Pharmaceutical agents, compositions, and methods relating thereto

1. A method for treating an insulin resistance disorder comprising administering a therapeutically effective amount of a compound of formula (2):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof, wherein:

R 8 is H or halogen;

X is H or halogen;

each R 5 ′ is independently H or halogen; and

each R is independently C 1-6 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

2. The method of claim 1 , wherein the insulin resistance disorder is diabetes, obesity, metabolic syndrome, insulin-resistance syndromes, syndrome X, insulin resistance, high blood pressure, hypertension, high blood cholesterol, hyperlipidemia, dyslipidemia, an atherosclerotic disease, hyperglycemia, hyperinsulinemia, hyperproinsulinemia, impaired glucose tolerance, delayed insulin release, a diabetic complication, a cancer, a disorder associated with pregnancy or poor female reproductive health, lipodystrophy, a cholesterol related disorder, osteoarthritis, osteoporosis, or a type II diabetes related vascular disorder.

3. The method of claim 2 , wherein the insulin resistance disorder is stroke, coronary artery disease, myocardial infarction, coronary heart disease, angina pectoris, congestive heart failure, cognitive functions in dementia, retinopathy, neuropathy, nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, endometrial cancer, breast cancer, prostate cancer, colon cancer, menstrual irregularities, infertility, irregular ovulation, polycystic ovarian syndrome (PCOS), gallstones, cholescystitis, cholelithiasis, gout, obstructive sleep apnea, or respiratory problems.

4. The method of claim 1 , wherein the compound is of formula (2′):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

5. The method of claim 1 , wherein R 8 is H.

6. The method of claim 1 , wherein X is H.

7. The method of claim 1 , wherein each R is independently C 1-3 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

8. The method of claim 1 , wherein each R is independently unsubstituted C 1-3 alkyl.

9. The method of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

10. The method of claim 9 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

11. The method of claim 1 , wherein the compound is administered intraperitoneally.

12. The method of claim 1 , wherein the compound is administered orally.

13. A method for treating diabetes comprising administering a therapeutically effective amount of a compound of formula (2):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof, wherein:

R 8 is H or halogen;

X is H or halogen;

each R 5 ′ is independently H or halogen; and

each R is independently C 1-6 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

14. The method of claim 13 , wherein the diabetes is type I diabetes or type II diabetes.

15. The method of claim 13 , wherein the compound is of formula (2′):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

16. The method of claim 13 , wherein R 8 is H.

17. The method of claim 13 , wherein X is H.

18. The method of claim 13 , wherein each R is independently C 1-3 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

19. The method of claim 13 , wherein each R is independently unsubstituted C 1-3 alkyl.

20. The method of claim 13 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

21. The method of claim 20 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

22. A method for treating a degenerative disease selected from the group consisting of cardiovascular disease and cardiac failure, Alzheimer's disease, Parkinson's diseases, and sarcopenia, comprising administering a therapeutically effective amount of a compound of formula (2):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof, wherein:

R 8 is H or halogen;

X is H or halogen;

each R 5 ′ is independently H or halogen; and

each R is independently C 1-6 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

23. The method of claim 22 , wherein the compound is of formula (2′):

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

24. The method of claim 22 , wherein R 8 is H.

25. The method of claim 22 , wherein X is H.

26. The method of claim 22 , wherein each R is independently C 1-3 alkyl, each of which, independently, may optionally be substituted 1-3 times by halogen.

27. The method of claim 22 , wherein each R is independently unsubstituted C 1-3 alkyl.

28. The method of claim 22 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

29. The method of claim 28 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, stereoisomer, or isotopic, conformational, or geometric isomer thereof.

30. A method of preparing a compound of formula (1):

or a salt thereof,

comprising treating a compound of formula:

or a salt thereof,

with an agent selected from the group consisting of (C 1-6 alkylC(O)) 2 O and 1,1′-carbonyldiimidazole (CDI); or treating a compound of formula:

or a salt thereof,

with morpholine;

wherein:

each of R 2 and R 3 is independently H or —C(O)—R, wherein each R is independently C 1-6 alkyl or 3-8 membered carbocyclic or heterocyclic, wherein R 2 and R 3 cannot be both H;

or R 2 together with R 3 form —(CH 2 ) n —C(O)—(CH 2 ) m —, wherein each of n and m is independently 0-3, and n+m≤3;

R 5 is —C 1-6 alkyl or —C 1-6 alkyl-CH(NH 2 )COOH;

R 8 is H or halogen; and

X is H or halogen,

wherein each of the carbocyclic, heterocyclic, —(CH 2 ) n —, and —(CH 2 ) m — moieties, independently, may optionally be substituted 1-3 times by —OH, halogen, NH 2 , CN, or C 1-6 alkyl; and

each C 1-6 alkyl moiety, independently, may optionally be substituted 1-3 times by —OH, halogen, NH 2 , or CN.

31. A method of preparing a pharmaceutical composition comprising a compound of formula (1):

or a pharmaceutically acceptable salt, ester, stereoisomer, or isotopic, conformational, or geometric isomer thereof, wherein:

each of R 2 and R 3 is independently H or —C(O)—R, wherein each R is independently a C 1-6 alkyl or a 3-8 membered carbocyclic or heterocyclic, wherein R 2 and R 3 cannot be both H;

or R 2 together with R 3 form —(CH 2 ) n —C(O)—(CH 2 ) m —, wherein each of n and m is independently 0-3, and n+m≤3;

R 5 is —C 1-6 alkyl or —C 1-6 alkyl-CH(NH 2 )COOH;

R 8 is H or halogen; and

X is H or halogen,

wherein each of the carbocyclic, heterocyclic, —(CH 2 ) n —, and —(CH 2 ) m — moieties, independently, may optionally be substituted 1-3 times by —OH, halogen, NH 2 , CN, or C 1-6 alkyl; and

each C 1-6 alkyl moiety, independently, may optionally be substituted 1-3 times by —OH, halogen, NH 2 , or CN,

the method comprising bringing into association the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or isotopic, conformational, or geometric isomer thereof, with one or more pharmaceutically acceptable carriers or excipients, and optionally one or more accessory ingredients.