MODULATORS OF GLUCOSE HOMEOSTASIS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS

• US 20110160222A1
• Filed: 07/06/2010
• Published: 06/30/2011
• Est. Priority Date: 11/26/2008
• Status: Abandoned Application

• Current Assignee: Metabolix Incorporated
• Original Assignee: Metabolix Incorporated
• Inventors: Chen, Xin, Zhu, Yan, Zhao, Zuchun, Ma, Jingyuan, Rabbat, Christopher J.
• Application Number:
  US12/830,911
• Publication Number:
  US 20110160222A1
• Time in Patent Office: Days
• US Class Current: 514/252.16
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Aryl 119 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.

Claims

1. A compound having the formula:

2. A compound of claim 1, wherein Ar¹ is 4-Y-Ph-.

3. A compound of claim 2, wherein Ar¹ is 4-(C_1-8 alkoxy)-Ph- or 4-(heteroaryl)-Ph-.

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

5. A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

6. A method of stimulating insulin production, said method comprising administering an effective amount of a compound of claim 1 to a mammal.

7. A method of stimulating glucose-dependent insulin secretion, said method comprising administering an effective amount of a compound of claim 1 to a mammal.

8. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 1 to a mammal.

9. A method of lowering blood triglyceride levels in a mammal, said method comprising administering an effective amount of a compound of claim 1 to a mammal.

10. A compound selected from the group consisting of

tert-butyl 4-(4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2);

tert-butyl 4-(4-(4-methoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (3);

tert-butyl 4-(4-(4-(4-(trifluoromethyl)phenoxy)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4);

tert-butyl 4-(4-(4-(1H-imidazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (5);

tert-butyl 4-(4-(4-(methylsulfonyl)phenylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (6);

tert-butyl 4-(4-(4-phenoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (7);

tert-butyl 4-(4-(4-(methylsulfonyl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (8);

tert-butyl 4-(4-(methyl(4-(methylsulfonyl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (9);

tert-butyl 4-(4-(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (10);

tert-butyl 4-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (11);

tert-butyl 4-(4-(biphenyl-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (12);

tert-butyl 4-(4-(4-benzoylphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (13);

tert-butyl 4-(4-(4-(2-phenylacetyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (14);

tert-butyl 3-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (15);

tert-butyl 3-(4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (16);

tert-butyl 4-(4-(4-(1,3,4-oxadiazol-2-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (17);

1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (18);

tert-butyl 4-(4-(4-(2-oxopyrrolidin-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (19);

tert-butyl 4-(4-(4-(1H-pyrrol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (20);

tert-butyl 4-(4-(4-(1,3-dioxoisoindolin-2-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (21);

tert-butyl 4-(4-(2-(pyrrolidin-1-ylmethyl)-4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (22);

tert-butyl 4-(4-(4-(pyrrolidin-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (23);

tert-butyl 4-(4-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1yl)piperidine-1-carboxylate (24);

tert-butyl 4-(4-(quinolin-6-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (25);

tert-butyl 4-(4-(2,6-dimethyl-4-nitrophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (26);

tert-butyl 4-(4-(4-aminophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (27);

tert-butyl 4-(4-(4-(2-methoxyethyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (28);

isopropyl 4-(4-(1,5-dioxaspiro[5.5]undecan-9-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (29);

tert-butyl 4-(4-(4-(3-methoxy-3-oxopropanoyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (30);

tert-butyl 4-(4-(1-(6-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (31);

tert-butyl 4-(4-(4-(4-acetylpiperazin-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (32);

tert-butyl 4-(4-(4-(1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (33);

tert-butyl 4-(4-(4-(tert-butoxycarbonylamino)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (34);

tert-butyl 4-(4-(4-acetamidophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (35);

tert-butyl 4-(4-(4-(N-methylacetamido)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (36);

tert-butyl 4-(4-(4-cyclopentylphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (37);

isopropyl 4-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (38);

isopropyl 4-(4-(4-phenoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (39);

isopropyl 4-(4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (40);

isopropyl 4-(4-(4-(2-trityl-2H-tetrazol-5-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (41);

isopropyl 4-(4-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (42);

isopropyl 4-(4-(4-(2-methyl-2H-tetrazol-5-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (43);

isopropyl 4-(4-(4-(2-allyl-2H-tetrazol-5-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (44);

isopropyl 4-(4-(4-(2-benzyl-2H-tetrazol-5-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (45);

isopropyl 4-(4-(1-benzyl-1H-indazol-5-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (46);

isopropyl 4-(4-((1-benzyl-1H-indazol-5-yl)(methyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (47);

tert-butyl 4-((4-(4-(methylsulfonyl)phenylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (48);

tert-butyl 4-((4-(4-(methylsulfonyl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (49);

tert-butyl 4-((4-(methyl(4-(methylsulfonyl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (50);

tert-butyl 4-((4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (51);

tert-butyl 4-((4-(4-benzoylphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (52);

tert-butyl 4-((4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (53);

tert-butyl 4-((4-(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-chlorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (54);

tert-butyl 4-((4-(4-phenoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (55);

tert-butyl 4-((4-(4-methoxyphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (56);

tert-butyl 4-((4-(5-(trifluoromethyl)pyridin-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (57);

tert-butyl 4-((4-(4-(1H-1,2,4-triazol-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (58);

tert-butyl 4-((4-(4-(1H-imidazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (59);

tert-butyl 4-((4-(4-(3-oxobutyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (60);

tert-butyl 4-((4-(4-acetylphenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (61);

tert-butyl 3-((4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carboxylate (62);

tert-butyl 3-((4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carboxylate (63);

1-(1-(isobutylsulfonyl)piperidin-4-yl)-4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (65);

4-(4-(methylsulfonyl)phenoxy)-1-(1-tosylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (66);

1-(1-(benzylsulfonyl)piperidin-4-yl)-4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (67);

1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (68);

tert-butyl 4-(7-(methyl(4-(methylsulfonyl)phenyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate (71);

tert-butyl 4-(7-(4-(methylsulfonyl)phenoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate (72);

ethyl 4-(7-(4-(methylsulfonyl)phenoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate (73);

tert-butyl 4-(8-methyl-6-(4-(methylsulfonyl)phenoxy)-9H-purin-9-yl)piperidine-1-carboxylate (74);

tert-butyl 4-(6-(4-(methylsulfonyl)phenoxy)-9H-purin-9-yl)piperidine-1-carboxylate (75);

tert-butyl 4-(6-(4-(methylsulfonyl)phenoxy)-8-phenyl-9H-purin-9-yl)piperidine-1-carboxylate (76);

isopropyl 4-(4-(4-(1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (77);

isopropyl 4-(4-(4-(2H-tetrazol-5-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (78);

tert-butyl 4-(4-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (79);

tert-butyl 4-(4-(2-amino-4-(ethylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (80);

tert-butyl 4-(4-(benzo[d]thiazol-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (81);

tert-butyl 4-(4-(1H-benzo[d]imidazol-2-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (82);

tert-butyl 4-(4-(2-oxobenzo[d][1,3]oxathiol-6-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (83);

tert-butyl 4-(4-(4-(5-mercapto-1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (84);

tert-butyl 4-(4-(4-(5-(methylthio)-1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (85);

4-(4-(1H-tetrazol-1-yl)phenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (86);

1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (87);

4-(2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (88);

4-(4-(1H-tetrazol-1-yl)phenoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (89);

4-(4-(1H-tetrazol-1-yl)phenoxy)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (90);

1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-4-(2-fluoro-4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (91);

1-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-(2-fluoro-4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (92); and

4-(2-fluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (93) or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 10.

12. A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 10.

13. A method of stimulating insulin production, said method comprising administering an effective amount of a compound of claim 10 to a mammal.

14. A method of stimulating glucose-dependent insulin secretion, said method comprising administering an effective amount of a compound of claim 10 to a mammal.

15. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 10 to a mammal.

16. A method of lowering blood triglyceride levels in a mammal, said method comprising administering an effective amount of a compound of claim 10 to a mammal.