Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the United States, there are more than 12 million diabetics, with 600,000 new cases diagnosed each year.
Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. There are many types of diabetes, but the two most common are Type I (also referred to as insulin-dependent diabetes mellitus or IDDM) and Type II (also referred to as non-insulin-dependent diabetes mellitus or NIDDM).
The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.
People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body. However, people who have diabetes either don't produce insulin or can't efficiently use the insulin they produce; therefore, they can't move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.
Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.
About 5% to 10% of the people who have diabetes have IDDM. These individuals don't produce insulin and therefore must inject insulin to keep their blood glucose levels normal. IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing β cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.
Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don't respond properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insulin levels, while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically non-apparent, making diagnosis difficult.
The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is likely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin's Principles and Practice of Medical Genetics 3rd Ed. 1:1401-1402 (1996)).
Many people with NIDDM have sedentary lifestyles and are obese; they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsulinemia and insulin resistance, a feature shared with NIDDM, hypertension and atherosclerosis.
The G-protein-coupled receptor GPR 40 functions as a receptor for long-chain free fatty acids (FFAs) in the body and as such is implicated in a large number of metabolic conditions in the body. For example it has been alleged that a GPR 40 agonist promotes insulin secretion whilst a GPR 40 antagonist inhibits insulin secretion and so depending upon the circumstances the agonist and antagonist may be useful as therapeutic agents for the number of insulin related conditions such as type 2 diabetes, obesity, impaired glucose tolerance, insulin resistance, neurodegenerative diseases and the like.
There is increasing evidences that lipids can also serve as extracellular ligands for a specific class of receptors and thus act as “nutritional sensors” (Nolan C J et al. J. Clinic. Invest., 2006, 116, 1802-1812 The free fatty acids can regulate cell function. Free fatty acids have demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and have been proposed to play a critical role in physiological glucose homeostasis.
GPR40, GPR120, GPR41 and GPR43 exemplify a growing number of GPCRs that have been shown to be activated by free fatty acids. GPR40 and GPR120 are activated by medium to long-chain free fatty acids whereas GPR 41 and GPR 43 are activated by short-chain fatty acid (Brown A J et al, 2003).
GPR 40 is highly expressed on pancreatic β-cells, and enhances glucose-stimulated insulin secretion (Nature, 2003, 422, 173-176, J. Bio. Chem. 2003; 278, 11303-11311, Biochem. Biophys. Res. Commun. 2003, 301, 406-410).
Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 is reported (Lett. to Nature 2003, 422, 173-176).
GlaxoSmithKline Research and Development, US published an article in Bioorg. Med. Chem. Lett. 2006, 16, 1840-1845 titled Synthesis and activity of small molecule GPR40 agonists. (Does this describe GW9508?) Another article titled Pharmacological regulation of insulin secretion in MIN6 cells through the fatty aid receptor GPR40: Identification of agonist and antagonist small molecules is reported in
Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKline, USA (Does this describe GW9508?)

Solid phase synthesis and SAR of small molecule agonists for the GPR 40 receptor is published in Bioorg. Med. Chem. Lett. 2007, 16, 1840-1845 by Glaxo SmithKline Res. & Dev. USA, including those with the following structures.

Johnson & Johnson Pharmaceutical Research and development, USA published “Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoic acid as a Novel Series of G-protein-coupled receptor 40 agonists (J. Med. Chem. 2007, 16, 2807-2817)
National Institutes of Health, Bethesda, Md. published “Bidirectional Iterative Approach to the Structural Delineation of the Functional Chemo print in GPR 40 for agonist Recognition (J. Med. Chem. 2007, 50, 2981-2990).
Discovery of diacyl phloroglucinols of the following formula
as a new class of GPR40 (FFAR1) agonists has been published by Piramal Life Sciences, Ltd. in Bioorg. Med. Chem. Left. 2008, 18, 6357-6361
Synthesis and SAR of 1,2,3,4-tetrahydroisoquinoline-1-ones as novel G-protein coupled receptor40 (GPR40) antagonists of the following formula has been published in Bioorg. Med. Chem. Lett. 2009, 19, 2400-2403 by Pfizer

Piramal Life Sciences Ltd. published “Progress in the discovery and development of small molecule modulators of G-protein coupled receptor 40 (GPR40/FFA1/FFAR1), an emerging target for type 2 diabetes” in Exp. Opin. Therapeutic Patents 2009, 19(2), 237-264.
There was a report published in Zhongguo Bingli Shengli Zazhi 2009, 25(7). 1376-1380 from Sun Yat. Sen University, Guangzhou, which mentions the role GPR 40 on lipoapoptosis.
A novel class of antagonists for the FFA's receptor GPR 40 was published in Biochem. Biophy. Res. Commun. 2009, 390, 557-563.

Merck Res. Laboratories published “Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists” having the following formula in Bioorg. Med. Chem. Lett. 2010, 20, 1298-1301

Discovery of TAK-875, a, potent, selective, and orally bioavailable GPR 40 agonist is reported by Takeda Pharmaceutical Ltd. ACS Med. Chem. Lett. 2010, 1(6), 290-294

In another report from University of Southern Denmark” Structure—Activity of Dihydrocinnamic acids and discovery of potent FFA1 (GPR40) agonist TUG-469” is reported in ACS Med. Chem. Lett. 2010, 1(7), 345-349.

The free fatty acid 1 receptor (FFAR1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes (ACS Med. Chem. Lett. 2010, 1(6), 290-294).
G-protein coupled receptor (GPR40) expression and its regulation in human pancreatic islets: The role of type 2 diabetes and fatty acids is reported in Nutrition Metabolism & Cardiovascular diseases 2010, 20(1), 22-25
Ranbaxy reported “Identification of Berberine as a novel agonist of fatty acid receptor GPR40” in Phytother Res. 2010, 24, 1260-63.
The following substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists are reported by Merck Res. Lab. in Bioorg. Med. Chem. Lett. 2011, 21, 3390-3394
CoMSIA study on substituted aryl alkanoic acid analogs as GPR 40 agonists is reported Chem. Bio. Drug. Des. 2011, 77, 361-372
Takeda further published “Design, Synthesis and biological activity of potential and orally available G-protein coupled receptor 40 agonists” in J. Med. Chem. 2011, 54(5), 1365-1378.
Amgen disclosed a potent orally bioavailable GPR 40 agonist AMG-837 in Bioorg. Med. Chem. Lett. 2012, 22, 1267-1270

Discovery of phenylpropanoic acid derivatives containing polar functionalities as Potent and orally bioavailable G protein-coupled receptor 40 Agonist for the treatment of type 2 Diabetes is reported in J. Med. Chem. 2012, 55, 3756-3776 by Takeda.
Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist is reported in ACS Med. Chem. Lett. 2012, 3(9), 726-730.
Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic acids: Discovery of a Non-free Fatty acid like, highly bioavailable G protein-coupled receptor 40/free acid receptor 1 agonist as a glucose-dependent insulinotropic agent is reported by Takeda in J. Med. Chem. 2012, 5, 3960-3974.
Bayer disclosed indane, dihydrobenzofuran, and tetrahydronaphthalene carboxylic acid derivatives and their use as antidiabetics in patent application no. WO 2004011446 with the following formulae

Takeda disclosed 3-(4-Benzyloxyphenyl) propanoic acid derivatives in a patent WO 2005063729 with the following general formula:

WO 2005086661 A1 (22 Sep. 2005, Amgen Inc.) disclosed compounds, pharmaceutical compositions and methods for use in treating metabolic disorders, having the following formula:Q-L1-P-L2-M-X-L3-A
US 2006/0004012, Akerman et al. disclosed certain compounds, pharmaceutical compositions and methods for use in treating metabolic disorders, the said compounds being GPR 40 agonists.
WO 06/038738 A1 (13 Apr. 2006, Takeda Pharmaceutical Ltd., Japan) disclosed certain receptor function regulating agent with the following general structure

Merck & Co. disclosed antidiabetic bicyclic compounds in WO2006083781. Disclosed therein are bicyclic compounds containing a phenyl or pyridyl ring fused to a cycloalkyl or heterocyclic ring, to which is attached a 5-membered heterocyclic ring, including pharmaceutically acceptable salts and prodrugs thereof, as agonists of G protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with the disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia are disclosed.
Merck & Co., in another patent application WO 2006083612 disclosed antidiabetic bicyclic compounds, wherein, the bicyclic compounds contain a fused pyridine ring including pharmaceutically acceptable salts and prodrugs thereof, as agonists of G protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with the disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. The compounds disclosed in the patent application has the following general structure:
wherein Z is selected from the group consisting of CR3R4CO2R5, —OCR3R4CO2R5, N(R6)(CR3R4CO2R5), —SCR3R4CO2R5, tetrazole, and the heterocyclic ring II.

Condensed ring compounds have been disclosed by Yasum et al. in a U.S. Pat. No. 7,820,837. The following formula mentioned in U.S. Pat. No. 7,517,910 claims compounds having a GPR 40 receptor function modulating action, which are useful as insulin secretagogues, agents for the prophylaxis or treatment of diabetes and the like

Novel Spiropiperidine compounds have been mentioned by Eli Lilly & Company in WO 2011066183

Eli Lilly also disclosed the following Spiropiperidines in patent application no. US20110092531

Novel 1,2,3,4-tetrahydroquinoline derivatives useful for the treatment of diabetes have been described by Eli Lilly & Company in patent application no. WO 2013025424

A patent application, WO 2013147443 titled “Preparation of β-substituted carboxylic acid derivatives for the treatment of diabetes” has been published by Daichi Sankyo.
Piramal Enterprises Limited has published a patent application no. WO 2013/128378 for phenyl alkanoic acid derivatives as GPR agonists with the structure below

Boehringer Ingelheim has published patent application numbers WO 2013/144097 & WO 2013/144098 titled “New indanyloxy dihydrobenzofuranyl acetic acid derivatives and their use as GPR receptor agonists” with the structures defined below

Novel therapeutic target for treatment of cancers and related therapies and methods are disclosed in patent application no. WO 2014145817 by Children's Medical Center Corporation.
WO 2014146604 disclosed certain fused ring compounds having GPR40 receptor function regulating action.
Tricyclic compound and use thereof has been published by SK Chemicals Co., Ltd. in patent application no. WO2014133361.
Certain antidiabetic bicyclic compounds have been disclosed in patent application no. WO2014130608.
Boehringer Ingelheim International disclosed certain other indanyloxy dihydrobenzofuranyl acetic acids in patent application nos. WO2013164292, WO2014122067, WO2014086712, and WO2014082918 & US20140148462, US20140221349 & US20140163025.
Takeda Pharmaceutical Company Limited have disclosed, fused cyclic compounds as GPR40 receptor modulators in a patent application no. EP2743268. Bristol-Myers Squibb has disclosed Dihydropyrazole GPR40 modulators in patent application nos. WO2014078611, WO2014078610, WO2014078609 & WO2014078608.
LG Life Sciences Limited has disclosed certain GPR40 receptor agonist in patent WO2014073904. Hancke Orozco et al. have disclosed compounds, compositions, and methods for decreasing intestinal glucose uptake and inducing incretin release in patent application no. US20140128333. Merck Sharp & Dohme Corp. disclosed antidiabetic tricyclic compounds in patents application nos. US20140045746, WO2014022528 and in another application disclosed certain bridged and fused antidiabetic compounds in patent US 20140038970.
Novel fluoro-substituted compounds capable of modulating the G-protein coupled receptor
GPR40 have been disclosed in patent application no. US20140058125.
Mochida Pharmaceutical Co. has disclosed Cyclic amide derivative in patent US20140057871. Negoro et al. have disclosed certain carboxylic acid compounds in patent application no. US20120035196. Several other patent applications have disclosed a varied number of compounds as GPR40 modulators. Some of the representative literature is provided below:
Chandra Sekhar Gudla et al have disclosed some new 3-substituted 3-(aryloxyaryl)-propanoic acid in IJCPS, 2014, Vol. 2(5), 852-861.
WO 2005095338, WO 2006038738, WO 2006083612, WO 2006083781, WO 2007013679, WO 2007136572, WO 2007136573. WO 2007049050. WO 20070123225, WO 2008002931, WO 2008054674, WO 2008054675. WO 200830520, WO 2008130514, WO 2008139987, WO 2009058237, WO 2009048527, WO 2009054423, U.S. Pat. No. 7,968,552, WO 2009038204. WO 2010045258. WO 2010012650, WO 2010085522, WO 2010085525, WO 2010085528, WO 2010091176, WO 2011044073, WO 2011052756, WO 2011078371, WO 2011069958, WO 2011083752, WO 2012111849, WO 2012108478, WO 2012074126, WO 2012020738, WO 2012004261, WO 2012010413, WO 2012010413, WO 2012011125 etc.
Drugs aimed at the pathophysiology associated with insulin dependent Type I diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidemia and hyperglycemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
Similarly, metabolic syndrome (syndrome X) which is characterized by hypertension and its associated pathologies including atherosclerosis, lipidemia, hyperlipidemia and hypercholesterolemia have been associated with decreased insulin sensitivity which can lead to abnormal blood sugar levels when challenged. Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
There is a continuing need for novel antiobesity and antidiabetic agents, particularly ones that are well tolerated with few adverse effects.
The present invention is directed to agonists of GPR 40 that are useful for the treatment of diabetes. In humans, GPR 40 is expressed in the pancreas. As discussed above, several GPR 40 agonists have been developed and are continuing to be developed. However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime.
We herein disclose novel compounds of formula (I) useful as antidiabetic, anti-obesity, hypolipidaemic, hypolipoproteinemic, and antihyperglycemic agents which may have beneficial effect in the treatment and/or prophylaxis of diseases caused by hyperlipidemia, diseases classified under Syndrome X and atherosclerosis, and methods for their preparation.
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