USRE49446EActiveUtility
Oxadiazolopyridine derivatives for use as ghrelin O-acyl transferase (GOAT) inhibitors
Est. expiryAug 5, 2036(~10.1 yrs left)· nominal 20-yr term from priority
A61K 31/437A61P 3/10C07D 491/048C07D 498/04C07D 519/00A61P 3/04
67
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0
Cited by
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References
37
Claims
Abstract
The present invention relates to compounds of general formula I,wherein the groups R1, R2 and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to ghrelin O-acyl transferase (GOAT) and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular obesity.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I)
wherein
X is CH or N;
R 1 is selected from the group consisting of CH 3 —CH 2 OH CH 3 , —CH 2 OH and Cl;
R 2 is independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, C 1-6 -alkyl, C 3-7 -cycloalkyl, OH, —O—(C 1-6 -alkyl), —O—(C 3-7 -cycloalkyl), —O—(C 1-3 -alkyl)-(C 3-7 -cyclo alkyl) —O—(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O-heterocyclyl, —O—(C 1-3 -alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C 1-3 -alkyl), —SO—(C 1-3 -alkyl), —SO 21-3 -alkyl) —SO 2 -(C 1-3 alkyl), —NH 2 , —NH—(C 1-6 -alkyl), —NH—(C 3-6 -cycloalkyl), —NH—(C 1-3 -alkyl)-heterocyclyl, —NH—(C 1-6 -alkyl-C(═O)—NH 2 —C(═O)—NH 2 —C(═O)—NH—(C 1-3 -alkyl) —NH—(C 1-6 -alkyl)-C(═O)—NH 2 , —C(═O)—NH 2 , —C(═O)—NH—(C 1-3 -alkyl), —C(═O)—N(C 1-3 -alkyl) 2 , —C(═O)OH, —C(═O)—O—(C 1-4 -alkyl), —C(═O)—(C 1-4 -alkyl), alkyl) —C 1-3 -alkyl-C(═O)—O—(C 1-4 -alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH 2 -groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C 1-3 -alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CN and C 1-3 -alkyl, which is optionally substituted with one or more F;
or, if two groups R 2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a O—CH 2 —O— —O—CH 2 —O—, —O—CH 2 —CH 2 —O— or —O—CH 2 —CH 2 —CH 2 —O— bridge, in which 1 or 2H 2 H atoms may be replaced with F or C 1-3 -alkyl; and
n is 1, 2 or 3;
wherein each of the above-mentioned alkyl groups may be substituted with one or more F;
or a pharmaceutically acceptable salt thereof.
2. A method for treating a disease or condition which is mediated by inhibiting the activity of the ghrelin O-acyl transferase (GOAT), the method comprising administering a compound of formula (I)
wherein
X is CH or N;
R 1 is selected from the group consisting of CH 3 —CH 2 OH CH 3 , —CH 2 OH and Cl;
R 2 is independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, C 1-6 -alkyl, C 3-7 -cycloalkyl, OH, —O—(C 1-6 -alkyl), —O—(C 3-7 -cycloalkyl), —O—(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O-heterocyclyl, —O—(C 1-3 -alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C 1-3 -alkyl), —SO—(C 1-3 -alkyl), —SO 21-3 -alkyl) —SO 2 —(C 1-3 -alkyl), —NH 2 , —NH—(C 1-6 -alkyl), —NH—(C 3-6 -cycloalkyl), —NH—(C 1-3 -alkyl)-heterocyclyl, —NH—(C 1-6 -alkyl)-C(═O )—NH 2 , —C(═O)—NH 2 , —C(═O)—NH—(C 1-3 -alkyl), —C(═O)—N(C 1-3 -alkyl) 2 , —C(═O)OH, —C(═O)—O—(C 1-4 -alkyl), —C(═O)—(C 1-4 -alkyl), alkyl) —C 1-3 -alkyl—C(═O)—O—(C 1-4 -alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH 2 -groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C 1-3 -alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CN and C 1-3 -alkyl, which is optionally substituted with one or more F;
or, if two groups R 2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a O—CH 2—O— —O—CH 2 —O—, —O—CH 2 —CH 2 —O— or —O—CH 2 —CH 2 —CH 2 —O— bridge, in which 1 or 2H 2 H atoms may be replaced with F or C 1-3 -alkyl; and
n is 1, 2 or 3;
wherein each of the above-mentioned alkyl groups may be substituted with one or more F;
or a pharmaceutically acceptable salt thereof,
to a patient in need thereof.
3. The method according to claim 1 , wherein
R 1 is —CH 3 ; and
n is 1 or 2,
or a pharmaceutically aceptable salt thereof.
4. The method according to claim 1 , wherein
R 2 is independently of each other selected from the group consisting of H, F, Cl, Br, CN, C 1-6 -alkyl, C 3-7 -cycloalkyl, OH, —O—(C 1-6 -alkyl), —O—(C 1-3 -alkyl)-(C 3-7 -cycloalkyl), —O— heterocyclyl —O-heterocyclyl, —O—(C 1-3 -alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C 1-3 -alkyl), —SO 2 —(C 1-3 -alkyl), —NH 2 , —NH—(C 1-6 -alkyl), —NH—(C 3-6 -cycloalkyl), —NH—(C 1-3 -alkyl)-heterocyclyl, —NH—(C 1-6 -alkyl)-C(═O)—NH 2 , —C(═O)—NH 2 , —C(═O)—NH—(C 1-3 -alkyl), —C(═O)—(C 1-4 -alkyl), —C 1-3 -alkyl-C(═O)—O—(C 1-4 -alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH 2 -groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C 1-3 -alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of a 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F and C 1-3 -alkyl, which is optionally substituted with one or more F;
or, if two groups R 2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a —O—CH 2 —O—, —O—CH 2 —CH 2 —O— or —O —CH 2 —CH 2 —CH 2 —O— —O—CH 2 —CH 2 —CH 2 —O— bridge,
or a pharmaceutically acceptable salt thereof.
5. The method according to claim 4 , wherein
R 2 is independently of each other selected from the group consisting of F, Cl, Br, CN, C 1-3 -alkyl, C 3-6 -cycloalkyl, —O—(C 1-4 -alkyl), —O—CH 2 -cyclopropyl, —O—CH 2 -heterocyclyl, —O-phenyl, —O-heteroaryl, —S—CH 3 , —NH 2 , —NH—(C 1-4 -alkyl), —NH—(C 3-5 -cycloalkyl), —NH—(CH 2 -heterocyclyl), —NH—(C 1-4 -alkyl)-C(═O)—NH 2 , —C(═O)—NH—(C 1-3 -alkyl), —C(═O)—(C 1-4 -alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, and
wherein each heterocyclyl group is selected from the group consisting of oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and CH 3 ,
wherein each heteroaryl group is selected from the group consisting of furanyl, isoxazolyl, thiazolyl and pyrazolyl, and
wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CH 3 and CF 3 ,
or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 , wherein
R 2 is independently of each other selected from the group consisting of F, Cl, Br, CN, CH 3 , C 3-5 -cycloalkyl, —O—(C 1-4 -alkyl), —O—CH 2 -heterocyclyl, —O-phenyl, —S—CH 3 , —NH 2 , —NH—(C 1-4 -alkyl), —NH—(C 3-5 -cycloalkyl), —NH—(CH 2 -heterocyclyl), —NH—(C 1-4 -alkyl)-C(═O)—NH 2 , heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, and
wherein each heterocyclyl group is selected from the group consisting of oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, OH and CH 3 , and
wherein each heteroaryl group is selected from the group consisting of furanyl and thiazolyl,
or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6 , wherein
R 2 is independently selected from the group consisting of:
F, Cl, Br, —CN, —CF 3 ,
—O—CH 3 , —O—CHF 2 , —O—CH 2 —CH 2 —F, —O—CH 2 —CHF 2 , —O—CH 2 —CF 3 , —O—CH 2 —CH 2 —CH 2 —F, —O—CH 2 —CF 2 —CH 3 ,
—S—CH 3 , —NH 2 , —NH—CH 2 —CH 2 —CH 2 —F, —NH—CH 2 —CH 2 —CHF 2 ,
or a pharmaceutically acceptable salt thereof.
8. The method according to claim 1 , where X is CH, or a pharmaceutically acceptable salt thereof.
9. The method according to claim 1 , where X is N, or a pharmaceutically acceptable salt thereof.
10. The method according to claim 1 , where the compound of formula (I) is of formula I.2
wherein
R 1 is CH 3 ;
R 2a and R 2b are each independently selected from the group consisting of:
H, F, Cl, Br, CN, —CF 3 ,
—O—CH 3 , —O—CHF 2 , —O—CH 2 —CH 2 —F, —O—CH 2 —CHF 2 , —O—CH 2 —CF 3 , —O—CH 2 —CH 2 —CH 2 —F, —O—CH 2 —CF 2 —CH 3 ,
—S—CH 3 , —NH 2 , —NH—CH 2 —CH 2 —CH 2 —F, —NH—CH 2 —CH 2 —CHF 2 ,
wherein at least one R 2a and R 2b is not H;
or a pharmaceutically acceptable salt thereof.
11. The method according to claim 1 , wherein the compound of formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the obesity patient is suffering from Prader-Willi syndrome.
13. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
19. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
24. The method according to claim 10, wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
28. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
29. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
30. The method according to claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.
31. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
32. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
33. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
34. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
35. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
36. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula
37. A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formulaCited by (0)
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