Inhibitors

A method of treatment of a disease selected from the group consisting:

• inflammatory host responses, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Huntington's disease, rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis,
• which comprises administering to a subject an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I),
• wherein said compound of formula (I) is the compound:
• or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein:
• (a) R1 represents heteroaryl, -carbocyclyl-heteroaryl, -C2-6alkenylheteroaryl, —C1-6alkylheteroaryl, or (CH2)aCR5R6(CH2)bheteroaryl wherein a and b independently represent integers 0-5 provided that a+b =0-5 and R5 and R6 are alkylene which together with the carbon to which they are attached form a C3-C5 cycloalkyl group;
• in which any of aforesaid heteroaryl groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl);
• and
• in which any of aforesaid carbocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen and C1-4alkoxy;
• (b) R2 and R3 are independently selected as follows,
• (i) R2 represents
• (1) H, C1-8alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —C1-4alkylaryl, —C1-4alkylheteroaryl, —C1-4alkylcarbocyclyl or —C1-4alkylheterocyclyl;
• in which any of aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, C1-6alkoxy-C1-6alkoxy-, nitro, halogen, haloC1-6alkyl, haloC1-6alkoxy, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl)-N(C1-4alkyl)(C1-4alkyl), —C1-4alkyl-N(C1-4alkyl)(C1-4alkyl), —C1-4alkoxy-N(C1-4alkyl)(C1-4alkyl), —N(C3-8cycloalkyll)(C3-8cycloalkyl), —N(—C1-6alkyl-C1-6alkoxy)(-C1-6alkyl-C1-6alkoxy), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and —C(O)NH(C3-10cycloalkyl);
• and
• in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen, —C(O)C1-6alkyl and C1-4alkoxy;
• or
• (2) phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, phenyl substituted by —O—C1-4alkyl-heterocyclyl, phenyl substituted by benzyloxy, phenyl substituted by carbocyclyl, phenyl substituted by carbocyclyl wherein said carbocyclyl is substituted by heterocyclyl, phenyl substituted by —O-carbocyclyl, heterocyclyl substituted by phenyl, carbocyclyl substituted by phenyl, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, —C1-4alkyl(phenyl substituted by phenyl), —C1-4alkyl(phenyl substituted by a monocyclic heteroaryl group), —C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), —C1-4alkyl(phenyl substituted by an —O-carbocyclyl group), —C1-4alkyl(phenyl substituted by benzyloxy), —C1-4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl or —C1-4alkyl(optionally substituted phenyl fused to optionally substituted heterocyclyl);
• in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy, and
• in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen, hydroxyl and C1-4alkoxy;
• and
• (ii) R3 represents H, —C1-4alkyl or aryl;
• in which aforesaid aryl may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)NH(C3-10cycloalkyl);
• or
• (c) R2 and R3 are jointly selected as follows,
• (1) R2 and R3 are joined to form a carbocyclyl ring which is optionally substituted by one or more C1-2alkyl groups;
• (2) R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy;
• or
• (3) R2 and R3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy;
• (d) X and Z are independently selected as follows,
• (i) X represents C═O, O, CR7R8, —O—CH2— or —CH2—CH2—;
• and
• (ii) Z represents —N—R4, O or CHR10, such that when X represents O, Z must represent CHR10;
• or
• (e) X and Z are jointly selected to represent two adjacent carbon atoms of a phenyl ring which is fused in that position and which is optionally substituted by one or more halogen or C1-2alkyl groups;
• and
• (f) Y represents CHR9, C═O or C═S;
• wherein,
• R4 represents H, —C1-8alkyl, —C(O)C1-6alkyl or —NH2;
• R7 and R8 independently represent H, —C1-4alkyl or aryl;
• in which said aforesaid aryl may be optionally substituted by C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, —C1-6thioalkyl, —SOC1-4alkyl, —SO2C1-4alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, —C(O)C1-6alkyl, —C(O)OC1-6alkyl,C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH2, —NHC1-4alkyl, —N(C1-4alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)NH(C3-10cycloalkyl);
• and
• R9 and R10 independently represent H or methyl;
• provided that the moiety —Y—Z—X— represents a moiety other than —C(═O)—N(—R4)—C(═O)— or —C(═S)—N(—R4)—C(═O)—.