Granted Patent B2

US 10,577,361 · App. 15/767,328 · Granted Mar 3, 2020

Abstract

Claims (104)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

G is aryl, a 5-6 membered heteroaromatic group, or an 8-11 membered heteroaromatic group; wherein each is optionally benzofused or optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

W is S, SO 2 , O, or NR 4 ;

n is 0 or 1;

m is 1 or 2;

p is 1 or 2;

q is 1;

z in the substituent Rz is an integer ranging from 1 to 7;

R in the substituent Rz is independently hydrogen or C 1-4 alkyl;

R 1 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy;

R 2 is hydrogen, F, C 1-4 alkyl, —OH, or C 1-4 alkoxy;

R 3 is hydrogen, F, C 1-4 alkyl, or C 1-4 alkoxy;

R 4 is hydrogen or C 1-4 alkyl;

G 1 is a phenyl group, a 5-6-membered heteroaromatic group, or a 8-11 membered heteroaromatic group; wherein each group is optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

Y is phenyl, a 5-6 membered heteroaromatic group, a saturated mono 3-7 membered carbocyclic group, or 8-11 membered bicyclic carbocyclic group in which one or more atom carbons may be replaced by NR 4 , O, S; any of which groups are optionally substituted by one or two substituents selected from the group consisting of Y′, halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , SO 2 NH 2 , and C(═O)O x R 4 ;

x is 0 or 1; and

Y′ is phenyl or a 5-6-membered heteroaromatic group optionally substituted by 1 or 2 R 2 groups;

with the proviso that G 1 , Y, and Y′ are not simultaneously phenyl.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IA):

wherein:

G is aryl or a 5-6 membered heteroaromatic group; either of which is optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

W is S, SO 2 , O, or NR 4 ;

n is O or 1;

m is 1 or 2;

p is 1 or 2;

z in the substituent Rz is an integer from 1 to 7;

R in the substituent Rz is independently hydrogen or C 1-4 alkyl;

R 1 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy;

R 2 is hydrogen, F, C 1-4 alkyl, OH, or C 1-4 alkoxy;

R 3 is hydrogen, F, C 1-4 alkyl, or C 1-4 alkoxy;

R 4 is hydrogen or C 1-4 alkyl;

G 1 is a phenyl group or a 5-6-membered heteroaromatic group, either of which is optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

Y is a phenyl, a 5-6 membered heteroaromatic group, or an saturated mono 3-7 membered carbocyclic group; any of which groups may be optionally substituted by one or two substituents selected from the group consisting of Y′, halogen, cyano, hydroxyl, amino, C 1 -4alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , SO 2 NH 2 , C(═O)O x R 4 ;

x is 0 or 1; and

Y′ is phenyl or a 5-6-membered heteroaromatic group optionally substituted by 1 or 2 R 2 groups;

with the proviso that G 1 , Y and Y′ are not simultaneously phenyl.

3. The compound of claim 2 , wherein

G is aryl which is optionally substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

W is S;

n is 1;

m is 1;

p is 1;

z in the substituent Rz is an integer from 1 to 7;

R in the substituent Rz is hydrogen;

R 2 and R 3 are each hydrogen;

R 4 is hydrogen or C 1-4 alkyl;

G 1 is a 5-membered heteroaromatic group containing 3 nitrogen atoms, which is optionally substituted by 1, 2, 3, or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, SF 5 , C(═O)NH 2 , and C(═O)OR 4 ;

Y is a phenyl or a 5- or 6-membered heteroaromatic group, either of which is optionally substituted by Y′; and

Y′ is phenyl or a 5-6-membered heteroaromatic group which is optionally substituted by 1 or 2 R 2 groups;

with the proviso that Y and Y′ are not simultaneously phenyl.

4. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

5. A method for treating a dopamine D 3 receptor disease in a patient having said disease, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

6. The method of claim 5 , wherein the dopamine D 3 receptor disease is a dyskinetic disorder, depression, anxiety, a cognitive impairment, an eating disorder, a sexual dysfunction, premature ejaculation, a sleep disorder, emesis, a movement disorder, obsessive-compulsive disorder, amnesia, aggression, autism, vertigo, dementia, a circadian rhythm disorder, or a gastric motility disorder.

7. A method of treating a psychosis or a psychotic condition in a patient having said psychosis or psychotic condition, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

8. A method of treating schizophrenia in a patient having schizophrenia, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

9. A method of treating a substance-related disorder or an addictive disorder in a patient having said disorder, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

10. A method of treating opioid use disorder in a patient having said disorder, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

11. A compound of the formula:

2-(4-fluorophenyl)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)morpholine or a pharmaceutically acceptable salt thereof;

(2S)-2-(4-fluorophenyl)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)morpholine or a pharmaceutically acceptable salt thereof;

(2R)-2-(4-fluorophenyl)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)morpholine or a pharmaceutically acceptable salt thereof;

4-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2S)-4-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2R)-4-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2S)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2R)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2R)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine hydrochloride;

(2S)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine hydrochloride;

4-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholine-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}benzamide or a pharmaceutically acceptable salt thereof;

4-[4-methyl-5-({3-[(2S)-2-[4-(trifluoromethyl)phenyl]morpholine-4-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide or a pharmaceutically acceptable salt thereof;

4-[4-methyl-5-({3-[(2R)-2-[4-(trifluoromethyl)phenyl]morpholine-4-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide or a pharmaceutically acceptable salt thereof;

4-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2S)-4-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

(2R)-4-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

5-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholine-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof;

4-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

6-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholin-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide or a pharmaceutically acceptable salt thereof;

3-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholin-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}benzamide or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-(3-{[4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-[4-(trifluoromethyl)phenyl]morpholine or a pharmaceutically acceptable salt thereof;

4-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholin-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}benzonitrile or a pharmaceutically acceptable salt thereof;

1-(4-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholine-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}phenyl)ethan-1-one or a pharmaceutically acceptable salt thereof;

4-{4-methyl-5-[(3-{2-[4-(trifluoromethyl)phenyl]morpholine-4-yl}propyl)sulfanyl]-4H-1,2,4-triazol-3-yl}benzene-1-sulfonamide or a pharmaceutically acceptable salt thereof;

2-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)morpholine or a pharmaceutically acceptable salt thereof;

4-{5-[(3-{2-[2-fluoro-4-(trifluoromethyl)phenyl]morpholin-4-yl}propyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide or a pharmaceutically acceptable salt thereof, 4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-2-(4-methylphenyl)morpholine or a pharmaceutically acceptable salt thereof;

4-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-2-(4-methylphenyl)morpholine or a pharmaceutically acceptable salt thereof, or

2-(4-bromophenyl)-4-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)morpholine or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.

13. A method for treating a dopamine D 3 receptor disease in a patient having said disease, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 11 .

14. The method of claim 13 , wherein the dopamine D 3 receptor disease is a dyskinetic disorder, depression, anxiety, a cognitive impairment, an eating disorder, a sexual dysfunction, premature ejaculation, a sleep disorder, emesis, a movement disorder, obsessive-compulsive disorder, amnesia, aggression, autism, vertigo, dementia, a circadian rhythm disorder, or a gastric motility disorder.

15. A method of treating a psychosis or a psychotic condition in a patient having said psychosis or psychotic condition, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 11 .

16. A method of treating schizophrenia in a patient having schizophrenia, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 11 .

17. A method of treating a substance-related disorder or an addictive disorder in a patient having said disorder, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 11 .

18. A method of treating opioid use disorder in a patient having said disorder, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 11 .

Assignments (8)