Di-substituted pyrazole compounds for the treatment of diseases

1. A Compound of Formula (I):

where

R 1 is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl rings are optionally substituted with 1, 2, or 3 R 1a and where the pyridinonyl is substituted on the nitrogen with R 1b and is additionally optionally substituted with 1, 2, or 3 R 1a ;

each R 1a is independently halo, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

R 1b is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

R 2 is

where 0, 1, or 2 of X 1 -X 4 are nitrogen and the remaining are CH or CR 2b , provided that 0-2 CR 2b are present;

R 2a is NR 5a S(O) 2 R 5b or NR 6a R 6b ;

each R 2b is independently halo, alkyl, haloalkyl, —NO 2 , or cyano;

R 3 is hydrogen, halo, alkyl, or haloalkyl;

R 4 is hydrogen, halo, alkyl, or haloalkyl;

R 5a and R 6a are independently hydrogen or alkyl; and

R 5b and R 6b are independently alkyl; haloalkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkyl; or heterocycloalkylalkyl; and

wherein each cycloalkyl, either alone or as part of another group, is independently optionally substituted with one or two groups independently selected from the group consisting of alkyl, halo, and haloalkyl; or

a pharmaceutically acceptable salt thereof;

provided that the compound is not N-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; N-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;

or a pharmaceutically acceptable salt thereof.

2. The Compound of claim 1 according to Formula (Ic):

3. The Compound of claim 1 according to Formula (Ib):

4. The Compound of claim 1 according to Formula (Id):

5. The Compound of claim 1 , where R 3 and R 4 are hydrogen.

6. The Compound of claim 1 , where R 2 is

7. The Compound of claim 1 , where R 2 is

8. The Compound of claim 1 , where R 2 is substituted with a first R 2b ; and when the R 2 ring is phenyl or pyridinyl, R 2 is additionally optionally substituted with a second R 2b .

9. The Compound of claim 8 , where the first R 2b is halo.

10. The Compound of claim 8 , where the first R 2b is —CN, —CH 3 , or —CF 3 .

11. The Compound of claim 1 , where R 2a is —NHS(O) 2 R 5b .

12. The Compound of claim 1 , where R 2a is —NHR 6b .

13. The Compound of claim 1 , where R 1a is alkyl.

14. The Compound of claim 1 , where R 1b is alkyl, haloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl where the heterocycloalkylalkyl is optionally substituted with an alkyl group on a ring nitrogen of the heterocycloalkyl ring.

15. The compound of claim 1 selected from the following formula:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a Compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A method of inhibiting or relieving a condition, disease, or disorder associated with abnormal activation of the SREBP pathway comprising administering to a patient in need thereof an effective amount of the Compound of claim 1 wherein the condition, disease, or disorder is selected from metabolic syndrome, hypertension, type 2 diabetes, dyslipidemia, obesity, reducing body weight, a metabolic disease, hyperlipidemia, a lipoprotein related disease, combined elevated cholesterol and elevated triglycerides, Frederickson Type IIb, familial combined hyperlipidemia, familial hypertriglyceridemia, Frederickson Type IV, hyperlipoproteinemia Type V, mixed hyperlipidemia, acquired hyperlipidemia, Fatty Liver Disease, Nonalcoholic Steatohepatitis, Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, post myocardial infarction management, peripheral vascular disease, cerebrovascular disease—thrombotic, type II diabetes mellitus, diabetic nephropathy, and cancer; or wherein the patient is in need of increased thermogenesis or in need of reducing body weight.

18. The method of claim 17 , wherein the cancer is selected from hepatocellular carcinoma, prostate cancer, post menopausal breast carcinoma, pancreatic adenocarcinoma, ovarian cancer, B cell lymphoma, leukemia, lung cancer, digestive and gastrointestinal cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, stomach cancer, gastric cancer, esophageal cancer, gall bladder cancer, appendix cancer, renal cancer, cancer of the central nervous system, skin cancer, a lymphoma, choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a blood cancer.

19. The method of claim 17 , wherein the condition, disease, or disorder is selected from metabolic syndrome, Frederickson Type IIb, familial combined hyperlipidemia, Frederickson Type IV, hyperlipoproteinemia Type V, mixed hyperlipidemia, Aquired hyperlipidemia, Fatty Liver Disease, nonalcoholic steatohepatitis, Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, hypertension, type 2 diabetes, dyslipidemia, obesity, hepatocellular carcinoma, prostate cancer, post-menopausal breast carcinoma, pancreatic adenocarcinoma, ovarian cancer, B cell lymphoma, leukemia, lung cancer, digestive and gastrointestinal cancer, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, stomach cancer, gastric cancer, esophageal cancer, gall bladder cancer, appendix cancer, renal cancer, cancer of the central nervous system, skin cancer, a lymphoma, choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a blood cancer; or wherein the patient is in need of increased thermogenesis or in need of reducing body weight.

20. The method of claim 17 , where the compound is selected from the following formula:

or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 , wherein the condition, disease, or disorder is selected from prostate cancer, post-menopausal breast carcinoma, pancreatic adenocarcinoma, leukemia, and liver cancer.

22. A method of reducing glucose, triglyceride, cholesterol, low-density lipoprotein, aspartate aminotransferase, and/or alanine aminotransferase levels, comprising administering to a patient in need thereof an effective amount of the Compound of claim 1 .

23. A method of reducing glucose, triglyceride, cholesterol, low-density lipoprotein, aspartate aminotransferase, and/or alanine aminotransferase levels, comprising administering to a patient in need thereof an effective amount of the Compound of claim 15 .