An object is to provide a compound having β-lactamase inhibitory activity. The object is achieved by a compound represented by formula (1), typified by a compound in which specific positions of a 5-membered ring having planarity are replaced by sulfamoyl and carboxy groups.

COMPOUNDS

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases.

##STR00001##

COMPOUNDS

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases.

##STR00001##

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases. ##STR00001##

The present invention provides compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof (wherein the substituents are as defined in the description). The compounds of the general formula (I) are inhibitors of factor XIa, and are useful in the prevention of and/or therapy for thromboembolic diseases. ##STR00001##

This invention is directed to novel carbocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

This invention is directed to novel carbocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

This invention is directed to novel carbocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

This invention is directed to novel carbocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

The present invention relates to compounds of formula I

##STR00001##

or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R.sub.1 is C.sub.1-C.sub.3alkyl optionally substituted with F, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.3alkoxy; X represents a bond or C.sub.1-C.sub.3alkylene optionally substituted with OH, ONO, ONO.sub.2; R.sub.2 is H, OH, ONO, ONO.sub.2, C(O)OH, C(O)OC.sub.1-C.sub.3alkyl, CHO, CN, C.sub.1-C.sub.3alkoxy, OC(O)H, OC(O)C.sub.1-C.sub.3alkyl, C(O)N(R.sub.6)OR.sub.7, OC.sub.1-C.sub.3alkylene-C(O)OH, OC.sub.1-C.sub.3alkylene-C(O)OC.sub.1-C.sub.3alkyl, OC.sub.1-C.sub.3alkylene-C(O)N(R.sub.6)OR.sub.7, S(O.sub.0-2)C.sub.1-C.sub.3alkyl, CR.sub.8NOR.sub.9, CR.sub.8NNR.sub.10R.sub.11, CR.sub.8NR.sub.12 or CR.sub.8NONO.sub.2; R.sub.3 is C.sub.1-C.sub.6alkyl optionally substituted with F, OH, ONO, ONO.sub.2, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.6cycloalkyl; C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl; R.sub.4 is C.sub.1-C.sub.6alkyl optionally substituted with C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, F, ONO, ONO.sub.2; C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl; R.sub.5 is H, SO.sub.2NR.sub.13R.sub.14, NHSO.sub.2NR.sub.13R.sub.14; R.sub.6 is H or C.sub.1-C.sub.3alkyl; R.sub.7 is H, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C.sub.1-C.sub.3alkyl, F; R.sub.8 is H, CH.sub.3 or C.sub.2H.sub.5; R.sub.9: H, C.sub.1-C.sub.3alkyl optionally substituted with OH, ONO, ONO.sub.2, CN, COOH, COOC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy, OC(O)H, OC(O)C.sub.1-C.sub.3alkyl, C(O)N(R.sub.6)OR.sub.7, OC.sub.1-C.sub.3alkylene-C(O)OH, OC.sub.1-C.sub.3alkylene-C(O)OC.sub.1-C.sub.3alkyl, OC.sub.1-C.sub.3alkylene-C(O)N(R.sub.6)OR.sub.7, S(O.sub.0-2)C.sub.1-C.sub.3alkyl; R.sub.10 and R.sub.11 are each independently H, C.sub.1-C.sub.3alkyl optionally substituted with OH, ONO, ONO.sub.2, CN, COOH, COOC.sub.1-C.sub.3, C.sub.1-C.sub.3alkoxy, OC(O)H, OC(O)C.sub.1-C.sub.3alkyl, C(O)N(R.sub.6)OR.sub.7, OC.sub.1-C.sub.3alkylene-C(O)OH, OC.sub.1-C.sub.3alkylene-C(O)OC.sub.1-C.sub.3alkyl, OC.sub.1-C.sub.3alkylene-C(O)N(R.sub.6)OR.sub.7, S(O.sub.0-2)C.sub.1-C.sub.3alkyl, or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C.sub.1-C.sub.3 alkyl; R.sub.12 is C.sub.1-C