Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors

A compound of Formula (I)

• wherein
• A is —O—, —S—, or —N(R5)—,
• wherein R5 is selected from the group consisting of:
• a) -hydrogen;
• b) -alkyl;
• c) -aryl;
• d) -heteroaryl;
• e) -cycloalkyl;
• f) -heterocyclyl;
• g) -alkylene-aryl;
• h) -alkylene-heteroaryl;
• i) -alkylene-cycloalkyl;
• and
• j) -alkylene-heterocyclyl;
• L1, L6, and L7 are independently selected from the group consisting of:
• a direct bond, —CH2—, —O—, —N(R6)—, —C(O)—, —CON(R6)—, —N(R6)C(O)—, —N(R6)CON(R7)—, —N(R6)C(O)O—, —OC(O)N(R6)—, —N(R6)SO2—, —SO2N(R6)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R6)SO2N(R7)—,
• wherein R6 and R7 are independently selected from the group consisting of:
• -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• Q1 and Q6 are independently selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
• G1 is selected from the group consisting of:
• heterocyclylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene group wherein G1 may be optionally substituted 1 to 7 times, wherein the substituents are independently selected from the group consisting of:
• a) -halo;
• b) -cyano;
• c) -nitro;
• d) -perhaloalkyl;
• e) —R8;
• f) -L2-R8;
• g) -L2-Q2-R8;
• and
• h) -Q2-L2-R8;
• wherein
• R8 is selected from the group consisting of hydrogen, -alkyl, -aryl, and alkylene-aryl;
• Q2 is selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
• L2 is selected from the group consisting of a direct bond, —CH2—, —O—, —N(R9)—, —C(O)—, —CON(R9)—, —N(R9)C(O)—, —N(R9)CON(R10)—, —N(R9)C(O)O—, —OC(O)N(R9)—, —N(R9)SO2—, —SO2N(R9)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R9)SO2N(R10)—,
• wherein R9 and R10 are independently selected from the group consisting of:
• -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• or R9 and R10 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• G6 is selected from the group consisting of:
• hydrogen, heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group, wherein G6 is optionally substituted 1 to 7 times, wherein the substituents are independently selected from the group consisting of:
• a) -halo;
• b) -cyano;
• c) -nitro;
• d) -perhaloalkyl;
• e) —R108;
• f) -L102-R108;
• g) -L102-Q102-R108;
• and
• h) -Q102-L102-R108;
• wherein
• R108 is selected from the group consisting of hydrogen, -alkyl, -aryl, and alkylene-aryl;
• Q102 is selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
• L102 is selected from the group consisting of a direct bond, —CH2—, —O—, —N(R109)·, —C(O)—, —CON(R109)—, —N(R109)C(O)—, —N(R109)CON(R110)—, —N(R109)C(O)O—, —OC(O)N(R109)—, —N(R109)SO2—, —SO2N(R109)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R109)SO2N(R110)—,
• wherein R109 and R110 are independently selected from the group consisting of:
• -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• or R109 and R110 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• R1, R2, R3, and R4 are independently selected from the group consisting of
• a) —H;
• b) —NH2;
• c) -carboxy;
• d) -cyano;
• e) -halogen;
• f) -nitro;
• g) —OH
• h) -alkyl;
• i) -aryl;
• j) -alkylene-aryl;
• k) —K-alkyl;
• l) —K-aryl;
• m) —K-alkylene-aryl;
• n) -L3-G2-G3;
• and
• o) -L8-Q8-L9-G8-L18-Q18-L19-G18;
• wherein at least one of R1, R2, R3, and R4 is not hydrogen;
• and
• wherein
• K is selected from the group consisting of:
• —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —SO2—, —SO2—NH—, —NH—SO2—, and —C(O)—;
• Q8 and Q18 are independently selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
• L3, L8, L9, L18, and L19 are independently selected from the group consisting of:
• a direct bond, —CH2—, —O—, —N(R26)—, —C(O)—, —CON(R26)—, —N(R26)C(O)—, —N(R26)CON(R27)—, —N(R26)C(O)O—, —OC(O)N(R26)—, —N(R26)SO2—, —SO2N(R26)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R26)SO2N(R27)—, —C(O)—N(R26)—C(═NH)—N(R27)—, and —C(O)—N(R26)—N(R27)—
• wherein R26 and R27 are independently selected from the group consisting of:
• hydrogen, -alkyl, -aryl, -alkylene-aryl, or R26 and R27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• G2 is selected from the group consisting of:
• direct bond, alkylene, alkenylene, alkynylene, and
• wherein
• L10 is selected from the group consisting of alkyline, cycloalkyline, heteroaryline, aryline, and heterocyclyline;
• L12 is selected from the group consisting of —O—, —C(O)—N(R11)—, —C(O)—O—, —C(O)—, and —N(R11)—CO—N(R12)—, wherein R11 and R12 independently comprise hydrogen, aryl, alkyl, and alkylene-aryl;
• L11 is selected from the group consisting of hydrogen, -alkyl, alkenyl, alkynyl, -aryl, -alkylene-aryl, -alkylene -heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH2, -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR13, -alkylene-C(O)—NR13R14, -alkylene-NR13R14, -alkylene-N(R13)—C(O)—R14, -alkylene-N(R13)—S(O)2—R14, and the side chain of a natural or non-natural amino acid, wherein
• R13 and R14 independently comprise hydrogen, -aryl, -alkyl, and -alkylene-aryl;
• or
• R13 and R14 may be taken together to form a ring having the formula —(CH2)q—Y—(CH2)r— bonded to the nitrogen atom to which R13 and R14 are attached, wherein q and r are, independently, 1, 2, 3, or 4;
• Y is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —(O)CO—, —NHSO2NH—, —OC(O)—, —N(R15)—, —N(C(O)R15)—, —N(C(O)NHR15)—, —N(SO2NHR15)—, —N(SO2R15)—, and —N(C(O)OR15)—, wherein R15 is selected from the group consisting of hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• or
• R13 and R14 may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;
• and
• G3 and G18 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group, wherein G3 and G18 may be optionally substituted 1 to 7 times, wherein the substituents are independently selected from group consisting of:
• a) -halo;
• b) —NH2;
• c) -carboxy;
• d) -cyano;
• e) -nitro;
• f) —OH;
• g) -haloalkyl;
• h) -perhaloalkyl;
• i) —R16;
• j) -L4-R16;
• k) -L4-Q4-R16;
• and
• l) -Q4-L4-R16;
• wherein
• R16 is selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and -alkylene-aryl;
• Q4 is selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
• L4 is selected from the group consisting of direct bond, —CH2—, —O—, —N(R18)—, —C(O)—, —CON(R18)—, —N(R18)C(O)—, —N(R18)CON(R19)—, —N(R18)C(O)O—, —OC(O)N(R18)—, —N(R18)SO2—, —SO2N(R18)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R18)SO2N(R19)—;
• wherein
• R18 and R19 are independently selected from the group consisting of:
• -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• G8 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group, wherein G8 may be optionally substituted 1 to 7 times, wherein the substituents are independently selected from group consisting of:
• a) -halo;
• b) —NH2;
• c) -carboxy;
• d) -cyano;
• e) -nitro;
• f) —OH;
• g) -haloalkyl;
• h) -perhaloalkyl;
• i) —R116;
• j) -L114-R116;
• k) -L114-Q114-R116;
• and
• l) -Q114-L114-R116;
• wherein
• R116 is selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and -alkylene-aryl;
• Q114 is selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
• L114 is selected from the group consisting of direct bond, —CH2—, —O—, —N(R118)—, —C(O)—, —CON(R118)—, —N(R118)C(O)—, —N(R118)CON(R119)—, —N(R118)C(O)O—, —OC(O)N(R118)—, —N(R118)SO2—, —SO2N(R118)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R118)SO2N(R119)—;
• wherein
• R118 and R119 are independently selected from the group consisting of:
• -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl groups in R1 to R119, L1 to L114, G1 to G18, and Q1 to Q114 may be optionally substituted 1-4 times with a substituent selected from the group consisting of:
• a) —H;
• b) -halo;
• c) -hydroxyl;
• d) -amino;
• e) -cyano;
• f) -carbamoyl;
• g) -carboxyl;
• h) -Z-alkyl;
• i) -Z-haloalkyl;
• j) -Z-perhaloalkyl;
• k) -Z-aryl;
• l) -Z-alkylene-aryl;
• m) -Z-cycloalkyl;
• n) -Z-alkylene-cycloalkyl;
• o) -Z-heterocyclyl;
• p) -Z-alkylene-heterocyclyl;
• q) -Z-heteroaryl;
• and
• r) -Z-alkylene-heteroaryl;
• wherein Z is selected from the group consisting of a direct bond, —CH2—, —O—, —N(H), —S—, SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —C(O)—O—, —NHSO2NH—, and —O—CO—,
• or a pharmaceutically acceptable salt, ester, or prodrug thereof.