Novel 2-amino-quinazoline derivatives useful as inhibitors of beta-secretase (BACE)

A compound of formula (II)

• wherein
• R0 is selected from the group consisting of hydrogen, methyl, and CF3;
• R1 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy and methyl-carbonyl;
• c is an integer from 0 to 1;
• A2 is selected from C1-4alkyl;
• wherein the C1-4alkyl is optionally substituted with one or more RY substituents;
• wherein each RY is independently selected from the group consisting of hydroxy, oxo, C1-4alkyl, C1-4alkoxy, hydroxy substituted C1-4alkyl, amino substituted C1-6alkyl, cycloalkyl, cycloalkyl-C1-4alkyl-, biphenyl, aryl, C1-4aralkyl, heteroaryl, heteroaryl-C1-4alkyl-, heterocycloalkyl, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl group, whether alone or as part of a substituent group is optionally substituted with a substituent selected from the group consisting of fluoro, chloro, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, —C(O)—(C1-4alkoxy), hydroxy substituted C1-4alkyl, fluoro substituted C1-4alkyl, fluoro substituted C1-4alkoxy, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• is selected from the group consisting of aryl, aryl-C1-4alkyl, cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl and spiro-heterocyclyl;
• wherein the aryl, cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halogen substituted C1-4alkyl, halogen substituted C1-4alkoxy, hydroxy substituted C1-4alkyl, hydroxy, carboxy, cyano, nitro, amino, C1-4alkylamino and di(C1-4alkyl)amino;
• provided that when c is 0 (i.e. A1 is absent), then
• is other than aryl or heteroaryl;
• Q3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NRA—, —NRA—C(O)—, —C(S)—NRA, —SO2—NRA, —SO—NRA, —OC(O)—NRA—, —NRA—C(O)O— and —O—SO2—NRA—;
• wherein each RA is independently selected from the group consisting of hydrogen, C1-8alkyl, hydroxy substituted C1-4alkyl, C1-4aralkyloxy substituted C1-4alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl-, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, —SO2—N(RCRD), 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein each RC and RD is independently selected from the group consisting of hydrogen and C1-4alkyl;
• R2 is selected from the group consisting of C1-10alkyl, cycloalkyl, aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, partially unsaturated carbocyclyl-C1-4alkyl-, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the C1-10alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, —C(O)—C1-4alkyl, —C(O)—C1-4aralkyl, —C(O)O—C1-4alkyl, —C(O)O—C1-4aralkyl, —C1-4alkyl-C(O)O—C1-4alkyl, —C1-4alkyl-S—C1-4alkyl, —C(O)—N(RLRM), —C1-4alkyl-C(O)—N(RLRM), —NRL—C(O)—C1-4alkyl, —SO2—N(RLRM), —C1-4alkyl-SO2—N(RLRM), C1-6alkyl, fluoro substituted C1-4alkyl, hydroxy substituted C1-4alkyl, carboxy substituted C1-4alkyl, C1-4alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein the phenyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C(O)O—C1-4alkyl, C(O)—C1-4alkyl, C1-4alkyl, fluoro substituted C1-4alkyl, C1-4alkoxy, nitro, cyano, amino, C1-4alkylamino and di(C1-4alkyl)amino;
• wherein each RL and RM is independently selected from the group consisting of hydrogen and C1-4alkyl;
• b is an integer from 0 to 1;
• L1 is selected from the group consisting of —O—, —S(O)0-2—, —NRN—, —C(O)—, —C(S)—, —C1-4alkyl-, -(hydroxy substituted C1-4alkyl)- and —(C2 4alkenyl)-;
• wherein RN is selected from the group consisting of hydrogen and C1-4alkyl;
• R3 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl, -heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the C1-6alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, hydroxy substituted C1-4alkyl, halogen substituted C1-4alkyl, cyano substituted C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, halogen substituted C1-4alkoxy, nitro, cyano, —R5, —O—R5, —S—R5, —SO2—R5, —SO2—NRP—R5, —NRA—SO2—R5, —NH2, —N(RP)—R5, —C(O)—R5, —C(O)—NH2, —C(O)—NRP—R5, —NRP—C(O)—R5 and —NRP—C(O)O—R5;
• wherein R5 is selected from the group consisting of C1-4alkyl, aryl, C1-4aralkyl, partially unsaturated carbocyclyl, cycloalkyl, cycloalkyl-C1-4alkyl-, partially unsaturated carbocyclyl-C1-4alkyl-, heteroaryl, heteroaryl-C1-4alkyl-, heterocycloalkyl and heterocyclyl-C1-4alkyl-;
• wherein the aryl, C1-4aralkyl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group may be optionally substituted with one or more substituent independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halogen, hydroxy, carboxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano and nitro;
• wherein RP is selected from the group consisting of hydrogen, C1-8alkyl, hydroxy substituted C1-4alkyl, C1-4aralkyloxy substituted C1-4alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, —SO2—N(RSRT), 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein each RS and RT is independently selected from the group consisting of hydrogen and C1-4alkyl;
• a is an integer form 0 to 3;
• each R10 is independently selected from the group consisting of hydroxy, halogen, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, —C(O)—NRVRW, —SO2—NRVRW, —C(O)—C1-4alkyl and —SO2-C1-4alkyl;
• wherein each RV and RW is independently selected from the group consisting of hydrogen and C1-4alkyl;
• alternatively RV and RW are taken together with the N atom to which they are bound to form a 5 to 6 membered saturated, partially unsaturated or aromatic ring structure;
• provided that the halogens on the halogenated-C1-4alkyl and the halogenated C1-4alkoxy are selected from chloro or fluoro;
• provided that when R0 is hydrogen, R1 is hydrogen, A1 is —CH2—,
• is phenyl, Q3 is —O—, R2 is methyl, b is an integer selected from 0 to 1 and L1 is selected from —O—, —NH— or —N(CH3)—, then R3 is other than methyl;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (CII)

• wherein
• R0 is selected from the group consisting of hydrogen, methyl, and CF3;
• c is an integer from 0 to 1;
• A2 is selected from the group consisting of C1-4alkyl;
• wherein the C1-4alkyl is optionally substituted with one or more RY substituents;
• wherein each RY is independently selected from the group consisting of hydroxy, oxo, C1-4alkyl, C1-4alkoxy, hydroxy substituted C1-4alkyl, amino substituted C1-6alkyl, cycloalkyl, cycloalkyl-C1-4alkyl-, biphenyl, aryl, C1-4aralkyl, heteroaryl, heteroaryl-C1-4alkyl-, heterocycloalkyl, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl group, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, —C(O)O-(C1-4alkyl), hydroxy substituted C1-4alkyl, fluoro substituted C1-4alkyl, fluoro substituted C1-4alkoxy, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• is selected from the group consisting of aryl, aryl-C1-4alkyl, cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl and spiro-heterocyclyl;
• wherein the aryl, cycloalkyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl group, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halogen substituted C1-4alkyl, halogen substituted C1-4alkoxy, hydroxy substituted C1-4alkyl, hydroxy, carboxy, cyano, nitro, amino, C1-4alkylamino and di(C1-4alkyl)amino;
• provided that when c is 0, then
• is other than aryl or heteroaryl;
• Q3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —OC(O)—, —C(O)—NRA, —NRA—C(O)—, —C(S)—NRA, —SO2—NRA—, —SO—NRA, —OC(O)—NRA—, —NRA—C(O)O— and —O—SO2—NRA—;
• wherein each RA is independently selected from the group consisting of hydrogen, C1-8alkyl, hydroxy substituted C1-4alkyl, C1-4aralkyloxy substituted C1-4alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, —SO2—N(RCRD), 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein each RC and RD is independently selected from the group consisting of hydrogen and C1-4alkyl;
• R2 is selected from the group consisting of C1-8alkyl, cycloalkyl, aryl, biphenyl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, partially unsaturated carbocyclyl-C1-4alkyl-, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the C1-8alkyl, cycloalkyl, aryl, partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, —C(O)—C1-4alkyl, —C(O)—C1-4aralkyl, —C(O)O—C1-4alkyl, —C(O)O—C1-4aralkyl, —C1-4alkyl-C(O)O—C1-4alkyl, —C1-4alkyl-S—C1-4alkyl, —C(O)—N(RLRM), —C1-4alkyl-C(O)—N(RLRM), —NRL—C(O)—C1-4alkyl, —SO2—N(RLRM), —C1-4alkyl-SO2—N(RLRM), C1-6alkyl, fluoro substituted C1-4alkyl, hydroxy substituted C1-4alkyl, carboxy substituted C1-4alkyl, C1-4alkoxy, —O—C1-4aralkyl, —O-(tetrahydropyranyl), —NH—OC(O)—CH2-(tetrahydropyranyl), —N(CH3)—OC(O)—CH2-(tetrahydropyranyl), nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, phenyl, 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein the phenyl or tetrahydropyranyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C(O)O—C1-4alkyl, C(O)—C1-4alkyl, OC(O)—C1-4alkyl, -C1-4alkyl-OC(O)—C1-4alkyl, —O—C1-4aralkyl, C1-4alkyl, fluoro substituted C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, nitro, cyano, amino, C1-4alkylamino and di(C1-4alkyl)amino;
• wherein each RL and RM is independently selected from the group consisting of hydrogen and C1-4alkyl;
• b is an integer from 0 to 1;
• L1 is selected from the group consisting of —O—, —S(O)0-2—, —NRN—, —C(O)—, —C(S)—, —C1-4alkyl-, -(hydroxy substituted C1-4alkyl)- and -(C2-4alkenyl)-;
• wherein RN is selected from the group consisting of hydrogen and C1-4alkyl;
• R3 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the C1-6alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, hydroxy substituted C1-4alkyl, halogen substituted C1-4alkyl, cyano substituted C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, halogen substituted C1-4alkoxy, nitro, cyano, —R5, —O—R5, —S—R5, —SO2—R5, —SO2—NRP—R5, —NRP—SO2—R5, —NH2, —N(RP)—R5, —C(O)—R5, —C(O)—NH2, —C(O)—NRP—R5, —NRP—C(O)—R5 and —NRP—C(O)O—R5;
• wherein R5 is selected from the group consisting of C1-4alkyl, aryl, C1-4aralkyl, partially unsaturated carbocyclyl, cycloalkyl, cycloalkyl-C1-4alkyl-, partially unsaturated carbocyclyl-C1-4alkyl-, heteroaryl, heteroaryl-C1-4alkyl-, heterocycloalkyl and heterocyclyl-C1-4alkyl-;
• wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituent independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halogen, hydroxy, carboxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano and nitro;
• wherein RP is selected from the group consisting of hydrogen, C1-8alkyl, hydroxy substituted C1-4alkyl, C1-4aralkyloxy substituted C1-4alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl-C1-4alkyl-, C1-4aralkyl, heteroaryl-C1-4alkyl-, heterocycloalkyl-C1-4alkyl- and spiro-heterocyclyl;
• wherein the cycloalkyl, aryl, heteroaryl, heterocycloalkyl or spiro-heterocyclyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, carboxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxy-carbonyl, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, —SO2—N(RSRT), 5-tetrazolyl and 1-(1,4-dihydro-tetrazol-5-one);
• wherein each RS and RT is independently selected from the group consisting of hydrogen and C1-4alkyl;
• a is an integer form 0 to 3;
• each R0 is independently selected from the group consisting of hydroxy, halogen, C1-4alkyl, C1-4alkoxy, halogen substituted C1-4alkyl, halogen substituted C1-4alkoxy, —C(O)—NRVRW, —SO2—NRVRW, —C(O)—C1-4alkyl and —SO2—C1-4alkyl;
• wherein each RV and RW is independently selected from the group consisting of hydrogen and C1-4alkyl;
• alternatively RV and RW are taken together with the N atom to which they are bound to form a 5 to 6 membered saturated, partially unsaturated or aromatic ring structure;
• provided that the halogens on the halogen substituted C1-4alkyl or the halogen substituted C1-4alkoxy are selected from the group consisting of chloro and fluoro;
• or a pharmaceutically acceptable salt thereof.