Analogs of fexaramine and methods of making and using

1. A compound, having a formula

or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein

R 1 is selected from aryl, heteroaryl, heterocyclic, alkenyl, cycloalkyl, cycloalkenyl or polycyclic;

R 2 is selected from alkyl, alkenyl, or cycloalkyl;

Y is selected from N, N—O or C—R 3d ;

R 3a , R 3b , R 3c and R 3d are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, hydroxyl or nitro;

R 4a and R 4b are each independently selected from hydrogen, deuterium, halide or alkyl;

L 1 and L 2 are independently selected from hydrogen, deuterium, alkyl, cycloalkyl, or together form a pi-bond; and

R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halide, alkyl, alkenyl, alkoxy, alkylthio, amino, sulfonyl, aminosulfonyl, aminocarbonyl, acyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl or nitro; or

any two adjacent groups selected together form an aryl, heteroaryl, cycloalkyl or heterocyclic ring; and

wherein

none of R 5a , R 5b , R 5c , R 5d or R 5e are —R x -L x -R x2 , where

R x is selected from O, NR x3 , sulfonyl or S;

R x3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl;

L x is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl or CR x4 R x5 ;

R x4 and R x5 are each independently selected from H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)OR x6 , or —C(O)NR x6 R x7 ;

R x6 and R x7 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl;

R x2 is selected from —C(O)L x2 R x8 or a carboxyl bioisostere;

L x2 is a bond or NR x3 ;

R x8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —OR x9 , N(R x9 ) 2 , —C(O)R x9 , —S(O) 2 R x9 , —C(O)OR x9 , —S(O) 2 N(R x9 ) 2 or C(O)N(R x9 ) 2 ; and

each R x9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl; and

if L 1 and L 2 are both hydrogen or together form a pi-bond then

Y is N or C-halogen; or

R 1 is polycyclic; or

R 4a is D; or

R 5a is F, Cl or I; or

R 5d and R 5e together form an aryl, heteroaryl, cycloalkyl or heterocyclic ring; or

R 5b and R 5c together form an aryl, cycloalkyl, nitrogen-containing heterocyclic or nitrogen-containing heteroaryl ring; or

any combination thereof.

2. The compound of claim 1 , the compound having a formula

3. The compound of claim 1 , wherein R 4a is deuterium.

4. The compound of claim 2 , wherein R 3d or R 5a or both are halogen.

5. The compound of claim 4 , wherein R 3d or R 5a or both are F.

6. The compound of claim 1 , wherein the polycyclic is selected from

or adamantane.

7. The compound of claim 6 , wherein the polycyclic is

8. The compound of claim 1 , wherein R 5c comprises a nitrogen-containing heteroaryl ring.

9. The compound of claim 8 , wherein R 5c is selected from pyridine, pyrazole, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrimidine, pyrazine, triazine, benzopyrazole, benzimidazole, indole, quinoline, indazole, purine, quinoxaline, or acridine.

10. The compound of claim 1 , having the formula

wherein Z is selected from N, CH, or C-alkyl;

R 6a , R 6c , R 6d and R 6g are each independently selected from H, D, halogen or alkyl; and

R 6h is selected from H, D, alkyl, cycloalkyl, aryl or heteroaryl.

11. The compound of claim 10 , wherein Z is N; R 6a , R 6c , R 6d and R 6g are all H; R 6h is methyl; or a combination thereof.

12. The compound of claim 1 , having a formula

wherein R 6a , R 6b , R 6c , and R 6d are each independently selected from H, D, halogen or alkyl;

G is a lone pair of electrons, or an oxygen;

R 6e and R 6f are each independently selected from alkyl, H or cycloalkyl; and

wherein R 3d or R 5a or both are halogen; or

R 4a is D; or

R 1 is polycyclic; or

any combination thereof.

13. The compound of claim 12 , wherein R 6e and R 6f are both methyl.

14. The compound of claim 1 , wherein the compound is selected from

15. A method of making a compound of claim 1 , the method comprising:

reacting an aldehyde with a first amine to form an imine;

reacting the imine with a reducing agent to form a second amine; and

reacting the second amine with an activated carboxylic acid derivative or a carboxylic acid to form an amide.

16. A composition, comprising a compound of claim 1 and an additional component.

17. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

18. The method of claim 17 , wherein the disorder or disease is selected from a metabolic disorder, inflammation in an intestinal region, a cell proliferation disease, alcoholic liver disease, non-alcoholic liver disease, a cholestatic disorder, an intestinal permeability disorder, a disease that causes or results from an altered intestinal microbiome, an inborn error of metabolism, a bile disorder, or an intestinal malabsorption disorder.

19. The method of claim 17 , wherein the disorder or disease is selected from obesity, diabetes, insulin resistance, dyslipidemia, necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, colon cancer, post-surgical inflammation, gastric carcinogenesis, fatty liver (steatosis), cirrhosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholestasis resulting from a drug, overlap syndrome (PBC plus autoimmune hepatitis), drug-induced cholestatic hepatitis, total parenteral nutrition (TPN)-induced cholestasis, ICU/sepsis-related cholestasis, obstetric cholestasis, graft vs. host disease, prolonged cholestasis due to hepatitis A, B or C infection, cholestasis due to cystic fibrosis, alcoholic hepatitis, progressive familial intrahepatic cholestasis (PFIC) syndromes, Alagille syndrome, biliary atresia, infectious colitis, type 1 diabetes, an intestinal permeability condition, an intestinal inflammation disorder, intestinal lesions, cirrhosis, cerebrotendinous xanthomatosis (CTX), benign biliary stricture, malignant biliary obstruction, bile acid diarrhea, short bowel syndrome, tropical sprue, environmental enteropathy, or volvulus.

20. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition of claim 16 .

21. The method of claim 20 , wherein the composition comprises an enteric coating.

22. The method of claim 17 , wherein the disorder or disease is a cancer of the intestine.

23. The method of claim 22 , wherein the cancer is colon cancer.

24. The method of claim 17 , wherein the disorder or disease is type 1 diabetes or type 2 diabetes.

25. The compound of claim 1 having a structure

26. The method according to claim 17 comprising administering the compound to the gastrointestinal tract of the subject.

27. The method according to claim 17 comprising orally administering the compound to the subject.

28. The method according to claim 20 comprising administering the composition to the gastrointestinal tract of the subject.

29. The method according to claim 20 comprising orally administering the composition to the subject.

30. A method of treating a disorder or disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 25 .

31. The compound according to claim 1 , selected from: