Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors
The present invention is directed to benzazole compounds that inhibit β-site amyloid precursor protein-cleaving enzyme (BACE) and that may be useful in the treatment or prevention of diseases in which BACE is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which BACE is involved.
1 . A compound of Formula (I)
wherein
A is —O—, —S—, or —N(R 5 )—,
wherein R 5 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;
L 1 , L 6 , and L 7 are independently selected from the group consisting of:
a direct bond, —CH 2 —, —O—, —N(R 6 )—, —C(O)—, —CON(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )CON(R 7 )—, —N(R 6 )C(O)O—, —OC(O)N(R 6 )—, —N(R 6 )SO 2 —, —SO 2 N(R 6 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 6 )SO 2 N(R 7 )—,
wherein R 6 and R 7 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
Q 1 and Q 6 are independently selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
G 1 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 G 1 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) —R 8 ;
f) -L 2 -R 8 ;
g) -L 2 -Q 2 -R 8 ; and
h) -Q 2 -L 2 -R 8 ;
wherein
R 8 is selected from the group consisting of hydrogen, -alkyl, -aryl, and alkylene-aryl;
Q 2 is selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
L 2 is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 9 )—, —C(O)—, —CON(R 9 )—, —N(R 9 )C(O)—, —N(R 9 )CON(R 10 )—, —N(R 9 )C(O)O—, —OC(O)N(R 9 )—, —N(R 9 )SO 2 —, —SO 2 N(R 9 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 9 )SO 2 N(R 10 )—,
wherein R 9 and R 10 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, and -alkylene-aryl; or R 9 and R 10 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;
G 6 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 G 6 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) —R 108 ;
f) -L 102 -R 108 ;
g) -L 102 -Q 102 -R 108 ; and
h) -Q 102 -L 102 -R 108 ;
wherein
R 108 is selected from the group consisting of hydrogen, -alkyl, -aryl, and alkylene-aryl;
Q 102 is selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
L 102 is selected from the group consisting of a direct bond, —CH 2 —, —O—, —N(R 109 )·, —C(O)—, —CON(R 109 )—, —N(R 109 )C(O)—, —N(R 109 )CON(R 110 )—, —N(R 109 )C(O)O—, —OC(O)N(R 109 )—, —N(R 109 )SO 2 —, —SO 2 N(R 109 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 109 )SO 2 N(R 110 )—,
wherein R 109 and R 110 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, and -alkylene-aryl; or R 109 and R 110 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;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of
a) —H;
b) —NH 2 ;
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) -L 3 -G 2 -G 3 ; and
o) -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 ;
wherein at least one of R 1 , R 2 , R 3 , and R 4 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)—, —SO 2 —, —SO 2 —NH—, —NH—SO 2 —, and —C(O)—;
Q 8 and Q 18 are independently selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;
L 3 , L 8 , L 9 , L 18 , and L 19 are independently selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 26 )SO 2 N(R 27 )—, —C(O)—N(R 26 )—C(═NH)—N(R 27 )—, and —C(O)—N(R 26 )—N(R 27 )—
wherein R 26 and R 27 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, -alkylene-aryl, or R 26 and R 27 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;
G 2 is selected from the group consisting of:
direct bond, alkylene, alkenylene, alkynylene, and
wherein
L 10 is selected from the group consisting of alkyline, cycloalkyline, heteroaryline, aryline, and heterocyclyline;
L 12 is selected from the group consisting of —O—, —C(O)—N(R 11 )—, —C(O)—O—, —C(O)—, and —N(R 11 )—CO—N(R 12 )—, wherein R 11 and R 12 independently comprise hydrogen, aryl, alkyl, and alkylene-aryl;
L 11 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-NH 2 , -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR 13 , -alkylene-C(O)—NR 13 R 14 , -alkylene-NR 13 R 14 , -alkylene-N(R 13 )—C(O)—R 14 , -alkylene-N(R 13 )—S(O) 2 —R 14 , and the side chain of a natural or non-natural amino acid, wherein
R 13 and R 14 independently comprise hydrogen, -aryl, -alkyl, and -alkylene-aryl; or
R 13 and R 14 may be taken together to form a ring having the formula —(CH 2 ) q —Y—(CH 2 ) r — bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein q and r are, independently, 1, 2, 3, or 4; Y is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —(O)CO—, —NHSO 2 NH—, —OC(O)—, —N(R 15 )—, —N(C(O)R 15 )—, —N(C(O)NHR 15 )—, —N(SO 2 NHR 15 )—, —N(SO 2 R 15 )—, and —N(C(O)OR 15 )—, wherein R 15 is selected from the group consisting of hydrogen, -alkyl, -aryl, and -alkylene-aryl; or
R 13 and R 14 may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring; and
G 3 and G 18 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 G 3 and G 18 may be optionally substituted 1 to 7 times, wherein the substituents are independently selected from group consisting of:
a) -halo;
b) —NH 2 ;
c) -carboxy;
d) -cyano;
e) -nitro;
f) —OH;
g) -haloalkyl;
h) -perhaloalkyl;
i) —R 16 ;
j) -L 4 -R 16 ;
k) -L 4 -Q 4 -R 16 ; and
l) -Q 4 -L 4 -R 16 ;
wherein
R 16 is selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and -alkylene-aryl;
Q 4 is selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
L 4 is selected from the group consisting of direct bond, —CH 2 —, —O—, —N(R 18 )—, —C(O)—, —CON(R 18 )—, —N(R 18 )C(O)—, —N(R 18 )CON(R 19 )—, —N(R 18 )C(O)O—, —OC(O)N(R 18 )—, —N(R 18 )SO 2 —, —SO 2 N(R 18 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 18 )SO 2 N(R 19 )—;
wherein
R 18 and R 19 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, and -alkylene-aryl;
G 8 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 G 8 may be optionally substituted 1 to 7 times, wherein the substituents are independently selected from group consisting of:
a) -halo;
b) —NH 2 ;
c) -carboxy;
d) -cyano;
e) -nitro;
f) —OH;
g) -haloalkyl;
h) -perhaloalkyl;
i) —R 116 ;
j) -L 114 -R 116 ;
k) -L 114 -Q 114 -R 116 ; and
l) -Q 114 -L 114 -R 116 ;
wherein
R 116 is selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and -alkylene-aryl;
Q 114 is selected from the group consisting of direct bond, alkylene, alkenylene, and alkynylene;
L 114 is selected from the group consisting of direct bond, —CH 2 —, —O—, —N(R 118 )—, —C(O)—, —CON(R 118 )—, —N(R 118 )C(O)—, —N(R 118 )CON(R 119 )—, —N(R 118 )C(O)O—, —OC(O)N(R 118 )—, —N(R 118 )SO 2 —, —SO 2 N(R 118 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 118 )SO 2 N(R 119 )—;
wherein
R 118 and R 119 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 R 1 to R 119 , L 1 to L 114 , G 1 to G 18 , and Q 1 to Q 114 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, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, and —O—CO—,
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
2 . The compound of Formula (I) in claim 1 , wherein A is —N(R 5 )—.
3 . The compound of Formula (I) in claim 1 , wherein A is —N(R 5 )—, and Q 1 , G 1 , L 6 , Q 6 , L 7 , and G 6 are taken together to form a group selected from the group consisting of: isoquinoline-3-yl, and (phenylethynyl)-pyridine-2-yl.
4 . The compound of Formula (I) in claim 1 , wherein A is —N(R 5 )—, and R 1 or R 4 is the group imidazole-2-ylcarbamoyl.
5 . The compound of Formula (I) in claim 1 , wherein A is —N(R 5 )—, and R 1 or R 4 is the group imidazole-2-ylcarbamoyl and R 2 and R 3 are hydrogen.
6 . The compound of Formula (I) in claim 1 , wherein
L 1 is —NH—C(O)—, —NH—, —C(O)—NH—, —NH—C(O)—NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, indole, isoquinoline, pyridine, pyrimidine, benzofuran, benzothiophene, benzimidazole, furan, imidazole, 1-oxo-1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, cinnoline, quinoxaline, [1,8]-naphthyridine, 2,3-dihydro-[1,4]-dioxino-[2,3-g]-isoquinoline, 1,3-dioxolo-[4,5-g]-isoquinoline, 1,3,4,9-tetrahydro-beta-carboline, thieno-[2,3-c]-pyridine, imidazole-[1,2-a]-pyridine, imidazole-[2,1-b]-thiazole, wherein G 1 is substutited or unsubstituted.
7 . The compound of Formula (I) in claim 1 , wherein
L 1 is —NH—C(O)—, —NH—, —C(O)—NH—, —NH—C(O)—NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, indole, isoquinoline, pyridine, pyrimidine, benzofuran, benzothiophene, benzimidazole, furan, imidazole, 1-oxo-1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, cinnoline, quinoxaline, [1,8]-naphthyridine, 2,3-dihydro-[1,4]-dioxino-[2,3-g]-isoquinoline, 1,3-dioxolo-[4,5-g]-isoquinoline, 1,3,4,9-tetrahydro-beta-carboline, thieno-[2,3-c]-pyridine, imidazole-[1,2-a]-pyridine, imidazole-[2,1-b]-thiazole, wherein G 1 is substutited or unsubstituted;
L 6 , Q 6 , L 7 are direct bonds, and
G 6 is hydrogen.
8 . The compound of Formula (I) in claim 1 , wherein
L 1 is —NH—C(O)—, —NH—, —C(O)—NH—, —NH—C(O)—NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, indole-2-yl, indole-3-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-5-yl, isoquinoline-6-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, benzimidazole-2-yl, 1-oxo-1,2-dihydroisoquinoline-3-yl, 1,2,3,4-tetrahydroisoquinoline-1-yl, 1,2,3,4-tetrahydroisoquinoline-3-yl, 1,2,3,4-tetrahydroisoquinoline-5-yl, 1,2,3,4-tetrahydroisoquinoline-6-yl, cinnoline-3-yl, quinoxaline-2-yl, [1,8]-naphthyridine-2-yl, 2,3-dihydro[1,4]dioxino[2,3-g]-isoquinoline-8-yl, 1,3-dioxolo[4,5-g]-isoquinoline-7-yl, 1,3,4,9-tetrahydro-beta-carboline-3-yl, thieno-[2,3-c]-pyridine-5-yl, thieno-[2,3-c]-pyridine-6-yl, imidazole-[1,2-a]-pyridine-2-yl, imidazole-[1,2-a]-pyridine-3-yl, or imidazole-[2,1-b]-thiazole-6-yl, wherein G 1 is substituted or unsubstituted;
L 6 , Q 6 , L 7 are direct bonds; and
G 6 is hydrogen.
9 . The compound of Formula (I) in claim 1 , wherein
L 1 is —NH—C(O)—, —NH—, —C(O)—NH—, —NH—C(O)—NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-5-yl, isoquinoline-6-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, or pyrimidine-4-yl, wherein G 1 is substituted or unsubstituted;
L 6 , Q 6 , L 7 are direct bonds; and
G 6 is hydrogen.
10 . The compound of Formula (I) in claim 1 , wherein
L 1 is —NH—C(O)—, —NH—, —C(O)—NH—, —NH—C(O)—NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl, wherein G 1 is substituted or unsubstituted;
L 6 is a direct bond, —CH 2 —, or —O—;
Q 6 is a direct bond, lower alkylene, or —C≡C—;
L 7 is a direct bond, —CH 2 —, or —O—; and
G 6 is phenyl, furan, pyridine, thiophene, cyclopropyl, cyclopentyl, cyclohexyl, imidazole, pyrazole, or isoxazole, wherein G 6 is substituted or unsubstituted.
11 . The compound of Formula (I) in claim 1 , wherein
L 1 is —N(H)—C(O)—, and
Q 1 , G 1 , L 6 , Q 6 , L 7 , and G 6 are taken together to form a group selected from the group consisting of: [1,3]Dioxolo[4,5-g]isoquinoline-7-yl, 1,2,3,4-tetrahydro-isoquinoline-6-yl, 1,2,3,4-tetrahydro-isoquinoline-3-yl, 1-(2-alkylsulfanyl-ethyl)-isoquinoline-3-yl, 1-(2-alkylsulfonyl-ethyl)-isoquinoline-3-yl, 1-(tetrahydro-pyran-4-yl)-isoquinoline-3-yl, 1-alkyl-6-haloalkoxy-isoquinoline-3-yl, 1-alkyl-7-haloalkoxy-isoquinoline-3-yl, 1-alkyl-isoquinoline-3-yl, 1-cycloalkylmethyl-7-alkoxy-isoquinoline-3-yl, 2,3-dihydro-[1,4]dioxino[2,3-g]isoquinoline-8-yl, 4-alkoxy-quinoline-2-yl, 5,8-dialkoxy-isoquinoline-3-yl, 6,7-Bis-(alkoxy-ethoxy)-isoquinoline-3-yl, 6,7-alkoxy-isoquinoline-1-yl, 7-alkoxy-1-alkyl-isoquinoline-3-yl, 7-alkoxy-isoquinoline-1-yl, 7-alkylsulfonyl-1-alkyl-isoquinoline-3-yl, 7-halo-8-alkoxy-isoquinoline-3-yl, 7-hydroxy-1-alkyl-isoquinoline-3-yl, 7-methanesulfonylamino-isoquinoline-3-yl, alkoxy-isoquinoline-3-yl, alkyl-isoquinoline-3-yl, benzyloxy-isoquinoline-3-yl, cycloalkoxy-isoquinoline-3-yl, isoquinoline-3-yl, 1-oxo-1,2-dihydro-isoquinoline-3-yl, isoquinoline-5-yl, and nitro-isoquinoline-3-yl.
12 . The compound of Formula (I) in claim 1 , wherein
L 1 is —N(H)—C(O)—, and
Q 1 , G 1 , L 6 , Q 6 , L 7 , and G 6 are taken together to form a group selected from the group consisting of: 2-(alkoxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-6-yl, 2-(alkoxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-3-yl, 2-(alkoxycarbonyl)-6,7-dialkoxy-1,2,3,4-tetrahydroisoquinoline-1-yl, 2-alkyl-1,2,3,4-tetrahydro-isoquinoline-3-yl, 2-alkylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-6-yl, 2-alkylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-yl, 2-benzenesulfonyl-1,2,3,4-tetrahydro-isoquinoline-6-yl, and 2-benzyl-1,2,3,4-tetrahydro-isoquinoline-6-yl.
13 . The compound of Formula (I) in claim 1 , wherein
L 1 is —N(H)—C(O)—, and
Q 1 , G 1 , L 6 , Q 6 , L 7 , and G 6 are taken together to form a group selected from the group consisting of: ((alkyloxyphenyl)-ethynyl)-pyridine-2-yl, ((alkylphenyl)-ethynyl)-pyridine-2-yl, ((halophenyl)-ethynyl)-pyridine-2-yl, ((thiophen-3-yl)-ethynyl)-pyridine-2-yl, (1-phenyl-ethoxy)-pyridine-3-yl, (3-cycloalkyl-prop-1-ynyl)-pyridine-2-yl, (3-hydroxy-3-methyl-but-1-ynyl)-pyridine-2-yl, (alkoxy)-pyridine-3-yl, (alkoxy-phenyl)-pyridine-3-yl, (alkoxy-phenylethynyl)-pyridine-2-yl, (alkyl-phenylethynyl)-pyridine-2-yl, (alkylsulfonyl-phenyl)-pyridine-2-yl, (alkylsulfonyl-phenylethynyl)-pyridine-2-yl, (alkynyl)-pyridine-2-yl, (alkynyl)-pyridine-3-yl, (aminomethyl-phenyl)-pyridine-2-yl, (benzyloxy)-pyridine-2-yl, (benzyloxy)-pyridine-3-yl, (carbamoyl-phenyl)-pyridine-2-yl, (cyanomethyl-phenyl)-pyridine-2-yl, (cyano-phenyl)-pyridine-2-yl, (cyano-phenyl)-pyridine-3-yl, (cyano-phenyl)-pyridine-4-yl, (cycloalkoxy)-pyridine-3-yl, (cycloalkyl-alkoxy)-pyridine-2-yl, (cycloalkyl-alkoxy)-pyridine-3-yl, (cycloalkylethynyl)-pyridine-2-yl, (cycloalkylethynyl)-pyridine-3-yl, (dialkylamino-phenylethynyl)-pyridine-2-yl, (dihalo-phenyl)-pyridine-3-yl, (haloalkoxy-phenyl)-pyridine-2-yl, (haloalkoxy-phenyl)-pyridine-3-yl, (haloalkyl-phenyl)-pyridine-2-yl, (halo-phenyl)-pyridine-2-yl, (halo-phenyl)-pyridine-3-yl, (halo-phenylethynyl)-pyridine-2-yl, (phenylalkoxy)-pyridine-2-yl, (phenyl-alkyl)-pyridine-3-yl, (phenylethynyl)-pyridine-2-yl, (phenylethynyl)-pyridine-3-yl, (phenylethynyl)-pyridine-4-yl, (pyridin-3-ylethynyl)-pyridine-2-yl, (thiophen-2-yl)-pyridine-2-yl, [2,3′]bipyridinyl-6-yl, [2,4′]bipyridinyl-6-yl, 2-(cyano-phenyl)-pyridine-4-yl, 2-(halo-phenoxy)-pyridine-3-yl, 2-(phenoxy)-pyridine-3-yl, phenethyl-pyridine-2-yl, 3-halo-6-(alk-1-ynyl)-pyridine-2-yl, 5-(phenoxy)-pyridine-3-yl, 6-(3-cyano-phenyl)-pyridine-2-yl, cyano-pyridine-2-yl, cyano-pyridine-3-yl, cyano-pyridine-4-yl, ethynyl-pyridine-2-yl, ethynyl-pyridine-3-yl, ethynyl-pyridine-4-yl, halo-pyridine-2-yl, halo-pyridine-3-yl, phenyl-pyridine-2-yl, phenyl-pyridine-3-yl, and phenyl-pyridine-4-yl.
14 . The compound of Formula (I) in claim 1 , wherein
L 1 is —N(H)—C(O)—, and
Q 1 , G 1 , L 6 , Q 6 , L 7 , and G 6 are taken together to form a group selected from the group consisting of: cinnoline-3-yl, quinoxaline-2-yl, [1,8]Naphthyridine-2-yl, cyano-phenyl, (cyano-phenyl)-phenyl, (pyridin-3-yl)-phenyl, (pyridin-4-yl)-phenyl, (haloalkyl-pyridin-2-yl)-phenyl, (haloalkyl-phenoxy)-phenyl, 2-(alkoxycarbonyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-yl, 1-phenyl-2-(alkoxycarbonyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-yl, 2,3,4,9-tetrahydro-1H-beta-carboline-3-yl, 6-(phenyl)-pyrimidine-4-yl, 6-(halophenyl)-pyrimidine-4-yl, 2,6-dialkoxy-pyrimidine-4-yl, thieno[2,3-c]pyridine-5-yl, thieno[3,2-c]pyridine-6-yl, 2-alkyl-imidazo[1,2-a]pyridine-3-yl, imidazo[1,2-a]pyridine-2-yl, 5-alkyl-imidazo[1,2-a]pyridine-2-yl, imidazo[2,1-b]thiazole-6-yl, and 8-alkyl-imidazo[1,2-a]pyridine-2-yl.
15 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 ,
wherein
L 8 is a direct bond, —CH 2 —, —C(O)—O—, —C(O)—N(R 26 )—, or —N(R 26 )—C(O)—,
Q 8 is a direct bond or alkylene,
L 9 is a direct bond,
G 8 is imidazole, 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine, imidazolepyridine, piperidine, 1,2,3,4-tetrahydroisoquinoline, phenyl, cycloalkyl, purine, isoquinoline, benzimidazole, oxazole, pyrrazole, pyrimidine, 4,5,6,7-tetrahydro-1H-benzimidazole, or furan, wherein G 8 is substituted or unsubstituted,
L 18 is a direct bond, —SO 2 —, —O—, or —C(O)—,
Q 18 is a direct bond or alkylene,
L 19 is a direct bond, and
G 18 is hydrogen, phenyl, quinoline, isoquinoline, cycloalkyl, pyridine, furan, alkyl, pyrrole, thiazole, imidazole, thiophene, or pyrrolidine, wherein G 18 is substituted or unsubstituted.
16 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 ,
wherein L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: piperidin-4-yl, and 1-(alkoxycarbonyl)-piperidin-4-yl.
17 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 , wherein L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: 1H-pyrazol-3-yl, imidazol-2-yl, imidazol-1-yl, 4,5-dialkyl-imidazol-2-yl, 4-phenyl-1H-imidazol-2-yl, 4-(halo-phenyl)-1H-imidazol-2-yl, 5-adamantan-1-yl-1H-imidazol-2-yl, 5-alkyl-1H-imidazol-2-yl, 5-benzyl-1H-imidazol-2-yl, 4-alkyl-oxazol-2-yl, and furan-2-ylmethyl.
18 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 , wherein L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: cycloalkyl, alkyl, 2-alkylsulfanyl-ethyl, (alkoxy-phenyl)-ethyl, (alkoxy-phenyl)-methyl, 2-(alkoxyphenyl)-ethyl, 2-(phenoxy-phenyl)-ethyl, 1-(alkylsulfonyl-phenyl)-ethyl, benzyl, cyano-benzyl, alkoxy-benzyl, alkyl-benzyl, alkylsulfonyl-benzyl, dihalo-benzyl, haloalkyl-benzyl, haloalkyl-halo-benzyl, haloalkoxy-benzyl, halo-benzyl, sulfamoyl-benzyl, alkoxyphenyl, halo-phenyl, and alkylsulfonyl-phenyl.
19 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 , wherein L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: benzimidazole-2-yl, benzimidazole-5-yl, benzimidazole-6-yl, isoquinoline-3-yl, isoquinoline-6-yl, 4,5,6,7-tetrahydro-benzimidazole-2-yl, 4,5,6,7-tetrahydro-benzothiazole-2-yl, 5,5-dialkyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl, 6-(alkyl)-4,5,6,7-tetrahydro-benzothiazol-2-yl, 1,2,3,4-tetrahydro-isoquinolin-6-yl, 2-(alkoxycarbonyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl, 7H-purin-8-yl, and 2-amino-pyrimidin-4-yl.
20 . The compound of Formula (I) in claim 1 , wherein
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 , wherein Q 8 , L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: (piperidin-3R-yl)methyl, (piperidin-3S-yl)methyl, (piperidin-4-yl)-methyl, (1-(alkoxycarbonyl)-piperidin-3-yl)-methyl, (1-(cycloalkylmethyl)-piperidin-3-yl)methyl, (1-(cycloalkylmethyl)-piperidin-4-yl)methyl, (piperidin-4-yl)-methyl, (1-(alkoxycarbonyl)-piperidin-4-yl)-methyl, [1-(alkoxycarbonyl)-piperidin-3R-yl]methyl, [1(alkoxycarbonyl)-piperidin-3S-yl]methyl, [1-(cycloalkylmethyl)-piperidin-3S-yl]methyl, [1-(cycloalkylmethyl)-piperidin-3R-yl]methyl, 1-(1-alkyl-1H-imidazol-2-ylmethyl)-piperidin-3-ylmethyl, 1-(1-alkyl-1H-imidazol-4-ylmethyl)-piperidin-3-ylmethyl, 1-(1H-imidazol-2-ylmethyl)-piperidin-3-ylmethyl, 1-(cycloalkylmethyl)-piperidin-3R-yl]methyl, 1-[1-(alkoxycarbonyl)-pyrrolidine-2R-ylmethyl]-piperidin-3-ylmethyl, 1-[1-(alkoxycarbonyl)-pyrrolidine-2S-ylmethyl]-piperidin-3-ylmethyl, 2-(piperidin-3-yl)-ethyl, 2-(piperidin-4-yl)-ethyl, 2-[1-(alkoxycarbonyl)-piperidin-3-yl]-ethyl, and 2-[1-(alkoxycarbonyl)-piperidin-4-yl]-ethyl.
21 . The compound of Formula (I) in claim 1 ,
A is —N(R 5 )—, and
R 1 or R 4 is -L 8 -Q 8 -L 9 -G 8 -L 18 -Q 18 -L 19 -G 18 , wherein Q 8 , L 9 , G 8 , L 18 , Q 18 , L 19 , and G 18 are taken together to form a group selected from the group consisting of: 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 3H-imidazo[4,5-c]pyridin-2-yl, 3H-imidazo[4,5-c]pyridin-2-yl, [5-(2,4-dialkoxy-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, (5-alkyl-3H-imidazol-4-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-[1-(alkoxycarbonyl)-pyrrolidin-2S-ylmethyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-[1-(alkoxycarbonyl)-pyrrolidin-2R-ylmethyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(1-alkyl-1H-imidazol-2-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(1-alkyl-1H-pyrrol-2-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(3-alkylsulfanyl-propyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(3-alkylsulfinyl-propyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(3-alkylsulfonyl-propyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(3H-imidazol-4-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(alkoxy-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(alkylsulfonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(alkoxycarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(cycloalkylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(halo-benzyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(imidazol-2-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-(quinolin-3-ylmethyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-alkyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-alkylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-alkylsulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-benzoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-cycloalkylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-furan-3-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-phenethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-pyridin-3-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-pyrrolidin-2S-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-thiazol-2-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, 5-thiophen-2-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl, and 5-thiophen-3-ylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl.
22 . The compound of claim 1 having the Formula (Ia)
wherein
L 1 is selected from the group consisting of:
a direct bond, —CH 2 —, —O—, —N(R 6 )—, —C(O)—, —CON(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )CON(R 7 )—, —N(R 6 )C(O)O—, —OC(O)N(R 6 )—, —N(R 6 )SO 2 —, —SO 2 N(R 6 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 6 )SO 2 N(R 7 )—,
wherein R 6 and R 7 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl;
Q 1 is selected from the group consisting of direct bond and alkylene;
G 1 is selected from the group consisting of:
aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group, wherein G 1 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) —R 8 ;
f) -L 2 -R 8 ;
g) -L 2 -Q 2 -R 8 ; and
h) -Q 2 -L 2 -R 8 ;
wherein
R 8 is selected from the group consisting of hydrogen, -alkyl, -aryl, and alkylene-aryl;
Q 2 is selected from the group consisting of a alkylene, alkenylene, and alkynylene;
L 2 is selected from the group consisting of a —CH 2 —, —O—, —N(R 9 )—, —C(O)—, —CON(R 9 )—, —N(R 9 )C(O)—, —N(R 9 )CON(R 19 )—, —N(R 9 )C(O)O—, —OC(O)N(R 9 )—, —N(R 9 )SO 2 —, —SO 2 N(R 9 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 9 )SO 2 N(R 10 )—,
wherein R 9 and R 10 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of
a) —H;
b) -alkyl;
c) -aryl;
d) -alkylene-aryl;
e) —K-alkyl;
f) —K-aryl;
g) —K-alkylene-aryl; and
h) -L 3 -G 2 -G 3 ;
wherein
K is selected from the group consisting of: —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —SO 2 —, —SO 2 —NH—, —NH—SO 2 —, and —C(O)—;
L 3 is selected from the group consisting of: a direct bond, —CH 2 —, —O—, —N(R 26 )—, —C(O)—, —CON(R 26 )—, —N(R 26 )C(O)—, —N(R 26 )CON(R 27 )—, —N(R 26 )C(O)O—, —OC(O)N(R 26 )—, —N(R 26 )SO 2 —, —SO 2 N(R 26 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 26 )SO 2 N(R 27 )— wherein R 26 and R 27 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl;
G 2 is selected from the group consisting of:
a direct bond, and
wherein
L 10 is selected from the group consisting of alkyline, cycloalkyline, heteroaryline, aryline, and heterocyclyline;
L 12 is selected from the group consisting of —O—, —C(O)—N(R 11 )—, —C(O)—O—, —C(O)—, and —N(R 11 )—CO—N(R 12 )—, wherein R 11 and R 12 independently comprise hydrogen, aryl, alkyl, and alkylene-aryl;
L 11 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-NH 2 , -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR 13 , -alkylene-C(O)—NR 13 R 14 , -alkylene-NR 13 R 14 , -alkylene-N(R 13 )—C(O)—R 14 , -alkylene-N(R 13 )—S(O) 2 —R 14 , and the side chain of a natural or non-natural amino acid, wherein
R 13 and R 14 independently comprise hydrogen, aryl, alkyl, and alkylene-aryl; or
R 13 and R 14 may be taken together to form a ring having the formula —(CH 2 ) q —Y—(CH 2 ) r — bonded to the nitrogen atom to which R 13 and R 14 are attached, wherein q and r are, independently, 1, 2, 3, or 4; Y is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —(O)CO—, —NHSO 2 NH—, —OC(O)—, —N(R 15 )—, —N(C(O)R 15 )—, —N(C(O)NHR 15 )—, —N(SO 2 NHR 15 )—, —N(SO 2 R 15 )—, and —N(C(O)OR 15 )—, wherein R 15 is selected from the group consisting of hydrogen, alkyl, aryl, and -alkylene-aryl; or
R 13 and R 14 may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring; and
G 3 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl group, wherein G 3 is optionally substituted 1 to 7 times, wherein the substituents are independently selected from group consisting of:
a) -halo;
b) -cyano;
c) -nitro;
d) -perhaloalkyl;
e) —R 16 ;
f) -L 4 -R 16 ;
g) -L 4 -Q 4 -R 16 ; and
h) -Q 4 -L 4 -R 16 ;
wherein
R 16 is selected from the group consisting of hydrogen, -alkyl, -aryl, and -alkylene-aryl;
Q 4 is selected from the group consisting of alkylene, -alkenylene, and -alkynylene;
L 4 is selected from the group consisting of —CH 2 —, —O—, —N(R 18 )—, —C(O)—, —CON(R 18 )—, —N(R 18 )C(O)—, —N(R 18 )CON(R 19 )—, —N(R 18 )C(O)O—, —OC(O)N(R 18 )—, —N(R 18 )SO 2 —, —SO 2 N(R 18 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 18 )SO 2 N(R 19 )—;
wherein
R 18 and R 19 are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, and -alkylene-aryl; and
wherein at least one of R 1 -R 4 is the group -L 3 -G 2 -G 3 ; and
R 5 is selected from the group consisting of:
a) -hydrogen; and
b) -alkyl; and
wherein the aryl and/or alkyl group(s) in R 1 to R 26 , L 1 to L 12 , G 1 to G 3 may be optionally substituted 1-4 times with a substituent selected from the group consisting of:
a) —H;
b) -halo;
c) -hydroxyl;
d) -cyano;
e) -carbamoyl;
f) -carboxyl;
g) -Z-alkyl;
h) -Z-aryl;
i) -Z-alkylene-aryl;
wherein Z is selected from the group consisting of —CH 2 —, —O—, —N(H), —S—, SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, and —O—CO—,
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
23 . The compound of Formula (Ia) in claim 22 ,
wherein
L 1 is —NH—C(O)—, —NH—, or a direct bond;
Q 1 is a direct bond;
G 1 is phenyl, biphenyl, naphthyl, indole, isoquinoyl, pyridine, or pyrimidine; and
wherein
at least one of R 1 -R 4 is the group -L 3 -G 2 -G 3 , wherein
L 3 is selected from the group consisting of
a) —CO 2 —;
b) —C(O)NH—; and
c) —NH—
G 2 is a direct bond, or alkylene; and
G 3 is selected from the group consisting alkyl, phenyl, naphthyl, biphenyl, alkylene-phenyl, pyrole, thiophene, indole, imidazole, tetrazole, thiazole, 1,3,4-thiadiazole, pyrimidine, pyridine, benzimidazole, and benzthiazole, wherein G 3 is optionally substituted 1 to 7 times with a group selected from the group consisting of:
a) -halo;
b) -cyano;
c) -nitro;
d) -perhaloalkyl;
e) —R 16 ;
f) -L 4 -R 16 ;
g) -L 4 -Q 4 -R 16 ; and
h) -Q 2 -L 4 -R 16 ;
wherein
R 16 is selected from the group consisting of hydrogen, -alkyl, -aryl, and -alkylene-aryl;
Q 4 is selected from the group consisting of alkylene, alkenylene, and alkynylene;
L 4 is selected from the group consisting of —CH 2 —, —O—, —N(R 18 )—, —C(O)—, —CON(R 18 )—, —N(R 18 )C(O)—, —N(R 18 )CON(R 19 )—, —N(R 18 )C(O)O—, —OC(O)N(R 19 )—, —N(R 18 )SO 2 —, —SO 2 N(R 18 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 18 )SO 2 N(R 19 )—;
wherein
R 18 and R 19 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl.
24 . The compound of Formula (Ia) in claim 22 , wherein
L 1 is a direct bond, —NH—C(O)—, or —NH—;
Q 1 is a direct bond;
G 1 is phenyl, biphenyl, isoquinoyl, pyridine, or pyrimidine; and
at least one of R 1 -R 4 is the group -L 3 -G 2 -G 3 , wherein
L 3 is —C(O)—NH—;
G 2 is
wherein
L 10 is defined as above,
L 11 is defined as above, and
L 12 is —C(O)—NH—; and
G 3 is selected from the group consisting alkyl, phenyl, naphthyl, biphenyl, alkylene-phenyl, pyrole, imidazole, tetrazole, thiazole, 1,3,4-thiadiazole, pyrimidine, pyridine, benzimidazole, and benzthiazole, wherein G 3 is optionally substituted 1 to 7 times with a group selected from the group consisting of
a) -halo;
b) -cyano;
c) -nitro;
d) -perhaloalkyl;
e) —R 16 ;
f) -L 4 -R 16 ;
g) -L 4 -Q 4 -R 16 ; and
h) -Q 2 -L 4 -R 16 ;
wherein
R 16 is selected from the group consisting of hydrogen, -alkyl, -aryl, and -alkylene-aryl;
Q 4 is selected from the group consisting of alkylene, alkenylene, and alkynylene;
L 4 is selected from the group consisting of —CH 2 —, —O—, —N(R 18 )—, —C(O)—, —CON(R 18 )—, —N(R 18 )C(O)—, —N(R 18 )CON(R 19 )—, —N(R 18 )C(O)O—, —OC(O)N(R 18 )—, —N(R 18 )SO 2 —, —SO 2 N(R 18 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, and —N(R 18 )SO 2 N(R 19 )—;
wherein
R 18 and R 19 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl.
25 . The compound of Formula (Ia) in claim 23 , wherein G 3 is imidazole or benzimidazole.
26 . The compound of Formula (Ia) in claim 24 , wherein G 3 is imidazole or benzimidazole.
27 . The compound of Formula (Ia) in claim 23 , wherein G 1 is isoquinoline.
28 . The compound of Formula (Ia) in claim 24 , wherein G 1 is isoquinoline.
29 . The compound of Formula (Ia) in claim 22 , having the formula
wherein
G 1 is unsubstituted 2-isoquinolin-3yl or pyridin-2yl; and
G 2 and G 3 together form a group selected from phenyl, isobutyl, n-butyl, 1H-imidazol-2-yl, [1,3,4]-thiadiazol-2yl, thiazol-2yl, 1H-imidazol-2-yl, benzothiazol-2-yl, pyridin-2-yl, pyridin-3-yl, and 4-phenyl-1H-imidazol-2-yl.
30 . The compound of Formula (Ia) in claim 22 , having the formula
wherein
L 11 is 2,2 dimethyl propyl, 2-chloro-benzyl, 2-fluorobenzy, 2-phenyl-ethyl, 3,4,5-trifluoro benzyl, 3,5-difluoro-benzyl, 3-chloro benzyl, 3-fluoro benzyl, 3-fluoro-phenyl, 3-methoxy phenyl, 3-trifluoromethyl benzyl, 4-chloro benzyl, 4-fluoro benzyl, 4-methoxy phenyl, 4-methyl benzyl, 4-phenyl-benzyl, Benzyl, Butyl-2yl, Isobutyl, Isopropyl, cyclopropyl, or phenyl,
n is 0 or 1 and
G 3 is 1H-benzimidazol-2-yl, 1H-imidazol-2-yl, pyridin-2yl, or thiazol-2yl.
31 . The compound of Formula (Ia) in claim 22 , having the formula
wherein
L 11 is benzyl or 3,5-difluorobenzyl, and
G 3 is methyl, isobutyl, 1H-imidazol-2yl, thiazol-2yl, benzthiazol-2yl, 1H-Benzimidazol-2-yl, 2-methyl-piperidine-1-carboxylic acid tert-butyl ester, or 3-methyl-piperidine-1-carboxylic acid tert-butyl ester.
32 . The compound of Formula (Ia) of claim 22 , having the formula
wherein
G 1 is unsubstituted 2-isoquinolin-3-yl, 5-bromopyridin-2-yl, phenyl, or pyridin-2-yl;
G 2 and G 3 are taken together to form a group selected from the group consisting of (benzthiazol-2yl)methyl, 1H-imidazol-2-yl, 2,4-dichlorobenzyl, 2,5-dichlorophenyl, 3-hydroxypropyl, 3-tert-butylphenyl, 4′-biphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methyl-benzyl, 4-phenoxyphenyl, 4-phenylthiazol-2yl, 4-phenyl-thiazol-2-yl, 4-tert-butyl-benzyl, benz1H-imidazol-2-yl, benzothiazol-6-yl, benzothiazol-2yl, benzyl, methyl, phenyl, pyridin-2-yl, and thiazol-2-yl.
33 . The compound of Formula (Ia) of claim 221 , having the formula
G 1 is 1,5-dimethyl-indole-2yl, 1-benzyl-indole-2-yl, 1H-imidazol-2-yl, 1H-Indazoline-3yl, 1H-indole-2yl, 1-methyl-Indazoline-3yl, 1-methyl-indole-2-yl, 1-n-propyl-indole-2yl, 2,4-difluorophenyl, 2-Chloro-phenyl, 2-fluoro-phenyl, 2-isoquinolin-3-yl, 3,4-dimethoxyphenyl, 3-Chloro-phenyl, 3-fluoro-phenyl, 3-methoxy-4-fluoro-phenyl, 4′-biphenyl, 4-fluorobenzyl, 4-fluorophenyl, 4-isopropyl-phenyl, 4-methoxy-phenyl, 4-nitro-phenyl, 4-phenyoxyphenyl, 4-tert-butyl-phenyl, 4-trifluoromethylphenyl, 5-Chloro-benzofuran-2-yl, 5-methyl-indole-2-yl, 5-phenoxy-pyridin-2-yl, 6,7-dimethoxy-2-isoquinolin-3-yl, benzofuran-2-yl, benzothiophene-2-yl, furan-3yl, naphthalin-2-yl, phenyl, quinolin-2yl, or quinolin-3yl; and
G 2 and G 3 are taken together to form a group selected from the group consisting of (1-methylbenzimidazole-2-yl)methyl, (1R)-phenyl ethyl, (1S)-phenyl ethyl, (5-methylfuran-2-yl)-methyl, (benzothiophene-2-yl)methyl, (benzthiazol-2-yl)methyl, (thiophene-2-yl)ethyl, (thiophene-2-yl)methyl, {1,3,4}-thiadiazol-2-yl, 1H-benziimidazol-2-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-2-yl, 1H-benzimidazole-2-yl methyl, 1H-imidazol-2-yl, 1H-indazole-5-yl, 2-(1H-benzimidazole-2-yl)-ethyl, 2,3,4,9-tetrahydro-1H-beta-carboline-2-yl, 2-phenyoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 4-phenyl-1H-imidazol-2-yl, benzthiazol-2yl, benzyl, ethyl, furan-2-yl methyl, phenethyl, phenyl, pyridin-2-yl, pyridin-3-yl, quinolin-3-yl, tert-butyl, thiazol-2-yl, and thiazole-2yl-methyl.
34 . The compound of Formula (Ia) of claim 22 , having the formula
wherein,
G 2 and G 3 are taken together to form a group selected from the group consisting of isopropyl, isobutyl, and phenyl.
35 . The compound of Formula (Ia) in claim 22 , having the formula
wherein R 1 , R 2 , R 3 , R 5 , G 1 , G 2 , and G 3 are as defined in claim 22 .
36 . The compound of Formula (Ia) in claim 22 , having the formula
wherein R 1 , R 2 , R 3 , R 5 , G 1 , G 2 , and G 3 are as defined in claim 22 .
37 . The compound of Formula (Ia) in claim 22 , having the formula
wherein R 1 , R 3 , R 5 , G 1 , G 2 , and G 3 are as defined in claim 22 .
38 . The compound of Formula (I) in claim 1 selected from the group consisting of:
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (4-phenyl-1H-imidazol-2-yl)-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid isobutyl-amide,
2-Pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid (1H-benzoimidazol-2-yl)-amide,
2-Naphthalen-2-yl-1H-benzoimidazole-5-carboxylic acid (1H-benzoimidazol-2-yl)-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid isobutyl-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid phenylamide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid butylamide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-(1H-imidazol-2-ylcarbamoyl)-cyclopentyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(2-fluoro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-phenyl-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(2-chloro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-(2-fluoro-phenyl)-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-biphenyl-4-yl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(3,5-difluoro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid {1R-[(1H-imidazol-2-ylcarbamoyl)-methyl]-3-phenyl-propyl}-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid {2-biphenyl-4-yl-1-[(1H-imidazol-2-ylcarbamoyl)-methyl]-ethyl}-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(3-fluoro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(1H-imidazol-2-ylcarbamoyl)-1S-(4-methoxy-phenyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(1H-imidazol-2-ylcarbamoyl)-1-phenyl-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(4-chloro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-p-tolyl-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-phenyl-1S-(thiazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-phenyl-1S-(pyridin-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-(3,4,5-trifluoro-phenyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(1H-imidazol-2-ylcarbamoyl)-1-(3-methoxy-phenyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-(3-trifluoromethyl-phenyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-3,3-dimethyl-butyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-benzoimidazol-2-ylcarbamoyl)-2-phenyl-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(4-fluoro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-biphenyl-4-yl-1-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-3-methyl-butyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(3-fluoro-phenyl)-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-methyl-butyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1S-(1H-imidazol-2-ylcarbamoyl)-2-methyl-propyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [2-(3-chloro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
3-(3,5-Difluoro-phenyl)-2S-[(2-isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-propionic acid methyl ester,
3-(3,5-Difluoro-phenyl)-2S-[(2-isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-propionic acid,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1S-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [1S-(1H-benzoimidazol-2-ylcarbamoyl)-2-phenyl-ethyl-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1S-methylcarbamoyl-ethyl]-amide,
2S-({2-[(2-Isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-3-phenyl-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [2-phenyl-1S-(thiazol-2-ylcarbamoyl)-ethyl]-amide,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (1S-isobutylcarbamoyl-2-phenyl-ethyl)-amide,
3-({2S-[(2-Isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-3-phenyl-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester,
2-Isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [1S-(benzothiazol-2-ylcarbamoyl)-2-phenyl-ethyl]-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-5-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (4-fluoro-phenyl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid phenylamide,
2-(Pyridin-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (4-chloro-phenyl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (4-methoxy-phenyl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid benzylamide,
2-(Pyridin-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (1H-benzoimidazol-2-yl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (3-hydroxy-propyl)-amide,
2-(Isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid methylamide,
Isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-(4-Chloro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid [7-(1H-benzoimidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [7-(benzothiazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [7-([1,3,4]thiadiazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(pyridin-3-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-[(1H-Indole-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-benzoimidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid [5-(1H-benzoimidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(1H-indazol-5-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(quinolin-3-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [5-(benzothiazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [5-(thiazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-Benzoylamino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid {4-[(furan-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid [4-(2-phenoxy-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(3-phenoxy-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(4-phenoxy-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(1S-phenyl-ethylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(1S-phenyl-ethylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-[(Benzo[b]thiophene-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(Naphthalene-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(Biphenyl-4-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(1H-Indole-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(3,5-Difluoro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Fluoro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid [4-(2-thiophen-2-yl-ethylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
soquinoline-3-carboxylic acid (7-phenylcarbamoyl-1H-benzoimidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid {4-[(5-methyl-furan-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid (7-benzylcarbamoyl-1H-benzoimidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid {4-[(thiophen-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid (7-phenethylcarbamoyl-1H-benzoimidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid (7-ethylcarbamoyl-1H-benzoimidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid (7-tert-butylcarbamoyl-1H-benzoimidazol-2-yl)-amide,
2-[(Benzofuran-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid [4-(1,3,4,9-tetrahydro-beta-carboline-2-carbonyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid {4-[(benzo[b]thiophen-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid {4-[(benzothiazol-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-carbamoyl]-1H-enzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid {4-[2-(1H-benzoimidazol-2-yl)-ethylcarbamoyl]-1H-benzoimidazol-2-yl}-amide,
2-[2-(4-Fluoro-phenyl)-acetylamino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Fluoro-3-methoxy-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(3,4-Dimethoxy-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid {4-[(thiazol-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
Isoquinoline-3-carboxylic acid {4-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-1H-benzoimidazol-2-yl}-amide,
2-(4-Trifluoromethyl-benzoylamino)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Phenoxy-benzoylamino)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Quinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Quinoline-2-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-[(Furan-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-tert-Butyl-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Nitro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Methoxy-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(1H-Imidazole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(4-Isopropyl-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(3-Fluoro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-(2-Fluoro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(5-Chloro-benzofuran-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
6,7-Dimethoxy-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
6,7-Dimethoxy-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-(2-Chloro-benzoylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
1H-Indazole-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-[(1-Methyl-1H-indole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
1-Methyl-1H-indazole-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(5-phenyl-1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
2-[(5-Methyl-1H-indole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(6-Phenoxy-pyridine-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(1-Benzyl-1H-indole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(1-Propyl-1H-indole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
2-[(1,5-Dimethyl-1H-indole-2-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide,
Isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-nitro-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-isobutyrylamino-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [6-benzoylamino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide,
Isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-(3-methyl-butyrylamino)-1H-benzoimidazol-2-yl]-amide, and
Isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-5-phenylacetylamino-1H-benzoimidazol-2-yl]-amide.
39 . A pharmaceutical composition comprising a compound of Formula (I) as in claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof.
40 . The pharmaceutical composition of claim 39 further comprising a pharmaceutical acceptable carrier, excipient, diluent, or mixture thereof.
41 . The pharmaceutical composition of claim 39 further comprising one or more therapeutic agents selected from the group consisting of:
anti-Alzheimer's agents, other betasecretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's) including ibuprofen, naproxen, diclofenac, N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics such as doxycycline and rifampin, agents that bind Aβ or that induce antibodies that bind Aβ, anti-Aβ antibodies, Aβ vaccines, RAGE/RAGE ligand interaction antagonists, and other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compound of Formula (I).
42 . The pharmaceutical composition of claim 39 wherein the compound of Formula (I) is present in a therapeutically effective amount.
43 . The pharmaceutical composition of claim 42 , wherein the therapeutically effective amount is an amount capable of inhibiting the interaction of BACE with its physiological ligands.
44 . The pharmaceutical composition of claim 42 , wherein said therapeutically effective amount of Formula (I) preferentially inhibits the interaction of BACE with its physiological ligands relative to the interaction of other secretases with their physiological ligands.
45 . A method comprising: administering to a subject a compound of Formula (I) in claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof.
46 . A method for inhibiting the interaction of BACE with its physiological ligands comprising: administering to a subject a compound Formula (I) of claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof.
47 . A method for increasing the α-secretory pathway in a subject comprising: administering to a subject a compound of Formula (I) in claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof.
48 . A method of treating or preventing a BACE mediated disease comprising: administering to a subject a therapeutically effective amount of a compound of Formula (I) in claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof.
49 . A method for treating a disorder or condition selected from Alzheimer's disease, mild cognitive impairment, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease or central or preipheral amyloid diseases comprising: administering to a subject an amount of a compound of Formula (I) in claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof, that is effective in treating said disorder or condition.
50 . A method for treating a disorder or condition, wherein the disorder or condition being treated is a dementia of the Alzheimer's type and is selected from the group consisting of dementia of the Alzheimer's type with early onset uncomplicated, dementia of the Alzheimer's type with early onset with delusions, dementia of the Alzheimer's type with early onset with depressed mood, dementia of the Alzheimer's type with late onset uncomplicated, dementia of the Alzheimer's type with late onset with delusions and dementia of the Alzheimer's type with late onset with depressed mood, comprising: administering to a subject an amount of a compound of Formula (I) of claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof, that is effective in treating said disorder or condition.
51 . A method for treating one or more conditions associated with plaque accumulation comprising: administering to a subject an effective amount of a compound of Formula (I) in claim 1 , or a pharmaceutically acceptable salt, ester, or prodrug thereof.
52 . The method of claim 51 , wherein administering the compound of Formula (I) reduces the rate of neurofibrillary tangle formation in the subject.
53 . The method of claim 51 , wherein administering the compound of Formula (I) reduces the rate of plaque accumulation in the subject.
54 . The method of claim 45 , wherein the compound of Formula (I) is administered in combination with a therapeutic agent selected from the group consisting of anti-Alzheimer's agents, other betasecretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's) including ibuprofen, naproxen, diclofenac, N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics such as doxycycline and rifampin, agents that bind Aβ or that induce antibodies that bind Aβ, anti-Aβ antibodies, Aβ vaccines, RAGE/RAGE ligand interaction antagonists, and other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
55 . The method of claim 45 , wherein the compound of Formula (I) is administered at a dosage level of from about 0.01 to 1000 mg/kg of the body weight of the subject being treated.
56 . The method of claim 45 , wherein the compound of Formula (I) is administered as a pharmaceutical composition.
57 . The method of claim 56 , wherein the pharmaceutical composition further comprises a pharmaceutical acceptable carrier, excipient, diluent, or mixture thereof.