Dopamine D2 receptor ligands
The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity. The present invention relates to novel compounds that modulate dopamine D2 receptors. In particular, compounds of the present invention show functional selectivity at the dopamine D2 receptors and exhibit selectivity downstream of the D2 receptors, on the 0-arrestin pathway and/or on the cAMP pathway.
1. A compound of Formula I:
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
X 0 is X-Cy 1 , C(O)NR 4 R 4′ , NR 4 C(O)R 4′ , or CR 3 R 3′ —NR 4 R 4′ , and is bonded to Z 1 or Z 2 ;
X is C(O), CR 3 R 3′ , NR 4 , O, S, S(O), or S(O) 2 , and is bonded to Z 1 or Z 2 ;
R 3 and R 3′ are each independently H, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;
each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R 17 ;
or R 4 and R 4′ on the same nitrogen atom together with the nitrogen atom form a monocyclic, 4- to 7-membered heterocyclyl ring optionally substituted with one or more R 18 ;
Z 1 is CR 7 ;
R 7 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 1 , absent;
R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S,
wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
Z 2 is CR 8 ;
R 8 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 2 , absent;
R 2 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
each R 18 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy; or two R 18 together with the carbon atom to which they are bonded form a C(O);
q is 0, 1, or 2;
R 20 and R 21 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and halogen;
Cy 1 is C 6 -C 10 aryl, benzyl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein each ring is aromatic or partially unsaturated, wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R 16 ;
each R 16 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—(C 1 -C 3 alkyl), S(O) q —(C 1 -C 3 ) alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ;
Z 3 is C(R 9 ) 2 ;
each R 9 is independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
p is 1;
Z′ is C(R 12 ) 2 ;
each R 12 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;
Z″ is C(R 13 ) 2 ;
each R 13 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;
Z 6 is C(R 14 ) 2 ;
v is 1;
each R 14 is independently H or C 1 -C 3 alkyl;
Z 4 is C(R 10 ) 2 ;
each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—C 1 -C 3 alkyl, S(O) q —C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ; or
two R 17 together with the carbon atoms to which they are bonded form a C 6 -C 10 aryl or heteroaryl optionally substituted with one or more R 19 , or
each R 19 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;
each R 10 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; or two R 10 together with the carbon atom to which they are bonded, form C(O);
Y is NR 6 , O, S, S(O), or S(O) 2 ;
R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
n is 0;
Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R 17 ;
provided that:
when X 0 or X forms a bond with Z 1 , then R 1 is not H;
when X 0 or X forms a bond with Z 2 , then R 2 is not H;
when X is bonded to Z 1 and is NR 4 , O, S, S(O), or S(O) 2 , then R 1 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;
when X is bonded to Z 2 and is NR 4 , O, S, S(O), or S(O) 2 , then R 2 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;
when X is NH and is bonded to Z 1 , and R 1 is C(O)NH 2 , then Cy 1 is not unsubstituted phenyl,
when X is CH 2 and is bonded to Z 1 , and R 1 is OH or halogen, then Cy 1 is not optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and
when X is C(O) and is bonded to Z 1 , Y is O, and R 1 is OH or methoxy, then Cy 1 is not optionally substituted phenyl.
2. The compound of claim 1 , having Formula (II):
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
3. The compound of claim 1 , having Formula (III):
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
X 0 is X-Cy 1 ; and
R 2 is halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
4. The compound of claim 1 , having formula (XI):
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R 17 ;
each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and
r is 0, 1, 2, 3, or 4.
5. The compound of claim 1 , having formula (XII):
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R 17 ;
each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and
r is 0, 1, 2, 3, or 4.
6. The compound of claim 1 , having formula (XIII):
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R 17 ;
each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and
r is 0, 1, 2, 3, or 4.
7. The compound of claim 1 , wherein the compound is of the formula:
Compound
Number
Formula
38
67
68
69
70
71
72
74
75
76
80
82
83
86
87
88
89
90
91
103
104
105
106
107
109
110
111
112
122
125
126
127
128
129
141
143
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
173
174
175
182
183
184
185
186
187
188
189
190
191
192
215
217
61
62
63
96
97
98
99
100
108
198
199
200
201
219
220
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, racemate, or tautomer thereof, and one or more pharmaceutically acceptable excipients or carriers.
9. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 0 is X-Cy 1 , and X is O.
10. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 0 is C(O)NR 4 R 4′ or NR 4 C(O)R 4′ .
11. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl optionally substituted with one or more R 16 .
12. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .
13. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.
14. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 2 is phenyl optionally substituted with one or more R 17 .
15. The compound of claim 1 , wherein the compound is of the formula:
Com-
pound
Num-
ber
Formula
76
90
91
110
122
146
157
or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 2 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
17. The compound of claim 2 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
18. The compound of claim 2 , a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
wherein g is 0, 1, 2, 3, 4, or 5.
19. The compound of claim 2 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
wherein g is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.
20. The compound of claim 2 , a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
wherein g is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.
21. The compound of claim 2 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
wherein t is 0, 1, 2, 3, 4 or 5.
22. The compound of claim 10 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 .