Spiroxazolidinone compounds
View Patent ↗Substituted spirocyclic amines of structural formula (I) are selective antagonists of the somatostatin subtype receptor 5 (SSTR5) and are useful for the treatment, control or prevention of disorders responsive to antagonism of SSTR5, such as Type 2 diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, Metabolic Syndrome, depression, and anxiety.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein each occurrence of Ra is independently selected from the group consisting of hydrogen, halogen, —C 1 -C 10 alkyl and halogen-substitutedC 1 -C 10 alkyl;
R 1 is selected from the group consisting of hydrogen, phenyl and heterocycle, wherein the phenyl or heterocycle is substituted with at least one substituent selected from α;
R 2 is selected from the group consisting of aryl and heterocycle, wherein the aryl or heterocycle is substituted with 1-5 substituents independently selected from α;
α is selected from the group consisting of:
halogen,
—C 1 -C 10 alkyl,
—C 3 -C 10 cycloalkyl,
heterocycle,
aryl,
—OH,
—O—C 1 -C 10 alkyl,
—O—C 3 -C 10 cycloalkyl,
—O-aryl,
—O-heterocycle,
—NRbS(O) 2 Rc,
—NRbRc,
—CN,
—NRbC(O)Rc,
—S(O) 2 Rb,
—S(O) 2 NRbRc,
—C(O)NRbRc,
—C(O)NRb(C 1 -C 10 alkyl-NH—C 1 -C 10 alkyl),
—NRbC(O)ORc,
—NRbC(O)NRcRd,
—NRbC(O)NH 2 ,
—NRbS(O) 2 Rc,
—NO 2 ,
—C(O)Rd,
—COORd, and
—OC(O)Rd,
wherein, Rb, Rc and Rd are independently selected from the group consisting of hydrogen, —C 1 -C 10 alkyl, —C 3 -C 10 cycloalkyl, aryl, and heterocycle; and wherein any —C 3 -C 10 cycloalkyl, aryl, or heterocycle is independently unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, NH 2 , N(CH 2 ) 2 , —C 3 -C 10 cycloalkyl, hetrocycle, —COORd, —OH, —O—C 1 -C 10 alkyl and —C 1 -C 10 alkyl; and wherein any —C 1 -C 10 alkyl or —OC 1 -C 10 alkyl is independently unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, —OH, —COORd, —C 3 -C 10 cycloalkyl and aryl; and
wherein n and m are each independently 1.
2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at each occurrence of Ra, Ra is hydrogen.
3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl.
4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridine.
5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted with —OH, —C 1 -C 10 alkyl, —COOH, —COO—C 1 -C 10 alkyl, —O—C 1 -C 10 alkyl, —C 3 -C 10 cycloalkyl, —SO 2 C 1 -C 10 alkyl, —CON(C 1 -C 10 alkyl) 2 NH 2 (C 1 -C 10 alkyl) or heterocycle, wherein the —C 1 -C 10 alkyl, —C 3 -C 10 cycloalkyl or —OC 1 -C 10 alkyl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen and —COOH.
6. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is imidazole, naphthalene, phenyl, pyridine, benzimidazole, indole, oxazole, thiazole, benzofuran, benzocyclopentane, benzotetrahydropyran or pyrazole.
7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl.
8. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is pyridine.
9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is imidazole.
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted with two substituents independently selected from α.
11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted with three substituents independently selected from α.
12. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted with 1-4 substituents selected from the group consisting of halogen, —C 1 -C 10 alkyl, —O—C 1 -C 10 alkyl, aryl, heterocycle and —C 3 -C 10 cycloalkyl wherein the aryl, —C 1 -C 10 alkyl, heterocycle, —O—C 1 -C 10 alkyl or —C 3 -C 10 cycloalkyl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, —C 1 -C 10 alkyl and —O—C 1 -C 10 alkyl.
13. A compound claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted with 1-3 substituents selected from the group consisting of —O—C 1 -C 10 alkyl, —O-halogen-substitutedC 1 -C 10 alkyl and halogen-substituted phenyl.
14. A compound, or pharmaceutically acceptable salt, selected from the group consisting of:
15. A method of treating a disorder, condition, or disease selected from the group consisting of Type 2 diabetes and insulin resistance, comprising administering a compound of claim 1 to a subject in need thereof.