FXR (NR1H4) modulating compounds

1. A compound having the structure of Formula (Ia):

wherein:

Q is phenylene substituted with one chloro;

Y is N;

R 1 is cyclopropyl or methyl;

R 2 and R 3 are chloro;

R 4 -A is:

 wherein the pyridylene is optionally substituted with one or two groups independently selected from halogen, C 1-4 -alkoxy, halo-C 1-4 -alkoxy, C 1-4 -alkyl, and halo-C 1-4 -alkyl, and R 4 is —CO 2 R 5 or —C(O)NR 5 R 6 ;

R 5 is hydrogen; and

R 6 is C 1-2 -alkyl optionally substituted with —CO 2 H or —SO 3 H;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is pyridylene substituted with one fluoro; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein A is unsubstituted pyridylene; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 4 is —CO 2 R 5 , and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein:

R 4 is —C(O)NR 5 R 6 ;

R 5 is hydrogen; and

R 6 is C 1-2 -alkyl, wherein said C 1-2 -alkyl is substituted with —SO 3 H or —CO 2 H;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 4 -A is:

or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. A compound having the following formula:

or a pharmaceutically acceptable salt thereof.

9. A compound having the following formula:

10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable excipient.

11. A method of treating a patient having an FXR mediated condition comprising administering a compound or pharmaceutically acceptable salt of claim 1 to a patient in need thereof.

12. The method of claim 11 , wherein the FXR mediated condition is selected from the group consisting of:

a chronic intrahepatic or some form of extrahepatic cholestatic condition;

liver fibrosis;

an obstructive inflammatory disorder of the liver;

chronic inflammatory disorder of the liver;

liver cirrhosis;

liver steatosis or an associated syndrome;

cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-borne forms of hepatitis;

liver failure or liver ischemia after major liver resection;

chemotherapy associated steatohepatitis (CASH);

acute liver failure; and

Inflammatory Bowel Disease.

13. The method of claim 11 , wherein the FXR mediated condition is selected from the group consisting of:

a lipid and lipoprotein disorder;

Type I Diabetes;

Type Il Diabetes;

clinical complications of Type I and Type Il Diabetes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifest long term Diabetes;

Non-Alcoholic Fatty Liver Disease (NAFLD);

Non-Alcoholic Steatohepatitis (NASH);

obesity;

a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabetes and abnormally high body-mass index;

acute myocardial infarction;

acute stroke; and

thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis.

14. The method of claim 11 , wherein the FXR mediated condition is selected from the group consisting of:

a non-malignant hyperproliferative disorder; and

a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis;

colon adenocarcinoma;

breast cancer;

pancreas adenocarcinoma;

Barrett's esophagus; and

other forms of neoplastic diseases of the gastrointestinal tract and the liver.

15. The method of claim 11 , wherein the FXR mediated condition is Non-Alcoholic Steatohepatitis (NASH).