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US 10,501,461 B2Granted
Tyrosine amide derivatives as Rho-kinase inhibitors
AssigneeChiesi Farmaceutici S.p.A.
InventorsAlessandro Accetta, Fabio Rancati, Anna Maria Capelli, David Edward Clark, Patrizia Tisselli, Christine Edwards, Gurdip Bhalay, Arnaud Jean Francois Auguste Cheguillaume
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Abstract
Tyrosine amide compounds of formula I described herein inhibit Rho Kinase and may be used for the treatment of many disorders associated with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).
Claims14
A compound of formula (I)
- wherein
- X1, and X2 are in each occurrence independently a CH group or a nitrogen atom;
- p is zero or an integer from 1 to 3;
- each R, when present, is a halogen;
- R0 and R1 are independently:
- —H,
- halogen,
- —NR7R8,
- —CN,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C1-C6) aminoalkyl,
- (C1-C6) alkoxy-(C1-C6) alkyl
- (C3-C10) cycloalkyl,
- (C2-C6) alkenyl,
- (C5-C7) cycloalkenyl,
- (C2-C6) alkynyl,
- (C2-C6) hydroxyalkynyl,
- aryl,
- heteroaryl, or
- (C3-C6) heterocycloalkyl
- wherein each of said aryl, heteroaryl and (C3-C6) heterocycloalkyl is optionally and independently substituted with one or more groups selected from the group consisting of:
- halogen,
- —OH,
- —CN,
- —NR7R8,
- —CH2NR7R8,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C2-C6) alkenyl,
- (C2-C6) alkynyl, and
- (C2-C6) hydroxyalkynyl;
- R2 and R3, are the same or different, and are selected from the group consisting of
- —H,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C1-C6) aminoalkyl,
- (C1-C6) alkoxy(C1-C6) alkyl,
- (C3-C10)cycloalkyl,
- (C3-C8)heterocycloalkyl,
- aryl,
- heteroaryl,
- aryl(C1-C6)alkyl,
- heteroaryl(C1-C6)alkyl
- (C3-C8)cycloalkyl(C1-C6)alkyl, and
- (C3-C8)heterocycloalkyl-(C1-C6)alkyl
- wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is further optionally substituted by one or more group selected independently from the group consisting of halogen, —CN, —OH, (C1-C8)alkyl, (C1-C6) haloalkyl, (C1-C10)alkoxy, aryl, aryl(C1-C6)alkyl, carbamoyl, (C1-C6) aminoalkyl, and (C1-C6) hydroxyalkyl;
- or
- R2 and R3, in the alternative, taken together with the nitrogen atom to which they are bonded form a mono- or bi-cyclic saturated or partially saturated heterocyclic radical, wherein said heterocyclic radical is optionally further substituted with one or more groups selected from the group consisting of
- halogen,
- hydroxyl,
- —NR7R8,
- —CH2NR7R8,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C2-C6) alkenyl,
- (C2-C6) alkynyl,
- (C2-C6) hydroxyalkynyl,
- (C1-C6) alkoxy (C1-C6) alkyl,
- (C1-C6) alkanoyl,
- carbamoyl,
- (C3-C6) cycloalkyl-carbonyl,
- (C3-C6) heterocycloalkyl-carbonyl,
- aryl(C1-C6)alkyl,
- aryl alkanoyl,
- arylsulfonyl,
- heteroaryl(C1-C6)alkyl,
- heteroaryl-carbonyl
- heteroaryloxyl,
- (C3-C6) cycloalkyl,
- (C3-C8)cycloalkyl(C1-C6)alkyl
- (C3-C6) heterocycloalkyl-(C1-C6) alkyl,
- aryl, and
- heteroaryl
- wherein each of said cycloalkyl, aryl, and heteroaryl is further optionally substituted by halogen, (C1-C8)alkyl, (C1-C10)alkoxy, (C1-C6)alkylthio, (C1-C6) aminoalkyl, (C1-C6) aminoalkoxyl, carbamoyl, or (C1-C6)alkyl-sulfonyl;
- R4 and R5 are at each occurrence independently selected from the group consisting of
- H,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C1-C6) aminoalkyl,
- (C1-C6) alkoxyl,
- (C1-C6) alkoxy-(C1-C6) alkyl,
- (C3-C6) cycloalkyl-(C1-C6) alkyl
- (C3-C6) heterocycloalkyl-(C1-C6) alkyl,
- (C3-C6) cycloalkyl-carbonyl
- (C3-C6) heterocycloalkyl-carbonyl
- aryl,
- heteroaryl, and
- (C3-C6) heterocycloalkyl;
- wherein any of said (C3-C6) cycloalkyl, aryl, heteroaryl, and (C3-C6) heterocycloalkyl is optionally and independently substituted with one or more groups selected from the group consisting of
- halogen,
- —OH, and
- (C1-C6) alkyl;
- R6 is selected from the group consisting of —H, (C1-C6) alkyl, and (C1-C6) haloalkyl;
- R7 and R8 are at each occurrence independently selected from the group consisting of
- H,
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C1-C6) aminoalkyl,
- (C1-C6) alkoxyl,
- (C1-C6) alkoxy-(C1-C6) alkyl,
- (C3-C6) heterocycloalkyl-(C1-C6) alkyl,
- aryl,
- heteroaryl, and (C3-C6) heterocycloalkyl;
- wherein any of said aryl, heteroaryl, and (C3-C6) heterocycloalkyl is optionally and independently substituted with one or more groups selected from the group consisting of
- halogen,
- —OH, and
- (C1-C6) alkyl;
- or
- R7 and R8 are taken together with the nitrogen atom to which they are linked, to form a 4 to 6 membered heterocyclic radical, wherein at least one further ring carbon atom in the said heterocyclic radical may be replaced by at least one group selected from N, S, or O, and said heterocyclic radical may be further optionally substituted by a group selected from the group consisting of
- H,
- —CN,
- halogen,
- -oxo,
- —NR7R8
- (C1-C6) alkyl,
- (C1-C6) haloalkyl,
- (C1-C6) hydroxyalkyl,
- (C1-C6) aminoalkyl,
- (C1-C6) alkoxyl,
- (C1-C6) alkoxy-(C1-C6) alkyl, and
- alkanoyl;
- or pharmaceutically acceptable salt thereof.
126 more elements
Dependencies are inferred from the claim text.