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.
1. A compound of Formula I:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
A-B is C(O)—NR 13 , C(O)—CR 11 R 12 , C(O)—O, CR 11 R 12 —NR 13 , CR 11 R 12 —O, CR 11 R 12 —C(O), NR 13 —C(O), NR 13 —CR 11 R 12 , O—CR 11 R 12 , or O—C(O);
R 11 and R 12 are each independently H, halogen, or C 1 -C 6 alkyl;
R 13 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, C(O)—C 1 -C 6 alkyl, C(O)-phenyl, C(O)O—C 1 -C 6 alkyl, C(O)NR 17 R 18 , S(O) 2 —C 1 -C 6 alkyl, or S(O) 2 NR 17 R 18 ;
R 17 and R 18 are each independently H, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
R 5 is H, halogen, OH, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, C(O)NR 17 R 18 , S—C 1 -C 6 alkyl, S(O)—C 1 -C 6 alkyl, S(O) 2 —C 1 -C 6 alkyl, S(O) 2 NR 17 R 18 , NR 17 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, phenyl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms 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 selected from N, O, and S;
provided that when A-B is NR 13 —C(O), NR 13 —CR 11 R 12 , O—CR 11 R 12 , or O—C(O), then R 5 is not OH, O—C 1 -C 6 alkyl, S—C 1 -C 6 alkyl, NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, or NR 17 S(O) 2 —C 1 -C 6 alkyl;
Z 2 is C(R 2 ) 2 or C(O);
Z 5 is C(R 2 ) 2 or C(O);
each R 2 is independently H, halogen, OH, C 1 -C 6 alkyl, CF 3 , O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycle, C 6 -C 10 aryl, O—C 6 -C 10 aryl, C(O)—C 1 -C 6 alkyl, C(O)NR 17 R 18 , NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, S(O) 2 NR 17 R 18 , or NR 17 S(O) 2 —C 1 -C 6 alkyl;
provided that when R 2 is bonded to a carbon atom adjacent to the nitrogen atom in
then R 2 is H, halogen, C 1 -C 6 alkyl, CF 3 , C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 10 aryl, C(O)—C 1 -C 6 alkyl, C(O)NR 17 R 18 , or S(O) 2 NR 17 R 18 ;
R 1 is H or C 1 -C 6 alkyl;
Cy 1 and Cy 2 are each independently C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, C 3 -C 10 cycloalkyl, C 5 -C 13 bicyclic group, or heterocyclyl comprising one or two 3- to 6-membered rings and one to four heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl, bicyclic group, and heterocycyl are each independently optionally substituted with one or more substituents independently selected from:
halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, C 6 -C 10 aryl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms selected from N, O, and S, and NR 17 R 18 ;
t is 2, 3, or 4;
each R 3 is independently H, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycle, OH, O—C 1 -C 6 alkyl, S—C 1 -C 6 alkyl, NR 17 R 18 , C(O)NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, NR 17 S(O) 2 —C 1 -C 6 alkyl, or S(O) 2 NR 17 R 18 , or
any two R 3 bonded to the same carbon atom, together with the carbon atom to which the two R 3 are bonded, form C═O, provided that the C═O is not directly bonded to the nitrogen atom in
provided that when X is O, S, or NR 16 , then the R 3 in the C(R 3 ) 2 directly bonded to X is not OH, O—C 1 -C 6 alkyl, S—C 1 -C 6 alkyl, NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, NR 17 S(O) 2 —C 1 -C 6 alkyl, or S(O) 2 NR 17 R 18 ;
X is a O, CR 14 R 15 , S, S(O), S(O) 2 , C═O, or NR 16 ;
R 16 is H, C 1 -C 6 alkyl, phenyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms selected from N, O, and S, C(O)—C 1 -C 6 alkyl, C(O)-phenyl, C(O)O—C 1 -C 6 alkyl, C(O)NR 17 R 18 , S(O) 2 —C 1 -C 6 alkyl, or S(O) 2 NR 17 R 18 ;
n is 0, 1, or 2;
each R 4 is independently H, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycle, OH, O—C 1 -C 6 alkyl, S—C 1 -C 6 alkyl, NR 17 R 18 , C(O)NR 17 R 18 , NR 17 C(O)—C 1 -C 6 alkyl, NR 17 S(O) 2 —C 1 -C 6 alkyl, or S(O) 2 NR 17 R 18 , or
any two R 4 bonded to the same carbon atom, together with the carbon atom to which the two R 4 are bonded, form C═O;
provided that when X is O, S, or NR 16 , then the R 4 in the C(R 4 ) u directly bonded to X is not OH, O—C 1 -C 6 alkyl, S—C 1 -C 6 alkyl, or NR 17 R 18 ; and
Cy 3 is C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, C 3 -C 10 cycloalkyl, C 5 -C 13 bicyclic group, or heterocyclyl comprising one or two 3- to 6-membered rings and one to four heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl, bicyclic group, and heterocycyl are each independently optionally substituted with one or more substituents independently selected from:
halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, C 6 -C 10 aryl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms selected from N, O, and S, and NR 17 R 18 provided that when (C(R 4 ) 2 ) n —X—(C(R 3 ) 2 ) t is (CH 2 ) 3-6 , then Cy 3 is not phenyl, which is optionally substituted, methylenedioxyphenyl, isoindoline-1,3,-dione, or dihydrobenzofuranyl.
2. The compound of claim 1 , having Formula II:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein z is 1, 2, 3, 4, 5, 6, 7, or 8.
3. The compound of claim 1 , having Formula IV:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 , Cy 2 , and Cy 3 are each independently phenyl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, C 5 -C 6 cycloalkyl, C 5 -C 13 bicyclic group, or heterocyclyl comprising one or two 3- to 6-membered rings and one to four heteroatoms selected from N, O, and S, wherein Cy 1 , Cy 2 , and Cy 3 are each independently optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 ;
each R 3 is the same and is selected from H and C 1 -C 3 alkyl;
R 5 is H or C 1 -C 3 alkyl;
R 13 is H or C 1 -C 3 alkyl;
R 17 and R 18 are each independently H or C 1 -C 3 alkyl; and
v is 1, 2, or 3.
4. The compound of claim 1 , having Formula V:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 , Cy 2 and Cy 3 are each independently phenyl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, or C 5 -C 13 bicyclic group, wherein Cy 1 , Cy 2 , and Cy 3 are each independently optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 ;
R 5 is H or C 1 -C 3 alkyl;
R 11 and R 12 are each independently H or C 1 -C 3 alkyl;
R 13 is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C(O)—C 1 -C 3 alkyl; and
R 17 and R 18 are each independently H or C 1 -C 3 alkyl.
5. The compound of claim 1 , having Formula VII:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 , Cy 2 and Cy 3 are each independently phenyl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, or C 5 -C 13 bicyclic group, wherein Cy 1 , Cy 2 , and Cy 3 are each independently optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 ;
R 17 and R 18 are each independently H or C 1 -C 3 alkyl; and
o is 1, 2, or 3.
6. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 1 , Cy 2 or Cy 3 is independently C 6 -C 10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms selected from N, O, and S, C 3 -C 10 cycloalkyl, or C 5 -C 13 bicyclic group, wherein the aryl, heteroaryl, cycloalkyl, and bicyclic group are each independently optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 .
7. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
8. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein A-B is C(O)—NR 13 .
9. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X is O.
10. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.
11. A compound of the formula:
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.
13. A method of modulating D2 receptor activity, comprising administering to a subject a compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.
14. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein the disease is:
an anxiety disorder;
a dissociative disorder;
a mood disorder;
an eating disorder;
a sleep disorder;
a developmental disorder;
a somatoform disorder;
a personality disorder;
a psychiatric syndrome;
a psychotic disorder;
substance abuse;
Parkinson's disease;
Huntington's disease;
Alzheimer's disease;
dementia;
Niemann-Pick disorder;
a pituitary disorder;
Tourette's syndrome;
Tourette-like disorder; or
restless leg syndrome.
15. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 3 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 , wherein R 17 and R 18 are each independently H or C 1 -C 3 alkyl.
16. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein —(C(R 4 ) 2 ) n —X—(C(R 3 ) 2 ) t — is —O—(CH 2 ) 2 —.
17. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is H or —CH 3 .
18. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein A-B is CR 11 R 12 —NR 13 .
19. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein A-B is CR 11 R 12 —O.
20. The compound of claim 1 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl, and Cy 2 is pyridyl, wherein the phenyl and the pyridyl are each independently optionally substituted with one or more substituents independently selected from halogen, CH 2 F, CHF 2 , CF 3 , C 1 -C 6 alkyl, OH, O—C 1 -C 6 alkyl, OCF 3 , OCHF 2 , OCH 2 F, and NR 17 R 18 , wherein R 17 and R 18 are each independently H or C 1 -C 3 alkyl.
21. The compound of claim 1 , wherein the compound is of the formula:
Compound
No.
Compound Formula
99
126
127
1
2
3
4
5
6
7
8
10
12
13
14
15
16
17
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
62
63
66
67
68
69
70
71
82
83
84
85
86
90
91
92
93
94
95
96
109
110
111
112
113
115
116
117
118
119
123
129
130
141
142
143
144
145
146
72
73
74
75
76
77
78
79
80
81
87
88
89
97
101
102
103
107
114
120
121
122
125
131
132
133
134
135
136
137
138
139
18
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , wherein the compound is of the formula:
Compound
No.
Compound Formula
99
3
25
35
63
69
70
144
72
79
103
125
133
136
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 11 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.
24. The method of claim 14 , wherein the disease is:
an anxiety disorder selected from phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder;
a dissociative disorder selected from dissociative amnesia, dissociative fugue, dissociative identity disorder, and depersonalization disorder;
a mood disorder selected from depression, dysthymia, bipolar disorder, mania, hypomania, and cyclothymic disorder;
an eating disorder selected from anorexia nervosa, bulimia nervosa, exercise bulimia, and binge eating disorder;
a sleep disorder selected from insomnia, hypersomnia, narcolepsy, nightmare disorder, sleep terror disorder, and sleepwalking;
a developmental disorder selected from autism spectrum disorder, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder;
a somatoform disorder selected from body dysmorphic disorder, conversion disorder, hypochondriasis disorder, pain disorder, and somatization disorder;
a personality disorder selected from antisocial personality disorder, borderline personality disorder, and narcissistic personality disorder;
a psychiatric syndrome selected from Capgras syndrome, De Clerambault syndrome, Othello syndrome, Ganser syndrome, Cotard delusion, Ekbom syndrome, Couvade syndrome, and Geschwind syndrome;
a psychotic disorder selected from brief psychotic disorder, delusional disorder, Schizoaffective disorder, Schizophrenia, Schizophreniform, and shared psychotic disorder;
substance abuse;
Parkinson's disease;
Huntington's disease;
Alzheimer's disease;
dementia;
Niemann-Pick disorder;
a pituitary disorder selected from pituitary adenoma and pituitary tumor;
Tourette's syndrome;
Tourette-like disorder; or
restless leg syndrome.
25. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 11 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein the disease is:
an anxiety disorder;
a dissociative disorder;
a mood disorder;
an eating disorder;
a sleep disorder;
a developmental disorder;
a somatoform disorder;
a personality disorder;
a psychiatric syndrome;
a psychotic disorder;
substance abuse;
Parkinson's disease;
Huntington's disease;
Alzheimer's disease;
dementia;
Niemann-Pick disorder;
a pituitary disorder;
Tourette's syndrome;
Tourette-like disorder; or
restless leg syndrome.
26. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 21 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein the disease is:
an anxiety disorder;
a dissociative disorder;
a mood disorder;
an eating disorder;
a sleep disorder;
a developmental disorder;
a somatoform disorder;
a personality disorder;
a psychiatric syndrome;
a psychotic disorder;
substance abuse;
Parkinson's disease;
Huntington's disease;
Alzheimer's disease;
dementia;
Niemann-Pick disorder;
a pituitary disorder;
Tourette's syndrome;
Tourette-like disorder; or
restless leg syndrome.
27. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 22 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein the disease is:
an anxiety disorder;
a dissociative disorder;
a mood disorder;
an eating disorder;
a sleep disorder;
a developmental disorder;
a somatoform disorder;
a personality disorder;
a psychiatric syndrome;
a psychotic disorder;
substance abuse;
Parkinson's disease;
Huntington's disease;
Alzheimer's disease;
dementia;
Niemann-Pick disorder;
a pituitary disorder;
Tourette's syndrome;
Tourette-like disorder; or
restless leg syndrome.
28. A method of modulating D2 receptor activity comprising administering to a subject a compound of claim 11 , or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.