Hydroxybenzamide derivatives and their use as inhibitors of HSP90

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R 1 is hydroxy or hydrogen; R 2 is hydroxy; methoxy or hydrogen; provided that at least one of R 1 and R 2 is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C 1-5 hydrocarbyl and optionally substituted C 1-5 hydrocarbyloxy; R 4 is selected from hydrogen; a group —(O) n —R 7 where n is 0 or 1 and R 7 is an optionally substituted acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C 1-5 hydrocarbyl-amino; or R 3 and R 4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR 5 R 6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R 1 , R 2 , R 3 , A, W, U and V are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 5 , R 6 , R 7 , R 8 , R 9 , p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Hydrobenzamide derivatives as inhibitors of Hsp90

The invention provides an acid addition salt of a compound of the formula (1). Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogs thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analog.

3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof, and combinations thereof with other anti-cancer agents, for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3.

BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS

The invention provides compounds of the formula (I): 3. A combination according to claim 1 , wherein Ris unsubstituted.4. A combination according to claim 1 , wherein Ris a substituted or unsubstituted non-aromatic carbocyclic group having from 3 to 6 ring members.5. A combination according to claim 4 , wherein the substituted or unsubstituted non-aromatic carbocyclic group Ris a cycloalkyl group.6. A combination according to claim 2 , wherein A is NH(C═O).7. A combination according to claim 5 , wherein Ris an unsubstituted cycloalkyl group and A is NH(C═O).8. A combination according to claim 1 , wherein at least one of the one or more other therapeutic agents is an anticancer agent selected from:topoisomerase inhibitors;alkylating agents;antimetabolites;DNA binders;microtubule inhibitors; andradiotherapy.9. A combination according to claim 8 , wherein at least one of the one or more other therapeutic agents is an anticancer agent selected from cisplatin claim 8 , cyclophosphamide claim 8 , doxorubicin claim 8 , irinotecan claim 8 , fludarabine claim 8 , 5FU claim 8 , taxanes claim 8 , and mitomycin C.10. A combination according to claim 1 , wherein the compound of the formula (VII) or salt or N-oxide thereof and one claim 1 , two claim 1 , three claim 1 , four or more other therapeutic agents are formulated together in a dosage form containing two claim 1 , three claim 1 , four or more therapeutic agents.11. A pharmaceutical composition comprising a combination as defined in claim 1 , together with one or more pharmaceutically acceptable carriers claim 1 , adjuvants claim 1 , excipients claim 1 , diluents claim 1 , fillers claim 1 , buffers claim 1 , stabilisers claim 1 , preservatives claim 1 , or lubricants.12. A pharmaceutical composition comprising a combination as defined in claim 8 , together with one or more pharmaceutically acceptable carriers claim 8 , adjuvants claim 8 , excipients claim 8 , diluents claim 8 , fillers claim 8 , buffers claim 8 , ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R, R, R, A, W, U and V are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer. 2. A compound according to where A-W is CH—CH claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.3. A compound according to wherein when U is NH or O claim 1 , then V is CRR and when U is absent or CH claim 1 , then V is NR claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically salt or solvate thereof.4. A compound according to where U is selected from CH claim 1 , NH and O claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.5. A compound according to where U is O and V is CRR claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.6. A compound according to wherein Ris unsubstituted methyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.7. A compound according to wherein Ris unsubstituted methyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.8. (canceled)9. A compound according to wherein Ris selected from Calkyl claim 1 , —Y—Ccarbocyclyl claim 1 , and —Z-(3-12 membered heterocyclyl) groups claim 1 , wherein said Calkyl groups may be optionally substituted by one or more Rgroups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more Rgroups claim 1 , or a tautomeric ...

NRF2 Regulators

The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators. 2. The compound or pharmaceutically acceptable salt according to wherein A is —C(O)ORand Ris hydrogen claim 1 , —Calkyl-N(R) claim 1 , —(CH)-morpholinyl claim 1 , —(CH)-imidazoyl claim 1 , —(CH)-pyrrolidinyl claim 1 , or —(CH)-piperidyl.3. The compound or pharmaceutically acceptable salt according to wherein A is —C(O)OH.4. The compound or pharmaceutically acceptable salt according to wherein Ris:{'sub': 1-3', '1-3, 'phenyl substituted by one, two, or three groups independently selected from —CN, —F, —Cl, Calkyl, and —O—Calkyl;'}{'sub': 1-3', '1-3, 'benzotriazolyl substituted by one, two, or three groups independently selected from —O—Calkyl and Calkyl; or'}{'sub': 2', '2', '1-3', '2, '—(CH)-triazolyl substituted by one or two groups independently selected from Calkyl or —CH-phenyl.'}5. The compound or pharmaceutically acceptable salt according to wherein Ris benzotriazolyl substituted by one or two groups independently selected from —O—Calkyl and Calkyl.7. The compound or pharmaceutically acceptable salt according to wherein Ris hydrogen claim 1 , —Cl claim 1 , Calkyl claim 1 , or —CF.8. The compound or pharmaceutically acceptable salt according to wherein each Ris hydrogen.10. The compound according to selected from the group consisting of:3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)phenyl)propanoic acid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)phenyl)propanoic acid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid;3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5] ...

3-CARBOXYLIC ACID PYRROLES AS NRF2 REGULATORS

The present invention relates to 3-carboxylic acid pyrrole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators. In particular, the compounds of this invention include a compound of Formula (I): 3. A compound of selected from:1-(3-(((S)-4-Methyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f]-[1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;1-(3-(((S)-4-butyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-2-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;2-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrrole-3-carboxylic acid;1-(3-(((S)-4-methyl-1,1-dioxido-7-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;1-(3-(((S)-4-ethyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid; 1-(3-(((S)-4-butyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;1-(3-(((S)-8-bromo-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;1-(3-(((S)-8-bromo-4-ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-2-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrrole-3-carboxylic acid;rac-2-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(2-methyl-3-(((S)-4-methyl-1,1- ...

Hydroxybenzamide Derivatives And Their Use As Inhibitors Of HSP90

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R 1 is hydroxy or hydrogen; R 2 is hydroxy; methoxy or hydrogen; provided that at least one of R 1 and R 2 is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C 1-5 hydrocarbyl and optionally substituted C 1-5 hydrocarbyloxy; R 4 is selected from hydrogen; a group —(O) n —R 7 where n is 0 or 1 and R 7 is an optionally substituted acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C 1-5 hydrocarbyl-amino; or R 3 and R 4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR 5 R 6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS

The invention provides a compound of formula (0): 11. A compound according to or a pharmaceutically acceptable salt or tautomer thereof claim 10 , wherein{'sup': '4', 'Ris hydrogen;'}v is 0;{'sup': '8', 'Ris hydrogen;'}{'sup': 9', '10, 'sub': '1-3', 'Ris an acyclic saturated Chydrocarbon group optionally substituted with one or more substituents selected from hydroxy and a phenyl group, the phenyl group being optionally substituted with one or more substituents R;'}{'sup': '10', 'Ris selected from fluorine, methyl, methoxy and dimethylamino;'}{'sup': '2', 'sub': 2', '3, 'Alkis selected from CHand CH(CH); and'}Z is CH.12. A compound according to any one of Examples 1 to 1134 as described herein claim 10 , or a pharmaceutically acceptable salt thereof.13. A pharmaceutical composition comprising a compound as defined in and a pharmaceutically acceptable excipient.14. (canceled)16. A combination of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and another therapeutic agent.1720-. (canceled)21. A compound according to claim 12 , wherein the compound is selected from:(2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide;(2R)-2-(6-{5-Chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-(2-methoxypyridin-4-yl)ethyl]propanamide;(R)-2-(6-(5-chloro-2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide;(R)-2-(6-(5-chloro-2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N—((S)-1-(6-(dimethylamino)pyridin-2-yl)-2-hydroxyethyl)propanamide;(2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-2-hydroxy-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]ethyl]propanamide; and(2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol ...

N-ARYL PYRAZOLES AS NRF2 REGULATORS

The present invention relates to N-aryl pyrazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators. In particular, the compounds of this invention include a compound of Formula (I): 3. The compound of selected from:1-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-(((S)-4-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid.1-(3-((8-fluoro-4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-((R or S)-1-((S)-4-Methyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)ethyl)phenyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid1-(3-((4,4-Dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-((2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-(((R)-4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-(((S)-4-ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid;1-(3-((7-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-5-(trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole- ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R, R, R, A, W, U and V are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer. 2. A compound according to where Ris H claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.3. A compound according to wherein when U is CH claim 1 , then V is NR claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.4. A compound according to where U is NH and V is CRR claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.5. (canceled)6. A compound according to wherein Ris unsubstituted methyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.7. A compound according to wherein Ris unsubstituted methyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.8. (canceled)9. A compound according to wherein Ris selected from Calkyl claim 1 , —Y—Ccarbocyclyl claim 1 , and —Z-(3-12 membered heterocyclyl) groups claim 1 , wherein said Calkyl groups may be optionally substituted by one or more Rgroups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more Rgroups claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.10. A compound according to wherein Ris selected from Calkyl and —Y—Ccarbocyclyl claim 1 , wherein said carbocyclyl groups may be ...

Nrf2 REGULATORS

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators. 2. The compound of claim 1 , wherein claim 1 ,{'sub': '1-3', 'B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —Calkyl and halo;'}{'sub': 2', '3, 'D is —C(O)OH, —C(O)NHSOCH, or tetrazolyl;'}{'sub': '1', 'Ris independently hydrogen or methyl or the two R, groups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': '2', 'Ris methyl or halo;'}{'sub': '2', 'Linker is —CH—;'}A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or tetrahydrobenzodiazepinyl;{'sub': 1-3', '1-3, 'each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —Calkyl, halo, CN, and —OCalkyl;'}{'sub': 1-3', '2', '1-3', '3-7, 'and the piperidinyl is unsubstituted or additionally substituted by pyrazolyl or oxadiazolyl each of which is unsubstituted or further substituted by —Calkyl or, when A is piperidinyl, it is unsubstituted or substituted by —SOR, wherein R is —Calkyl, phenyl or Ccycloalkyl;'}{'sub': 2', '4-7', '2', '2', '5-7, 'and each of the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups is independently unsubstituted or additionally substituted by one or two substituents independently selected from —CH—Ccycloalkyl, —CH-oxepane and —CH—C; and'}X is independently CH or N;or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 , wherein claim 1 ,{'sub': '1-3', 'B is benzotriazolyl which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —Calkyl and halo;'}D is —C(O)OH;{'sub': 1', '1, 'Ris independently hydrogen or methyl or the two Rgroups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': '2', 'Ris methyl or halo;'}{'sub': '2', 'Linker is —CH—;'}A ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R, R, R, R, R, R, R, R, R, R, p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer. 2. A compound as defined in claim 1 , wherein Q represents N claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.3. A compound as defined in claim 1 , wherein ring E represents pyridyl claim 1 , pyridazinyl or phenyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.45-. (canceled)6. A compound as defined in claim 1 , wherein Rrepresents methyl claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.7. A compound as defined in claim 1 , wherein Rand Rare hydrogen claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof.8. A compound as defined in claim 1 , or a tautomeric or stereochemically isomeric form claim 1 , N-oxide claim 1 , pharmaceutically acceptable salt or solvate thereof claim 1 , wherein:{'sup': 3a', '3b', 'b, 'sub': 1-6', '(2-q)', '1-6', 'q', '2', 's', '2', 's', '3-12', '3-12', '1-6, '(i) Rand Rare independently selected from hydrogen, Calkyl, —C(═O)NH(Calkyl), —(CH)-(3-12 membered heterocyclyl), —(CH)—Ccarbocyclyl, C(═O)-(3-12 membered heterocyclyl), and —C(═O)—Ccarbocyclyl wherein said Calkyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3a', '3b', 'x', 'y', 'z', 'x', 'y', 'b, 'sub': 1-6', '5', '2', 's', '(2-q)', '1-6', 'q', '2', 's, '(ii) one of Rand Rrepresents ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): 2. A pharmaceutical composition as defined in claim 1 , wherein Q represents N.3. A pharmaceutical composition as defined in claim 1 , wherein ring E represents pyridyl claim 1 , pyridazinyl or phenyl.4. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents methyl.5. A pharmaceutical composition as defined in claim 1 , wherein Rand Rare hydrogen.6. A pharmaceutical composition as defined in claim 1 , wherein:{'sup': 3a', '3b', 'b, 'sub': 1-6', '(2-q)', '1-6', 'q', '2', 's', '2', 's', '3-12', '3-12', '1-6, '(i) Rand Rare independently selected from hydrogen, Calkyl, —C(═O)NH(Calkyl), —(CH)-(3-12 membered heterocyclyl), —(CH)—Ccarbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—Ccarbocyclyl wherein said Calkyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3a', '3b, '(ii) one of Rand Rrepresents hydrogen and the other represents{'sub': 1-6', 's', '2', 's, 'sup': x', 'y', 'x', 'y, 'Calkyl, optionally substituted by halogen, —(CRR)—O—R; —(CH)—NRC(═O)R);'}{'sub': (2-q)', '1-6', 'q, '—C(═O)NH(Calkyl);'}{'sub': 2', 's, '—(CH)-(3-6 membered heterocyclyl); or'}—C(═O)-(3-6 membered heterocyclyl){'sup': 'b', 'wherein said heterocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iii) Ris hydrogen, and Ris —CH-(6 membered saturated heterocyclyl), wherein said heterocyclyl group may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iv) Ris hydrogen, and Ris —CH-(4-morpholinyl) optionally substituted by one or more Rgroups.'}7. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents hydrogen.8. A pharmaceutical composition as defined in claim 1 , wherein;{'sup': 6', '7', 'x', 'y', 'z', 'x', 'y', 'z, 'sub': 1-6', '3-6', 's', 's, '(i) Rand Rare independently selected from hydrogen, Calkyl, —Y—Ccarbocyclyl; —Z-(3-12 ...

Hydrobenzamide derivatives as inhibitors of hsp90

The invention provides an acid addition salt of a compound of the formula ( 1 ). Also provided by the invention are processes for preparing the compound of formula ( 1 ) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula ( 1 ) and its ethyl analogue.

Nrf2 REGULATORS

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators. 3. The compound of wherein:{'sub': 2', '2', '1-3, 'B is benzotriazolyl or —(CH)triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl and halo;'}D is —C(O)OH;{'sub': '1', 'Ris independently hydrogen or methyl or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': 1-3', '1-3, 'A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, or tetrahydro-pyrido-oxazepinyl, all of which may be unsubstituted or substituted by 1, 2, or 3 substituents chosen from: —Calkyl, halo, CN, and —O Calkyl; and'}n is 1 or 2or a pharmaceutically acceptable salt thereof.4. The compound of claim 1 , wherein{'sub': '1-3', 'B is benzotriazolyl or phenyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, halo and CN;'}D is —C(O)OH;{'sub': 1', '1-3, 'Ris independently hydrogen or Calkyl;'}{'sub': 1-3', '1-3', '2', '3', '3-6, 'A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl, or tetrahydro-pyrido-oxazepinyl, all of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, halo, CN, —OCalkyl, —CH—O—CH, Cspirocycloalkyl, and OH; and'}n is 1;or a pharmaceutically acceptable salt thereof.5. The compound of claim 1 , wherein{'sub': '1-3', 'B is benzotriazolyl which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl;'}D is —C(O)OH;{'sub': 1', '1-3, 'Ris independently hydrogen or Calkyl;'}{'sub': 1-3', '1-3, 'A is tetrahydrobenzoxazepinyl which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, —OCalkyl, CN and halo; and'}n is 1;or a pharmaceutically acceptable salt thereof.6. The compound of wherein:{'sub': 2', '2', '1-3, 'B is ...

Nrf2 REGULATORS

The present invention relates to aryl analogs Formula (I), pharmaceutical compositions containing them and their use as Nrf2 regulators. 4. A compound which is:3-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)-4-chlorophenyl]-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-[4-chloro-3-({[(cyclopentyloxy)carbonyl](methyl)amino}methyl)phenyl]-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-[3-({[(butan-2-yloxy)carbonyl](methyl)amino}methyl)-4-chlorophenyl]-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)-4-methylphenyl]-3-(7-methoxy-1methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-[4-chloro-3-({[(cyclohexyloxy)carbonyl](methyl)amino}methyl)phenyl]-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)-4-chlorophenyl]-3-(7-methoxy-1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-{3-[(dimethylcarbamoyl)methoxy]-4-methylphenyl}-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-(4-methyl-3-{[methyl(4nitrophenoxycarbonyl)amino]methyl}phenyl)propanoic acid;3-[4-chloro-3-({[(cyclopentyloxy)carbonyl](methyl)amino}methyl)phenyl]-3-(7-methoxy -1-methyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-{3-[({[(1-methoxy-2-methylpropan-2-yl)oxy]carbonyl}(methyl)amino)methyl]-4-methylphenyl}propanoic acid;3-(3-{[N-(cyclohexylmethyl)acetamido]methyl}-4-methylphenyl)-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-{3-[(N-benzylacetamido)methyl]-4-methylphenyl}-3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)propanoic acid;3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[4-methyl-3-({N-[(3-methylphenyl)methyl]acetamido}methyl)phenyl]propanoic acid;3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[3-({N-[(2,3-dimethylphenyl)methyl]acetamido}methyl)-4-methylphenyl]propanoic acid;3-(1,4-dimethyl-1H-1,2,3-benzotriazol-5-yl)-3-[3-({N-[(4-methoxyphenyl)methyl] ...

Nrf2 REGULATORS

Provided are aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators. 2. The compound of claim 1 , wherein claim 1 ,{'sub': 2', '2', '1-3, 'B is benzotriazolyl or —(CH)triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from: —Calkyl and halo;'}{'sub': 2', '3, 'D is —C(O)OH, —C(O)NHSOCH, or tetrazolyl;'}{'sub': 1', '1, 'Ris independently hydrogen or methyl or the two Rgroups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': '2', 'Ris methyl or halo;'}{'sub': '2', 'Linker is —CH—;'}A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or tetrahydrobenzodiazepinyl;{'sub': 1-3', '1-3, 'All of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, halo, CN, or —OCalkyl;'}{'sub': 1-3', '2', '1-3', '3-7, 'And the piperidinyl may additionally be substituted by pyrazolyl or oxadiazolyl each of which may be further substituted by —Calkyl or, when A is piperidinyl, it may be substituted by —SOR, wherein R is —Calkyl, phenyl or Ccycloalkyl;'}{'sub': 2', '4-7', '2', '2', '5-7, 'And the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups may be additionally independently substituted by —CH—Ccycloalkyl, —CH-oxepane or a —CH—C; and'}X is independently CH or N;or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 , wherein claim 1 ,{'sub': 2', '2', '1-3, 'B is benzotriazolyl, or —(CH)triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from—Calkyl and halo;'}D is —C(O)OH;{'sub': 1', '1, 'Ris independently hydrogen or methyl or the two Rgroups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': '2', 'Ris methyl or halo;'}{'sub': '2', 'Linker is —CH—;'}A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl ...

Nrf2 REGULATORS

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators. 3. The method of wherein:{'sub': 2', '2', '1-3, 'B is benzotriazolyl or —(CH)triazolyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl and halo;'}D is —C(O)OH;{'sub': '1', 'Ris independently hydrogen or methyl or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;'}{'sub': 1-3', '1-3, 'A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, or tetrahydro-pyrido-oxazepinyl, all of which may be unsubstituted or substituted by 1, 2, or 3 substituents chosen from: —Calkyl, halo, CN, and —OCalkyl; and'}n is 1 or 2or a pharmaceutically acceptable salt thereof.4. The method of claim 1 , wherein:{'sub': '1-3', 'B is benzotriazolyl or phenyl each of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, halo and CN;'}D is —C(O)OH;{'sub': 1', '1-3, 'Ris independently hydrogen or Calkyl;'}{'sub': 1-3', '1-3', '2', '3', '3-6, 'A is tetrahydrobenzoxazepinyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl, or tetrahydro-pyrido-oxazepinyl, all of which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, halo, CN, —OCalkyl, —CH—O—CH, Cspirocycloalkyl, and OH; and'}n is 1;or a pharmaceutically acceptable salt thereof.5. The method of claim 1 , wherein:{'sub': '1-3', 'B is benzotriazolyl which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl;'}D is —C(O)OH;{'sub': 1', '1-3, 'Ris independently hydrogen or Calkyl;'}{'sub': 1-3', '1-3, 'A is tetrahydrobenzoxazepinyl which may be unsubstituted or substituted by 1, 2, or 3 substituents independently chosen from —Calkyl, —OCalkyl, CN and halo; and'}n is 1;or a pharmaceutically acceptable salt thereof.6. The method of wherein:{'sub': 2', '2', '1-3, 'B is benzotriazolyl ...

3,4-DISUBSTITUTED 1H-PYRAZOLE COMPOUNDS AND THEIR USE AS CYCLIN DEPENDENT KINASE AND GLYCOGEN SYNTHASE KINASE-3 MODULATORS

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. 2. A method according to wherein Ris hydrogen.3. A method according to wherein Ris an unsubstituted or substituted monocyclic carbocyclic or heterocyclic group wherein the carbocyclic and heterocyclic groups are substituted by one or more substituent groups Ror R; wherein Ris as defined in and Ris selected from halogen claim 1 , hydroxy claim 1 , trifluoromethyl claim 1 , cyano claim 1 , nitro claim 1 , carboxy claim 1 , a group R-Rwherein Ris a bond claim 1 , O claim 1 , CO claim 1 , XC(X) claim 1 , C(X)X claim 1 , XC(X)X claim 1 , S claim 1 , SO claim 1 , or SO claim 1 , and Ris selected from hydrogen and a Chydrocarbyl group optionally substituted by one or more substituents selected from hydroxy claim 1 , oxo claim 1 , halogen claim 1 , cyano claim 1 , nitro claim 1 , carboxy and monocyclic non-aromatic carbocyclic or heterocyclic groups having from 3 to 6 ring members; wherein one or more carbon atoms of the Chydrocarbyl group may optionally be replaced by O claim 1 , S claim 1 , SO claim 1 , SO claim 1 , XC(X) claim 1 , C(X)Xor XC(X)X; Xis O or S; and Xis ═O or ═S.7. A method according to wherein the compound of formula (II) is 4-(2 claim 1 ,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide or a salt or a solvate thereof.8. A method according to wherein the disease state or condition is mediated by a cyclin dependent kinase (CDK).9. A method according to wherein the disease state or condition is mediated by one or more CDK kinases selected from CDK1 claim 8 , CDK2 claim 8 , CDK4 and CDK5.10. A method according to wherein the disease state or condition is mediated by CDK1 and/or CDK2.11. A method according to wherein the disease state or condition is mediated by glycogen ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): 2. A pharmaceutical composition as defined in claim 1 , wherein Q represents N.3. A pharmaceutical composition as defined in claim 1 , wherein ring E represents pyridyl claim 1 , pyridazinyl or phenyl.4. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents methyl.5. A pharmaceutical composition as defined in claim 1 , wherein Rand Rare hydrogen.6. A pharmaceutical composition as defined in claim 1 , wherein:{'sup': 3a', '3b', 'b, 'sub': 1-6', '(2-q)', '1-6', 'q', '2', 's', '2', 's', '3-12', '3-12', '1-6, '(i) Rand Rare independently selected from hydrogen, Calkyl, —C(═O)NH(Calkyl), —(CH)-(3-12 membered heterocyclyl), —(CH)—Ccarbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—Ccarbocyclyl wherein said Calkyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3a', '3b', 'x', 'y', 'z', 'x', 'y', 'b, 'sub': 1-6', 's', '2', 's', '(2-q)', '1-6', 'q', '2', 's, '(ii) one of Rand Rrepresents hydrogen and the other represents: Calkyl, optionally substituted by halogen, —(CRR)—O—R; —(CH)—NRC(═O)R); —C(═O)NH(Calkyl); —(CH)-(3-6 membered heterocyclyl); or —C(═O)-(3-6 membered heterocyclyl) wherein said heterocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iii) Ris hydrogen, and Ris —CH-(6 membered saturated heterocyclyl), wherein said heterocyclyl group may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iv) Ris hydrogen, and Ris —CH-(4-morpholinyl) optionally substituted by one or more Rgroups.'}7. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents hydrogen.8. A pharmaceutical composition as defined in claim 1 , wherein;{'sup': 6', '7', 'x', 'y', 'z', 'x', 'y', 'z, 'sub': 1-6', '3-6', 's', 's, '(i) Rand Rare independently selected from hydrogen, Calkyl, —Y—Ccarbocyclyl; —Z-(3-12 membered heterocyclyl); ...

BIARYL PYRAZOLES AS NRF2 REGULATORS

The present invention relates to biaryl pyrazole compounds of Formula (I) 8. A compound of selected from:5-Cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid1-{3-[3-(Dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid1-(3-{3-[Cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid1-(3-{3-[Cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid1-{3-[3-(azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid1-(3-{3-[Bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid1-{3-[3-(Azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid1-(3-{3-[(Cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid5-[(cis)-3-Acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid (cis racemate)1-(3-{3-[(Cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid1-(3-{2-Chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid5-Cyclopropyl-1-(3-({2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)- ...

NRF2 REGULATORS

The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators. 2. The compound or pharmaceutically acceptable salt according to wherein A is —C(O)ORand Ris hydrogen claim 1 , —Calkyl-N(R) claim 1 , —(CH)-morpholinyl claim 1 , —(CH)-imidazolyl claim 1 , —(CH)-pyrolidinyl claim 1 , or —(CH)-piperidyl.3. The compound or pharmaceutically acceptable salt according to wherein A is —C(O)OH.4. The compound or pharmaceutically acceptable salt according to wherein Ris:{'sub': 1-3', '1-3, 'phenyl substituted by one, two, or three groups independently selected from —CN, —F, —Cl, Calkyl, and —O—Calkyl;'}{'sub': 1-3', '1-3, 'benzotriazolyl substituted by one, two, or three groups independently selected from —O—Calkyl and Calkyl; or'}{'sub': 2', '2', '1-3', '2, '—(CH)-triazolyl substituted by one or two groups independently selected from Calkyl or —CH-phenyl.'}5. The compound or pharmaceutically acceptable salt according to wherein Ris benzotriazolyl substituted by one or two groups independently selected from —O—Calkyl and Calkyl.7. The compound or pharmaceutically acceptable salt according to wherein Ris hydrogen claim 1 , —Cl claim 1 , Calkyl claim 1 , or —CF.8. The compound or pharmaceutically acceptable salt according to wherein each Ris hydrogen.10. The compound according to selected from the group consisting of:3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)phenyl)propanoic acid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)phenyl)propanoic acid;3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid;3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((3-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5] ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): 2. A method as defined in claim 1 , wherein Q represents N.3. A method as defined in claim 1 , wherein ring E represents pyridyl claim 1 , pyridazinyl or phenyl.4. A method as defined in claim 1 , wherein Rrepresents methyl.5. A method as defined in claim 1 , wherein Rand Rare hydrogen.6. A method as defined in claim 1 , wherein:{'sup': 3a', '3b', 'b, 'sub': 1-6', '(2-q)', '1-6', 'q', '2', 's', '2', 's', '3-12', '3-12', '1-6, '(i) Rand Rare independently selected from hydrogen, Calkyl, —C(═O)NH(Calkyl), —(CH)-(3-12 membered heterocyclyl), —(CH)—Ccarbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—Ccarbocyclyl wherein said Calkyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3a', '3b, '(ii) one of Rand Rrepresents hydrogen and the other represents{'sub': 1-6', 's', '2', 's, 'sup': x', 'y', 'z', 'x', 'y, 'Calkyl, optionally substituted by halogen, —(CRR)—O—R; —(CH)—NRC(═O)R);'}{'sub': (2-q)', '1-6', 'q, '—C(═O)NH(Calkyl);'}{'sub': 2', 's, '—(CH)-(3-6 membered heterocyclyl); or'}—C(═O)-(3-6 membered heterocyclyl){'sup': 'b', 'wherein said heterocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iii) Ris hydrogen, and Ris —CH-(6 membered saturated heterocyclyl), wherein said heterocyclyl group may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iv) Ris hydrogen, and Ris —CH-(4-morpholinyl) optionally substituted by one or more Rgroups.'}7. A method as defined in claim 1 , wherein Rrepresents hydrogen.8. A method as defined in claim 1 , wherein;{'sup': 6', '7', 'x', 'y', 'z', 'x', 'y', 'z, 'sub': 1-6', '3-6', 's', 's, '(i) Rand Rare independently selected from hydrogen, Calkyl, —Y—Ccarbocyclyl; —Z-(3-12 membered heterocyclyl); —(CRR)—C(═O)OR; and —(CRR)—O—R; or'}{'sup': 6', '7, '(ii) Rand Rare both methyl; or'}{'sup': 6', '7', 'b, '(iii ...

BICYCLIC HETEROCYCLE COMPOUNDS AND THEIR USES IN THERAPY

The invention relates to bicyclic heterocycle compounds of formula (I): 2. A pharmaceutical composition as defined in claim 1 , wherein Q represents N.3. A pharmaceutical composition as defined in claim 1 , wherein ring E represents pyridyl claim 1 , pyridazinyl or phenyl.4. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents methyl.5. A pharmaceutical composition as defined in claim 1 , wherein Rand Rare hydrogen.6. A pharmaceutical composition as defined in claim 1 , wherein:{'sup': 3a', '3b', 'b, 'sub': 1-6', '(2-q)', '1-6', 'q', '2', 's', '2', 's', '3-12', '3-12', '1-6, '(i) Rand Rare independently selected from hydrogen, Calkyl, —C(═O)NH(Calkyl), —(CH)-(3-12 membered heterocyclyl), —(CH)—Ccarbocyclyl, —C(═O)-(3-12 membered heterocyclyl), and —C(═O)—Ccarbocyclyl wherein said Calkyl, heterocyclyl and carbocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3a', '3b, '(ii) one of Rand Rrepresents hydrogen and the other represents{'sub': 1-6', 's', '2', 's, 'sup': x', 'y', 'z', 'x', 'y, 'Calkyl, optionally substituted by halogen, —(CRR)—O—R; —(CH)—NRC(═O)R);'}{'sub': (2-q)', '1-6', 'q, '—C(═O)NH(Calkyl);'}{'sub': 2', 's, '—(CH)-(3-6 membered heterocyclyl); or'}—C(═O)-(3-6 membered heterocyclyl){'sup': 'b', 'wherein said heterocyclyl groups may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iii) Ris hydrogen, and Ris —CH-(6 membered saturated heterocyclyl), wherein said heterocyclyl group may be optionally substituted by one or more Rgroups; or'}{'sup': 3b', '3a', 'b, 'sub': '2', '(iv) Ris hydrogen, and Ris —CH-(4-morpholinyl) optionally substituted by one or more Rgroups.'}7. A pharmaceutical composition as defined in claim 1 , wherein Rrepresents hydrogen.8. A pharmaceutical composition as defined in claim 1 , wherein;{'sup': 6', '7', 'x', 'y', 'z', 'x', 'y', 'z, 'sub': 1-6', '3-6', 's', 's, '(i) Rand Rare independently selected from hydrogen, Calkyl, —Y—Ccarbocyclyl; —Z-( ...

(morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles

3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators

benzolactam compounds as protein kinase inhibitors

a invenção fornece um composto da fórmula (0): ou um sal, n-óxido ou tautômero farmaceuticamente aceitáveis do mesmo. os compostos são inibidores de erk1/2 quinases e serão úteis no tratamento de condições mediadas por erk1/2. os compostos são, portanto, úteis em terapia, em particular no tratamento do câncer. The invention provides a compound of formula (O): or a pharmaceutically acceptable salt, n-oxide or tautomer thereof. The compounds are erk1 / 2 kinase inhibitors and will be useful in treating erk1 / 2 mediated conditions. The compounds are therefore useful in therapy, particularly in cancer treatment.

Benzimidazole derivatives and their use as protein kinases inhibitors

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R 1 , R 2 , R 3 , A, W, U and V are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Pharmaceutical compounds

The invention provides compounds having activity as inhibitors of cyclin dependent kinases, glycogen synthase kinase-3 and Aurora kinases for use in the treatment of disease states and conditions such as cancer that are mediated by the kinases. The compounds have the general formula (I). Also included within formula (I) are the salts, solvates and N-oxides of the compounds.

Imidazole derivatives and their use as modulators of cyclin dependent kinases

Nrf2 regulators

Provided are aryl analogs，pharmaceutical compositions containing them and their use as NRF2 regulators.

1h-indazole-3-carboxamide compounds as cyclin dependent kinases (cdk) inhibitors

Nrf2 regulators

Hydroxybenzamide derivatives and their use as inhibitors of hsp90

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyloxy; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl- amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The compounds have activity as Hsp90 inhibitors.

BENZOLACTAM COMPOUNDS USED AS KINASE PROTEIN INHIBITORS

Hydroxybenzamide derivatives and their use as inhibitors of Hsp90

The invention provides compounds of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R

Hydroxybenzamide derivatives and their use, method of preparation and pharmaceutical compositions

Foreliggende oppfinnelse tilveiebringer forbindelser med formel (I): eller salter, tautomerer, solvater og N-oksider derav; hvori R1 er hydroksy eller hydrogen; R2 er hydroksy; metoksy eller hydrogen; forutsatt at minst en av R1 og R er hydroksy; R3 er valgt fra hydrogen; halogen; cyano; eventuelt substituert C1-5 hydro-karbyl og eventuelt substituert C1-5 hydrokarbyloksy; R4 er valgt fra hydrogen; en gruppe -(O)n-R7 hvor n er 0 eller 1 og R7 er en eventuelt substituert acyklisk C1-5 hydro-karbylgruppe eller en monocyklisk, karbocyklisk eller heterocyklisk gruppe som har 3 til 7 ringledd; halogen; cyano; hydroksy; amino; og eventuelt substituert mono- eller di-C1-5 hydrokarbylamino; eller R3 og R4 sammen med en monocyklisk, karbocyklisk eller heterocyklisk ring med 5 til 7 ringledd; og NR5R6 danner en eventuelt substituert bicyklisk heterocyklisk gruppe med 8 til 12 ringledd av hvilke opp til 5 ringledd er heteroatomer valgt fra oksygen, nitrogen og svovel. Forbindelsene har aktivitet som Hsp90 inhibitorer. The present invention provides compounds of formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R 1 is hydroxy or hydrogen; R 2 is hydroxy; methoxy or hydrogen; provided that at least one of R 1 and R is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyl oxy; R 4 is selected from hydrogen; a group - (O) n-R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic, carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbylamino; or R3 and R4 together with a monocyclic, carbocyclic or heterocyclic ring having 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulfur. The ...

Nrf2 regulators

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.

NRF2 regulators

Piperazinyl compounds and their uses in cancer therapy

Provided are bicycle-heterocycle compounds, of the general formula (I), where the variables are as defined in the specification. Preferably the variable Q is N. Examples of the compounds include 1-(6-Bromo-2,3-dihydro-indol-1-yl)-2-((R)-3-methyl-piperazin-1- yl)-ethanone, 3,3-Dimethyl-1-[(2S)-2-[(3R)-3-methylpiperazin-1-yl]butanoyl]-2,3-dihydro-1H-indole-6-carbonitrile, hydrochloride salt and 1-{ 6-Benzyl-3,3-dimethyl-1H,2H,3Hpyrrolo[3,2-c]pyridin-1-yl} -2-[(2R,5R)-5-methyl-2-[(piperidin-1-yl)carbonyl]piperazin-1-yl]ethan-1-one dihydrochloride. The compounds may antagonise inhibitors of apoptosis proteins (IAPs). The compounds may be useful in the treatment of cancer.

Hydrobenzamide derivatives as inhibitors of hsp90

3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. Formula (0). In formula (0): X is a group R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases

The invention provides a compound of the formula (I): for use in medicine: or salts or tautomers or N-oxides or solvates thereof; wherein R1 is an optionally substituted heterocyclic group having from 3 to 12 ring members provided that the cyclic group joined to the pyrazole contains at least one heteroatom selected from N, O or S; A is a bond or -Y-(B)n-; B is C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; n is 0 or 1; Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from optionally substituted carbocyclic and heterocyclic groups having from 3 to 12 ring members or an optionally substituted C1-8 hydrocarbyl group; with the proviso that R1 is not formula (II): where X, R3’ and R4’ are defined in the claims.

Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases

The invention provides a compound of the formula (I): for use in medicine: or salts or tautomers or N-oxides or solvates thereof; wherein R 1 is an optionally substituted heterocyclic group having from 3 to 12 ring members provided that the cyclic group joined to the pyrazole contains at least one heteroatom selected from N, O or S; A is a bond or —Y—(B) n —; B is C═O, NR g (C═O) or O(C═O) wherein R g is hydrogen or C 1-4 hydrocarbyl optionally substituted by hydroxy or C 1-4 alkoxy; n is 0 or 1; Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length; R 2 is hydrogen; halogen; C 1-4 alkoxy (e.g. methoxy); or a C 1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C 1-4 alkoxy (e.g. methoxy); R 3 is selected from optionally substituted carbocyclic and heterocyclic groups having from 3 to 12 ring members or an optionally substituted C 1-8 hydrocarbyl group; with the proviso that R 1 is not formula (II): where X, R 3′ and R 4′ are defined in the claims.

Benzimidazole derivatives and their use as protein kinases inhibitors

Benzolactam compounds as protein kinase inhibitors

The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

Hydroxybenzamide derivatives and their use as inhibitors of hsp90

Nrf2 regulators

Provided are aryl analogs of Formula (I), pharmaceutical compositions containing them and their use as NRF2 regulators.

Hydroxybenzamide derivatives and their use as inhibitors of hsp90

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N -oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 5 , R 6 , R 7 , R 8 , R 9 , p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (l): (see formula I) or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

N-aryl pyrazoles as nrf2 regulators

The present invention relates to N-aryl pyrazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators. In particular, the compounds of this invention include a compound of Formula (I).

3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. Formula (0). In formula (0): X is a group R1-A-NR4-or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. In formula (0): X is a group R 1 -A-NR 4 — or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO 2 , C═O, NR g (C═O) or O(C═O) wherein R g is hydrogen or C 1-4 hydrocarbyl optionally substituted by hydroxy or C 1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R 1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C 1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C 1-4 hydrocarbyloxy, amino, mono- or di-C 1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO 2 ; R 2 is hydrogen; halogen; C 1-4 alkoxy (e.g. methoxy); or a C 1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C 1-4 alkoxy (e.g. methoxy); R 3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R 4 is hydrogen or a C 1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C 1-4 alkoxy (e.g. methoxy).

HYDROXYBENZAMIDE DERIVATIVES AND THEIR USE AS INHIBITORS OF HSP90

Hydroxybenzamide derivatives and their use as inhibitors of hsp90

The invention provides a compound for use as an inhibitor of Hsp90, the compound having the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; C 1-5 hydrocarbyl and C 1-5 hydrocarbyloxy; wherein the C 1-5 hydrocarbyl and C 1-5 hydrocarbyloxy moieties are each optionally substituted by one or more substituents selected from hydroxy, halogen, C 1-2 alkoxy, amino, mono- and di-C 1-2 alkylamino, and aryl and heteroaryl groups of 5 to 12 ring members; R4 is selected from hydrogen; a group -(O)n-R7 where n is 0 or 1 and R7 is an acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and mono- or di-C 1-5 hydrocarbyl-amino, wherein the acyclic Ci-5 hydrocarbyl group and the mono and di-C 1-5 hydrocarbylamino moieties in each instance are optionally substituted by one or more substituents selected from hydroxy, halogen, C 1-2 alkoxy, amino, mono- and di-C 1-2 alkylamino, and aryl and heteroaryl groups of 5 to 12 ring members; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and R5 and R6 are as defined in the claims.

Pharmaceutical compounds

The invention provides compounds having activity as inhibitors of cyclin dependent kinases, glycogen synthase kinase-3 and Aurora kinases for use in the treatment of disease states and conditions such as cancer that are mediated by the kinases. The compounds have the general formula (I). Also included within formula (I) are the salts, solvates and N-oxides of the compounds.

Benzimidazole derivatives and their use as protein kinases inhibitors

Benzolactam compounds as protein kinase inhibitors.

La invención proporciona un compuesto de la fórmula (0):(ver formula) o una sal, N-óxido o tautómero farmacéuticamente aceptable de este. Los compuestos son inhibidores de las ERK1/2 cinasas y serán útiles en el tratamiento de las afecciones mediadas por ERK1/2. Los compuestos son, por lo tanto, útiles en la terapia, en particular en el tratamiento de cáncer.

BENZIMIDAZOLD DERIVATIVES AND USE THEREOF AS PROTEINKINASE INHIBITORS

Imidazole derivatives and their use as modulators of cyclin dependent kinases

Hydrobenzamide derivatives as inhibitors of hsp90

The invention provides an acid addition salt of a compound of the formula (1) Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analogue.

Benzimidazole derivatives and their use as protein kinases inhibitors

A combination comprising: (i) a compound of the formula (VII): or a salt, N-oxide or solvate thereof; and (ii) one or more other therapeutic agents.

Benzolactam compounds as protein kinase inhibitors

The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

Bicyclic heterocycle compounds and their uses in therapy.

La invención se refiere a compuestos heterociclos biciclicos de fórmula (1):(Ver Formula) o formas tautoméricas o estereoquímicamente isoméricas, N-óxidos, sus sales farmacéuticamente aceptables o sus solvatos; en donde R1, Ra2, R2b, R3a, R3b, R5, R6, R7, R8, R9, p y E son como se encuentran definidos en la presente; a composiciones farmacéuticas que comprenden dichos compuestos y el uso de dichos compuestos en el tratamiento de enfermedades, por ejemplo, el cáncer.

Pyrimidine derivatives as hsp90 inhibitors

The invention provides a compound for use as an inhibitor of Hsp90, the compound having the formula (I): or salts, tautomers, solvates or N-oxides thereof; wherein: A is N or a group CR3; R1 is a monocyclic or bicyclic carbocyclic or heterocyclic ring of 5 to 10 ring members of which up to two ring members may be heteroatoms selected from N, O and S and the remainder are carbon atoms, the carbocyclic or heterocyclic ring being optionally substituted by one or more substituent groups independently selected from R10; and R2, R3 and R10 are as defined in the claims.

Hydrobenzamide derivatives as inhibitors of hsp90

The invention provides an acid addition salt of a compound of the formula (1) Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analogue.

3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) modulators

Pharmaceutical compounds

Nrf2 regulators

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

Heteroaryl / aryl analog derivatives actve as nrf2 regulators and pharmaceutical compositions thereof

La presente invención se refiere a análogos arílicos, a composiciones farmacéuticas que los contienen y a su uso como reguladores de NRF2.

Nrf2 regulators

Documntm2-20 12/2017 The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 5 , R 6 , R 7 , R 8 , R 9 , p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Benzolactam compounds as protein kinase inhibitors

The invention provides a compound of formula (0):or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein:n is 1 or 2;X is CH or N;Y is selected from CH and C—F;Z is selected from C—Rz and N;R1 is selected from:-(Alk1)t-Cyc1; wherein t is 0 or 1;Optionally substituted C1-6 acyclic hydrocarbon groupsR2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms;R3 is hydrogen or a group L1-R7;R4 is selected from hydrogen; methoxy; and optionally substituted C1-3 alkyl; andR4a is selected from hydrogen and a C1-3 alkyl group;wherein Rz, Alk1, Cyc1, L1 and R7 are defined herein;provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof.The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

Nrf2 regulators

Δικυκλικες ετεροκυκλικες ενωσεις και χρησεις αυτων στη θεραπεια

Η εφεύρεση αφορά δικυκλικές ετεροκυκλικές ενώσεις του τύπου (Ι) ή ταυτομερικές ή στερεχημικά ισομερικές μορφές, Ν-οξείδια, φαρμακευτικά αποδεκτά άλατα ή τα επιδιαλυτώματα αυτών· όπου το R1, R2a, R2b, R3a, R3b, R5, R6, R7, R8, R9, p και Ε είναι όπως ορίζεται στο παρόν· φαρμακευτικές συνθέσεις που περιλαμβάνουν τις εν λόγω ενώσεις και τη χρήση των εν λόγω ενώσεων στη θεραπεία νόσων, π.χ. του καρκίνου.

NRF2-regulatorer

Ρυθμιστες nrf2

Παρέχονται αρυλικά ανάλογα, φαρμακευτικές συνθέσεις που τα περιέχουν και η χρήση τους ως ρυθμιστές NRF2.

Nrf2 regulators

Provided are aryl analogs of Formula (l), pharmaceutical compositions containing them and their use as NRF2 regulators.

Nrf2 reguliatoriai

Compostos análogos de aril, composição farmacêutica compreendendo os mesmos e uso dos mesmos para o tratamento de desordens respiratórias ou não-respiratórias

REGULADORES DE NRF2. A presente invenção refere-se a análogos de aril, composições farmacêuticas que contêm os mesmos e seu uso como reguladores de NRF2.

Composto regulador do nrf2, composição farmacêutica compreendendo o dito composto e uso do mesmo para o tratamento de transtornos associados com a regulação de nrf2

REGULADORES DO NRF2. A presente invenção refere-se a análogos arila, a composições farmacêuticas contendo os mesmos e a seu uso como reguladores do NRF2.

Nrf2-säätelijöitä

Arylcyclohexyl pyrazoles as nrf2 regulators

methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators.

Nrf2 regulatori

Nrf2 regulatorji

Regulatory nrf2

Nrf2 regulatori

Bicyclic heterocycle compounds and their uses in therapy

The invention relates to bicyclic heterocycle compounds of formula (I):or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R1, R2a, R2b, R3a, R3b, R5, R6, R7, R8, R9, p and E are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

Benzolactam compounds as protein kinase inhibitors

Benzolaktamo junginiai kaip baltymų kinazės inhibitoriai

Bentsolaktaamiyhdisteitä proteiinikinaasin estäjinä

Benzolactam compounds as protein kinase inhibitors

The invention provides a compound of formula (2): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.

Benzolactamforbindelser som proteinkinaseinhibitorer

Reguladores de NRF2

La presente invención se refiere a composiciones que comprenden los compuestos de fórmula (I) para su uso como reguladores de NRF2. (Traducción automática con Google Translate, sin valor legal)

Nrf2 regulators

Provided are aryl analogs of Formula (I), pharmaceutical compositions containing them and their use as NRF2 regulators.

Benzolactam compounds as protein kinase inhibitors

The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof; wherein: n is 1 or 2; X is CH or N; Y is selected from CH and C-F; Z is selected from C-Rz and N; R1 is selected from: - (Alk1)t-Cyc1; wherein t is 0 or 1; - Optionally substituted C1-6 acyclic hydrocarbon groups R2 is selected from hydrogen; halogen; and C1-3 hydrocarbon groups optionally substituted with one or more fluorine atoms; R3 is hydrogen or a group L1-R7; R4 is selected from hydrogen; methoxy; and optionally substituted C1-3 alkyl; and R4a is selected from hydrogen and a C1-3 alkyl group; wherein Rz, Alk1, Cyc1, L1 and R7 are defined herein; provided that the compound is other than 6-benzyl-3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and 3-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}-7,8-dihydro-1,6-naphthyridin-5(6H)-one and salts and tautomers thereof. The compounds are inhibitors of ERK1/2 kinases and will be useful in the treatment of ERK1/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.