Isoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2
View Patent ↗The present invention relates to a compound represented by formula I: and pharmaceutically acceptable salts thereof. The compounds of formula I are inhibitors of diacylglyceride O-acyltransferase 2 (“DGAT2”) and may be useful in the treatment, prevention and suppression of diseases mediated by DGAT2. The compounds of the present invention may be useful in the treatment of hepatic steatosis, diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cardio-renal diseases such as chronic kidney diseases and heart failure and related diseases and conditions.
1. A compound having structural Formula I:
or a pharmaceutically acceptable salt thereof wherein:
—X═Y— is —N═CH—, —CH═CH—, or —CH═N—;
M is
(1) bond,
(2) (C 1-2 )alkylene unsubstituted or substituted by 1-2 (C 1-3 )alkyl, halo, or phenyl,
(3) —NH—,
(4) (C 3-6 )cycloalkyl unsubstituted or substituted by 1-2 halo,
(5) 4- to 6-membered heterocyclyl containing 1-2 N heteroatoms, wherein the heterocyclyl is unsubstituted or substituted by —C(O)O(C 1-4 )alkyl,
(6) —(C 3-6 )cycloalkyl-S(O) 2 —*, or
(7) —CH 2 —O—*, wherein CH 2 is unsubstituted or substituted by 1-2 methyl;
wherein * indicates the point of attachment to ring A;
ring A is
(1) 4- or 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S,
(2) fused 7- to 10-membered heterocyclyl containing 1-4 heteroatoms selected from the group consisting of N, O, and S,
(3) aryl,
(4) fused phenyl,
(5) 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, or
(6) fused 8- to 10-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S,
(7) fused 5- to 10-membered bicyclic carbocyclyl, or
(8) 7- to 11-membered spirocyclic carbocyclyl;
wherein each ring is unsubstituted or substituted by 1-2 R 2 groups;
R 1 is
(2) (C 1-3 )alkyl-O—(C 1-6 )alkyl-,
(3) (C 1-3 )alkyl-OC(O)—(C 1-6 )alkyl-, or
ring B is
(1) phenyl, or
(2) 4- or 6-membered heterocyclyl containing 1-2 N heteroatoms;
R 2 is
(1) halo,
(2) halo(C 1-6 )alkyl,
(3) (C 1-6 )alkyl,
(4) (C 1-3 )alkoxy,
(5) halo(C 1-3 )alkoxy,
(6) cyano,
(7) hydroxy,
(8) phenyl unsubstituted or substituted by CF 3 , hydroxy, or halo,
(9) oxo,
(10) (C 1-3 )alkyl-S(O) 2 —,
(11) —C(O)O(C 1-4 )alkyl,
(12) (C 3-6 )cycloalkyl,
(13) phenoxy,
(14) benzyl,
(15) 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, wherein the heteroaryl is unsubstituted or substituted by 1-2 methyl,
(16) 4- to 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclyl is unsubstituted or substituted by oxo,
(17) —CH 2 -heteroaryl, wherein heteroaryl is a 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, and wherein the heteroaryl is unsubstituted or substituted by hydroxyl,
R 3 is
(1) halo,
(2) cyano,
(3) (C 1-6 )alkyl,
(4) —C(O)O(C 1-4 )alkyl,
(5) —OC(O)N(H)(C 1-4 )alkyl,
(6) (C 1-3 )alkoxy,
(7) halo(C 1-3 )alkoxy,
(8) hydroxy,
(9) —C(O)N(R 4 ) 2
(10) (C 1-6 )alkyl-COOH,
(11) (C 1-3 )alkyl-O—(C 1-3 )alkyl, or
(12) —C(O)-heterocyclyl, wherein heterocyclyl is a 4- to 6-membered monocyclic ring containing 1-2 heteroatoms selected from the group consisting of N, O, and S,
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;
m is 0, 1, 2, or 3; and
n is 0, 1 or 2.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or fused phenyl.
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.
7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, or fused 8- to 10-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein ring A is 1,2,4-oxadiazolyl, 1H-pyrazolyl, quinolinyl, isoquinolinyl, indolizinyl, isoxazolyl, furanyl, pyridinyl, oxazolyl, benzo[d]isoxazolyl, quinoxalinyl, 1,2-dihydrophthalazinyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl, pyrazinyl, 4H-1,2,4-triazolyl, 1H-tetrazolyl, or pyrimidinyl.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1-3 )alkyl-O—(C 1-6 )alkyl- or (C 1-3 )alkyl-OC(O)—(C 1-6 )alkyl-.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is a bond; —NH—; (C 1-2 )alkylene unsubstituted or substituted by 1-2 (C 1-3 )alkyl, halo, or phenyl; or (C 3-6 )cycloalkyl unsubstituted or substituted by 1-2 halo.
14. The compound of claim 1 , which is
1
2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-((5-(3-(trifluoromethoxy)phenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
2
methyl 3-(8-((2-(4-(trifluoromethyl)phenyl)acetamido)methyl)isoquinolin-5-yl)benzoate,
3
methyl 3-(8-(((1R,2R)-2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-
yl)benzoate,
4
methyl 3-(8-((2-(3-methyl-1,2,4-oxadiazol-5-
yl)cyclopropanecarboxamido)methyl)isoquinolin-5-yl)benzoate,
5
methyl 3-(8-((1-(4-(trifluoromethyl)phenyl)piperidine-4-
carboxamido)methyl)isoquinolin-5-yl)benzoate;
6
methyl 3-(8-((2-(4-phenoxyphenyl)acetamido)methyl)isoquinolin-5-yl)benzoate,
7
methyl 3-(8-((3-(tert-butyl)-1-methyl-1H-pyrazole-5-carboxamido)methyl)isoquinolin-5-
yl)benzoate,
8
methyl 3-(8-((1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-
carboxamido)methyl)isoquinolin-5-yl)benzoate,
9
methyl 3-(8-((1-methyl-3-propyl-1H-pyrazole-5-carboxamido)methyl)isoquinolin-5-
yl)benzoate,
10
methyl 3-(8-((spiro[2.4]heptane-1-carboxamido)methyl)isoquinolin-5-yl)benzoate,
11
8-((isoquinoline-1-carboxamido)methyl)-5-(3-(methoxycarbonyl)phenyl)isoquinolin-2-
ium,
12
8-((isoquinoline-5-carboxamido)methyl)-5-(3-(methoxycarbonyl)phenyl)isoquinolin-2-
ium,
13
methyl 3-(8-((1-methyl-1H-pyrazole-5-carboxamido)methyl)isoquinolin-5-yl) benzoate,
14
ethyl 3-(8-((2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-yl)benzoate,
15
N-((5-(3-ethoxyphenyl)isoquinolin-8-yl)methyl)-2-phenylcyclopropanecarboxamide,
16
(1R,2R)-N-((5-(3-cyanophenyl)isoquinolin-8-yl)methyl)-2-
phenylcyclopropanecarboxamide,
17
2-phenyl-N-((5-(3-(trifluoromethoxy)phenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
18
N-((5-(3-(methoxymethyl)phenyl)isoquinolin-8-yl)methyl)-2-
phenylcyclopropanecarboxamide,
19
N-((5-(3-isopropoxyphenyl)isoquinolin-8-yl)methyl)-2-phenylcyclopropanecarboxamide,
20
isopropyl 3-(8-((2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-yl)benzoate,
21
3-(8-((2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-yl)phenyl tert-
butylcarbamate,
22
3-(8-((2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-yl)benzamide,
23
(1S,2S)-2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
24
(1R,2S)-2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
25
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)indolizine-2-carboxamide,
26
5-cyclopropyl-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)isoxazole-3-
carboxamide,
27
3-(furan-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-phenylpropanamide,
28
5-bromo-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)nicotinamide,
29
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-
carboxamide,
30
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(3-phenyl-1,2,4-oxadiazol-5-
yl)propanamide,
31
2-(2,3-dichlorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
32
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)quinoline-8-carboxamide,
33
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)isoquinoline-4-carboxamide,
34
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(1H-pyrazol-1-yl)benzamide,
35
3-ethyl-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-methyl-1H-pyrazole-5-
carboxamide,
36
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-
carboxamide,
37
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)oxazole-5-carboxamide,
38
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)oxazole-2-carboxamide,
39
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-
3-carboxamide,
40
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)quinoxaline-6-carboxamide,
41
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-(pyridin-2-yl)piperidine-3-
carboxamide,
42
(S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyl-4,5-dihydrooxazole-4-
carboxamide,
43
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-methyl-4-oxo-3,4-
dihydrophthalazine-1-carboxamide,
44
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-methyl-3-propyl-1H-pyrazole-5-
carboxamide,
45
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)quinoline-5-carboxamide,
46
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)acetamide,
47
2-(4-chlorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide
48
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-
(trifluoromethyl)phenyl)acetamide,
49
2-(2-fluorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
50
2-(2-chlorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
51
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(2-
(trifluoromethyl)phenyl)acetamide,
52
2-(3-fluorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
53
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-phenoxyphenyl)acetamide,
54
2-(3-chlorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
55
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(2-phenoxyphenyl)acetamide,
56
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-
(methylsulfonyl)phenyl)acetamide,
57
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethoxy)phenyl)acetamide,
58
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(2,3,4-trifluorophenyl)acetamide,
59
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(2,4,5-trifluorophenyl)acetamide,
60
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3,4,5-trifluorophenyl)acetamide,
61
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(2-
(trifluoromethoxy)phenyl)acetamide,
62
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-
(trifluoromethoxy)phenyl)acetamide,
63
2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)acetamide,
64
2-(2-(4-fluorophenyl)thiazol-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)acetamide,
65
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4-(1H-pyrazol-1-yl)benzamide
66
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-
carboxamide,
67
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4-(2-oxopyrrolidin-1-yl)benzamide,
68
3-(3,5-dimethyl-1H-pyrazol-1-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)benzamide,
69
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(1H-tetrazol-1-yl)isonicotinamide,
70
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyloxazole-4-carboxamide,
71
2-((5-hydroxy-1,2,3-oxadiazol-3(2H)-yl)methyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)benzamide,
72
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-phenyl-1,2,4-oxadiazole-3-
carboxamide,
73
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyl-1H-imidazole-4-
carboxamide,
74
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-phenyl-1H-pyrazole-3-carboxamide
75
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-phenylpyrazine-2-carboxamide,
76
4-(isoxazol-3-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)benzamide,
77
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-phenylisonicotinamide,
78
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-(trifluoromethyl)phenyl)thiazole-
4-carboxamide,
79
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-phenyl-1H-pyrazole-4-carboxamide,
80
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-phenylisoxazole-5-carboxamide,
81
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(5-phenyl-4H-1,2,4-triazol-3-
yl)acetamide,
82
2′-hydroxy-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-[1,1′-biphenyl]-4-
carboxamide,
83
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-phenylfuran-2-carboxamide,
84
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4-(piperidin-1-yl)benzamide,
85
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1,3-diphenyl-1H-pyrazole-5-
carboxamide,
86
4′-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-[1,1′-biphenyl]-4-
carboxamide,
87
3′-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-[1,1′-biphenyl]-3-
carboxamide,
88
3′-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-[1,1′-biphenyl]-4-
carboxamide,
89
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-phenylthiazol-2-yl)acetamide,
90
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(1H-tetrazol-1-yl)benzamide,
91
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(1H-tetrazol-1-yl)benzamide,
92
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)isoquinoline-5-carboxamide,
93
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-phenylpiperazin-1-yl)acetamide,
94
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(1-methyl-1H-pyrazol-4-
yl)propanamide,
95
tert-butyl 3-(2-(((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)amino)-2-oxoethyl)-3-
phenylpyrrolidine-1-carboxylate,
96
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-phenyl-3,4-dihydro-2H-pyrrole-2-
carboxamide,
97
2-(4-chlorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
98
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)spiro[2.4]heptane-1-carboxamide,
99
2-(3-bromophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
100
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)spiro[2.5]octane-1-carboxamide,
101
2-(2-bromophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
102
2-(4-fluorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
103
1-((4-chlorophenyl)sulfonyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
104
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(pyridin-3-
yl)cyclopropanecarboxamide,
105
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(pyridin-2-
yl)cyclopropanecarboxamide,
106
2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
107
2-(3-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
108
(1S,2S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-
5-yl)cyclopropanecarboxamide,
109
2-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-
phenylcyclopropanecarboxamide,
110
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxamide,
111
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-methyl-2-(4-
(trifluoromethyl)phenoxy)propanamide,
112
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-methyl-2-((5-
(trifluoromethyl)pyridin-2-yl)oxy)propanamide,
113
1-benzyl-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1H-1,2,3-triazole-4-
carboxamide,
114
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-methyl-2-((4-
(trifluoromethyl)pyridin-2-yl)oxy)propanamide,
115
1-benzyl-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1H-pyrazole-4-carboxamide,
116
2-(5-bromopyridin-2-yl)-2,2-difluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)acetamide,
117
1-benzyl-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-methyl-1H-pyrazole-3-
carboxamide,
118
5-bromo-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)pyrimidine-2-carboxamide,
119
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-(trifluoromethyl)nicotinamide,
120
5-bromo-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenylnicotinamide,
121
5-bromo-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-
(trifluoromethyl)nicotinamide,
122
2-(5-bromopyridin-3-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)acetamide,
123
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-(4-
(trifluoromethyl)phenyl)cyclobutanecarboxamide,
124
2-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)acetamide,
125
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-methyl-2-(4-
(trifluoromethyl)phenyl)butanamide,
126
(S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)butanamide,
127
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-4-(trifluoromethyl)nicotinamide
128
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-(4-
(trifluoromethyl)phenyl)piperidine-4-carboxamide,
129
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-5-phenylnicotinamide,
130
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide,
131
5-bromo-2-fluoro-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)nicotinamide,
132
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-phenyl-5-(trifluoromethyl)-1H-
pyrazole-4-carboxamide,
133
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(trifluoromethyl)isonicotinamide,
134
2-([1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
135
2-(3-fluorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
136
2-(4-cyanophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
137
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethoxy)phenyl)propanamide,
138
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenylpropanamide,
139
2-(2-fluorophenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
140
(R)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
141
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)propanamide,
142
(S)-2-(6-methoxynaphthalen-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
143
2-(6-methoxynaphthalen-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
144
(1S,2R)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)cyclopropanecarboxamide,
145
(S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
146
(S)-2-(4-isobutylphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
147
2-(3,5-bis(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
148
2-(3-chloro-4-cyclohexylphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
149
(R)-2-(3,5-bis(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
150
N-((5-(3-methoxyphenyl)quinolin-8-yl)methyl)-2-(4-(trifluoromethyl)phenyl)acetamide,
151
1-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)urea,
152
1-(2,3-dichlorophenyl)-3-((5-(3,5-dimethoxyphenyl)isoquinolin-8-yl)methyl)urea,
153
methyl 2-(3-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)ureido)benzoate,
154
N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-1-methyl-1H-pyrazole-3-carboxamide,
155
methyl 3-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)benzoate,
156
ethyl 3-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)propanoate,
157
1-([1,1′-biphenyl]-3-yl)-3-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)urea,
158
1-(2,3-dichlorophenyl)-3-((5-(1-phenylvinyl)isoquinolin-8-yl)methyl)urea,
159
1-(2,3-dichlorophenyl)-3-((5-(3-methoxypropyl)isoquinolin-8-yl)methyl)urea,
160
1-(2,3-dichlorophenyl)-3-((5-(3-hydroxyphenyl)isoquinolin-8-yl)methyl)urea,
161
3-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)-N-methylbenzamide,
162
tert-butyl 4-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)-5,6-
dihydropyridine-1(2H)-carboxylate,
163
3-(4-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)phenyl)propanoic acid,
164
3-(4-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)phenyl)propanoic acid,
165
tert-butyl 3-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)-5,6-
dihydropyridine-1(2H)-carboxylate,
166
1-(2,3-dichlorophenyl)-3-((5-(3-(morpholine-4-carbonyl)phenyl)isoquinolin-8-
yl)methyl)urea,
167
1-(2,3-dichlorophenyl)-3-((5-(2,5-dihydro-1H-pyrrol-3-yl)isoquinolin-8-yl)methyl)urea,
168
methyl 2-(8-((3-(2,3-dichlorophenyl)ureido)methyl)isoquinolin-5-yl)benzoate,
169
1-([1,1′-biphenyl]-2-yl)-3-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)urea,
170
1-(2,4-difluorophenyl)-3-((5-(3-methoxyphenyl)quinolin-8-yl)methyl)urea,
171
1-(2,3-dichlorophenyl)-3-((5-(3-methoxyphenyl)quinolin-8-yl)methyl)urea, or
172
N-((4-(3-methoxyphenyl)naphthalen-1-yl)methyl)-2-phenylcyclopropanecarboxamide,
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , which is
1
(1R,2R)-N-((5-(3-cyanophenyl)isoquinolin-8-yl)methyl)-2-phenylcyclopropanecarboxamide,
2
(1S,2S)-N-((5-(3-cyanophenyl)isoquinolin-8-yl)methyl)-2-phenylcyclopropanecarboxamide,
3
(1R,2S)-2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
4
(1S,2R)-2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
5
(S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyl-4,5-dihydrooxazole-4-
carboxamide,
6
(R)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyl-4,5-dihydrooxazole-4-
carboxamide,
7
(1S,2S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-
yl)cyclopropanecarboxamide,
8
(1R,2R)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-
yl)cyclopropanecarboxamide,
9
(S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)butanamide,
10
(R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)butanamide,
11
(R)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
12
(S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
13
(S)-2-(6-methoxynaphthalen-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
14
(R)-2-(6-methoxynaphthalen-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
15
(1S,2R)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)cyclopropanecarboxamide,
16
(1R,2S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)cyclopropanecarboxamide,
17
(S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
18
(R)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
19
(S)-2-(4-isobutylphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
20
(R)-2-(4-isobutylphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)propanamide,
21
(R)-2-(3,5-bis(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
22
(S)-2-(3,5-bis(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , which is
1
(trans)-N-((5-(3-cyanophenyl)isoquinolin-8-yl)methyl)-2-
phenylcyclopropanecarboxamide,
2
(cis)-2-(4-methoxyphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)cyclopropanecarboxamide,
3
(R/S)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-phenyl-4,5-dihydrooxazole-
4-carboxamide,
4
(trans)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-
oxadiazol-5-yl)cyclopropanecarboxamide,
5
(R/S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)butanamide,
6
(R/S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
7
(R/S)-2-(6-methoxynaphthalen-2-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
8
(cis)-N-((5-(3-methoxyphenyl)isoquinolin-8-yl)methyl)-2-(4-
(trifluoromethyl)phenyl)cyclopropanecarboxamide,
9
(R/S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
10
(R/S)-2-(4-isobutylphenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
11
(R/S)-2-(3,5-bis(trifluoromethyl)phenyl)-N-((5-(3-methoxyphenyl)isoquinolin-8-
yl)methyl)propanamide,
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprised of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method of treating atherosclerosis, hepatic steatosis, atherosclerosis, type-2 diabetes mellitus, obesity, hyperlipidemia, or hypercholesterolemia in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
19. The method according to claim 18 for treating atherosclerosis.