl, phenyl(C,-C)alkenyl, where the phenyl portion is optionally substituted by one or more moieties selected from the group consisting of Br, CL, F, I, hydroxy, nitro, amino, mono- or di-(C,-C)alkylamino, (C,-Cy)alkyl and (C,-Cq)alkoxy;g) a group of formula NRdRe in which Rq and Re are independently selected from hydrogen, a C1-12 alkyl! group, a C312 cycloalkyl group, S(O),-phenyl,phenyl, a heterocycloalkyl-(C,-Cg)alkyl, wherein the heterocycloalkyl is a four, five, six or seven menbered heterocyclic ring which has one or more heteroatoms selected from the group consisting of O, S and N, or R, and R, are each, independently,a group of formula CORf wherein Rf represents hydrogen, NR,R_, (C,-C,)alkoxy, amino-(C,-Cyalkoxy~(C,-Cyalkoxy, mono-(C,-C,)alkyl-amino-(C,-C4)alkoxy-(C,-C)alkoxy, N,N-di-(C,-Cy)alkyl-amino-(C,-C,)alkoxy-(C,-Cy)alkoxy, a C1-12 alkyl group, a C3. 12 cycloalkyl group, a phenyl Cj. alkyl group or phenyl wherein in each case the alkoxy, the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro, (C,-Cyalkyl, (C,-C,)alkoxy,di-(C,-Cgalkyl-amino-(C,-C,)alkoxy, pyrrolidine which is optionally substituted with a (C,-Cg)alkyl, or an amino group of formula NRhR;j wherein Rp and Rj are as defined above,h) a group of formula O(CH2)m Rginwhichmis2,3,40r5and Rg represents hydroxy or a group of formula NRdRe in which Rq and Re are as definedS above; or Rg represents a group of formula COR, wherein Ry is as defined above andmis 1, 2, 3,4 or 5,1) nitro,J) optionally substituted phenyl Cj.¢ alkyl,kK) optionally substituted phenyl Cj_¢ alkoxy1) cyano,m) a C, salkenyloxy group,n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following : trifluoromethyl or nitro,0) hydroxyamidino,p) aminomethyl,q) formamidomethyl,r) a Cj. alkythio group s) phenyl t) a C2-4 alkenyl group or a C2-4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following : a C1.6 alkyl group, a C1-¢ alkoxy group or halo, u) CHO, v) dihydroxyborane w) tetrazolyl;R3,R4,Rs5and Rg independently represent a) H, b) halo, c) a C1.¢ alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of formula NRhR;j wherein Ry, and Rj are as defined below, d) a C, alkoxy group optionally substituted by one or more of the following: hydroxy, a C, ,alkoxy, halo or an amino group of formula NRhRj wherein Rp and Rj are as defined below provided that these groups are not attached to the carbon which is attached to the oxygen of the alkoxy group, €) optionally substituted phenoxy, f) hydroxy, g) a group formula COR in which Rj represents hydroxy, a Cj. alkoxy group or Ra represents a group of formula NRy Rc in which Rp and R¢ independently represent hydrogen, a Cj. alkyl group or phenyl wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of formula NRhR; wherein Rp and Rj independently represent hydrogen ora Ci.¢ alkyl group, (C,-C,)heterocycloalkyl-(C,-Cy)alkyl (heterocycloalkyl = pyridine, morpoline, piperazine, and N-methylpiperazine) or wherein Rp and Rj together with the nitrogen atom to which they are attached represent a five, six or seven membered saturated heterocyclic nng which optionally contains an additional hetero atom selected from O, S or N and is optionally substituted by a Ci-¢ alkyl group, h) a group of formula NRd Re in which Rg and Re are independently selected from hydrogen, a C1-12 alkyl group, a C3.12 cycloalkyl group or phenyl or a group of formula CORf wherein Rf represents hydrogen, a C1-12 alkyl group , a C3-12 cycloalkyl group , a phenyl C}.¢ alkyl group or phenyl wherein in each case the alkyl group, the cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of formula NRhR; wherein Rp and Rj are as defined above i) a group of formula O(CH2)m Rg in which mis 2, 3, 4 or 5 and Rg represents hydroxy or a group of formula NR3Re in whichRg and Re are as defined above; or Rg represents a group of formula COR, wherein Ra is as defined above and m is 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl C1. alkyl, 1) optionally substituted phenyl C1.g alkoxy m) cyano or 0) a Co. 4 alkenyl group or a C2.4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following: a C1.¢ alkyl group, a C1-6 alkoxy group or halo.AMENDED SHEET ® WO 00/27822 : PCT/US99/26105 =78. The compound of formula I as claimed in any one of claims 13 to 54 and 71 to 77, specifically as hereinbefore described and exemplified and not claimed in any one of claims 55 to 58 and 67 to 70. !79. The compound of formula I including any new and inventive integer or combination of integers, substantially as herein described.80. The pharmaceutical composition as claimed in claim 59, substantially as hereinbefore described or exemplified.81. The pharmaceutical composition including any new and inventive integer or combination of integers, substantially as herein described.82. The use of a compound of formula I as claimed in claim 62, substantially as hereinbefore described or exemplified.83. The use of a compound of formula I including any new and inventive integer or combination of integers, substantially as herein described.84. A compound of formula I or a composition comprising thereof as claimed in any one of claims 1 to 54, 59, 71 to 81 whenever supplied with instructions for the use thereof in inhibiting protein kinase activity.85. A compound of formula I or a composition comprising thereof as claimed in claim 84 when the instructions are in printed or written form.86. A compound of formula I or a composition comprising thereof as claimed in claim 85 supplied in a package or container having the said instructions provided therein or thereon.
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US6462036B1 (en) | 1998-11-06 | 2002-10-08 | Basf Aktiengesellschaft | Tricyclic pyrazole derivatives |
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-
1999
- 1999-11-04 PL PL99348210A patent/PL348210A1/en not_active Application Discontinuation
- 1999-11-04 SK SK528-2001A patent/SK5282001A3/en unknown
- 1999-11-04 JP JP2000581002A patent/JP2003517447A/en active Pending
- 1999-11-04 ID IDW00200101001A patent/ID30132A/en unknown
- 1999-11-04 WO PCT/US1999/026105 patent/WO2000027822A2/en not_active Application Discontinuation
- 1999-11-04 TR TR2001/02277T patent/TR200102277T2/en unknown
- 1999-11-04 BR BR9915132-4A patent/BR9915132A/en not_active IP Right Cessation
- 1999-11-04 CA CA002350235A patent/CA2350235A1/en not_active Abandoned
- 1999-11-04 AU AU19091/00A patent/AU762992B2/en not_active Ceased
- 1999-11-04 HU HU0200310A patent/HUP0200310A3/en unknown
- 1999-11-04 CN CN99814744A patent/CN1335836A/en active Pending
- 1999-11-04 EP EP99962700A patent/EP1127051A2/en not_active Withdrawn
- 1999-11-04 CZ CZ20011563A patent/CZ20011563A3/en unknown
- 1999-11-04 KR KR1020017005726A patent/KR20010086005A/en not_active Application Discontinuation
- 1999-11-04 IL IL14258499A patent/IL142584A0/en unknown
-
2001
- 2001-04-27 BG BG105481A patent/BG105481A/en unknown
- 2001-05-04 ZA ZA200103610A patent/ZA200103610B/en unknown
- 2001-05-04 NO NO20012219A patent/NO20012219L/en not_active Application Discontinuation
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2002
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WO2000027822A3 (en) | 2000-08-10 |
TR200102277T2 (en) | 2002-01-21 |
CZ20011563A3 (en) | 2003-02-12 |
ID30132A (en) | 2001-11-08 |
NO20012219D0 (en) | 2001-05-04 |
CN1335836A (en) | 2002-02-13 |
NO20012219L (en) | 2001-06-13 |
PL348210A1 (en) | 2002-05-06 |
HUP0200310A2 (en) | 2002-11-28 |
CA2350235A1 (en) | 2000-05-18 |
SK5282001A3 (en) | 2002-01-07 |
HK1042895A1 (en) | 2002-08-30 |
JP2003517447A (en) | 2003-05-27 |
AU762992B2 (en) | 2003-07-10 |
HUP0200310A3 (en) | 2002-12-28 |
KR20010086005A (en) | 2001-09-07 |
AU1909100A (en) | 2000-05-29 |
BG105481A (en) | 2001-12-29 |
BR9915132A (en) | 2001-08-07 |
IL142584A0 (en) | 2002-03-10 |
EP1127051A2 (en) | 2001-08-29 |
WO2000027822A2 (en) | 2000-05-18 |
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