Radiolabeled glutaminyl cyclase (QC) inhibitors and uses of same

A radiolabeled glutaminyl cyclase (QC) inhibitor for use as an imaging agent, comprising:

• a radiolabel selected from the group consisting of 2H (D or deuterium), 3H (T or tritium), 11C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, and 131I:
• and
• a QC inhibitor compound of formula (I),
• or a pharmaceutically acceptable salt, including all tautomers and stereoisomers thereof;
• wherein
• R1 represents heteroaryl, -carbocyclyl-heteroaryl, —C2-6alkenylheteroaryl, —C1-6-alkylheteroaryl, 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-C5cycloalkyl 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(01-4alkyl)(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;
• R2 represents H, C1-8alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —C1-4 alkylaryl, —C1-4alkyl heteroaryl, —C1-4alkylcarbocyclyl or —C1-4alkyl heterocyclyl;
• 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, O3-6alkenyloxy-, O3-6alkynyloxy-, —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 R2 represents 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;
• 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, —SO2C1-4 alkyl, C1-6alkoxy-, —O—C3-8cycloalkyl, C3-8cycloalkyl, —SO2C3-8cycloalkyl, —SOC3-6 cycloalkyl, 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(C1-4 alkyl)(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)N H(C3-10cycloalkyl);
• or R2 and R3 are joined to form a carbocyclyl ring which is optionally substituted by one or more C1-2alkyl groups;
• or 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 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;
• X represents C═O, O, S, CR7R8, —O—CH2— or —CH2—CH2—;
• Y represents CHR9, C═O or C═S;
• Z represents —N—R4, O or CHR10, such that when X represents O or S, Z must represent CHR10;
• or X and Z 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;
• R4 represents H, —C1-8alkyl, —C(O)C1-6alkyl or —NH2;
• R7 and R8 independently represent H, —C1-4 alkyl or aryl;
• in which said aforesaid aryl may be optionally substituted by C1-6alkyl, C2-6 alkenyl, 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(C1-4 alkyl)(C1-4alkyl), —C(O)NH2, —C(O)NH(C1-4alkyl) and, —C(O)NH(C3-10cycloalkyl);
• 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)—.