OA17701A - Novel heterocyclic compounds. - Google Patents

Novel heterocyclic compounds. Download PDF

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Publication number
OA17701A
OA17701A OA1201600153 OA17701A OA 17701 A OA17701 A OA 17701A OA 1201600153 OA1201600153 OA 1201600153 OA 17701 A OA17701 A OA 17701A
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OAPI
Prior art keywords
methyl
phenyl
benzyl
oxy
hex
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OA1201600153
Inventor
Ranjit C. Desai
Brijeshkumar Srivastava
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Cadila Healthcare Limited
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Abstract

The present invention relates to novel GPR 40 agonists of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

Description

The présent invention relates to novel GPR 40 agonists of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their préparation, use of these compounds in medicine and the intermediates involved in their préparation.
The présent invention is directed to G-protein coupled receptor (GP CR) agonists that are useful for the treatment of obesity, diabètes and related metabolic disorders.
The compounds of the general formula (I) lower blood glucose, regulate peripheral satiety, lower or modulate triglycéride levels and/or cholestérol levels and/or low-density lipoproteins (LDL) and raises the high-density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is bénéficiai. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabètes and many other related conditions.
The compounds of general formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.
These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin résistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolérance. The glucose intolérance can lead to non-insulin dépendent diabètes mellitus (NIDDM, Type 2 diabètes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin résistance. Diabètes is no longer considered to be associated only with glucose metabolism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prévention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, like arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and rénal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage rénal diseases, like microalbuminuria and albuminuria, which may be resuit of hyperglycemia or hyperinsulinemia.
BACKGROUND OF THE INVENTION
Diabètes 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.
Diabètes 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 diabètes, but the two most common are Type I (also referred to as insulin-dependent diabètes mellitus or IDDM) and Type II (also referred to as non-insulin-dependent diabètes mellitus or NIDDM).
The etiology of the different types of diabètes is not the same; however, everyone with diabètes 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 hâve diabètes rely on insulin, a hormone made in the pancréas, to move glucose from the blood into the cells of the body. However, people who hâve diabètes either don't produce insulin or can't efficiently use the insulin they produce; therefore, they can't move glucose into their cells. Glucose accumulâtes in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.
Diabètes is a syndrome with interrelated metabolic, vascular, and neuropathie components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin sécrétion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and rénal complications. Abnormalities in the peripheral and autonomie nervous Systems are also part of the diabetic syndrome.
About 5% to 10% of the people who hâve diabètes hâve 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 pancréas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabètes, strikes young and older adults alike.
Approximately 90 to 95% of people with diabètes hâve Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin résistant: the cells don't respond properly to the hormone, so glucose accumulâtes 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 hâve normal or even elevated blood insulin levels, while other NIDDM patients hâve inadéquate insulin production (Rotwein, R. et al. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are âge 30 or older, and half of ail new cases are âge 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 diffîcult.
The primary pathogenic lésion on NIDDM has remained elusive. Many hâve suggested that primary insulin résistance of the peripheral tissues is the initial event. Genetic epidemiological studies hâve supported this view. Similarly, insulin sécrétion abnormalities hâve 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 Rimoiris Principles and Practice of Medical Genetics 3rd Ed. 1:1401-1402 (1996)).
Many people with NIDDM hâve 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 résistance, 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 promûtes insulin sécrétion whilst a GPR 40 antagonist inhibits insulin sécrétion 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 diabètes, obesity, impaired glucose tolérance, insulin résistance, neurodegenerative diseases and the like.
There is increasing évidences that lipids can also serve as extracellular ligands for a spécifie class of receptors and thus act as “nutritional sensors” (Nolan CJ et al. J. Clinic. Invest., 2006, 116, 1802-1812The free fatty acids can regulate cell function. Free fatty acids hâve demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and hâve been proposed to play a critical rôle in physiological glucose homeostasis.
GPR40, GPR120, GPR41 and GPR43 exemplify a growing number of GPCRs that hâve 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 shortchain fatty acid (Brown AJ et al, 2003).
GPR 40 is highly expressed on pancreatic β-cells, and enhances glucose-stimulated insulin sécrétion (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 sécrétion 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 molécule GPR40 agonists. (Does this describe GW9508?)Another article titled Pharmacological régulation of insulin sécrétion in MIN6 cells through the fatty acid receptor GPR40: Identification of agonist and antagonist small molécules is reported in
Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKline, USA (Does this describe
GW9508?)
O
OH
GW 9508
Solid phase synthesis and SAR of small molécule 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 Sériés of G-protein -coupled receptor 40 agonistsf J. Med. Chem. 2007, 16, 2807-2817) National Institutes of Health, Bethesda, Maryland published “Bidirectional Itérative Approach to the Structural Délinéation of the Functional Chemo print in GPR 40 for agonist Récognition (J. Med. Chem. 2007, 50, 2981-2990).
Discovery of diacyl phloroglucinols of the following formula
O OH O as a new class of GPR40 (FFAR1) agonists has been published by Piramal Life Sciences, Ltd. in Bioorg. Med. Chem. Lett. 2008, 18, 6357-6361
Synthesis and SAR of 1,2,3,4-tetrahydroisoquinoline-l-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
O
Piramal Life Sciences Ltd. published “Progress in the discovery and development of small molécule modulators of G-protein coupled receptor 4O(GPR4O/FFA1/FFAR1), an emerging target for type 2 diabètes” in Exp. Opin. Therapeutic Patents 2009, 19(2), 237264.
There was a report published in Zhongguo Bingli Shengli Zazhi 2009, 25(7), 1376-1380 from Sun Yat. S en University, Guangzhou, which mentions the rôle 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.
N41(DC260126)
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, sélective, and orally bioavailable GPR 40 agonist is reportedbyTakeda Pharmaceutical Ltà. ACSMed. Chem. Lett. 2010, 7(6), 290-294
TAK-875
EC50=14 nM
Ki= 38 nM
In another report from University of Southern Denmark” Structure -Activity of Dihydrocinnamic acids and discovery of potent FFA1 (GPR40) agonist TUG-469” is reported mACSMed. 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 sécrétion, has emerged as an attractive target for the treatment of type 2 diabètes (ACSMed. Chem. Lett. 2010, 1(6), 290-294). G-protein coupled receptor (GPR40) expression and its régulation in human pancreatic islets: The rôle of type 2 diabètes 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
O
O
1. EC50=0.74 μΜ
Cl
O
4. EC50=0.970 μΜ
2. R-|=CJ ( ECS0=1.358 μΜ)
3. ^= CF3 ( EC50=0.686 μΜ)
5. ECS0=2.484 μΜ
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, 57(5), 13651378.
Amgen disclosed a potent orally bioavailable GPR 40 agonist AMG-837 in Bioorg. Med.
Chem. Lett. 2012, 22, 1267-1270
Discovery of phenylpropanoic acid dérivatives containing polar functionalities as Potent and orally bioavailable G protein-coupled receptor 40 Agonist for the treatment of type 2 Diabètes 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 vaACS Med. Chem. Lett. 2012, 3(9), 726-730.
Optimization of (2,3-Dihydro-l-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 -dépendent insulinotropic agent is reported by Takeda in J. Med. Chem. 2012, 55, 3960-3974.
Bayer disclosed indane, dihydrobenzoforan, and tetrahydronaphthalene carboxylic acid dérivatives and their use as antidiabetics in patent application no. WO 2004011446 with the following formulae
Takeda disclosed 3-(4-Benzyloxyphenyl) propanoic acid dérivatives in a patent WO
2005063729 with the following general formula:
O
WO 2005086661 Al (22 September 2005, Amgen Inc.) disclosed compounds, pharmaceutical compositions and methods for use in treating metabolic disorders, having the following formula:
q-iAp-iâm-x-iAa
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 Al (13th April 2006, Takeda Pharmaceutical Ltd., Japan) disclosed certain receptor fonction regulating agent with the following general structure
B1
Merck & Co. disclosed antidiabetic bicyclic compounds in W02006083781. Disclosed therein are bicyclic compounds containing a phenyl or pyridyl ring fosed 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 usefol as therapeutic compounds, particularly in the treatment of Type 2 diabètes 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 fosed 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 diabètes 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:
(R2)p Z
wherein Z is selected from the group consisting of CR3R4CO2R5, -OCR3R4CO2R5, N (Rô) (CR3R4CO2R5), -SCR3R4CO2R5, tetrazole, and the heterocyclic ring II.
Condensed ring compounds hâve been disclosed by Yasum et al. in a patent US 7820837. The following formula mentioned in US 7517910 claims compounds having a GPR 40 receptor fonction modulating action, which are usefol as insulin secretagogues, agents for the prophylaxis or treatment of diabètes and the like
Novel Spiropiperidine compounds hâve 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 dérivatives usefol for the treatment of diabètes hâve been described by Eli Lilly & Company in patent application no. WO 2013025424
A patent application, WO 2013147443 titled “Préparation of β- substituted carboxylic acid dérivatives for the treatment of diabètes” has been published by Daichi Sankyo.
Piramal Enterprises Limited has published a patent application no. WO 2013/128378 for phenyl alkanoic acid dérivatives as GPR agonists with the structure below RxYX(R4)n
RyAA^CH^COOR, r3 z r2
Boehringer Ingelheim has published patent application numbers WO 2013/144097 & WO
2013/144098 titled “New indanyloxy dihydrobenzoforanyl acetic acid dérivatives and their use as GPR receptor agonists” with the structures defined below
Novel therapeutic target for treatment of cancers and related thérapies and methods are disclosed in patent application no. WO 2014145817 by Children’s Medical Center Corporation.
WO 2014146604 disclosed certain fosed ring compounds having GPR40 receptor fonction regulating action.
Tricyclic compound and use thereof has been published by SK Chemicals Co., Ltd. in patent application no. WO2014133361.
Certain antidiabetic bicyclic compounds hâve been disclosed in patent application no. W02014130608.
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 hâve 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. W02014078611, W02014078610, W02014078609 & W02014078608.
LG Life Sciences Limited has disclosed certain GPR40 receptor agonist in patent W02014073904. Hancke Orozco et al. hâve 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 hâve been disclosed in patent application no. US20140058125.
Mochida Pharmaceutical Co. has disclosed Cyclic amide dérivative in patent US20140057871. Negoro et al. hâve disclosed certain carboxylic acid compounds in patent application no. US20120035196. Several other patent applications hâve disclosed a varied number of compounds as GPR40 modulators. Some of the représentative literature is provided below:
Chandra Sekhar Gudla et al hâve 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, US 7968552, 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 EP 1731505 Al, WO 2011/046851, WO 2014/171762 Al, etc.
Drugs aimed at the pathophysiology associated with insulin dépendent Type I diabètes and non-insulin dépendent Type II diabètes hâve many potential side effects and do not adequately address the dyslipidemia and hyperglycemia in a high proportion of patients. Treatment is ofiten 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 hâve 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 présent invention is directed to agonists of GPR 40 that are useful for the treatment of diabètes. In humans, GPR 40 is expressed in the pancréas. As discussed above, several GPR 40 agonists hâve 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 présent treatment régimes, hâve lesser side effects and require a lower dosage régime.
We herein disclose novel compounds of formula (I) useful as antidiabetic, anti-obesity, hypolipidaemic, hypolipoproteinemic, and antihyperglycemic agents which may hâve bénéficiai effect in the treatment and/or prophylaxis of diseases caused by hyperlipidemia, diseases classified under Syndrome X and atherosclerosis, and methods for their préparation.
The main objective of the présent invention is to provide novel GPR40 agonists represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
In an embodiment of the présent invention is provided processes for the préparation of compounds represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts.
In a further embodiment of the présent invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In yet another embodiment is provided a pharmaceutical composition comprising the compound of formula (I) and a second suitable therapeutic agent for the treatment of diabètes, obesity and other related disorders.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the présent invention relates to compounds of the general formula (I)
Formula (I) their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein each of RI; R2j R3, R4, Rs, Rô, at each occurrence independently represents H, halogen, hydroxyl, CN, NO2, CHO, COOH, CO, optionally substituted groups selected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH2 or optionally substituted NHCO-linear or branched (Ci-Cg)alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR C(O)R; and SO2R wherein ‘R’ at each occurrence independently represents optionally substituted groups selected from H, linear or branched (Ci-Cô)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetrerocyclylalkyl, heteroaryl, heteroaralkyl groups; In an altemate embodiment, R3 and R4 together may form an oxo group;
‘A’ is selected from 3-7 member partially saturated, unsaturated or saturated ring which may further be having one or more than one heteroatom selected from O, S, or N;
Each of Έ’ & ‘D’ may independently be either nitrogen or carbon. ‘F’ may be selected from C, N or O; ‘G’ may be présent or absent and when présent represents either a bond or is selected from O, S, NRa, wherein ‘Ra’ represents linear or branched (Ci-Cô) alkyl;
m =1-3; each of ‘n’, ‘r’, ‘p’ and‘s’ independently represents an integer ranging from 0 to 6;q-0-4;
‘X’ may be présent or absent and when présent is selected from CH2, O, S, and NRa, SO2NH; wherein Ra is as defined earlier;
‘T’is selected from oxygen, -NH, S, SO, SO2 or NRa> wherein Raisas defined earlier; each of R7 and R8 independently may be selected (C2-C4)alkyne, nitrile, or a cycloalkyl; Altematively R7 and R8 may combine with the carbon atom to which it is attached to form a 3-7 membered cyclic ring which may optionally further hâve one or more than one heteroatom selected from S, N, or O;
R9 & Rio may be selected from hydrogen, alkyl, alkoxy, and halogen groups.
A preferred embodiment of the présent invention relates to compound of the general Formula (I’)
Formula (I’) their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein
Each of Ri, R2j R3 and R4 at each occurrence independently represents H, halogen, hydroxyl, CN, NO2, CHO, COOH, CO, optionally substituted groups selected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH2 or optionally substituted NHCO-linear or branched (Ci-Cg)alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR C(O)R and SO2R wherein ‘R’ at each occurrence independently represents optionally substituted groups selected from H, linear or branched (Ci-Cô)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetrerocyclylalkyl, heteroaryl, heteroaralkyl groups;
In an altemate embodiment, R3 and R4 together may form an oxo group;
‘A’ is selected from 3-7 member partially saturated, unsaturated or saturated ring which may further be having one or more than one heteroatom selected from O, S, or N;
Each of Έ’ & ‘D’ may independently be either nitrogen or carbon. ‘F’ may be selected from C, N or O;
Each of ‘n’, er’ and‘s’ independently represents an integer ranging from 0 to 6;
each of R5 and Rô independently may be selected (C2-C4)alkyne, nitrile, or a cycloalkyl; Altematively R5 and Re may combine with the carbon atom to which it is formed to form a
3-7 membered cyclic ring which may optionally further hâve one or more than one heteroatom selected from S, N, or O;
The preferred heterocycles representing
may be selected from the following bicyclic rings mentioned below
The substituent
-COOH may be optionally replaced wherever possible with bioisosteric replacements such as:
„CN / P ,oh 'N
H h,
Il n \ H
O
and the like;
When any of the groups from Ri to Rio are substituted with one or many groups, the substituents may be independently selected from the groups comprising hydroxyl, oxo, 25 halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, hetero cyclyloxy, hetero cyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its dérivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl dérivatives, sulfonyl dérivatives, sulfonic acid and its dérivatives.
The aryl group may be an aromatic system containing one, two or three rings wherein such rings may be attached together in a dépendent manner or may be fiised; in a preferred embodiment such aryl group may be selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl groups;
The heteroaryl group represents 5 to 8 membered aromatic radicals, which may be single or fused containing one or more hetero atoms selected from O, N or S; in a preferred embodiment such groups may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidinyl, pyrazolopyrimidonyl, azaquinazolinyl, azaquinazolinoyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, thienopyrimidonyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, quinazolonyl, pyrimidonyl, pyridazinyl, triazinyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, b enzo triazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl groups;
The term “heterocyclyl” represents saturated, partially saturated or unsaturated ringshaped radicals, the heteroatoms being selected from nitrogen, sulfur or oxygen; in a preferred embodiment such groups may be selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl,
2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, and the like;
examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole groups.
The “alkyl” group used either alone or in combination with other radicals, dénotés a linear or branched radical containing one to six carbons, selected from methyl, ethyl, zz-propyl, zso-propyl, zz-butyl, sec-butyl, tert-butyl, amyl, Aamyl, zz-pentyl, zz-hexyl, and the like;
- the “alkenyl” group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl and the like; the “alkenyl” group includes dienes and trienes of straight and branched chains;
- the “alkynyl” group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like. The term “alkynyl” includes di- and tri-ynes;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; The terms “bicycloalkyl” means more than one cycloalkyl groups fused together;
- the “cycioalkenyl” group used either alone or in combination with other radicals, are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3cyclohexenyl and the like;
- the “alkoxy” group used either alone or in combination with other radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, ί-butoxy, zso-butoxy, pentyloxy, hexyloxy, and the like;
- the “cycloalkoxy” group used either alone or in combination with other radicals, is selected from groups containing an cycloalkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like;
- the “aryloxy” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like;
- the “aralkyl” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an alkyl radical, as defîne above, more preferably groups selected from benzyl, phenethyl, and the like;
- the “aralkoxy” group used either alone or in combination with other radicals, is selected from groups containing an aralkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from benzyloxy, phenethyloxy, and the like;
- the “heteroaralkyl” group used either alone or in combination with other radicals, is selected from groups containing an heteroaryl radical, as defined above, attached directly to an alkyl radicals, as define above, more preferably groups selected from pyridinealkyl, thiophenealkyl, quinolinealkyl, and the like;
- the “alkenoxy” group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like;
- the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(Ci-C6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
- the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
- the “perhaloalkoxy” group is selected from a suitable perhaloalkyl radical, as defined above, directly attached to an oxygen atom, more preferably groups selected from trifluoromethoxy, trifluoroethoxy, and the like;
- the groups “heteroaryloxy”, “heteroaralkoxy”, “heterocycloxy”, “heterocylylalkoxy” are selected from suitable heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom;
- the “acyl” group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, rio-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
- the “acyloxy” group used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, zxo-butanoyloxy, benzoyloxy and the like;
- the “acylamino” group used either alone or in combination with other radicals, is 10 selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH, CgHsCONH and the like, which may be substituted;
- the “mono-substituted amino” group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (Ci-
Cô)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, npropylamine, n-butylamine, n-pentylamine and the like;
- the ‘disubstituted amino” group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or different selected from (Ci-Cô)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like;
- the “arylamino” used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamino, 7V-methyl anilino and the like;
- the “oxo” or “carbonyl” group used either alone (-C-O-) or in combination with other radicals such as alkyl described above, for e.g. “alkylcarbonyl”, dénotés a carbonyl radical (-C-O-) substituted with an alkyl radical described above such as acyl or alkanoyl;
- the “carboxylic acid” group, used alone or in combination with other radicals, dénotés a -COOH group, and includes dérivatives of carboxylic acid such as esters and amides;
- the “ester” group used alone or in combination with other radicals, dénotés -COOgroup, and includes carboxylic acid dérivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where 10 the heterocyclic group, as defined earlier, which may optionally be substituted;
- the “amide” group used alone or in combination with other radicals, represents an aminocarbonyl radical (H2N-C=O), wherein the amino group is mono- or disubstituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl amide, ethyl amide, diethyl amide, and the like;
- the “aminocarbonyl” group used either alone or in combination with other radicals, may be selected from ‘aminocarbonyl’, ‘aminocarbonylalkyl”, “nalkylaminocarbonyl”, “N-arylaminocarbonyl”, “Ν,Ν-dialkylaminocarbonyl”, “Nalkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and “N-alkyl-Nhydroxyaminocarbonylalkyl”, each of them being optionally substituted. The terms 20 “N-alkylaminocabonyl” and “Ν,Ν-dialkylaminocarbonyl” dénotés aminocarbonyl radicals, as defined above, which hâve been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” dénoté amiocarbonyl 25 radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term “aminocarbonylalkyl” includes alkyl radicals substituted with aminocarbonyl radicals;
- the “hydroxyalkyl” group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like;
- the “aminoalkyl” group used alone or in combination with other radicals, dénotés an amino (-NH2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term “alkylamino” used herein, alone or in combination with other radicals, dénotés an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and disubstituted alkylamino;
- the “alkoxyalkyl” group used alone or in combination with other radicals, dénotés an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like;
- the “alkylthio” group used either alone or in combination with other radicals, dénotés a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted;
- the “thioalkyl” group used either alone or in combination with other radicals, dénotés an alkyl group, as defined above, attached to a group of formula -SR’, where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.
- the “alkoxycarbonylamino” group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;
- the “aminocarbonylamino”, “alkylaminocarbonylamino”, “dialkylaminocarbonylamino” groups used alone or in combination with other radicals, is a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above;
- the “amidino” group used either alone or in combination with other radicals, represents a -C(=NH)-NH2 radical; the “alkylamidino” group represents an alkyl radical, as described above, attached to an amidino group;
- the “alkoxyamino” group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group;
- the “hydroxyamino” group used either alone or in combination with other radicals, represents a -NHOH moiety, and may be optionally substituted with suitable groups selected from those described above;
- the “sulfenyl” group or “sulfenyl dérivatives” used alone or in combination with other radicals, represents a bivalent group, -SO- or RXSO, where Rx is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above;
- the “sulfonyl” group or “sulfones dérivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical SO2-, or RxSO2-, where Rx is as defined above. More preferably, the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, “arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
- the “sulfonyloxy” group used either alone or in combination with other radicals, with other terms such as alkylsulfonyloxy, represents a divalent radical -SO3-, or RXSC>3-, where Rx is as defined above. More preferably, the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyloxy radical, such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and the like, “arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as benzenesulfonyloxy and the like
Suitable groups and substituents on the groups may be selected from those described anywhere in the spécification.
Particularly useful compounds may be selected from (5)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoic acid (1);
Lithium 3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3cyanopropanoic acid;
3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid;
Lithium 3-cyano-3-(4-((3-((3-(trifhioromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid;
3-cyano-3-(4-((3-((2,2-dioxido-lH-thieno[3,4-c]pyrrol-5(3H,4H,6H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
$)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((l-(tert-butoxycarbonyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((2 -methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((3,4-dihydroquinolin-l(2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; $)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3 -(4-((3-((3,4-dihydroisoquinolin-2( 1 H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
calcium$)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridm-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate$)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
calcium$)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate$)-3-(4-((3-((2-methyl-6,7dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
$)-3-(4-((3-((2-(Difluoromethyl)-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
Calcium $)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
Calcium $)-3-(4-((3-((3,4-dihydroisoquinolin-2( 1 H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoate;
$9-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3)-3-(4-((3 -(( 1 -Methylpyrrolo [3,4-c]pyrazol-5( 1 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4ynoic acid;
(S)-3 -(4-((3 -(Indolin-1 -ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$9-3-(4-((3-((5,6-Dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$9-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(lH)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid; $9-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
6-(3-((4-($9-l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5Hpyrrolo[3,4-d]pyrimidin-6-ium formate;
l-(3-((4-($9-l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-l,2,3,4tetrahydroquinolin-l-ium formate;
$9-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$9-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yI)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$9-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(lH,4H,6H)-ylmethyl)benzyl)oxy)phenyl)hex-4ynoic acid;
$9-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$9-5-(3-((4-(l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7tetrahydrothieno [3,2-c]pyridine-2-carboxylic acid;
3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
$9-3-(4-((3-((1 -methyl-6,7-dihydro-1 H-pyrrolo [3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-amino-6,7-dihydrothiazolo [5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
Calcium (5)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
(S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
((5)-3-(4-((3 -((2-isopropylpyrrolo [3,4-c]pyrazol-5(2H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo [l,5-a]pyrazin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3 S)-3 -(4-((3 -((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3 S)-3 -(4-((3 -((2-phenylpyrrolidin-1 -yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid; (5)-3-(4-((3-(Pyrrolidin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
(S)-3-(4-((3-(Piperidin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
(5)-3-(4-((3 -((1 -isopropylpyrrolo [3,4-c]pyrazol-5 ( 1 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
(R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(R) -3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(3/J-3-(4-((3-((6,7-Dihydro-[l,2,3]triazolo[l,5-a]pyrazin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
3-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
fSJ-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(SJ-3-(4-((3-((2-(pyrrolidine-l-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(5)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
Calcium (S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
(SJ-3-(4-((3-((2-NitiO-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
(S) -3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido [4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
(S)-3-(4-((3-((2-Amino-7,8-dihydropyrido [4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid; (3/)-3-(4-((3-((7,8-Dihydro-l,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoic acid;
(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
(37)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
$)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
$)-3-(4-((3-((2-((Methylamino)methyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
The following compounds can be synthesized following the similar procedure as described for example 1 with suitable modifications as are well known to a person skilled in the art and are considered to be encompassed within the scope of the présent invention.
3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoic acid
3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid
3-cyano-3-(4-((3-((2,2-dioxido-lH-thieno[3,4-c]pyrrol-5(3H,4H,6H)yl)methyl)benzyl)oxy)phenyl)propanoic acid .0
O
3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid
(S)-3-(4-((3-((2 -methoxy-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
$9-3-(4-((3-((2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-(methylsulfo nyl)-5H-p yrrolo [3,4-d]pyrimidin-6(7H)-
(5)-3-(4-((3-((6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)methyl)benzyI)oxy)phenyl)hex-4ynoic acid
OH (S)-3-(4-((3-((2-(2,2,2-trifluoroethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-isopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-(dimethylamino)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-(tert-butyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-oxo-l,2,6,7-tetrahydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(S)-3-(4-((3-((2-cyano-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)5 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(3S)-3-(4-((3-((4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
(3S)-3-(4-((3-((4-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
The novel compounds of this invention may be prepared using the reactions and techniques described in the below section along with, whenever appropriate other suitable 15 processes known to a skilled person. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the présent invention and also that certain steps may be modified, altered, obvious steps added or deleted in order to optimize as well as required for preparing the 5 compounds of the présent invention. Such, obvious changes should also be considered as being part of the présent invention.
Scheme 1: Compounds of general formula (I) may be prepared according to the scheme described below
A compound of formula (I) can be prepared in accordance with reactions as depicted in scheme 1.
The first step involves the reaction of substituted carboxylic acid (intermediate 1 a) with an appropriate substituted heterocycle (intermediate 2a) under peptide bond formation conditions to give intermediate 3a. The ester of intermediate 3a can be reduced using a 15 suitable reducing agent such as diisobutylaluminum hydride, lithium aluminum hydride or sodium borohydride etc. to give intermediate 4a. Intermediate 4a can be further reacted with compounds of formula II under Mitsunobu conditions to give intermediate 5a.
Mitsunobu conditions involve reacting an alcohol intermediate 4a with a nucleophile such as a phénol (formula II), using a suitable phosphine such as tributyl phosphine, triphenyl phosphine, or triethyl phosphine and an azodicarbonyl such as ADDP or an azodicarboxylate (DEAD).
Altematively, intermediate 4a can be converted to compound having suitable leaving group such as mesylate dérivative (intermediate 6a) using an appropriate set of reactants and conditions such as methanesulfonyl chloride and triethylamine.
The intermediate 6a can be reacted with compound of formula II using diisopropyl ethylamine or césium carbonate to give intermediate 5a.
The intermediate 5a can be hydrolyzed to give carboxylic acid dérivative of formula (I) using bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
In an optional step, a pharmaceutically acceptable sait of a compound of formula (I) can be formed by reaction of appropriate compound of formula (I) with a pharmaceutically acceptable base or with and acid in a suitable solvent under standard conditions. Optionally, the formation of such salts can occur simultaneously upon hydrolysis of an ester intermediate.
The formation of such salts is well known and appreciated in the art.
The compounds of the présent invention can be used either alone or in combination with one or more therapeutic agents selected from insulin, insulin dérivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1 analogs, DPP-IV inhibitors, GPR-119 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and other anti-obesity agents or pharmaceutically acceptable salts thereof. Such use will dépend on the condition of the patient being treated and is well within the scope of a skilled practitioner.
Following the general process described above, including suitable modifications and additions which are within the scope of a skilled person, the following compounds of formula (1) were prepared as follows:
1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Broker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCI3.
Example 1 (3)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy) phenyl)hex-4ynoic acid (1)
Scheme 2:
intermediate 5
Procedure:
i. Methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate ( intermediate 3)
To 3-(methoxycarbonyl)benzoic acid intermediate 1 (10 g, 55.5 mmol) was added thionyl chloride (16.21 mL, 222 mmol) in small portions at 25 °C followed by a drop of dimethylformamide. The reaction mixture was stirred under refluxing for 3 h. Excess thionyl chloride was evaporated under reduced pressure at 100 °C. The 4,5,6,7tetrahydrothieno[3,2-c]pyridine hydrochloride intermediate 2 (12.19 g, 69.4 mmol) was dissolved in 100 mL of water, to that added solution of sodium hydroxide (4.44 g, 111 mmol) in 25 mL of water. Free base of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine was extracted in dichloromethane (75 mL), dried over anhydrous potassium carbonate. The acid chloride was dissolved in anhydrous dichloromethane (75 mL) and cooled to 0 °C.
To the reaction mixture added drop wise triethylamine (15.47 mL, 111 mmol) followed by solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in dichloromethane(75 mL) drop by drop at 0 °C. The reaction mixture was warmed to 25 °C and stirred it for 3 h. Progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-water (125 mL), adjusted pH ~4 with 10% HCl and extracted with dichloromethane (3 x 100 mL). The combined organic fractions were washed with 5% sodium hydroxide (100 mL) followed by brine (100 mL), dried over anhydrous Na2SO4 and evaporated on a rotatory evaporator under reduced pressure to afford crude amide intermediate 3.
The crude product was purified by flash column chromatography using 230-400 mesh silica-gel as a stationary phase and 10-50% ethyl acetate - hexanes as a mobile phase afforded pure methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate (12 g, 39.8 mmol, 71.7 % yield) ii. (3-((6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol ( intermediate 4)
To a solution of methyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate intermediate 3 (12 g, 39.8 mmol) in dry THF (100 mL) was added LÎA1H4 (3.02 g, 80 mmol) in small portions at 25 °C. The reaction mixture was stirred under refluxing for 3 h. The progress of reaction was monitored by TLC by using mobile phase 30% ethyl acetate in hexane. Suspension of aqueous sodium sulfate was added drop wise to the reaction mixture to quench excess LÎA1H4. Ethyl acetate (150 mL) was added to the reaction mixture and refluxed for 30 min and decanted ethyl acetate, this process was repeated three times to ensure no product in white slug of lithium sulfate and aluminum hydroxide. The combined organic fractions were dried over anhydrous Na2SO4 and evaporated on a rotatory evaporator under reduced pressure to afford crude product as pale yellow sticky mass of intermediate 4.
The crude alcohol intermediate 4 was purified by flash column chromatography using 230-400 mesh silica-gel as stationary phase and 10-50% ethyl acetate - hexane as a mobile phase afforded pure (3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)phenyl)methanol intermediate 4 (5.41 g, 20.86 mmol, 52.4 % yield).
iii. (5)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid (1)
17701 T \
To a solution of (3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol intermediate 4 (0.16g, 0.617 mmol) in 5 mL of anhydrous tetrahydrofuran was added triethylamine (0.258 ml, 1.851 mmol) followed by methanesulfonyl chloride (141 mg, 1.234 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-water (25 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic fractions were dried over anhydrous Na2SO4 and evaporated on a rotatory evaporator under reduced pressure to afford 3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl mesylate intermediate (5) as pale yellow sticky mass.
To a solution of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate intermediate 6 (162 mg, 0.740 mmol) in Acetonitrile (5.00 ml) was added césium carbonate (603 mg, 1.851 mmol) followed by solution of 3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl mesylate 5 in 2 mL of acetonitrile at 25 °C. Reaction mixture was stirred for 3 h at 75 °C. Progress of the reaction was monitored by TLC. After completion of the reaction, volatiles were evaporated off under reduced pressure. The reaction mixture was poured into icewater (25 mL) and product was extracted with dichloromethane (3 x 25 mL). The combined organic fractions were dried over anhydrous Na2SÛ4 and evaporated on a rotatory evaporator under reduced pressure to afford crude product as pale yellow sticky mass. Ethereal hydrochloride solution was added to the crude product, ether was evaporated off and residue was triturated with ethyl acetate afforded 65 mg of (5)-methyl 3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoate hydrochloride intermediate (7). Ester hydrochloride sait intermediate 7 (60 mg, 0.121 mmol) was hydrolyzed using mixture of THF (2 mL) and MeOH (1 mL) was added NaOH (24.19 mg, 0.605 mmol) in water (1 mL) at 25 °C. Reaction mixture was stirred for 12 h at 25 °C. Progress of the reaction was monitored by TLC. After completion of the reaction, volatiles were evaporated off, the residue was treated with ice-water (5 mL), adjusted pH ~4 (IN HCl), extracted with dichloromethane (3 x 25 mL) and dried over anhydrous Na2SO4. Evaporation of solvents on a rotatory evaporator under reduced pressure to afford crude product. Crude acid was purified by préparative TLC to afford (5)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoic acid 1 (42 mg, 0.094 mmol, 78 % yield) *H NMR (DMSO-4, 400 MHz) δ: 7.42 (s, 1H), 7.37-7.24 (m, 6H), 6.94 (d, J= 8.4 Hz, 2H), 6.75 (d, J= 5.2 Hz, 1H), 5.07 (s, 2H), 3.94 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78-
2.72 (m, 4H), 2.57-2.55 (m, 2H), 1.77 (d, J= 1.6 Hz, 3H); ESIMS: 446.2 (M+H)+.
The following compounds can be prepared by following the general scheme 1 and the process described in Example 1 above, including their suitable modifications well within the scope of a skilled person.
Example 2
Lithium 3 -(4-((3 -((4H-furo [3,4-c]pyrrol-5 (6H)-yl)methyl)benzyl)oxy)phenyl)-3 cyanopropanoic acid
*H NMR (DMSO-ik, 400 MHz) δ: 7.44 (s, 1H), 7.35-7.28 (m, 7H), 6.98 (d, J= 8.8 Hz,
2H), 6.09 (s, 2H), 4.27 (dd, J= 6.4, 8.4 Hz, 1H), 3.86 (s, 2H), 3.57 (s,
4H), 2.53-2.41 (m, 1H), 2.33-2.32 (m, 1H)
Example 3
3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid
CN o
*H NMR: (CDC13, 400MHz):- 7.47 (d, J= 5.2Hz, 1H), 7.37 - 7.23 (m, 6H), 7.11 (d, J= 5.2Hz, 1H), 6.92 (d, J= 8.8Hz, 2H), 5.06 (s, 2H), 4.77 - 4.68 (m, 2H), 4.19 (t, J= 7.6Hz, 1H), 3.55 (t, J= 6.8Hz, 2H), 3.06 - 2.98 (m, 3H), 2.88 - 2.82 (m, 1H)
Example 4
Lithium 3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin7 (8H)-yl)methyl)b enzyl) oxy)phenyl)prop anoic acid
JH NMR (CD3OD, 400 MHz) δ: 7.48 (s, 1H), 7.39-7.36 (m, 3H), 7.31 (dd, = 2, 6.8 Hz,
2H), 6.98 (dd, J = 2.4, 6.8 Hz, 2H), 5.10 (s, 2H), 4.30-4.26 (m, 1H), 4.18 (t, J = 5.2 Hz,
2H), 3.89 (s, 2H), 3.83 (s, 2H), 2.97 (t, J = 5.6 Hz, 2H), 2.74 (dd, J = 8.8, 15.6 Hz, 1H),
2.58 (dd, J = 8.8, 15.6 Hz, 1H).
Example 5
-cyano-3 -(4-((3 -((2,2-dioxido-1 H-thieno[3,4-c]pyrrol-5 (3H,4H,6H)yl)methyl)benzyl)oxy)phenyl)propanoic acid
JH NMR (CD3OD, 400 MHz) δ: 7.66 (d, 1H), 7.60-7.51 (m, 3H), 7.35 (dd, J = 2, 6.8 Hz, 2H), 7.03 (dd, J = 2, 6.4 Hz, 2H), 5.17 (s, 2H), 4.60 (s, 2H), 4.35-4.31 (m, 1H), 4.28 (s, 4H), 3..94 (s, 4H), 2.99 (dd, J = 8.4, 16.8 Hz, 1H), 2.85 (dd, J = 6.4, 16.4 Hz, 1H).
Example 6
3-cyano-3-(4-((3-((6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid
CN o
*H NMR (CDC13, 400 MHz) δ: 7.58 (s, 1H), 7.37-7.32 (m, 2H), 7.22-7.16 (m, 4H), 6.88 (dd, J = 2, 6.8 Hz, 2H), 6.71 (d, J= 5.2 Hz, 1H), 5.00 (s, 2H), 4.18-4.14 (m, 1H), 3.99 (s, 2H), 3.88 (s, 2H), 3.19-3.16(m, 2H), 3.03-3.00 (m, 2H), 2.87-2.81 (m, 1H), 2.70-2.64 (m, 1H).
Example 7 (S)-3-(4-((3-((2 -methyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
'H NMR (CDCI3, 400 MHz) δ: 7.38-7.25(m, 6H), 6.88 (d, J= 5.2 Hz, 2H), 6.33 (s, 1H), 5.04-4.98 (m, 2H), 4.05-4.00 (m, 1H), 3.80-3.71 (m, 2H), 3.64-3.55 (m, 2H), 2.92-2.61 (m, 6H), 2.39 (s, 3H), 1.82 (d, J = 2.4 Hz, 3H).
Example 8 ($-3-(4-((3-((l-(tert-butoxycarbonyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
NMR (CDC13, 400 MHz) δ: 7.47-7.38 (m, 4H), 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J =
3.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 5.94 (d, J = 3.2 Hz, 2H), 5.05 (s, 2H), 4.08 (s, 2H),
4.05-4.01 (m, 1H), 3.85 (s(br), 2H), 3.30-3.15 (m, 4H), 2.78 (dd, J = 8.8, 15.2 Hz, 1H),
2.65 (dd,J=8, 15.2 Hz, 1H), 1.80 (d, 7 = 2.4 Hz, 3H), 1.59 (s, 9H).
Example 9 (3)-3-(4-((3 -((6,7-dihydro-1 H-pyrrolo [3,2-c]pyridin-5(4H)10 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
H *H NMR (CDCI3, 400 MHz) δ: 8.51 (s, 1H), 7.42-7.33 (m, 4H), 7.25 (d, J = 8.9 Hz, 2H),
6.81 (d, J = 9 Hz, 2H), 6.63 (t, J = 2.4 Hz, 1H), 5.89 (t, J = 2.4 Hz, 1H), 5.06 (s, 2H), 4.07-3.99 (m, 3H), 3.87 (s, 2H), 3.08 (s(br), 2H), 2.80-2.74 (m, 3H), 2.61 (m, 1H), 1.80 (d,
J = 2.4 Hz, 3H)
ExamplelO ($-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDC13, 400 MHz) δ: 7.41-7.38 (m, 4H), 7.27 (d, J = 8.4 Hz, 2H), 6.85 (d, J =
8.4 Hz, 2H), 5.19-5.08 (m, 2H), 4.04-3.91 (m, 1H), 3.75 (s(br), 4H), 2.87-2.69 (m, 4H),
2.66 (s, 3H), 2.58-2.41 (m, 2H), 1.80 (d, J = 2.4 Hz, 3H)
Example 11 (S)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
ΌΗ *H NMR (CDC13, 400 MHz) δ: 7.40-7.26 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 5.12 (dd, J =
12.8, 18.4 Hz, 2H), 4.15-4.12 (m, 2H), 4.04-3.99 (m, 1H), 3.86-3.69 (m, 4H), 3.00-2.85 (m, 2H), 2.82 (dd, J = 6.8, 15.2 Hz, 1H), 2.65 (dd, J = 6.8, 15.2 Hz, 1H), 1.82 (J = 2 Hz, 3H).
Example 12 (3)-3-(4-((3 -(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid trifluoroacetic acid
ΌΗ *H NMR (CDCI3, 400 MHz) δ: 7.52-7.44 (m, 2H), 7.42-7.34 (m, 4H), 7.31-7.26 (m, 4H),
6.85 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H), 4.70(s, 2H), 4.34-4.29 (m, 2H), 4.04-4.00 (m, 1H), 3.32 (s, 2H), 2.85-2.78 (m, 1H), 2.70-2.63 (m, 1H), 1.80 (d, J = 2.4 Hz, 3H).
Example 13 (S)-3 -(4-((3 -((3,4-dihydroquinolin-1 (2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
ΌΗ ’H NMR (CDC13, 400 MHz) δ: 7.32-7.22 (m, 6H), 6.99-6.90 (m, 4H), 6.60-6.57 (m, 1H),
6.50 (d, J= 8.4 Hz, 2H), 5.02 (s, 2H), 4.49 (s, 2H), 4.06 (s(br), 1H), 3.36 (s(br), 2H), 3.02-
2.78 (m, 4H), 2.02-2.00 (m, 2H), 1.80 (s, 3H).
Example 14 (5)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDCI3, 400 MHz) δ: 7.42-7.36 (m, 3H), 7.32-7.25 (m, 3H), 6.90 (d, J = 8.4 Hz, 2H), 6.66 (s, 1H), 5.05 (s, 2H), 4.06-4.02 (m, 1H), 3.94-3.92 (m, 2H), 3.68 (s(br), 2H), 3.01 (s(br), 2H), 2.88-2.85 (m, 2H), 2.80-2.74 (m, 1H), 2.69-2.63 (m, 1H), 1.83 (d, J = 2.4 Hz, 3H).
Example 15 (5)-3-(4-((3-((3,4-dihydroisoquinolin-2(lH)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDCI3, 400 MHz) δ: 7.47(s, 1H), 7.42-7.27 (m, 5H), 7.22-7.15 (m, 3H), 7.057.02 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.10-5.03 (m, 2H), 4.10-4.06 (m, 1H), 2.02-2.00 (m, 2H), 1.80 (s, 3H)., 3.87-3.80 (m, 4H), 2.96-2.86 (m, 4H), 2.86-2.80 (m, 1H), 2.78-2.74 (m, 1H), 1.86 (d, J= 2.4 Hz, 3H).
Example 16 cal cium(5J-3-(4-((3-((2-methyl-6,7-dihydrothieno [3,2-c]pyridin-5 (4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(5)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate
*H NMR (DMSO-cZtf, 400 MHz) δ: 7.40 (s, 1H), 7.35-7.23 (m, 5H), 6.88 (d, J = 8.4 Hz, 2H), 6.41 (s, 1H), 5.04 (s, 2H), 4.00 (s(br), 1H), 3.64 (s, 2H), 3.32 (s, 2H), 2.68 (s, 4H), 2.40-2.37 (m, 1H), 2.33 (s, 3H), 2.27-2.21 (m, 1H), 1.74 (d, J = 2 Hz, 3H).
Example 17 calcium('5)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(SJ-3-(4-((3-((2-methyl-6,7dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate
*H NMR (DMSO-ûfc, 400 MHz) δ: 7.41 (s, 1H), 7.34-7.23 (m, 5H), 6.89 (d, J = 8.8 Hz,
2H), 5.01 (s, 2H), 4.05-3.99 (m, 1H), 3.68 (s, 2H), 3.56 (s, 2H), 2.76-2.74 (m, 2H), 2.68 (s(br), 2H), 2.56 (s, 3H), 2.40-2.36 (m, 1H), 2.26-2.22 (m, 1H), 1.73 (d, J = 2.4 Hz, 3H).
Example 18 (S)-3-(4-((3-((2-(Difluoromethyl)-6,7-dihydrothieno [3,2-c]pyridin-5(4H)15 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
Ή NMR (CDC13, 400 MHz) δ: 7.39-7.26 (m, 6H), 6.91-6.59 (m, 4H), 5.03 (s, 2H), 4.12-
4.10 (m, 1H), 3.73 (s, 2H), 3.55 (s, 2H), 2.88-2.64 (m, 6H), 1.82 (d, J =
2.4 Hz, 3H).
Example 19
Calcium (SJ-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridm-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate
!H NMR (DMSO-î7(5, 400 MHz) δ: 7.41 (s, 1H), 7.37-7.24 (m, 5H), 6.93-6.89 (m, 3H), 5.06 (s, 2H), 3.96-3.94 (m, 1H), 3.66 (s, 2H), 3.38 (s, 2H), 2.71 (s, 4H), 2.49-2.32 (m, 2H),
1.76 (d, 7 = 2.4 Hz, 3H).
Example 20
Calcium (S)-3 -(4-((3-((3,4-dihydroisoquinolin-2( 1 H)-yl)methyl)benzyl)oxy)phenyl)hex-4-
*H NMR (DMSO-tZg, 400 MHz) δ: 7.37 (s, 1H), 7.35-7.23 (m, 5H), 7.11-7.07 (m, 3H),
6.98-6.97 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.99-3.97 (m, 1H), 3.64 (s, 2H),
3.52 (s, 2H), 2.79-2.77 (m, 2H), 2.65-2.64 (m, 2H), 2.42-2.36 (m, 1H), 2.28-2.22 (m, 1H),
1.74 (d, 7=2.4 Hz, 3H).
Example 21 (5)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
rHNMR (CDC13, 400 MHz) δ: 8.94 (s, 1H), 8.30 (s, 1H), 7.45 (s, 1H), 7.38-7.25 (m, 5H),
6.86 (dd, 7= 2, 6.8 Hz, 2H), 5.15-5.09 (m, 2H), 4.06-4.03 (m, 1H), 3.78-3.62 (m, 4H), 2.89-2.73 (m, 6H), 1.82 (d, 7 = 2.4 Hz, 3H).
Example 22 f5j-3-(4-((3-((l-Methylpyrrolo[3,4-c]pyrazol-5(lH,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDC13,400 MHz) δ: 7.43-7.24 (m, 6H), 7.17(s, 1H), 6.88 (td, J = 5.2, 8.4 Hz, 2H), 5.03 (s, 2H), 4.07 (s, 2H), 4.02-3.97 (m, 5H), 3.75 (s, 3H), 2.78-2.72 (m, 1H), 2.662.60 (m, 1H), 1.80 (d, J = 2.4 Hz, 3H).
Example 23 (3 S)-3 -(4-((3 -(6-Oxa-3 -azabicyclo [3.1.1 ]heptan-3 -ylmethyl)benzyl)oxy)phenyl)hex-4ynoic acid
ΌΗ ‘H NMR (CDCI3, 400 MHz) 0:7.53-7.25 (m, 6H), 6.89 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H),
4.54-4.52 (m, 2H), 4.05-3.93 (m, 3H), 3.24-2.94 (m, 4H), 2.81-2.75 (m, 1H), 2.69-2.63 (m, 1H), 2.42 (d, J = 8.8 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H).
Example 24 (S)-3-(4-((3-(Indolin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid
ΌΗ ’H NMR (CDCI3, 400 MHz) δ: 7.41 (s, 1H), 7.37-7.25 (m, 5H), 7.10-7.05 (m, 2H), 6.93-
6.89 (m, 2H), 6.70-6.66 (m, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.03 (s, 2H), 4.26 (s, 2H), 4.07-
4.02 (m, 1H), 3.30 (t, J = 8.4 Hz, 2H), 2.96 (t, J= 8.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.73-
2.67 (m, 1H), 1.83 (d, J = 2.4 Hz, 3H).
Example 25 (5)-3-(4-((3-((5,6-Dihydro-[l, 2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
’H NMR (CD3OD, 400 MHz) δ: 8.50 (s, 1H), 7.49 (s, 1H), 7.40-7.35 (m, 3H), 7.28 (d, J =
6.8 Hz, 2H), 6.93 (d, J = 6.8 Hz, 2H), 5.01 (s, 2H), 4.15-4.11 (m, 2H), 4.00-3.97 (m, 1H), 3.87-3.83 (m, 4H), 2.97-2.94 (m, 2H), 2.66-2.62 (m, 2H), 1.81 (d, J = 2.4 Hz, 3H).
Example 26 (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
’H NMR (CDCI3, 400 MHz) δ: 7.52-7.20 (m, 6H), 6.81 (d, J = 8.8 Hz, 2H), 5.21-5.12 (m, 2H), 4.00-3.95 (m, 1H), 3.78-3.67 (m, 2H), 3.23-2.59 (m, 8 H), 2.04-1.97 (m, 1H), 1.81 (d, J = 2.4 Hz, 3H), 1.00-0.96 (m, 4H).
Example 27 (3S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyirol-2(lH)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid
HCOOH *H NMR (CDCI3, 400 MHz) δ: 8.45 (s(br), 0.78 H, HCOOH), 7.52-7.15 (m, 9H), 7.16 (d, J = 7.2 Hz, 1H), 6.78 (dd, J= 2.8, 11.6 Hz, 2H), 5.12 (s, 2H), 4.05-4.00 (m, 1H), 3.93-3.68 (m, 4H), 3.04-3.01 (m, 2H), 2.83-2.78 (m, 3H), 2.68-2.64 (m, 1H), 2.58-2.40 (m, 6H), 1.77 (d, J = 2.4 Hz, 3H).
Example 28 (S)-3-(4-((3-((4H-Thieno [2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
’H NMR (CDC13, 400 MHz) δ: 7.43 (s, 1H), 7.39-7.24 (m, 6H), 6.86 (d, J = 8.4 Hz, 2H),
6.80 (d, J= 5.2 Hz, 1H), 5.06-4.99 (m, 2H), 4.17-4.00 (m, 7H), 2.77-2.71 (m, 1H), 2.65-
2.59 (m, 1H), 1.80 (d, J= 2.4 Hz, 3H).
Example 29
6-(3-((4-( Y-l-carboxypent-3-yn-2-yI)phenoxy)methyl)benzyl)-6,7-dihydro-5H- pyrrolo [3,4-d]pyrimidin-6-ium formate
‘HNMRiCDCb, 400 MHz) δ: 8.98 (s, 1H), 8.63 (s, 1H), 8.37 (s, 1H), 7.45 (s, 1H), 7.37-
7.31 (m, 3H), 7.25 (d, J= 8.8 Hz ,2H), 6.93 (d, J= 8.8Hz , 2H), 5.08 (s, 2H), 3.95 - 3.90 (m, 7H), 2.55- 2.52 (m, 1H ), 2.12 (s, 3H).
Example 30 l-(3-((4-(f5)-l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-l,2,3,4tetrahydroquinolin-l-ium formate
1HNMR(CDC13, 400 MHz) δ 8.21 (s), 0.28 (formate), 7.33 - 7.28 (m, 3H), 7.25 (d, J= 8.8
Hz , 2H), 7.19 (d, J= 7.2 Hz, 1H), 6.91 (d, J= 8.4 Hz, 2H), 6.55 (d, J= 2.8 Hz, 1H), 6.51
- 6.48 (dd, J= 8.8 Hz & 2.8 Hz, 1H), 6.39 (d, J= 8.8 Hz, 1H), 5.0 (s, 2H), 4.39 (s, 2H),
3.95 - 3.90 (m, 3H ), 3.60 (m, 4H), 3.24 (t, 3H), 2.70 (m, 2H), 2.58 (d, 2H), 2.06 (t, 2H), 1.07-1.08 (s, 3H).
Example 31
$)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
!H NMR (CDC13, 400 MHz) δ: 7.41-7.30 (m, 3H), 7.35-7.27 (m, 3H), 6.90 (d, J= 8.4 Hz,
2H), 5.07 (s, 1H), 4.07-4.02 (m, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 2.98-2.95 (m, 2H), 2.86-
2.68 (m, 5H), 1.83 (d, J = 2.4 Hz, 3H).
Example 32
$)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDCI3, 400 MHz) δ: 7.39-7.35 (m, 3H), 7.29-7.26 (m, 3H), 6.90 (d, J= 8.4 Hz, 2H), 5.05 (s, 2H), 4.06-4.01 (m, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.92-2.66 (m, 6H), 1.82 (d, J =2.4 Hz, 3H).
Example 33
$)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(lH,4H,6H)-ylmethyl)benzyl)oxy)phenyl) hex-4ynoic acid
’H-NMR (CDCl3,400 MHz):- δ 7.32-7.53 (m, 3H), 7.19-7.29 (m, 4H), 6.82-6.84 (m, 2H),
5.16 (s, 2H), 3.90-4.06(m, 5H), 3.57 (s, 2H), 2.80-2.85 (m, 1H), 1.81 (s, 3H);
Example 34 (S)-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
^-NMR ( DMSO, 400 MHz):- δ 7.38 (s, 1H), 7.23-7.33 (m, 5H), 6.92 (d, >8.8 Hz, 2H),
6.56 (s, 1H), 5.35 (s, 2H), 3.91-3.94 (m, 1H), 3.72-3.84 (m, 4H), 3.40-3.50 (m, 2H(merged), 2.86-2.94 (m, 2H), 2.73-2.76 (m, 2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);
Example 35 (S)-5-(3-((4-(l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid
Ή NMR: (DMSO-d6, 400MHz):- 7.42 (s, 1H), 7.34 - 7.31 (m, 2H), 7.27 - 7.26 (m, 1H),
7.22 (d, J= 8.8Hz, 2H), 6.99 (s, 1H), 6.90 (d, 8.8Hz, 2H), 5.09 (s, 2H), 3.95 - 3.91 (m,
1H), 3.65 (s, 2H), 3.29 (s, 2H), 2.74 - 2.71 (m, 4H), 2.63 - 2.52 (m, 2H), 1.76 (s, 3H).
Example 36
3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)~ yl)methyl)benzyl)oxy)phenyl)propanoic acid
OH ’H NMR: (DMSO-i/g, 400MHz):- 7.46 (s, 1H), 7.37 - 7.31 (m, 3H), 7.14 (t, J= 8Hz, 2H),
6.81 - 6.79 (m, 2H), 6.44 (s, 1H), 5.05 (s, 2H), 3.78 (s, 2H), 3.32 (s, 2H), 2.82 - 2.74 (m, 4H), 2.49 - 2.44 (m, 2H), 2.36 - 2.34 (m, 4H), 1.30- 1.28 (m, 1H), 0.49 - 0.47 (m, 1H), 0.27 - 0.24 (m, 2H), 0.004 - 0.002 (m, 1H).
Example 37 (5)-3-(4-((3-((1-methyl-6,7-dihydro-lH-pyrrolo [3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid
JH NMR (CDC13, 400 MHz): δ 7.53 (s, 1H), 7.47 - 7.32 (d, 3H), 7.24 - 7.12 (m, 2H),
6.85 (d, 2H), 6.51 (d, 1H), 5.58 (d, 1H), 5.0-4.95 (d, 2H), 3.9-4.1 (m, 1H), 3.87 (d, 1H),
3.80 (d, 1H), 3.48 (s, 3 H), 2.9-3.1 (m, 3H), 1.08 (m, 3H).
Example 38 (5)-3-(4-((3-((2-amino-6,7-dihydrothiazolo [5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid
*H NMR (DMSO-dô, 400 MHz) : δ 8.23 (s, 1H), 7.40 (s, 1H), 7.35 (d, 2H), 7.32 - 7.24 (m, 3H), 6.93 (d, J= 8.4Hz, 2H), 6.68 (s, 2H), 5.06 (s, 2H), 3.9 - 4.0 (m, 1H), 3.35 (s, 3H), 2.70 - 2.66 (m, 2H ), 2.58 (d, 2H), 2.44 (d, 3H).
Example 39
Calcium (5)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate
Ή NMR (CDC13, 400 MHz) δ: 7.39 (s, 1H), 7.36-7.23 (m, 5H), 6.88 (d, J= 8.8 Hz, 2H),
6.78 (s, 1H), 5.04 (s, 2H), 3.99 (s(br), 1H), 3.65 (s, 2H), 3.34 (s, 2H), 2.70 (s(br), 4H), 2.37-
2.31 (m, 1H), 2.25-2.19 (m, 1H), 1.73 (d, J = 2.4 Hz, 3H).
Example 40 (5)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR: (DMSO-£/6, 400MHz):-12.22 (br s, 1H), 7.76 (br s,lH), 7.42 (s, 1H), 7.37 -
7.25 (m, 7H), 6.94 (d, 7= 8.8Hz, 2H), 5.07 (s, 2H), 3.95 - 3.91 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78 - 2.76 (m, 2H), 2.72 - 2.70 (m, 2H), 2.60 - 2.57 (m, 2H), 1.77 (s, 3H).
Example 41 ((S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H-NMR(DMSO, 400 MHz): δ 12.25 (m, 2H), 7.48-7.51 (m, 2H), 7.39 (s, 3H), 7.27 (d, J = 8.8 Hz, 2H), 6.95(d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.40-4.47 (m, 1H), 4.10-4.20 (m, 2H), 3.70-3.90 (m, 4H), 2.66-2.66 (m, 2H), 1.77 (s, 3H), 1.36-1.38 (m, 6H);
Example 42 f5)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)b enzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR: (DMSO-îZô, 400MHz):-12.22 (br s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.37 - 7.24 (m, 5H), 6.92 (d, J= 8.4Hz, 2H), 5.07 (s, 2H), 3.95 - 3.91 (m, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.46 (s, 2H), 2.84 - 2.81 (m, 2H), 2.74 - 2.70 (m, 2H), 2.58 - 2.53 (m, 2H), 1.90 (s, 3H).
Example 43 (S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
^-NMRÎDMSO, 400 MHz): δ 8.83 (s, 1H), 7.24-7.41 (m, 6H), 6.92-6.94 (m, 2H), 5.09 (s, 2H),3.91-3.94 (m, 1H), 3.73 (s, 2H), 3.45 (s, 2H), 2.86-2.94 (m, 2H), 2.73-2.76 (m, 2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);
Example 44 (S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
^NMR: (DMSO-iZe, 400MHz):- 9.79 (s, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.36 - 7.31 (m, 3H), 7.26 - 7.24 (d, J= 8 Hz, 2H), 6.94 - 6.92 (d, J = 8 Hz, 2H), 5.07 (s, 2H), 3.93 (br s, 1H), 3.70 (s, 2H), 3.50 (s, 2H), 2.89 (s, 2H), 2.74 (s, 2H), 1.76 (s, 3H), 1.23 (s, 2H).
Example 45
S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo [l,5-a]pyrazin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid
*H NMR (DMSO-d6, 400 MHz) : δ 7.41 (s, 1H), 7.35 (d, J= 6A Hz , 2H), 7.30 (m, 1H),
7.25 (d, J= 8.8 Hz, 2H), 6.93 (d, J= 8.4 Hz, 2H), 5.73 (s, 1H), 5.07 (s, 2H), 3.96 - 3.92 (m, 3H), 3.68 (s, 2H), 3.52 (s, 2H ), 2.84 (t, 2H), 2.66 (t, 2H), 2.08 (s, 3H), 1.77 (s, 3H)
Example 46 ($-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
!H NMR: (DMSO-iZg, 400MHz):- 7.42 (s, 1H), 7.35 - 7.24 (m, 6H), 7.1 - 6.93 - 6.91 (m, 2H), 5.07 (s, 2H), 3.9 (m, 1H), 3.68 (s, 2H), 3.41 (s, 2H), 2.71 - 2.70 (m, 2H), 2.67 - 2.66 (m, 6H), 1.76 (s, 3H).
Example 47 f$-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
‘H NMR: (DMSO-76, 400MHz):- 7.53 (s, 1H), 7.40 - 7.22 (m, 4H), 7.1 - 6.68 (m, 3H), 5.08 (s, 2H), 4.12-4.03 (m, 1H), 3.78-3.71 (m, 2H), 3.50 (s, 2H), 3.17 (s, 6H), 2.95-
2.88 (m, 2H), 2.83-2.63 (m, 2H), 1.83 (s, 3H).
Example 48 (3 S)-3 -(4-((3 -((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
*H NMR (CDC13, 400 MHz) δ: 7.93-7.90 (m, 2H), 7.82-7.76 (m, 2H), 7.53-7.16 (m, 7H), 5 6.92-6.86 (m, 3H), 5.11-5.01 (m, 3H), 4.45-4.30 (m, 1H), 4.07-3.98 (m, 3H), 3.30-3.20 (m, 1H), 3.097-3.090 (m, 3H), 3.03 (s, 1H), 2.87-2.68 (m, 4H), 2.33-1.98 (m, 8H), 1.84-
1.82 (m, 5H), 1.62-1.60 (m, 4H)
Example 49 (S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)10 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
‘HNMR (CDCI3, 400 MHz) δ: 8.48 (s, 1H), 7.43-7.27 (m, 6H), 6.91 (dd, 7= 8.8, 2 Hz,
2H), 5.07 (s, 2H), 4.07-4.03 (m, 1H), 3.80 (s, 2H), 3.72 (s, 2H), 3.32 (s, 3H), 3.15-3.09 (m, . 2H), 2.92-2.89 (m, 2H), 2.84-2.78 (m, 1H), 2.74-2.68 (m, 1H), 1.83 (d, J = 2.4 Hz, 3H)
Example 50 [2)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
‘H NMR (CDCls, 400 MHz) δ: 8.09 (s, 1H), 7.53-7.26 (m, 6H), 6.87 (dd, J = 6.8, 2 Hz, 2H), 5.17-5.08 (m, 2H), 4.07-4.02 (m, 1H), 3.98 (s, 3H), 3.75 (s(br), 2H), 3.58 (s(br), 2H), 2.88-2.63 (m, 6H), 1.82 (d, J= 2.4 Hz, 3H)
Example 51 (3 S)-3 -(4-((3 -((2-phenylpyrrolidin-1 -yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
OH ^-NMRiCDCl·,, 400 MHz): δ 7.43-7.45 (m, 2H), 7.21-7.35 (m, 9H), 6.89-6.91 (d, J = 8 Hz, 2H), 5.0 (s, 2H), 4.03 (m, 1H), 3.81-3.85 (m, 1H), 3.37-3.41 (m, 1H), 3.11-3.17 (m, 3H), 2.74-2.80 (m, 1H), 2.64-2.69 (m, 1H), 3.37-2.14-2.51 (m, 2H), 1.85-1.92 (m, 1H),
1.81 (s, 3H), 1.71-1.75 (m, 2H);
Example 52 (S)-3-(4-((3-(Pyrrolidin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid
ΌΗ *H NMR (CD3OD, 400 MHz) δ: 8.51 (s, 1H, HCOOH), 7.60 (s, 1H), 7.55-7.45 (m, 3H),
7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 4.34 (s, 2H), 4.02-3.98 (m, 1H), 3.27-3.24 (m, 4H), 2.62-2.50 (m, 2H), 2.08-2.04 (m, 4H), 1.80 (d, J = 2.4 Hz, 3H) Example 53 (S)-3-(4-((3-(Piperidin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid
*H NMR (CD3OD, 400 MHz) δ: 8.50 (s, 1H, HCOOH), 7.58-7.43 (m, 4H), 7.29 (d, J =
8.8, Hz, 2H), 6.91 (d, J” = 8.8 Hz, 2H), 5.15 (s, 2H), 4.23 (s, 2H), 4.09-4.03 (m, 1H), 3.12-
3.08 (m, 4H), 2.63-2.49 (m, 2H), 1.83-1.79 (m, 7H), 1.64-1.61 (m, 2H)
Example 54 (5)-3-(4-((3 -(( 1 -isopropylpyrrolo [3,4-c]pyrazol-5( 1 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid
!H NMR (CD3OD, 400 MHz) δ: 8.41 (s, 1H, HCOOH), 7.54 (s, 1H), 7.43-7.40 (m, 3H),
7.29 (dd, J = 7.2, 2 Hz, 2H), 7.21 (s, 1H), 6.93 (dd, J = 6.8, 2 Hz, 2H), 5.11 (s, 2H), 4.45-
4.41 (m, 1H), 4.14 (s, 2H), 4.07 (s, 2H), 4.02-3.95 (m, 1H), 3.88 (s, 2H), 2.63-2.59 (m, 2H), 1.80 (d, J = 2.4 Hz, 3H), 1.42 (d, J = 6.8 Hz, 6H).
Example 55 (R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid
’H NMR (CDC13, 400 MHz) δ: 8.31 (s, 0.36 H, Residual HCOOH), 7.47-7.25 (m, 6H),
6.86 (td, J = 9.6, 2.8 Hz, 2H), 6.34 (s, 1H), 5.04 (s, 2H), 4.07-4.01 (m, 3H), 3.8 (s(br), 2H),
3.20-3.12 (m, 2H), 2.97-2.95 (m, 2H), 2.78-2.73 (m, 1H), 2.66-2.61(m, 1H), 2.41 (s, 3H),
1.80 (d, J =2.4 Hz, 3H).
Example 56 (R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
‘H NMR (CDC13, 400 MHz) δ: 8.15 (s, 0.3H, Residual HCOOH), 7.41-7.27 (m, 6H), 6.88 (d, J = 8.4 Hz, 2H), 5.15-5.07 (m, 2H), 4.06-4.02 (m, 1H), 3.90-3.82 (m, 4H), 2.96-2.92 (m, 2H), 2.88-2.64 (m, 7H), 1.82 (d, J = 2.4 Hz, 3H)
Example 57 (3^-3-(4-((3-((6,7-Dihydro-[l,2,3]triazolo[l,5-a]pyrazin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
‘H NMR (CD3OD, 400 MHz) δ: 7.59-7.58 (m, 2H), 7.58-7.43 (m, 3H), 7.29 (d, J= 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H), 4.58-4.55 (m, 2H), 4.19 (s, 2H), 4.15 (s, 2H), 4.01-3.97 (m, 1H), 3.44-3.41 (m, 2H), 2.70-2.58 (m, 2H), 1.81 (d, J = 2.4 Hz, 3H). Example 58
3-(4-((3 -((2-Methyl-6,7-dihydrothieno [3,2-c]pyridin-5 (4H)-yl)methyl)b enzyl) oxy)phenyl)hex-4-ynoic acid
*H NMR (CDCI3, 400 MHz) δ: 7.42-4.27 (m, 5H), 6.87 (dd, 11.2, 3 Hz, 2H), 6.34 (s,
1H), 5.05 (s, 2H), 4.06-4.02 (m, 2H), 3.98 (s, 2H), 3.74 (s, 2H), 3.10-3.04 (m, 2H), 2.92-
2.89 (m, 2H), 2.79-2.73 (m, 1H), 2.67-2.61 (m, 1H), 2.41 (s, 3H), 1.81 (d, J= 2.4 Hz, 3H).
Example 59
3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid:
*H NMR (CDC13, 400 MHz) δ: 7.42-7.35 (m, 4H), 7.29-7.27 (m, 2H), 6.88 (d, J = 8.8 Hz,
2H), 5.14-5.07 (m, 2H), 4.06-4.03 (m, 1H), 3.93-3.85 (m, 4H), 2.99-2.97 (m, 2H), 2.86-
2.64 (m, 7H), 1.82 (d, J = 2.4 Hz, 3H
Example 60
Calcium (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-
!H NMR (DMSO-î7(î, 400 MHz) δ: 7.39 (s, 1H), 7.36-7.23 (Μ, 5H), 6.88 (d, J= 8.8 Hz,
2H), 5.03 (s, 2H), 4.02-3.99 (m, 1H), 3.69 (s, 2H), 3.39 (s, 2H), 2.80-2.77 (m, 2H), 2.72-
2.69 (m, 2H), 2.41-2.36 (m, 1H), 2.27-2.21 (m, 1H), 1.73 (d, 2.4 Hz, 3H).
Example 61 (S?)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
’H NMR: (DMSO-rig, 400MHz):- 8.34 (br s, 1H), 7.41 (s, 1H), 7.36 - 7.29 (m, 3H), 7.27 -
7.24 (m, 3H), 6.67 (d, J= 8.4Hz, 2H), 5.07 (s, 2H), 3.95 - 3.91 (m, 1H), 3.67 (s, 2H), 3.42 (s, 2H), 2.77 - 2.66 (m, 5H), 2.57 - 2.51 (m, 2H), 1.76 (s, 3H), 0.67 - 0.62 (m, 2H), 0.53 0.49 (m, 2H
Example 62
$)-3-(4-((3-((2-(pyrrolidine-l-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
II o
OH *H NMR: (DMSO-de, 400MHz):- 7.42 (s, 1H), 7.37 - 7.26 (m, 3H), 7.25 - 7.13 (m, 3H),
6.93 (d, J= 8.8Hz, 2H), 5.07 (s, 2H), 3.94 - 3.87 (m, 1H), 3.68 (br s, 4H), 3.43 (br s, 4H),
2.80 - 2.73 (m, 4H), 2.59 - 2.50 (m, 2H), 2.91 - 1.81 (m, 4H), 1.76 (s, 3H)
Example 63
$)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
ΌΗ *H NMR (CD3OD, 400 MHz) δ: 7.56 (s, 1H), 7.50-7.41 (m, 3H), 7.28 (d, J = 8.8 Hz, 2H),
6.92 (d, 8.8 Hz, 2H), 6.35 (s, 1H), 5.12 (s, 2H), 4.15 (s, 2H), 4.01-3.97 (m, 1H), 3.84 (s, 2H), 3.25-3.22 (m, 2H), 2.96-2.93 (m, 2H), 2.66-2.53 (m, 2H), 2.10 (s, 3H), 1.79 (d, J = 2.4 Hz, 3H).
Example 64
Calcium $)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate ’H NMR (DMSO-ck, 400 MHz) δ:7.38 (s, 1H), 7.34-7.24 (m, 5H), 6.88 (d, J = 8 Hz, 2H), 5.02 (s, 2H), 4.02-4.01 (m, 1H), 3.66 (s, 2H), 3.26 (s, 2H), 2.73-2.71 (m, 2H), 2.58 (s, 2H), 2.41-2.37 (m, 1H), 2.27-2.24 (m, 1H), 2.03-2.00 (m, 1H), 1.72 (s, 3H), 0.98-.093 (m, 2H), 0.86-0.82 (m, 2H).
Example 65 (3)-3-(4-((3-((2 -Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid
Y NMR (CD3OD, 400 MHz) δ: 7.80 (s, 1H), 7.69 (s, 1H), 7.61-7.52 (m, 3H), 7.30 (d, J =
8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 4.54 (s, 2H), 4.30 (s, 2H), 4.01-3.99 (m, 1H), 3.66 (s(br), 2H), 3.31-3.27 (m, 2H), 2.69-2.58 (m, 2H), 1.80 (d, J = 2.4 Hz, 3H) Example 66 (3)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid
ΌΗ ’H NMR (CD3OD, 400 MHz) δ: 8.00 (s, 1H), 7.54 (s, 1H), 7.45-7.42 (m, 3H), 7.28 (d, J =
8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H), 4.01-3.99 (m, 3H), 3.74 (s, 2H), 3.14 (s, 6H), 3.10-3.07 (m, 2H), 2.90-2.87 (m, 2H), 2.64-2.60 (m, 2H), 1.80 (d, J= 2.4 Hz, 3H).
Example 67 (3)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid
ΌΗ
H NMR (CD3OD, 400 MHz) δ: 8.10 (s, 1H), 7.67 (s, 1H), 7.62-7.54 (m, 3H),
7.30 (dd, J = 6.8, 1.6 Hz, 2H), 6.96 (d, J = 6.8, 1.6 Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H),
4.25 (s, 2H), 4.01-3.99 (m, 1H), 3.63 (s, 2H), 3.09-3.05 (m, 2H), 2.70-2.58 (m, 2H), 1.80 (d,J=2.4 Hz, 3H)
Example 68 (3/)-3-(4-((3-((7,8-Dihydro-l,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl) hex-4ynoic acid
rH NMR (CD3OD, 400 MHz) δ: 8.59 (d, J = 4 Hz, 1H), 7.87 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.62-7.51 (m, 4H), 7.30 (dd, J = 8.8, 2 Hz, 2H), 6.96 (d, J = 8.8, 2 Hz, 2H), 5.17 (s, 2H), 4.57 (s, 2H), 4.49 (s, 2H), 4.01-3.97 (m, 1H), 3.75-3.72 (m, 2H), 3.41-3.38 (m, 2H), 2.69-2.58 (m, 2H), 1.80 (d, J = 2.4 Hz, 3H).
Example 69 (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid ch3
*H NMR (CD3OD, 400 MHz) δ: 7.66 (s, 1H), 7.60-7.52 (m, 2H), 7.30 (dd, 6.8, 2 Hz, 2H), 6.90 (dd, J = 6.8, 2 Hz, 2H), 6.50 (s, 1H), 5.17 (s, 2H), 4.51 (s, 2H), 4.18 (s, 2H), 4.01-3.97 (m, 1H), 3.12-3.09 (m, 2H), 2.67-2.60 (m, 2H), 1.80 (d, J= 2.4 Hz, 3H), 1.000.97 (m, 2H), 0.66-0.64 (m, 2H)
Example 70 (3/)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid
‘H NMR (CD3OD, 400 MHz) δ: 7.68 (s, 1H), 7.62-7.54 (m, 3H), 7.30 (d, J = 8.8 Hz, 2H),
6.95 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H), 4.56 (s, 2H), 4.40 (s, 2H), 4.01-3.97 (m, 1H), 3.67 (s(br), 2H), 3.07-3.04 (m, 2H), 2.69-2.58 (m, 2H), 2.20 (s, 3H), 1.80 (d, J = 2.4 Hz, 3H).
Example 71 fS)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid
*H NMR (CD3OD, 400 MHz) δ: 7.66 (s, 1H), 7.62-7.53 (m, 3H), 7.30 (d, J = 8.8 Hz, 2H),
6.95 (d, J = 8.8 Hz, 2H), 6.53 (s, 1H), 5.17 (s, 2H), 4.51 (s, 2H), 4.20 (s, 2H), 4.01-3.97 (m, 1H), 3.57 (s(br), 2H), 2.81-2.78 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 2.69-2.57 (m, 2H),
1.80 (d, J = 2.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).
Example 72 (S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
!H NMR (CD3OD, 400 MHz) δ: 7.56-7.55 (m, 2H), 7.49-7.42 (m, 3H), 7.28 (dd, J= 6.8,
Hz, 2H), 6.93 (dd, J= 6.8, 2 Hz, 2H), 5.12 (s, 2H), 4.09 (s, 2H), 4.01-3.97 (m, 1H), 3.88 (s, 2H), 3.18-3.14 (m, 2H), 3.07-3.04 (m, 2H), 2.66-2.56 (m, 2H), 2.50 (s, 3H), 1.79 (d, J = 2.4 Hz, 3H)
Example 73
$)-3-(4-((3-((2-((Methylamino)methyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid
’H NMR (CD3OD, 400 MHz) δ: 7.67 (s, 1H), 7.62-7.60 (m, 1H), 7.55-7.53 (m, 2H), 7.30 (dd, J = 6.8, 2 Hz, 2H), 7.03 (s, 1H), 6.96 (dd, J = 6.8, 2 Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H), 4.36 (s, 2H), 4.27 (s, 2H), 4.01-3.98 (m, 1H), 3.62 (s(br), 2H), 3.24-3.21 (m, 2H), 2.71 (s, 3H), 2.69-2.62 (m, 2H), 1.81 (d, J = 2.4 Hz, 3H).
The novel compounds of the présent invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (1 or pharmaceutical compositions containing them are useful as ligands of the GPR 40 receptor suitable for humans and other warm blooded animais, and may be administered either by oral, topical or parentéral administration.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
Biological Activity:
The biological activity of the compounds of the présent invention was tested in the following in vitro and in vivo models mentioned here.
Summary of the in vitro screening protocol
To détermine the EC50 of the compounds on intracellular Ca2+ flux using a fluorescent assay (FLIPR)
GPR40 expressing stable cells were seeded at 25,000 numbers /well. 50pL/well of assay buffer (20mM HEPES+ IX HBSS) was added to the cells and the cells were cultured for 20 min at 37°C. Cells were loaded with 50pL/well of Calcium 5 dye and cultured for 45 min at 37°C.
The cells were challenged with compounds at a top concentration of 1000 nM (1:3 step down dilution - 10 points). Intracellular Calcium flux was assessed by use of Screen Works 3.1 tool and statistical analysis was carried using Graph Pad Prism 4
Many of the compounds of the présent invention demonstrated nanomolar potency and significant % stimulation on intracellular Ca2+ flux when measured using fluorescent (FLIPR) assay
The compounds exhibited potency in nanomolar range. (Tablel)
Table 1: In vitro EC50 values of the GPR 40 agonists of the présent invention in FLIPR assay
Compound EC50(nM)
1 117
7 1.8
16 2.72
17 10.2
19 2.32
22 36.3
Promoter-luciferase assay to measure GPR40 activation
GPR40 activation was measured in HEK293 cells stably transfected with GPR40 cDNA (ChemiBrite cell lines from Millipore, US). These cells were transiently transfected with a pGL2 (Promega Inc.) plasmid having a 5XSRE sequence, cloned 5’ of a luciferase gene along with a β-galactosidase plasmid as normalizing control. Briefly, 35000 cells/well were seeded in a 96 well plates. After overnight incubation at 37° C, the cells were washed with PBS and transfected with the 5X-SRE-Luciferase plasmid and the β-galactosidase plasmid. 6 h post transfeciion, media was removed and replaced with fresh media with different concentration of drugs and incubated for 16 more hours. The cells were then lysed in 50pL of Glo-Lysis buffer (Promega) for 30 min at room température. The cells were then centrifuged and lysâtes were collected. Luciferase activity was measured by adding 100 pL of luciferase substrate (Promega) in 20pL of lysate and measuring the luminescence in luminometer. The β-galactosidase activity was also measured by adding 20pL of lysâtes with 20pL of β-galactosidase buffer (Promega) and monitoring the absorbance at 415 nm. Luciferase values were divided by β- galactosidase values to normalize transfection effïciency (Table 2)
Table 2: In vitro EC50 values of the GPR 40 agonists of the présent invention in Luciferase assay.
Compound # EC50 (nM) Compound # EC50 (nM) Compound # EC50 (nM)
1 7.5 23 5.3 51 3.0
7 1.49 24 0.7 55 56.5
8 11.8 26 4.1 58 3.7
10 16.9 30 4.5 60 5.6
12 5.6 31 9.7 61 12.6
13 0.8 32 4.8 62 3.0
14 0.8 35 204 63 4.4
15 4.6 38 17.8 64 1.2
16 4.6 39 1.7 65 1.6
17 4.7 40 8 68 11.9
18 8.8 43 7.3 69 0.8
19 0.2 44 4.8 71 0.4
20 2.7 46 6 72 2.3
21 2.8 47 9
22 31.46 50 20.8
Most of the compounds of the présent invention were evaluated against CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 and there was no significant CYP inhibitory effect. The compounds did not show significant hERG binding at 10 μΜ.
In Vivo efficacy studies:
Primary Screening Protocol for GRP40 agonist test compounds in n-STZ rat model
Wistar rat pups of 1-2 day old injected with Streptozotocin (STZ) at 120 mg/kg dose by intraperitoneal route. Ail pups allowed grow normally and at the âge of 12-14 week they were screen for glucose intolérance by performing the oral glucose tolérance test by tail clip method using glucometer. Animais showing glucose intolérance were selected for 15 évaluation of test compound. Three to seven days of rest period animais were kept on ovemight fasting. Next day moming blood glucose levels measured using glucometer and animais were grouped such that their pretreatment glucose levels were not significantly different between groups. Animais were administered with test compound and then then 15-60 min after the compound administration “O” min blood glucose levels were measured and immediately glucose load at 2 g/kg was administered orally. Blood glucose 5 levels were measured at 30, 60 and 120 min after glucose load using by tail clip method using glucometer. Blood was also collected at 10 min after glucose load for measurement of insulin levels. Glucose area under the curve (AUC) was calculated using Graph Pad Prism software and % réduction in AUC-glucose vs vehicle treated control was calculated (Table 3).
Table 3: Effïcacy of the GPR 40 agonist of the présent invention in n-STZ rat model
Compound Dose (per oral) % improvement in AUC glucose vs. control
7 0.1 mg/Kg 30.4
1 mg/Kg 46.0
10 mg/Kg 57.0
10 0.1 mg/Kg 21.1
1 mg/Kg 35.7
10 mg/Kg 45.0
16 1 mg/Kg 44.6
10 mg/Kg 59.6
17 1 mg/Kg 37.1
10 mg/Kg 44.7
60 1 mg/Kg 44
10 mg/Kg 47
64 1 mg/Kg 46
10 mg/Kg 47
In the n-STZ rat OGTT model the ED50 of compounds 16, 60 & 64 has been found 0.05 mg/Kg, 0.04 mg/Kg & 0.09 mg/Kg respectively.
Few compounds hâve exhibited significant pharmacokinetics parameters in rats (Table 4)
Table 4: Pharmacokinetics parameters of compounds 16, 60 & 64
Parameters 16 60 64
Dose (po) mg/Kg 3 3 3
Tmax (h) 0.25 1 2
Cmax (P-g/tuL) 5.92±2.10 7.77Ü.94 8.06i2.19
AUC (0-t) 7.63Ü.27 52.52±12.62 82.42i27.63
Ti/2, po (h) 1.77±0.42 5.45i0.79 4.5Ü0.61
Mean résidence time (h) 2.19±0.31 5.74i0.10 6.59i0.93
iv dose (mg/Kg) 1 1 1
C0(pg/mL) 5.02±0.37 3.39i0.33 10.16il.54
AUC (0-t) (pg.h/mL) 3.18i0.40 18.61i2.17 56.14i4.35
Vss (L/Kg) 0.34±0.03 0.33i0.01 0.16i0.01
CL (mL/min./Kg) 5.26±0.65 0.89i0.10 0.27i0.03
Ti/2, iv(h) 1.45±0.12 5.57Ü.46 7.77Ü.07
Mean résidence time (h) 1.09±0.07 6.28i0.77 10.07il.36
%F 83 93 45
The compounds of formula (I) or pharmaceutical compositions containing them are suitable for humans and other warm blooded animais, and may be administered either by oral, topical or parentéral administration for the treatment of various disease conditions 5 associated with dyslipidemia, obesity etc.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
The quantity of active component, that is, the compounds of formula (I) according to this 10 invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

Claims (8)

  1. We Claim:
    1. Compound of the general Formula (Γ)
    Formula (I’) their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein Each of Ri, R2, R3 and R4 at each occurrence independently represents H, halogen, hydroxyl, CN, NO2, CHO, COOH, CO, optionally substituted groups selected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH2 or optionally substituted NHCO-linear or branched (Cj-Côjalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR C(O)R and SO2R wherein ‘R’ at each occurrence independently represents optionally substituted groups selected from H, linear or branched (Ci-Cô)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetrerocyclylalkyl, heteroaryl, heteroaralkyl groups;
    ‘A’ is selected from 3-7 member partially saturated, unsaturated or saturated ring which may further having one or more than one heteroatom selected from O, S, or N; Each of Έ’ & ‘D’ is independently either nitrogen or carbon;
    ‘F’ is selected from C, N or O;
    Each of ‘n’, ‘r’ and‘s’ independently represents an integer ranging from 0 to 6;
  2. 2. The compound as claimed in claim 1 wherein the heterocycles representing
    5 is selected from the following bicyclic rings
  3. 3. The compound as claimed in claim 1 wherein the COOH is replaced wherever possible with bioisosteric replacements selected from
    O / ,° ^c'.n.°h H
    N'1
    Il N ·, ’ \ H
  4. 4. The compound as claimed in claim 1 wherein any of the groups from Ri to Rô are substituted with one or many groups, the substituents is independently selected from the groups comprising hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, hetero aryloxy, hetero aralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its dérivatives selected from esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl dérivatives, sulfonyl dérivatives, sulfonic acid and its dérivatives.
  5. 5. The compound according to claim 1 selected from the group consisting of (5)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid ;
    Lithium 3 -(4-((3 -((4H-furo [3,4-c]pyrrol-5 (6H)-yl)methyl)benzyl)oxy)phenyl)-3 cyanopropanoic acid;
    3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)methyl)benzyl)oxy)phenyl)propanoic acid;
    Lithium 3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-
    a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoic acid;
    3-cyano-3-(4-((3-((2,2-dioxido-1 H-thieno [3,4-c]pyrrol-5(3 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
    3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
    (5)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((l-(tert-butoxycarbonyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3 -(4-((3 -((3,4-dihydroquinolin-1 (2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)b enzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3 -((3,4-dihydroisoquinolin-2( 1 H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoic acid;
    calcium($-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate($-3-(4-((3-((2-methyl-6,7dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    calcium($-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate($-3-(4-((3-((2-methyl-6,7dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    f$-3-(4-((3-((2-(Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    Calcium ($-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    Calcium ($-3-(4-((3-((3,4-dihydroisoquinolin-2(lH)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    ($-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (S)-3 - (4-((3 -((1 -Methylpyrrolo[3,4-c]pyrazol-5 ( 1 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-
    4-ynoic acid;
    ($-3-(4-((3 -(Indolin-1 -ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid ;
    ($-3-(4-((3-((5,6-Dihydro-[l, 2,4]triazolo[4,3-a]pyrazin-7(8H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    ($-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (3S)-3-(4-((3-((5-BenzylhexahydropynOlo[3,4-c]pyrrol-2(lH)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
    (5)-3-(4-((3 -((4H-Thieno [2,3 -c]pyrrol-5 (6H)-yl)methyl)benzyl)oxy)phenyl)hex-4ynoic acid;
  6. 6-(3-((4-((5)-l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5Hpyrrolo[3,4-d]pyrimidin-6-ium formate;
    l-(3-((4-((5)-l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-l, 2,3,4tetrahydroquinolin-l-ium formate;
    (5)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(lH,4H,6H)-ylmethyl)benzyl)oxy)phenyl)hex-4ynoic acid;
    (5)-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno [3,2-c]pyridin-5 (4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-5-(3-((4-(l-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7tetrahydrothieno [3,2-c]pyridine-2-carboxylic acid;
    3 -cyclopropyl-3 -(3 -((3 -((2-methyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid;
    (5)-3-(4-((3-((l-methyl-6,7-dihydro-lH-pyrrolo [3,2-c]pyridin-5(4H)-yl)methyl) benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-amino-6,7-dihydrothiazolo [5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy) phenyl)hex-4-ynoic acid;
    Calcium (5)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    (S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (S)-3-(4-((3 -((2-isopropylpyrrolo [3,4-c]pyrazol-5 (2H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo [l,5-a]pyrazin-5(4H)-yl)methyl)benzyl) oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (3 S)-3 -(4-((3 -((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1 yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5/)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (3S)-3-(4-((3-((2-phenylpyrrolidin-l-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-(Pyrrolidin-l-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
    (5)-3-(4-((3 -(Piperidin-1 -ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
    (5)-3-(4-((3 -(( 1 -isopropylpyrrolo[3,4-c]pyrazol-5 ( 1 H,4H,6H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with formic acid;
    (R)-3-(4-((3-((2-methyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((6,7-Dihydro-[l,2,3]triazolo[l,5-a]pyrazin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    3-(4-((3 -((2-Methyl-6,7-dihydrothieno [3,2-c]pyridin-5 (4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    Calcium (5)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    (5)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)b enzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    Calcium (5)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;
    (5)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (5)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
    (5J-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
    (5)-3-(4-((3-((7,8-Dihydro-l,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-
    4-ynoic acid;
    (5)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
    (5)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
    (5)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid;
    (S)-3 -(4-((3 -((2-((Methylamino)methyl)-6,7-dihydrothieno [3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroacetic acid;
    6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Γ) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
  7. 7. A pharmaceutical composition comprising compound of formula (F) along with suitable excipients suitable for the treatment of various disease conditions associated with dyslipidemia, obesity etc.
  8. 8. Use of a compound as claimed in any preceding claim in the préparation of a médicament for the prévention or treatment of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabètes a condition associated with GPR40 receptor function in a mammal.
OA1201600153 2013-11-14 2014-11-03 Novel heterocyclic compounds. OA17701A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IN3577/MUM/2013 2013-11-14

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Publication Number Publication Date
OA17701A true OA17701A (en) 2017-09-19

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