Substituted 2-Aminopyrimidine-4-Ones, Their Pharmaceutical Compositions And Their Use In The Treatment And/Or Prevention Of Ab-Related Pathologies

A compound of formula I:

• wherein
• R1 is selected from hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C5-7cycloalkenyl, aryl, heteroaryl, heterocyclyl, C1-16alkylC3-6cycloalkyl, C1-16alkylaryl, C1-6alkylheteroaryl and C1-6alkylheterocyclyl, wherein the C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C5-7cycloalkenyl, aryl, heteroaryl, heterocyclyl, C1-6alkylC3-6cycloalkyl, C1-6alkylaryl, C1-6alkylheteroaryl and C1-6alkylheterocyclyl is optionally substituted with one, two or three A;
• R2 is selected from hydrogen, nitro, cyano, -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, and -Q-C1-6alkylheterocyclyl, wherein said -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, and -Q-C1-6alkylheterocyclyl is optionally substituted by one, two or three R7;
• -Q- is a direct bond, —CONH—, —CO—, —CON(C1-6alkyl)-, —CON(C3-6cycloalkyl)-, —SO—, —SO2—, —SO2NH—, —SO2N(C1-6alkyl)-, —SO2N(C3-6cycloalkyl)-, —NHSO2—, —N(C1-6alkyl)SO2—, —NHCO—, —N(C1-6alkyl)CO—, —N(C3-6cycloalkyl)CO— or —N(C3-6cycloalkyl)SO2—;
• R3 is (C(R27)(R28))nR6, C2-4alkenylR6, C2-4alkynylR6, C5-7cycloalkenylR6, nitro or cyano and if n>1 then each C(R27)(R28) is independent of the others;
• R27 and R28 are independently selected from hydrogen, C1-6alkyl, cyano, halo and nitro;
• or R27 and R28 together form oxo, C3-6cycloalkyl or heterocyclyl;
• R4 and R5 are selected from hydrogen, nitro, cyano, -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, and -Q-C1-6alkylheterocyclyl, wherein said -Q-C1-6alkyl, -Q-C2-6alkenyl, -Q-C2-6alkynyl, -Q-C3-6cycloalkyl, -Q-C5-7cycloalkenyl, -Q-C1-6alkylC3-6cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C1-6alkylaryl, -Q-C1-6alkylheteroaryl, -Q-heterocyclyl, and -Q-C1-6alkylheterocyclyl is optionally substituted by one, two or three R7;
• or
• R4 and R5 may optionally join together to form a C3-7cycloalkyl, C5-7cycloalkenyl or heterocycle ring optionally substituted by one, two or three R7;
• or
• R4 or R5, which are connected to the carbon directly adjacent to the carbon to which R2 and R3 are connected, join together with either R2 or R3 to form a C3-7cycloalkyl, C5-7cycloalkenyl or heterocycle ring optionally substituted by one, two or three R7;
• R6 is selected from methyl, C3-6cycloalkyl, heterocyclyl, aryl and heteroaryl wherein each of the said methyl, C3-6cycloalkyl, heterocyclyl, aryl of and heteroaryl is optionally substituted with from one to four R7, and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with from one to four A with the proviso that the bicyclic ring is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
• R7 is selected from halogen, nitro, CHO, C0-6alkylCN, OC1-6alkylCN, C0-6alkylOR8, OC2-6alkylOR8, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylNR8R9, OC2-6alkylNR3R9, OC2-6alkylOC2-6alkylNR3R9, NR3OR9, C0-6alkylCO2R8, OC1-6alkylCO2R8, C0-6alkylCONR8R9, OC1-6alkylCONR8R9, OC2-6alkylNR3(CO)R9, C0-6alkylNR3 (CO)R9, O(CO)NR8R9, NR8(CO)OR9, NR8(CO)NR8R9, O(CO)OR8, O(CO)R8, C0-6alkylCOR3, OC1-6alkylCOR3, NR8(CO)(CO)R8, NR8(CO)(CO)NR8R9, C0-6alkylSR8, C0-6alkyl(SO2)NR3R9, OC1-6alkylNR3(SO2)R9, OC0-6alkyl(SO2)NR8R9, C0-6alkyl(SO)NR8R9, OC1-6alkyl(SO)NR8R9, OSO2R8, SO3R8, C0-6alkylNR8(SO2)NR8R9, C0-6alkylNR3(SO)R9, OC2-6alkylNR8(SO)R8, OC1-6alkylSO2R3, C1-6alkylSO2R3, C0-6alkylSOR3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl, and OC2-6alkylheterocyclyl, wherein any C1-16alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl, and OC2-6alkylheterocyclyl may be optionally substituted by one or more R14, and wherein any of the individual aryl or heteroaryl groups may be optionally fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with from one to four A with the proviso that said bicyclic ring system is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
• R14 is selected from halogen, nitro, CHO, C0-6alkylCN, OC1-6alkylCN, C0-6alkylOR3, OC1-16alkylOR8, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylNR8R9, OC2-6alkylNR3R9, OC2-6alkylOC2-6alkylNR3R9, NR3OR9, C0-6alkylCO2R3, OC1-6alkylCO2R3, C0-6alkylCONR3R9, OC1-6alkylCONR3R9, OC2-6alkylNR3(CO)R9, C0-6alkylNR3 (CO)R9, O(CO)NR8R9, NR8(CO)OR9, NR8(CO)NR8R9, O(CO)OR8, O(CO)R8, C0-6alkylCOR3, OC1-6alkylCOR3, NR8(CO)(CO)R8, NR8(CO)(CO)NR8R9, C0-6alkylSR8, C0-6alkyl(SO2)NR8R9, OC2-6alkylNR8(SO2)R9, OC0-6alkyl(SO2)NR3R9, C0-6alkyl(SO)NR3R9, OC1-6alkyl(SO)NR3R9, OSO2R8, OR8, SO3R8, C0-6alkylNR8(SO2)NR8R9, C0-6alkylNR3(SO)R9, OC2-6alkylNR8(SO)R8, OC1-6alkylSO2R3, C1-6alkylSO2R3, C0-6alkylSOR3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and OC2-6alkylheterocyclyl wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and OC2-6alkylheterocyclyl may be optionally substituted by from one to four A;
• R8 and R9 are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and C1-6alkylNR10R11, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl and C0-6alkylheterocyclyl are optionally substituted by A;
• or
• R8 and R9 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S that is optionally substituted by A;
• whenever two R8 groups occur in the structure then they may optionally together form a 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, that is optionally substituted by A;
• R10 and R11 are independently selected from hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheterocyclyl and C0-6alkylheteroaryl, wherein the C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, and C0-6alkylheterocyclyl are optionally substituted by A;
• or
• R10 and R11 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S optionally substituted by A;
• m is 1 or 2;
• n is 0, 1, 2 or 3;
• A is selected from oxo, halogen, nitro, CN, OR12, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylC3-6cycloalkyl, C0-6alkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC2-6alkylNR12R13, NR12R13, CONR12R13, NR12(CO)R13, O(CO)C1-6alkyl, (CO)OC1-6alkyl, COR12, (SO2)NR12R13, NSO2R12, SO2R12, SOR12, (CO)C1-6alkylNR12R13, (SO2)C1-6alkylNR12R13, OSO2R12, and SO3R12 wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylaryl, C0-6alkylheteroaryl, C0-6alkylheterocyclyl and C0-6alkylC3-6cycloalkyl groups may be optionally substituted with halo, OSO2R12, SO3R12, nitro, cyano, OR12, C1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy;
• R12 and R13 are independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl and heterocyclyl wherein said C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted by one, two or three hydroxy, cyano, halo or C1-3alkyloxy;
• or
• R12 and R13 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O and S optionally substituted by hydroxy, C1-3alkyloxy, cyano or halo;
• provided that either any of the aryl or heteroaryl groups in R1, R2, R3, R4 or R5 is substituted with a OSO2R8, SO3R8, OSO2R12 or SO3R12 group;
• or
• provided that when any of the individual aryl or heteroaryl groups in R1, R2, R3, R4 or R5 are fused with a 4, 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclyl group to form a bicyclic ring system where the bicyclic ring system is optionally substituted with between from one and to four A, the bicyclic ring is not an indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system;
• or
• provided that when R1 is C3-6alkynyl or C5-7cycloalkenyl, said groups are optionally substituted with one, two or three A;
• or
• provided that Q is selected from —NHSO2—, —N(C1-6alkyl)SO2—, —SO2NH—, —SO2N(C1-6alkyl)-, —SO2N(C3-6cycloalkyl)- and —N(C3-6cycloalkyl)SO2—;
• or
• provided that R3 is selected from C2-4alkenylR6, C2-4alkynylR6, C5-7cycloalkenylR6 and nitro;
• or
• provided that R2 is selected from nitro, C2-6alkynyl, C5-7cycloalkenyl and C2-6alkenyl group where the C2-6alkynyl, C5-7cycloalkenyl and C2-6alkenyl group is optionally substituted by one, two or three R7;
• or
• provided that R4 or R5 are independently selected from nitro, C2-6alkynyl, C5-7cycloalkenyl of and C2-6alkenyl group where the C2-6alkynyl, C5-7cycloalkenyl and C2-6alkenyl group is optionally substituted by one, two or three R7;
• or
• provided that when Q is —SO— or —SO2— that the said —SO— or —SO2— group connect to carbons;
• as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.