FIELD OF THE INVENTION

The present invention relates to certain compounds, their use in therapy, as well as to pharmaceutical compositions comprising said compounds. Specifically, the invention relates to certain compounds and pharmaceutical compositions including these compounds for the treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, and bone disorders.

BACKGROUND OF THE INVENTION

Two main types of diabetes mellitus exist, type 1 and 2. Type 2 diabetes mellitus (T2DM) affects more than 300 million people worldwide and is therefore a serious health burden to the health care system, affecting patients in a multitude of ways, including cardiovascular disease, blindness, amputations, etc. (Defossa E., Wagner M., Bioorganic&Medicinal Chemistry Letters, 24, 2991-3000 (2014), Poitout, V., C.-H. Lin D., Drug discovery today, 00, 1-8 (2013). T2DM is characterized by hyperglycemia due to glucose intolerance. Treatment strategies are most commonly based on glycemic control, since an insufficient pancreatic insulin production or insulin action resistance is the cause of T2DM. The first line of treatment can involve changes in diet and exercise, however as the disease progresses, pharmacotherapy or drugs may be implemented.

There are mainly two classes of T2DM drugs including insulin sensitizers (e.g. metformin, thiazolidinediones) or insulin secretagogues (e.g. sulfonylureas, glinides, glucagon like peptide-1 (GLP-1 (incretin hormone))-based drugs). The GLP-1-based drugs include GLP-1 agonists, enhancing GLP-1 levels or inhibitors of the GLP-1 degradation. Recent success with GLP-1 based drugs has spurred research in the direction to look at other pancreatic islet GPCRs that may be targeted for glycemic control. The FFA1 receptor or GPR40 receptor has surfaced as an interesting target. It is expressed in pancreatic beta cells, enteroendocrine I, K and L cells and also recently reported in the brain. FFA1/GPR40 was deorphanised in 2003 acting as a fatty acid (medium-to-long) receptor and is a rhodopsin (class A) 7-transmembrane family member. It is predicted to trigger the phospholipase C hydrolysis of membrane phospholipids to produce DAG (diacylglycerol) and IP3 (inositol-3 -phosphate). Potent agonists are endogenous fatty acids such as EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid) and linoleic acid, and synthetic agonists are usually composed of the same type of generic structure including an acidic head group and a hydrophobic tail. Increasing clinical data published on targeting the GPR40 pathway for treatment of T2DM supports GPR40 as an important receptor. Takeda has developed an oral FFA1 agonist TAK-875 (fasiglifam), which has shown promising results in early stage clinical trials with a dose-dependent decrease in glucose levels and lower tendency to cause hyperglycemia in healthy subjects and diabetic patients. Recent findings indicate that fasiglifam acts as a partial agonist with ago-allosteric properties. Amgen has developed a partial agonist, AMG 837, which was the first to enter clinical trials. Eli Lilly has developed a selective full agonist LY2881835, which is in part similar in structure to AMG 837. GSK has also developed GW9508, a small molecule agonist. There are several papers describing the GPR40 receptor and potential agonists (Christiansen et al., ACS Med. Chem. Lett. 2010, 1, 345-349; Haider et al., Expert Opin. Ther. Patents (2013) 23(12): 1581-1590; E.

Defossa, M. Wagner, Bioorg. Med. Chem. Lett. 24 (2014) 2991-3000; Negoro, et al., ACS Med. Chem. Lett. 2010, 1, 290-294).

Another interesting GPCR activated by long-chain fatty acids (e.g. linoleic acid, arachidonic acid, EPA and DHA) is GPR120. GPR120 is expressed in intestines, lungs, adipose tissue and pro-inflammatory macrophages. The stimulation of GPR120 triggers release of GLP- 1, enhancing e.g. insulin sensitization. No GPR120 agonist is in clinical trials at this stage. There are several papers on GPR120 and its potential role as a target for the treatment of metabolic disease and potential agonists (Suckow et al., doi: 10.1074/jbc.Ml 14.568683, J. Biol. Chem. published online April 17, 2014, 289, 15751-15763; Zhang and Leung, Drug Design, Development and Therapy 2014:8, 1013-1027; Haider et al., Expert Opin. Ther. Patents (2013) 23(12): 1581-1590; Shimpukade et al. J. Med. Chem. 2012, 55, 4511-4515). Anti-diabetic compounds targeting GPR120 based on phenyl thiazole and phenyl oxazole derivatives are described in W0103501 (IRM LLC). This was followed up by replacement of the carboxylic group with tetrazole isosteres for better lipophilicity, described in WO 103500 (IRM LLC). Other GPR120 modulators were described in W0008831 (IRM LLC). Also, a series of p-amino- substituted benozoic acid derivatives are described in WO121570 (IRM LLC). A series of dihydrobenzofuran derivatives are described in W0080537, W0159297 (Metabolex Inc.), and a series of pyrazole, thiadiazole, imidazole, triazole and oxazole derivatives are described in W0048207 (Metabolex Inc.). Isoindolin-1-one and benzisothiazole dioxide derivatives as GPR120 agonists are described in WO104195 (Banyu Pharmaceutical) and phenylisoxazol-3-ol derivatives in US0130559 (Banyu Pharmaceutical). Alpha acids from the naturally occurring alpha-lupulic acid demonstrate beneficial effects for treatment of obesity, inflammation and metabolic disorders, and has also been shown to act as agonists for GPR120, WO058649 (Kindex Therapeutics LLC). Certain long-chain fatty acid derivatives have also been described as agonists for both GPR40 and GPR120 in WO 038204 (Pharma Frontier Co. Ltd.). SUMMARY OF THE INVENTION

The present invention relates to new compounds, to their use in therapy, as well as to a pharmaceutical composition comprising said compounds. More specifically the invention relates to certain compounds or pharmaceutical compositions comprising said compounds for the treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically, diabetes and, even more specifically, type 2 diabetes.

One aspect of the present invention is a compound of the general formula I. The compounds of formula I can be used for treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes, and even more specifically, type 2 diabetes. The structure of general formula I is shown below: wherein: n is 1, 2 or 3; p is 1 or 2

R is O, NH, CH ₂ or S; and

A is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - O-B; -S-B; or -NH-B, wherein B is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or a an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

One aspect of the present invention is a compound (compound 1:1) and corresponding compound analogues of compound 1 (compound 1:2 - 1:10) of the following formulas and corresponding names listed below:

Compound 1:1

[6-({3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl}methoxy)-2,3-dihydro-1- b enzofuran-3 -y 1 ] methanesulfinic aci d,

Compound 1:2

(6-{[3-(2,6-dimethylphenyl)phenyl]methoxy}-2,3-dihydro-1- benzofuran-3-yl)methanesulfmic acid,

Compound 1:3

(6- { [4-(2-methoxyphenyl)phenyl]methoxy } -2,3 -dihydro- 1 -benzofuran-3 -yl)methanesulfmic acid,

Compound 1:4

(6- { [3 -(4-methoxy-2-methylphenyl)phenyl]methoxy } -2,3 -dihydro- 1 -benzofuran-3 - yl)methanesulfmic acid, Compound 1:5

[6-({3-[4-(trifluoromethyl)phenyl]phenyl}methoxy)-2,3-dih ydro-1-benzofuran-3- yljmethanesulfmic acid, Compound 1:6

{ 6- [(2 -phenylphenyl)m ethoxy ] -2, 3 -dihydro- 1 -benzofuran-3 -yl } methanesulfmic acid, Compound 1:7

[5-({3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl}methoxy)-2,3-dihydro-lH- inden-1-yl]methanesulfmic acid,

Compound 1:8

[6-({3-[4-(3-methanesulfonylpropoxy)-2, 6-dimethylphenyl]phenyl}methoxy)-l, 2,3,4- tetrahydronaphthalen-1-yl]methanesulfmic acid, Compound 1:9

[2-({3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl}methoxy)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl]methanesulfmic acid , Compound 1:10

[7-( { 3 - [4-(3 -methanesulfonylpropoxy)-2,6-dimethylphenyl]phenyl } methoxy)-3 ,4-dihy dro-2H- 1 - b enzopy ran-4-y 1 ] methanesulfmi c aci d, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. These compounds are useful for treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes, and even more specifically, type 2 diabetes. Another aspect of the invention is a compound (compound 2:1) and corresponding compound analogues of compound 2 (compound 2:2 - 2:5) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes, and even more specifically, type 2 diabetes, including: Compound 2:1

[6-({ spiro[5.5]undec- 1 -en-2-yl }methoxy)-2, 3 -dihydro- 1 -benzofuran-3 -yljmethanesulfmic acid, Compound 2:2

[6-({spiro[4.5]dec-6-en-7-yl}methoxy)-2,3-dihydro-1-benzo furan-3-yl]methanesulfmic acid, Compound 2:3

[6-({spiro[5.5]undecan-2-yl}methoxy)-2,3-dihydro-1-benzof uran-3-yl]methanesulfmic acid, Compound 2:4

[6-({ spiro[5.5]undec-2-en-2-yl }methoxy)-2,3 -dihydro- 1 -benzofuran-3 -yljmethanesulfmic acid, Compound 2:5

[6-({ spiro[5 6]dodec- 1 -en-2-yl }methoxy)-2, 3 -dihydro- 1 -benzofuran-3 -yljmethanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 3:1) and corresponding compound analogues of compound 3 (compound 3:2 - 3:6) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes, and even more specifically, type 2 diabetes, including:

Compound 3 : 1

[6-(2-phenoxyethoxy)-2,3-dihydro-1-benzofuran-3-yl]methan esulfmic acid, Compound 3:2

(6-{2-[4-(trifluoromethyl)phenoxy]ethoxy}-2,3-dihydro-1-b enzofuran-3-yl)methanesulfinic acid, Compound 3:3

{6-[2-(2,4-dichlorophenoxy)ethoxy]-2,3-dihydro-1-benzofur an-3-yl}methanesulfmic acid, Compound 3 :4 {6-[2-(3-phenylphenoxy)ethoxy]-2,3-dihydro-1-benzofuran-3-yl }methanesulfmic acid, Compound 3:5

{6-[2-(3-chlorophenoxy)ethoxy]-2,3-dihydro-1-benzofuran-3 -yl}methanesulfmic acid, and Compound 3:6

{6-[2-(2-methylphenoxy)ethoxy]-2,3-dihydro-1-benzofuran-3 -yl}methanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 4:1) and corresponding compound analogues of compound 4 (compound 4:2 - 4:10) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 4:1

(6-phenoxy-2, 3 -dihydro- l-benzofuran-3-yl)methanesulfmic acid, Compound 4:2

[6-[4-(trifluoromethyl)phenoxy]-2,3-dihydro-1-benzofuran- 3-yl]methanesulfmic acid, Compound 4:3

[6-(3-phenylphenoxy)-2,3-dihydro-1-benzofuran-3-yl]methan esulfmic acid, Compound 4:4

[6-(4-chl oro-2-methylphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 4:5

[6-(3 -m ethoxyphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 4:6

[6-(4-phenylylphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 4:7

[6-(2 -phenylylphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 4:8

[6-(2, 6-dichlorophenoxy)-2, 3 -dihydro- l-benzofuran-3-ylJmethanesulfmic acid, Compound 4:9

[6-(4-pyridin-2-yloxy)-2,3-dihydro-1-benzofuran-3-yl]meth anesulfmic acid, Compound 4:10

[6-(pyrimidin-4-yloxy)-2,3-dihydro-1-benzofuran-3-yl]meth anesulfmic acid, Compound 4:11

3-(6-(2-fluoro-3-chloro-5~(5-methylthiazol-2-yloxy)phenyl )chroman-2-yl)propan~l~sulfinic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 5:1) and corresponding compound analogues of compound 5 (compound 5:2 - 5:12) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 5 : 1

[6-([2-(cyanomethyl)phenyl)ethynyl]-2,3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 5:2

(6-[(2-methylphenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-y l)methanesulfmic acid, Compound 5:3

(6-[(2-cyanophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-yl )methanesulfmic acid, Compound 5:4

[6-([2-(methylsulfonyl)phenyl)ethynyl]-2,3-dihydro-1-benz ofuran-3-yl]methanesulfmic acid, Compound 5:5 (6-[(2-flurophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-yl)me thanesulfmic acid, Compound 5:6

(6-[(4-flurophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-yl )methanesulfmic acid, Compound 5:7

[6-(pyridin-2-ylethynyl)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 5:8

[6-(pyridin-3 -ylethynyl)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid, Compound 5:9

[6-(pyrimidin-4-ylethynyl)-2,3-dihydro-1-benzofuran-3-yl] methanesulfmic acid, Compound 5:10

[6-((2-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)-2,3-dih ydrobenzofuran-3-yl]methanesulfmic acid,

Compound 5:11

[6-(biphenyl-3-ylethynyl)-2,3-dihydro-1-benzofuran-3-yl]m ethanesulfmic acid, Compound 5:12 [6-(3 -phenylprop- 1 -yn- 1 -yl)-2, 3 -dihydro- 1 -benzofuran-3 -yljmethanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a compound of the general formula II for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: wherein:

Ri is H, CN, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

X is H, halo or CN; and

Ai is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - 0-B1; -S-B1; or-NH-B1, wherein Bi is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 6: 1/Chemotype IIA) and corresponding compound analogues of compound 6 (compound 6:2 - 6:16) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including Compound 6:1

2-(4-{[3-(2, 6-dimethyl phenyl) phenyl]methoxy}phenyl)ethane-1-sulfinic acid

Compound 6:2

2-(4-{[3-(2,6-dimethylphenyl)phenyl]methoxy}phenyl)-2-(1 -methyl-1 H-imidazol-2-yl)ethane-1-sulfinic acid Compound 6:3

2-(4-{[3-(2,6-dimethylphenyl)phenyl]methoxy}phenyl)-2-(1 ,2-oxazol-5-yl)ethane-1-sulfinic acid Compound 6:4 2-[4-([3-(2,6-dimthylphenyl)phenyl]methoxy)phenyl-2-(pyridin -3-yl)ethane-1-sulfmic acid,

2-[4-([3-(2,6-dimthylphenyl)phenyl]methoxy)phenyl-2-(pyri midin-5-yl)ethane-1-sulfmic acid,

2-[4-([3-(2, 6-dimthylphenyl)phenyl]methoxy)phenyl-2-(l -methyl- lH-l, 2, 4-triazole-5-yl)ethane- 1-sulfinic acid, 2-[4-([3-(2, 6-dimthylphenyl)phenyl]methoxy)phenyl-2-(l -methyl- 1H- 1,2,3, 4-tetrazole-5- yl)ethane- 1-sulfinic acid,

2-(l -methyl- lH-1, 2, 4-triazol-5-yl)-2-(4-[(3-[4-

(trifluoromethyl)phenyl]phenyl)methoxy]phenyl)ethane- 1-sulfinic acid,

2-(1-methyl-lH-imidazole-2-y1)-2-(4-[(3-[4-

(trifluoromethyl)phenyl]phenyl)methoxy]phenyl)ethane-l -sulfinic acid,

2-(l-methyl-1H-

1,2,3,4-tetrazol-5-yl)-2-(4-[(3-[4-(trifluoromethyl)pheny l]phenyl)methoxy]phenyl)ethane-1- sulfmic acid,

2-(4-[(3-[4-(trifluoromethyl)phenyl]phenyl)methoxy]phenyl )pent-3-yne- 1 -sulfinic acid,

2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]pent-3-yn e-1-sulfmic acid,

2-(4-[(3 -[4-(3 -methanesulfonyl propoxy)-2, 6-dim ethyl phenyl jphenyl )methoxy]phenyl )pent-3- yne-1-sulfinic acid,

2-(4-[(5-chloro-2,3-dihydro-lH-inden-1-yl)oxy]phenyl)pent -3-yne-1-sulfmic acid, 2-(4-[(6-chloro-1,2,3,4-tetrahydronapthalen-1-yl)oxy]phenyl) pent-3-yne-1-sulfmic acid,

2-(4-[(5-chloro-2, 3-dihy dro-lH-inden-1 -yl)oxy]phenyl)-2-(l -methyl- lH-imidazol -2 -yl)ethane-1- sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof .

Another aspect of the invention is a compound (compound 7: 1/Chemotype IIB) and corresponding compound analogues of compound 7 (compound 7:2 - 7:7) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including Compound 7 : 1

2-(4-{2-[phenyl(l,3-thiazol-2-yl)amino]ethoxy}phenyl)etha nesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 8: 1/Chemotype IIC) and corresponding compound analogues of compound 8 (compound 8:2 - 8:18) of the following formulas and corresponding names for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: Compound 8:1

Sodium 4-(4-[(cyanomethyl)phenyl]ethynyl)-2-fluorophenyl)ethanesulf mate,

Sodium 4-(4-([(cyanomethyl)phenyl]ethynyl)phenyl)ethanesulfmate,

Sodium 2-(2-fluoro-4-[(2-methylphenyl)ethynyl]phenyl)ethanesulfmate , Sodium 2-(4-[(2-cyanophenyl)ethynyl]-2-fluorophenyl)ethanesulfmate,

Sodium 2-(2-cyano-4-[(2-fluorophenyl)ethynyl]phenyl)ethanesulfmate,

Sodium 2-(2-fluoro-4-[(4-fluorophenyl)ethynyl]phenyl)ethanesulfmate ,

Sodium 2-[2-fluoro-4-([2-(methylsulfonyl)phenyl]ethynyl)phenyl]etha nesulfmate,

Sodium 2-[2-fluro-4-(pyridin-4-ylethynyl)phenyl]ethanesulfmate,

Sodium 2-[2-fluro-4-(pyridin-3-ylethynyl)phenyl]ethanesulfmate,

Sodium 2-[2-fluro-4-(pyrimidin-4-ylethynyl)phenyl]ethanesulfmate,

Sodium 2-[2-fluro-4-(3-phenylprop-1-yn-yl)phenyl]ethanesulfmate,

Sodium 2-[2-fluro-4-([4-(methylsulfanyl)butoxy]phenyl]ethynyl)pheny l]ethanesulfmate,

Sodium 2-[2-fluro-4-(2-[4-(4-methanesulfonylbutoxy)phenyl]ethynyl)p henyl]ethane-1-sulfmic acid,

Sodium 2-[2-fluro-4-(2-[2-(3-methanesulfonylbutoxy)phenyl]ethynyl)p henyl]ethane-1-sulfmic acid,

Sodium 2-[2-fluro-4-[(2-[3-(methylsulfanyl)propoxy]phenyl]ethynyl)p henyl]ethanesulfmate, 2-[4-(biphenyl-3-ylethynyl)-2-fluorophenyl]ethanesulfmic acid, 2-(4-([2-(cyanomethyl)phenyl]ethynyl)phenyl)pent-3-yne-1-sul fmic acid,

2-(2-fluro-4-((2-methylphenyl)ethynyl)phenyl)-2-(l -methyl- lH-imidazol-2-yl)ethanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 9: 1/Chemotype IID) and corresponding compound analogues of compound 9 (compound 9:2) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 9:1

2-[2-fluoro-4-((E)-2-phenylethenyl)phenyl]ethanesulfmic acid,

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(E)-2-phenylethenyl]p henyl)ethanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 10:l/Chemotype HE) and corresponding compound analogues of compound 10 (compound 10:2) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 10 2-(2-(fluoro-4-(2-phenylehtyl)phenyl)ethanesulfmic acid,

2-(1-methyl- lH-imidazol -2 -yl)-2-[4-(2-phenylethenyl)phenyl]ethanesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 11 : 1/Chemotype IIF) and corresponding compound analogues of compound 11 (compound 11:2 — 11:3) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 11

2-(4-[2-(4-chlorophenoxy)ethoxy]phenyl)ethanesulfmic acid, 2-(4-[2-(4-chlorophenoxy)ethoxy]phenyl)-2-(1-methyl-1H-imida zol-2-yl)ethanesulfmic acid,

2-(4-[2-(4-chlorophenoxy)ethoxy]phenyl)pent-3-yne-1-sulfm ic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 12:l/Chemotype IIG) and corresponding compound analogues of compound 12 (compound 12:2 - 12:4) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 12

2-(4-[(spiro[5.5]undec-2-en-2-yl)methoxy]phenyl)ethane-1- sulfmic acid,

2-(4-[(spiro[5.5]undec-1-en-2-yl)methoxy]phenyl)pent-3-yne-1 -sulfmic acid,

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(spiro[5.5]undec-2-en -2-yl)methoxy]phenyl)ethane-1- sulfmic acid,

2-(4-[(4-[(2-azaspiro[5.5]undecan-2-yl)methyl]phenyl)meth oxy]phenyl)pent-3-yne-1-sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 13:l/Chemotype IIH) and corresponding compound analogues of compound 13 (compound 13:2) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 13

2-(4-[(4-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]phenyl) methoxy]phenyl)pent-3-yne-1-sulfmic acid, 2-(l-methyl-lH.imidazol-2-yl)-2-(4-[(4-[(1,2,3,4-tetrahydroq uinolin-1- yl)methyl]phenyl)methoxy]phenyl)ethane-1-sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a compound of the general formula Ilia or Illb for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

wherein:

R ₂ is H, unsubstituted or substituted alkyl, unsubstituted or substituted akynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

Xi is independently CH ₂ , S or O; and

A ₂ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - 0-B ₂ ; -S-B _I ; or-NH-B ₂ , wherein B ₂ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 14:l/Chemotype II-I) and corresponding compound analogues of compound 14 (compound 14:2 - 14:3) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 14:1 2-(2-(4-methylphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl)pent- 3-yne-1-sulfmic acid, 2-[2-(3-fluorophenyl)-2, 3-dihy dro-1,4-benzodioxin-6-yl]-2-(1-methyl-1H-imidazol -2 -yljethane-

1 -sulfmic acid,

2-[2-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-5-yl]-2-(1 -methyl-1H-imidazol-2-yl)ethane-1- sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a compound of the general formula IV for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: wherein:

X is H, halo, or unsubstituted or substituted alkyl; and

A ₃ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - 0-B ₃ ; -S-B ₃ ; or -NH-B ₃ , wherein B ₃ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another aspect of the invention is a compound (compound 15:1) and corresponding compound analogues of compound 15 (compound 15:2 - 15:11) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 15:1

3-[3-fluoro-4-([5-fluoro-2-(4,5,6,7-tetrahydro-l,3-benzot hiaozl-2- yl)phenyl]methoxy)phenyl]propane-1-sulfmic acid,

3-[3-fluoro-4-([5-fluoro-2-(5-methyl-l,3-thiazol-2-yl)phe nyl]methoxy)phenyl]propane-1-sulfmic acid,

3-[4-([5-fluoro-2-(5-methyl-l,3-thiazol-2-yl)phenyl]metho xy)phenyl]propane-1-sulfmic acid,

3-[4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl]methoxy)p henyl]propane- 1 -sulfinic acid, 3-[4-(2-[5-fluoro-2-(5-methylthiophen-2-yl)phenyl]ethyl)phen yl]propane-1-sulfmic acid,

3-[4-(l-fluoro-2-[5-fluoro-2-(5-methylthiophen-2-yl)pheny l]ethyl)phenyl]propane-1-sulfmic acid,

3-[4-(l,l-difluoro-2-[5-fluoro-2-(5-methylthiophen-2-yl)p henyl]ethyl)phenyl]propane-1-sulfmic acid,

3-[4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl]methoxy)- 2-methylphenyl]propane-l -sulfinic acid,

3-[2-fluoro-4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl]met hoxy)-phenyl]propane-1-sulfmic acid,

3-(4-(E)-2-[5-fluoro-2-(5-methylthiophen-2-yl)phenyl]ethe nyl)phenyl]propane-1-sulfmic acid,

3-[4-(2-[5-fluoro-2-(5-methylthiophen-2-yl)phenyl]ethynyl )phenyl]propane-1-sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. Another aspect of the invention is a compound (compound 16:1) and corresponding compound analogues of compound 16 (compound 16:2) of the following formulas and corresponding names listed below for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

Compound 16:1

3-(4-{2-[phenyl(pyridin-2-yl)amino]ethoxy}phenyl)propane- 1-sulfmic acid, Compound 16:2

3-(4-{2-[phenyl(l,3-thiazol-2-yl)amino]ethoxy}phenyl)prop ane-1-sulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

A further aspect of the invention relates to the use of the compounds and compound analogues described herein including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof for the treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes. Yet an aspect is the use of the compounds and compound analogues described herein including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes. Yet an aspect is the use of the compounds and compound analogues described herein an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of the receptor FFA1/GPR40.

Yet an aspect is the use of the compounds and compound analogues described herein including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of the receptor GPR120.

Yet an aspect is the use of the compounds and compound analogues described herein including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of both the receptor GPR120 and FFA1/GPR40.

Yet an aspect is the use of the compounds and compound analogues described herein including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof and their corresponding sulfonic acids (and esters), which may be metabolites of the sulfmic acids. In some aspects, the compounds or compounds analogues described herein are sodium salts. In some aspects, the compounds and compound analogues described herein are sulfmate compounds. In some aspects, the compounds and compound analogues described herein are sulfmic acid compounds.

Yet an aspect is a compound of the present invention is a metabolite (i.e. having undergone metabolism or biotransformation in the subject). In some aspects, a compound of the present invention is a sulfmic acid (or its corresponding sulfmate salt) compound or a sulfonic acid (or its corresponding sulfonate salt) compound. In some aspects, a compound of the present invention may be a sulfmic acid metabolite, which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(0) ₂ 0H or -S(0) ₂ 0- group replacing a -S(0)OH or - S(O)O- group in the compound) or a corresponding sulfmate ester of the compound (e.g., a compound having a -S(0)0(Ci- ₆ alkyl) group replacing a -S(0)OH or S(O)O- group in the compound). In some aspects, a compound of the present invention is a sodium salt. In some aspects, a compound of the present invention is a sulfmate salt (e.g. a sodium sulfmate salt).

Yet an aspect is a method for the treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, whereby a compound compound or compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof is administered to a subject, such as a mammal, preferably a human, in need of such treatment. Other features and advantages of the invention will be apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. When a range is employed ( e.g ., a range from x to y) it is meant that the measurable value is a range from about x to about y, or any range therein, such as about xi to about yi, etc. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Accordingly, as used in the present disclosure, whether in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a process the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a molecule, compound, or composition, the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention relates to new compounds, to their use in therapy, as well as to a pharmaceutical composition comprising, consisting essentially of or consisting of said compounds. More specifically, the invention relates to certain compounds for the treatment of metabolic disorders. Even more specifically, the invention relates to certain compounds or pharmaceutical compositions comprising, consisting essentially of or consisting of said compounds for the treatment of diabetes mellitus, specifically type diabetes mellitus.

Consequently, one aspect of the present invention is a compound of the general formula I for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: wherein: n is 1, 2 or 3; p is 1 or 2;

R is O, NH, CH2 or S; and

A is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - O-B; -S-B; or -NH-B, wherein B is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some aspects of the present invention, A is -O-B. In some aspects, A is -CºC-D, wherein D is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some aspects, R is O, and n is 1 or 2. In some aspects, R is CH _2. In some aspects of the present invention, the compounds of formula I include the following structure: wherein:

R is O, C, NH or S and the ring-structure including R can be a five-, six, or seven- membered ring system.

In some embodiments, the compound of the invention may be represented by compound 1 (compound 1:1) and compound 1 analogues (compound 1:2 - 1:10). (6-[(3-[4(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]pheny l)methoxy]-2, 3, dihydro-1- benzofuran-3-yl)methanesulfmic acid [6-([3-(2,6-dimethylphenyl)phenyl]methoxy)-2,3,dihydro-1-ben zofuran-3-yl]methanesulfmic acid

[6-([4-(2-methoxyphenyl)phenyl]methoxy)-2,3,dihydro-1-ben zofuran-3-yl]methanesulfmic acid

[6-([3-(4-methoxy-2-methylphenyl)phenyl]methoxy)-2, 3, dihydro- l-benzofuran-3- yljmethanesulfinic acid (6-[(3-[4-(trifluoromethyl)phenyl]phenyl)methoxy]-2, 3, dihydro- l-benzofuran-3- yl)methanesulfmic acid

(6-[(2-phenylphenyl)methoxy]-2,3,dihydro-1-benzofuran-3-y l)methanesulfmic acid

(5-[(3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl)methoxy]-2,3-dihydro-1H- inden-1-yl)methanesulfmic acid

(6-[(3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl)methoxy]-1,2,3,4- tetrahydronapthalen-1-yl)methanesulfmic acid

(2-[(3-[4-(3-methanesulfonylpropoxy)-2,6-dimethylphenyl]p henyl)methoxy]-6,7,8,9-5H- benzo[7]annulen-5-yl)methanesulfmic acid

(7-[(3-[4-(3-methanesulfonylpropoxy)-2, 6-dim ethyl phenyl ]phenyl)methoxy]-3,4-dihydro2H- 1 - benzopyran-4-yl)methanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 2 (compound 2: 1) and compound 2 analogues (compound 2:2 - 2:5)

Compound 2

(6-[(spiro[5.5]undec-1-en-2-yl)methoxy]-2,3-dihydro-1-ben zofuran-3-yl)methanesulfmic acid

(6-[(spiro[4.5]dec-6-en-7-yl)methoxy]-2,3-dihydro-1-benzo furan-3-yl)methanesulfmic acid

(6-[(spiro[5.5]undecan-2-yl)methoxy]-2,3-dihydro-1-benzof uran-3-yl)methanesulfmic acid

6-[(spiro[5.5]undec-2-en-2-yl)methoxy]-2,3-dihydro-1-benz ofuran-3-yl)methanesulfmic acid

(6-[(spiro[5.6]dodec-1-en-2-yl)methoxy]-2,3-dihydro-1-ben zofuran-3-yl)methanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 3 (compound 3:1) and compound 3 analogues (compound 3:2 - 3:6)

Compound 3

[6-(2 -phenoxyethoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

[6-(2-[4-(trifluoromethyl)phenoxy]ethoxy)-2,3-dihydro-1-b enzofuran-3-yl)methanesulfmic acid

[6-[2-(2,4-dichlorophenoxy)ethoxy]-2,3-dihydro-1-benzofur an-3-yl)methanesulfmic acid

[6-[2-(3-phenylphenoxy)ethoxy]-2,3 -dihydro- l-benzofuran-3-yl)methanesulfmic acid

[6-[2-(3-chlorophenoxy)ethoxy]-2,3-dihydro-1-benzofuran-3 -yl)methanesulfmic acid

[6-[2-(2-methylphenoxy)ethoxy]-2,3-dihydro-1-benzofuran-3 -yl)methanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 4 (compound 4:1) and compound 4 analogues (compound 4:2 - 4:13).

Compound 4

(6-phenoxy-2, 3 -dihydro- l-benzofuran-3-yl)methanesulfmic acid

(6-[4-(trifluoromethyl)phenoxy]-2,3-dihydro-1-benzofuran- 3-yl)methanesulfmic acid

[6-(3-phenylphenoxy)-2,3-dihydro-1-benzofuran-3-yl]methan esulfmic acid

[6-(4-chl oro-2-methylphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

[6-(3 -m ethoxyphenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

[6-(4-phenylphenoxy)-2,3-dihydro-1-benzofuran-3-yl]methan esulfmic acid [6-(2-phenylphenoxy)-2,3-dihydro-1-benzofuran-3-yl]methanesu lfmic acid

[6-(2, 6-di chi orophenoxy)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 5 (compound 5:1) and compound 5 analogues (compound 5:2 - 5:12). Compound 5

[6-([2-(cyanomethyl)phenyl]ethynyl)-2,3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

(6-[(2 -methylphenyl)ethynyl]-2, 3 -dihydro- l-benzofuran-3-yl)methanesulfmic acid

(6-[(2-cyanophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-yl )methanesulfmic acid

[6-([2-(methylsufonyl)phenyl]ethynyl)-2,3-dihydro-1-benzo furan-3-yl]methanesulfmic acid

(6-[(2-fluorophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-y l)methanesulfmic acid

(6-[(4-fluorophenyl)ethynyl]-2,3-dihydro-1-benzofuran-3-y l)methanesulfmic acid [6-(pyridin-2-ylethynyl)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

[6-(pyridin-3 -ylethynyl)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid

[6-(pyrimidin-4-ylethynyl)-2,3-dihydro-1-benzofuran-3-yl] methanesulfmic acid

[6-((2-(3-(methylsulfonyl)propoxy)phenyl)ethynyl)-2,3-dih ydrobenzofuran-3-yl]methanesulfmic acid

[6-(biphenyl-3-ylethynyl)-2,3-dihydro-1-benzofuran-3-yl]m ethanesulfmic acid

[6-(3 -phenylprop- 1 -yn- 1 -yl)-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments of the present invention is a compound of the general formula II for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: wherein:

Ri is H, CN, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

X is H, halo or CN; and Ai is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - 0-Bi; -S-Bi; or -NH-B1, wherein Bi is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some aspects, Ai is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some aspects, Ai is -CºC-D, wherein D is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some aspects, D is selected from the group consisting of: H; phenyl; //-heptyl; benzyl; homobenzyl; cyclopropyl; cyclopentyl; cyclohexyl;

. In some aspects, Ai is -CH=CH-Ph or -CH2-CH2-Ph. In some aspects, Ri is H. In some aspects, Ri is unsubstituted or substituted alkynyl or unsubstituted or substituted heteroaryl. In some embodiments, X is H, F or CN.

In some aspects, the compounds of formula II include the following structure:

Generic wherein the heteroaryl group of Ri can be optionally substituted. Ri is H, alkyl, aryl, heteroaryl, CN, alkene, alkyne. A is C, O, S, NH with substitution. The phenyl ring may contain a F or CN group.

In some embodiments, the compound of the invention may be represented by compound 6: 1/Chemotype IIA and compound 6 analogues (compound 6:2 - 6:16).

Compound 6

2-[4-([3-(2,6-dimethlyphenyl)phenyl]methoxy)phenyl]ethane -1-sulfmic acid

2-(4-((3-(2,6-dimethylphenyl)phenyl)methoxy)phenyl)-2-(1- methyl-1H-imidazol-2-yl)ethane-1- sulfmic acid

2-(4-((3-(2,6-dimethylphenyl)phenyl)methoxy)phenyl)-2-(l, 2-oxazol-5-yl)ethane-1-sulfmic acid

2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]-2-(py ridin-3-yl)ethane-1-sulfmic acid 2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]-2-(pyrim idin-5-yl)ethane-1-sulfmic acid

2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]-2-(l- methyl-lH-l,2,4-triazol-5- yl)ethane-1-sulfmic acid

2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]-2-(l-meh tyl-lH-1,2,3,4-triazol-5- yl)ethane-1-sulfmic acid

2-(l -methyl- lH-1, 2, 4-triazol-5-yl)-2-(4-[(3-[4-

(trifluoromehtyl)phenyl]phenyl)methoxy]phenyl)ethane-1-su lfmic acid

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(3-[4-

(trifluoromethyl)phenyl]phenyl)methoxy]phenyl)ethane-1-su lfmic acid

2-(1-methyl- 1H-1,2,3,4-tetrazol-5-yl)-2-(4-[(3-[4- (trifluoromehtyl)phenyl]phenyl)methoxy]phenyl)ethane-1-sulfm ic acid

2-(4-[(3-[4-(trifluorc>mehtyl)phenyl]phenyl)methoxy]ph enyl)pent-3-yne- 1-sulfinic acid

2-[4-([3-(2,6-dimethylphenyl)phenyl]methoxy)phenyl]pent-3 -yne-1-sulfmic acid

-(4-[(3 -[4-(3 -methanesulfonyl propoxy)-2, 6-dim ethyl phenyl phenyl ]methoxy)phenyl ]pent-3-yne- -sulfinic acid -(4-[(5-chloro-2,3-dihydro-lH-inden-1-yl)oxy]phenyl)pent-3-y ne-1-sulfmic acid -(4-[(6-chloro-1,2,3,4-tetrahydronapthalen-1-yl)oxy]phenyl)p ent-3-yne-1-sulfmic acid

2-(4-[(5-chloro-2, 3-dihydro-lH-inden-1-yl)oxy]phenyl)-2-(l -methyl- lH-imidazol -2 -yl)ethane-1- sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 7: 1/Chemotype IIB and compound 7 analogues (compound 7:2 - 7:7)

Compound 7

2-(4-(pyridin-2-yloxy)phenyl)ethanesulfmic acid

2-(4-[(2-phenylpyridin-4-yl)oxy]phenyl)ethanesulfmic acid

2-(4-phenoxyphenyl)ethanesulfmic acid 2-[4-(3-phenoxyphenyl)phenyl]ethane-1-sulfmic acid

2-(l -methyl- lH-imidazol-2-yl)-2-[4-(3-phenoxyphenyl)phenyl]ethane-1-sulf mic acid

2-[4-(4-methanesulfonylphenoxy)phenyl]pent-3-yne-1-sulfmi c acid

2-(4-{2-[phenyl(l,3-thiazol-2-yl)amino]ethoxy}phenyl)etha nesulfmic acid, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. In some embodiments, the compound of the invention may be represented by compound

8:l/Chemotype IIC and compound 8 analogues (compound 8:2 - 8:18).

Compound 8:1

Sodium 4-(4-[(cyanomethyl)phenyl]ethynyl)-2-fluorophenyl)ethanesulf mate Sodium 4-(4-([(cyanomethyl)phenyl]ethynyl)phenyl)ethanesulfmate

Sodium 2-(2-fluoro-4-[(2-methylphenyl)ethynyl]phenyl)ethanesulfmate

Sodium 2-(4-[(2-cyanophenyl)ethynyl]-2-fluorophenyl)ethanesulfmate

Sodium 2-(2-cyano-4-[(2-fluorophenyl)ethynyl]phenyl)ethanesulfmate Sodium 2-(2-fluoro-4-[(4-fluorophenyl)ethynyl]phenyl)ethanesulfmate

Sodium 2-[2-fluoro-4-([2-(methylsulfonyl)phenyl]ethynyl)phenyl]etha nesulfmate

Sodium 2-[2-fluro-4-(pyridin-4-ylethynyl)phenyl]ethanesulfmate

Sodium 2-[2-fluro-4-(pyridin-3-ylethynyl)phenyl]ethanesulfmate

Sodium 2-[2-fluro-4-(pyrimidin-4-ylethynyl)phenyl]ethanesulfmate

Sodium 2-[2-fluro-4-(3-phenylprop-1-yn-yl)phenyl]ethanesulfmate

Sodium 2-[2-fluro-4-([4-(methylsulfanyl)butoxy]phenyl]ethynyl)pheny l]ethanesulfmate

Sodium 2-[2-fluro-4-(2-[4-(4-methanesulfonylbutoxy)phenyl]ethynyl)p henyl]ethane-1-sulfmic acid

Sodium 2-[2-fluro-4-(2-[2-(3-methanesulfonylbutoxy)phenyl]ethynyl)p henyl]ethane-1-sulfmic acid

Sodium 2-[2-fluro-4-[(2-[3-(methylsulfanyl)propoxy]phenyl]ethynyl)p henyl]ethanesulfmate

2-[4-(biphenyl-3-ylethynyl)-2-fluorophenyl]ethanesulfmic acid

2-[4-([2-(cyanomethyl)phenyl]ethynyl)phenyl]pent-3-yne-1- sulfmic acid 2-{2-fluoro-4-[(2-methylphenyl)ethynyl]phenyl}-2-(l -methyl- l//-imidazol-2-yl)ethanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 9:l/Chemotype IID and compound 9 analogues (compound 9:2)

Compound 9:1

2-[2-fluoro-4-((E)-2-phenylethenyl)phenyl]ethanesulfmic acid

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(E)-2-phenylethenyl]p henyl)ethanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 10: 1/Chemotype HE and compound 10 analogues (compound 10:2)

Compound 10:1

2-(2-(fluoro-4-(2-phenylehtyl)phenyl)ethanesulfmic acid 2-(l -methyl- lH-imidazol -2 -yl)-2-[4-(2-phenylethenyl)phenyl]ethanesulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 11 : 1/Chemotype IIF and compound 11 analogues (compound 11:2 - 11 :3). Compound 11:1

2-(4-[2-(4-chlorophenoxy)ethoxy]phenyl)ethanesulfmic acid

2-(4-[2-(4-chlorophenoxy)ethoxy]phenyl)-2- (1-methyl-1H-imidazole-2-yl)ethanesulfmic acid 2-(4-(2-(4-chlorophenoxy)ethoxy)phenyl)pent-3-yne-1-sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 12:l/Chemotype IIG and compound 12 analogues (compound 12:2 - 12:4). Compound 12:1

2-(4-[(spiro[5.5]undec-2-en-yl)methoxy]phenyl)ethane-1-su lfmic acid

2-(4-[(spiro[5.5]undec-1-en-yl)methoxy]phenyl)pent-3-yne- 1-sulfmic acid

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(spiro[5.5]undec-2-en -yl)methoxy]phenyl)ethane-1-sulfmic acid

2-(4-[(4-[(azaspiro[5.5]undec-2-yl)methyl]phenyl)methoxy] phenyl)pent-3-yne-1-sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some embodiments, the compound of the invention may be represented by compound 13:l/Chemotype IIH and compound 13 analogues (compound 13:2).

Compound 13

2-(4-[(4-[(1,2,3,4-tetrahydroquinolin-1-yl)methyl]phenyl) methoxy]phenyl)pent-3-yne-sulfmic acid

2-(1-methyl-1H-imidazol-2-yl)-2-(4-[(4-[(1,2,3,4-tetrahyd roquinolin-1- yl)methyl]phenyl)methoxy]phenyl)ethane- 1 -sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of the general formula Ilia or Illb for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including:

wherein:

R2 is H, unsubstituted or substituted alkyl, unsubstituted or substituted akynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

Xi is independently CH ₂ , S or O; and

A ₂ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - 0-B ₂ ; -S-B ₁ ; or -NH-B ₂ , wherein B ₂ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

In some aspects, A ₂ is substituted aryl. In some aspects, A ₂ is:

In some aspects R ₂ is substituted heteroaryl. In some aspects, R ₂ is -CºC-CH ₃ .

In some aspects, the compunds of formula Ilia or Illb have the following structure: Generic structure for compounds 14

R = Aryl, heteroaryl, acetylene, H, alkyl x = o, S, c

In some embodiments, the compound of the invention may be represented by compound 14:l/Chemotype II-I and compound 14 analogues (compound 14:2 - 14:3).

Compound 14:1

2-[2-(4-methylphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]pe nt-3-yne-1-sulfmic acid 2-[2-(3-fluorophenyl)-2, 3-dihy dro-1,4-benzodioxin-6-yl]-2-(l -methyl- lH-imidazol -2 -yljethane- 1 -sulfmic acid

2-[2-(4-fluorophenyl)-2,3-dihydro- l-benzofuran-5-yl]-2-(l -methyl lH-imidazol-2-yl)ethane-1- sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. Another embodiment of the present invention is a compound of the general formula IV for treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including: wherein:

X is H, halo, or unsubstituted or substituted alkyl; and

A ₃ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; - O-B ₃ ; -S-B ₃ ; or -NH-B ₃ , wherein B ₃ is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. In some aspects, wherein Di is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

In some aspects, the compounds of general formula IV include:

Generic Structure

A= Any atom other than H (preferably O, C, N, S)

In some embodiments, the compound of the invention may be represented by compound 15:1/GPR120 and compound 15 analogues (compound 15:2 - 15:11).

Compound 15:1

3-[3-fluoro-4-([5-fluoro-2-(4,5,6,7-tetrahydro-l,3-benzot hiaozl-2- yl)phenyl]methoxy)phenyl]propane-1-sulfmic acid 3-[3-fluoro-4-([5-fluoro-2-(5-methyl-l,3-thiazol-2-yl)phenyl ]methoxy)phenyl]propane-1-sulfmic acid

3-[4-([5-fluoro-2-(5-methyl-l,3-thiazol-2-yl)phenyl]metho xy)phenyl]propane-1-sulfmic acid

3-[4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl]methoxy)p henyl]propane- l -sulfinic acid

3-[4-(2-[5-fluoro-2-(5-methylthiophen-2-yl)phenyl]ethyl)p henyl]propane-1-sulfmic acid

3-[4-(1-fluoro-2-[5-fluoro-2-(5-methylthiophen-2-yl)phenyl]e thyl)phenyl]propane-1-sulfinic acid

3-[4-(1,1-difluoro-2-[5-fluoro-2-(5-methylthiophen-2-yl)p henyl]ethyl)phenyl]propane-1-sulfmic acid

3-[4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl]methoxy)- 2-methylphenyl]propane- 1-sulfinic acid

3-[2-fluoro-4-([5-fluoro-2-(5-methylthiophen-2-yl)phenyl] methoxy)-phenyl]propane-1-sulfmic acid

3-[4-((E)-2-[5-fluoro-2-(5-methylthophen-2-yl)phenyl]ethe nyl)phenyl]propane-1-sulfmic acid

3-[4-(2-[5-fluoro-2-(5-methylthophen-2-yl)phenyl]ethynyl) phenyl]propane-1-sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof. In some embodiments, the compound of the invention may be represented by compound 16:l/GPR120-addendum and compound 16 analogues (compound 16:2)

Compound 16:1 3-(4-{2-[phenyl(pyridin-2-yl)amino]ethoxy}phenyl)propane-1-s ulfmic acid

3-(4-{2-[phenyl(l,3-thiazol-2-yl)amino]ethoxy}phenyl)prop ane-1-sulfmic acid including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof.

A further aspect of the invention relates to the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof for the treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, and bone disorders.

A further aspect of the invention relates to the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof for the treatment of diabetes mellitus, more specifically type 2 diabetes mellitus. Yet an aspect is the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of metabolic disorders including for example diabetes, obesity, metabolic syndrome, fatty liver disease, and bone disorders. Yet another aspect is the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of diabetes mellitus, more specifically type 2 diabetes mellitus.

Yet an aspect is the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of the receptor FFA1/GPR40.

Yet an aspect is the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of the receptor GPR120.

Yet an aspect is the use of the compounds and compound analogues described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof as an agonist of both the receptor GPR120 and FFA1/GPR40.

Yet an aspect is a compound of the present invention is a metabolite (i.e. having undergone metabolism or biotransformation in the subject). In some aspects, a compound of the present invention is a sulfmic acid (or its corresponding sulfmate salt) compound or a sulfonic acid (or its corresponding sulfonate salt) compound. In some aspects, a compound of the present invention may be a sulfmic acid metabolite, which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(0) ₂ OH or -S(0) ₂ 0 group replacing a -S(0)OH or - S(0)0 group in the compound) or a corresponding sulfmate ester of the compound (e.g., a compound having a -S(0)0(Ci- ₆ alkyl) group replacing a -S(0)OH or S(O)O- group in the compound). In some aspects, a compound of the present invention is a sodium salt. In some aspects, a compound of the present invention is a sulfmate salt (e.g. a sodium sulfmate salt).

Yet an aspect is a method for the treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, whereby a compound or compound analogue described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof is administered to a subject such as mammal, preferably a human, in need of such treatment.

Yet an aspect is a method for the treatment of diabetes mellitus, more specifically type 2 diabetes mellitus, whereby a compound or compound analogue described herein, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof is administered to a subject, such as a mammal, preferably a human, in need of such treatment. Thus, a compound of the invention may include FFA1/GPR40 receptor agonists that fully and those that partially activate the FFA1/GPR40 receptor and those compounds that can stimulate or activate the FFA1/GPR40 receptor. In some embodiments, a FFA1/GPR40 receptor agonist may be defined to include any compound that can stimulate or activate the FFA1/GPR40 receptor. In some embodiments, the compound of the invention is an FFA1/GPR40 receptor specific agonist and binds selectively to the FFA1/GPR40 receptor.

Furthermore, a compound of the invention may include GPR120 receptor agonists that fully and those that partially activate the GPR120 receptor and those compounds that can stimulate or activate the GPR120 receptor. In some embodiments, a GPR120 receptor agonist may be defined to include any compound that can stimulate or activate the GPR120 receptor. In some embodiments, the compound of the invention is a GPR120 receptor specific agonist and binds selectively to the GPR120 receptor.

Furthermore, a compound of the invention may include both FFA1/GPR40 and GPR120 receptor agonists that fully and those that partially activate both the FFA1/GPR40 and GPR120 receptors and those compounds that can stimulate or activate both the FFA1/GPR40 and GPR120 receptors. In some embodiments, a FFA1/GPR40 and GPR120 receptor agonist may be defined to include any compound that can stimulate or activate both the FFA1/GPR40 and GPR120 receptor. In some embodiments, the compound of the invention is both a FFA1/GPR40 and GPR120 receptor specific agonist and binds selectively to both the FFA1/GPR40 and GPR120 receptor.

The compounds of the present invention may have a different metabolic profile compared to a corresponding carboxylic acid compound (i.e., a compound having a -COOH or -COO group replacing a -S(0)OH or S(O)O- group in the compound. These corresponding carboxylic acid compounds are typically metabolised to an acyl-glucuronide and such metabolism can give rise to reactive metabolites that cause liver toxicity and drug induced liver injury (Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16; Regan S, Maggs J, Hammond T, Lambert C, Williams D and Park BK (2010) Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos 31 : 367-395; Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25 : 1-16).

For example, the compounds of the present invention may only be metabolised by oxidative pathways, such as Cyp oxidation, and/or may minimise the formation of acyl glucuronide-like metabolites compared to a corresponding carboxylic acid compound. A compound of the present invention may have a different distribution profile when orally dosed in-vivo, such as increased exposure in the liver versus plasma, compared to a corresponding carboxylic acid compound.

A compound of the present invention may break down in-vivo via a different metabolic pathway than a corresponding carboxylic acid compound and/or the compound of the invention may have beneficial liver safety effects and/or improved liver safety and/or improved efficacy compared to a corresponding carboxylic acid compound.

The compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.

The compounds of the invention may also be combined with other known compounds in the art for treatment of metabolic disorders including, for example diabetes, obesity, metabolic syndrome, fatty liver disease, bone disorders, more specifically diabetes and even more specifically type 2 diabetes, including, but not limited, to DPP -IV inhibitors, GLP-1 agonists, SGLT-2, sulfonylureas, biguanides (for example metformin), thiazolidinones, A-glucosidase inhibitors and the like.

The compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, for use as a pharmaceutical (e.g. for use in medicine).

For the purpose of the present invention, the term ’’alkyl”, either alone or as part of a radical, includes straight or branched chain alkyl of the general formula C _n H _2n+1.

The term ”Cm-Cn alkyl”, wherein m and n are both integers and m > n, refers to alkyl having from m to n carbon atoms. For example, C1-C6 alkyl includes methyl, ethyl, n-propyl and isopropyl.

For the purpose of the present invention, unless otherwise specified or apparent from the context, the term ’’halogen” refers to F, Cl, Br or I; preferably F, Cl and Br; in particular F and Cl.

The term “alkoxy” refers to a radical of the formula -OR, wherein R is an alkyl moiety as defined herein.

The term “alkylamino” refers to a radical of the formula -RNHR'R ² , wherein R, R ¹ , R ² is an alkyl moiety as defined herein. The term “carbocyclyl” refers to a cyclic moiety containing only carbon (C, CH or CH ₂ ) in the ring.

The term “polycyclic” refers to e.g. fused or bridged rings.

An unsaturated cyclic moiety may be either aromatic or non-aromatic and containing one or several double or triple bonds in the ring.

The term “aromatic” refers to an unsaturated cyclic hydrocarbon group having a conjugated pi electron system that contains 4n+2 electrons where n is an integer greater than or equal to 1. Aromatic molecules are typically stable and are depicted as a planar ring of atoms with resonance structures that consist of alternating double and single bonds, for example benzene or naphthalene.

The term “aryl” refers to an aromatic group in a single or fused carbocyclic ring system having from 6 to 15 ring atoms, in some instances 6 to 10, and to alkyl groups containing said aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, 1 -naphthyl, 2- naphthyl and benzyl. Aryl as defined herein also includes groups with multiple aryl rings which may be fused, as in naphthyl and anthracenyl, or unfused, as in biphenyl and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated or aromatic, for example, indanyl or tetrahydronaphthyl (tetralinyl). All such aryl groups may also be optionally substituted as described below.

The term “heterocycle” or “heterocyclic” refers to saturated or partially unsaturated monocyclic, bicyclic or tricyclic groups having from 3 to 15 atoms, in some instances 3 to 7, with at least one heteroatom in at least one of the rings, said heteroatom being selected from O, S or N. Each ring of the heterocyclic group can contain one or two O atoms, one or two S atoms, one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. The fused rings completing the bicyclic or tricyclic heterocyclic groups may contain only carbon atoms and may be saturated or partially unsaturated. The N and S atoms may optionally be oxidized and the N atoms may optionally be quaternized. Heterocyclic also refers to alkyl groups containing said monocyclic, bicyclic or tricyclic heterocyclic groups. Examples of heterocyclic rings include, but are not limited to, 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl. All such heterocyclic groups may also be optionally substituted as described below

The term “heteroaryl” refers to an aromatic group in a single or fused ring system having from 5 to 15 ring atoms, in some instances 5 to 10, which have at least one heteroatom in at least one of the rings, said heteroatom being selected from O, S or N. Each ring of the heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. The fused rings completing the bicyclic or tricyclic groups may contain only carbon atoms and may be saturated, partially unsaturated or aromatic. In structures where the lone pair of electrons of a nitrogen atom is not involved in completing the aromatic pi electron system, the N atoms may optionally be quaternized or oxidized to the N-oxide. Heteroaryl also refers to alkyl groups containing said cyclic groups. Examples of monocyclic heteroaryl groups include, but are not limited to pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrol opyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. All such heteroaryl groups may also be optionally substituted as described below.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

The term “substituted” when used with the terms alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl refers to an alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group having one or more of the hydrogen atoms of the group replaced by substituents independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, cyclalykyloxy, haloalkoxy, aryloxy, acyl, amino, amido, carboxy, carboxyalkyl, carboxyaryl, halo, oxo, mercapto, sulfmyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino, ureido and groups of the formulas are independently selected from hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl or unsubstituted heteroaryl; and wherein Rkk and R _nn are independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl or unsubstituted heteroaryl. Alternatively, R _gg and R _hh , R _jj and R _kk or R _pp and R _qq together form a heterocyclic ring of 3 to 8 members, optionally substituted with unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, hydroxy, alkoxy, aryloxy, acyl, amino, amido, carboxy, carboxyalkyl, carboxyaryl, mercapto, sulfmyl, sulfonyl, sulfonamido, amidino, carbamoyl, guanidino or ureido, and optionally containing one to three additional heteroatoms selected from O, S or N. In addition, the term “substituted” for aryl and heteroaryl groups includes as an option having one of the hydrogen atoms of the group replaced by cyano, nitro or trifluorom ethyl.

A substitution is made provided that any atom’s normal valency is not exceeded and that the substitution results in a stable compound. Generally, when a substituted form of a group is present, such substituted group is preferably not further substituted or, if substituted, the substituent comprises only a limited number of substituted groups, in some instances 1, 2, 3 or 4 such substituents.

In any structural formula, a substituent may be depicted as not being in a fixed location. However, aspects of the present invention encompass the substituent as being fixed on any position on the depicted ring structure, i.e., the substituent may be attached to the 1, 2, 3, 4, 5, 6, or 7 position of a ring structure of a compond of the present invention.

Any chiral center in a compound of the invention having a specified configuration is indicated as R or S using the well-known Cahn-Ingold-Prelog priority rules. Also, in any structural formula a chiral center having a specified configuration, (i.e. R or S) may be indicated using to indicate that the bond to R is directed out of the paper and towards the reader, and R to indicate that the bond to R is directed out of the paper and away from the reader.

As used herein, a “compound” refers to the compound itself, including an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof, unless otherwise specified within the specific text for that compound. Except, when otherwise indicated, e.g. by indication of (R) or (S) configuration at a given location, all stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Consequently, compounds of the invention may exist in enantiomeric or racemic or diastereomeric forms or as mixtures thereof. The processes for preparation can utilize racemates or enantiomers as starting materials. When racemic and diastereomeric products are prepared, they can be separated by conventional methods, which for example are chromatographic or fractional crystallization.

The term "solvate" refers to a complex of variable stoichiometry formed e.g. by a compound of the invention and a solvent. The solvent is a pharmaceutically acceptable solvent, such as water, which should not interfere with the biological activity of the solute.

Some compounds of the present invention can exist in a tautomeric form which are also intended to be encompassed within the scope of the present invention. “Tautomers” refer to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that the compounds of the invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomeric form.

The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, and such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds

As used herein, the term “salt” such as a pharmaceutically acceptable salt and can include acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na ⁺ , K ⁺ , Li ⁺ , alkali earth metal salts such as Mg ²⁺ or Ca ²⁺ , or organic amine salts.

By "pharmaceutically acceptable salt" it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemi sulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or formed with organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxy ethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2- naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p- toluenesulfonic acid, trimethylacetic acid; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include e.g. diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, and tromethamine. Acceptable inorganic bases include e.g. aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

For the purpose of the present invention "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

Also provided herein is a pharmaceutical composition comprising, consisting essentially of, consisting of a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with at least one pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier.

The term "effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

Pharmaceutically acceptable excipients for use in formulating a compound according to the invention as described and claimed herein, are for example, vehicles, adjuvants, carriers or diluents, which are well-known to those skilled in the art. Pharmaceutical excipients useful in formulating a compound as herein claimed and disclosed are found in e.g. Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).

As used herein, the term “metabolite” means a product of metabolism of a compound of the present invention, or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salts thereof, that exhibits a similar activity in vivo to said compound of the present invention.

As used herein, the term “mixing” means combining, blending, stirring, shaking, swirling or agitating. The term “stirring” means mixing, shaking, agitating, or swirling. The term “agitating” means mixing, shaking, stirring, or swirling. The term "prodrug" is intended to include any compounds which are converted by metabolic or hydrolytic processes within the body of a subject to an active agent that has a formula within the scope of the present invention. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in Prodrugs, Sloane, K. B., Ed.; Marcel Dekker: New York, 1992, incorporated by reference herein in its entirety. The compounds of the present invention can also be prepared as prodrugs, for example pharmaceutically acceptable prodrugs. The terms “pro-drug” and “prodrug” are used interchangeably herein and refer to any compound which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals ( e.g ., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. The term “prodrug” includes a compound of the present invention covalently linked to one or more pro-moieties, such as an amino acid moiety or other water- solubilizing moiety. A compound of the present invention may be released from the pro-moiety via hydrolytic, oxidative, and/or enzymatic release mechanisms. In an embodiment, a prodrug composition of the present invention exhibits the added benefit of increased aqueous solubility, improved stability, and improved pharmacokinetic profiles. The pro-moiety may be selected to obtain desired prodrug characteristics. For example, the pro-moiety, e.g., an amino acid moiety or other water solubilizing moiety such as phosphate may be selected based on solubility, stability, bioavailability, and/or in vivo delivery or uptake. The term “prodrug” is also intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a subject. Prodrugs in the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo , to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that, may be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g, N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g. ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) N- Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like, See Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985). The compounds of the invention can be administered by any suitable means, for example, orally, such as in the form of tablets, pills, dragees, aqueous or oily suspensions or solutions, elixirs, syrups, capsules, granules or powders; sublingually; buccally; parenterally, such as by e.g. subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions). For parenteral administration, a parenterally acceptable aqueous or oily suspension, emulsion or solution is employed, which is pyrogen free and has requisite pH, isotonicity, osmolality and stability.

Those skilled in the art are well able to prepare suitable formulations and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in the scientific literature [eg. Langer, Science 249:1527-1533 (1990)].

Other examples of possible methods of administering the compounds of the invention are nasal administration including administration to the nasal membranes, such as by inhalation spray; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.

The present compounds can also be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the invention can also be administered liposomally. The precise nature of the carrier or other material will depend on the route of administration and those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature. Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of the invention can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms, which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.

Exemplary compositions for parenteral administration include injectable solutions, emulsions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, oil or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositories, which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.

The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, the extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration, as well as the stage and severity of the disease. The dose will also be determined by the route (administration form), timing and frequency of administration. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 20 mg/kg/day, and most preferably 0.1 to 10 mg/kg/day, for adult humans. For oral administration, the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.5 to 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated, for example 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, 400, 500, 600 and 800 mg.

Parenterally, especially intracerebroventricularly or intraperitoneally, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during a constant rate infusion. Advantageously, compounds of the present invention may be administered in single doses, e.g. once daily or more seldom, or in a total daily dosage administered in divided doses of two, three or four times daily.

Moreover, the compounds of the present invention can be administered in combination with another compound, such as a particular agent(s), in a manner that contemplates administering the compounds of the present invention prior to initiating therapy with the particular agent(s) in order to prevent and/or treat the effects of the particular agent(s).

The term “treatment” as used throughout the specification and claims encompasses any type of action that imparts a benefit to a subject, including delaying, and/or reducing the progression of one or more symptom(s) and/or condition(s), reducing the severity of one or more symptom(s) and/or condition(s), etc. Those skilled in the art will appreciate that the benefit imparted by the treatment according to the methods of the present invention is not necessarily meant to imply cure or complete prevention. In one embodiment, the treatment is to relieve the patient of the signs and symptoms of the disease or condition, or to ameliorate the condition of the patient suffering from the disease or disorder or to prevent progression of the disease or condition.

As used herein, “treating,” “treatment” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. However, “treatment” does not necessarily entail a cure for the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

"Prevent", "prevention", and grammatical variants thereof, as used herein, refer to avoiding the onset of a disease, disorder and/or a clinical symptom(s) in a subject relative to what would occur in the absence of the methods of the present invention. In some embodiments, prevention is complete, resulting in the total absence of the disease, disorder and/or clinical symptom(s). In some embodiments, prevention is partial, resulting in avoidance of some aspects of the disease, disorder and/or clinical symptom(s)

A "kit" as used herein refers to a collection or assembly of parts and optionally a set of written instructions.

"Diabetes" as used herein can refer to a disease diagnosed as diabetes according to the diagnostic standard, for example, of WHO (World Health Organization), Japan Diabetes Society, American Diabetes Association or European Association for the Study of Diabetes and includes Type 1 diabetes, Type 2 diabetes, gestational or pregnancy diabetes, and the like. Type 2 diabetes can be characterized by its resistance to the action of insulin, i.e., “insulin resistance.” “Insulin resistance” can mean a disease diagnosed as insulin resistance, based on the insulin resistance index (fasting blood sugar (mg/dL)x fasting insulin (microU/mL)÷405) or on the results obtained by examination by glucose clamp method or the like.

"Bone disorder" as used herein refers to bone related diseases such as osteoporosis, rheumatoid arthritis or osteoarthritis.

The term "patient(s)" include mammalian (including human) patient(s) (or “subject(s)”). As used herein, a “subject” is interchangeable with a “subject in need thereof’. A “subject” includes a mammal. The mammal can be e.g ., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. In one embodiment, the mammal is a human and may be male or female, and any particular stage of growth or development, for example, newborn, neonate, infant, child, juvenile, adolescent, adult, and geriatric. In some embodiments, the subject may be a laboratory animal or a domesticated animal.

Other features and advantages of the present invention are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.

EXAMPLES

Example 1

Synthesis of Compounds

Reaction scheme for Sodium [6-((3-[4-(3-methanesulfonylpropoxy)-2,6- dimethylphenyl]phenyl)methoxy )-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmate (Compound 1:1)

 Experimental Procedure for preparation of Compound 1:1:

Step-1: Preparation of Compound 1-la:

4-Bromo-3,5-dimethylphenol (20.0 g, 108.04 mmol, 1.0 eq.) and 3-formylphenylboronic acid (19.43 g, 129.64 mmol, 1.2 eq.) were suspended in 1M aqueous solution of sodium carbonate (292 mL). Ethanol (100 mL) and toluene (300 mL) was added to this suspension. The reaction mixture was degassed with argon gas and Pd(PPh ₃ ) ₄ (6.24 g, 5.402 mmol, 0.05 eq.) was added. Then the reaction was heated to 80°C or 18 h under argon atmosphere. The solution was then cooled to RT, filtered through celite, the filtrate concentrated and the aq. mixture extracted with ethyl acetate. The organic layers were dried over Na ₂ S0 ₄ and concentrated to obtain crude compound. Crude compound was purified by column chromatography on silica gel (230-400 mesh) using 2-4% of ethyl acetate in pet-ether as an eluent to afford Compound 1-la (7.5 g, 33%). LC-MS: 1.93mins, [M+H] ⁺ 227

Step-2: Preparation of Compound 1-lb:

To a stirred solution of 3 -(methylthio)-l -propanol (5.0 g, 47.16 mmol, l.Oeq.), N,N,N,N- tetramethylhexanediamine (0.8 lg, 4.72 mmol, O.leq.) and triethylamine (9.9ml, 70.75mmol, 1.5eq.) in toluene (48mL) was added p-toulenesulfonyl chloride (13.4 g, 70.75 mmol, 1.5eq.) drop-wise under inert atmosphere. The reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, sat. NaCl solution and dried over Na ₂ S0 , concentrated to obtain the crude compound. Crude compound was purified by column chromatography on silica gel (100-200 mesh) using 2-4% of ethyl acetate in pet ether as an eluent to afford Compound 1-lb (5.8 g, 47.2%). LC-MS: 2.14mins, [M+H] ⁺ 261

Step-3: Preparation of Compound 1-lc:

To a stirred solution of Compound 1-lc (5.8 g, 22.30 mmol, 1.0 eq.) in methanol (120mL) was added Oxone® (27.57 g, 44.61 mmol, 2.0 eq.) in water (120 mL) dropwise at 0°C for 10-15 min. After completion of addition, the reaction was stirred at RT for 16 h. After completion, the reaction was diluted with water, extracted with ethyl acetate. The organic layer was washed with water, sat. NaCl solution and dried over Na2S04, concentrated to give the product Compound 1- lc (5.0 g, 76.7%). LC-MS: 1.61mins, [M+H]+ 293 Step-4: Preparation of Compound 1-ld:

To a stirred solution of Compound 1-la (3.3 g, 14.3 mmol) and Compound 1-lc (5.0 g, 17.1 mmol) in DMF (29 mL) was added K2CO3 (2.6 g, 18.6 mmol), then the reaction was heated to 100°C for 20 h. After completion of the reaction, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, sat. NaCl solution and dried over Na ₂ S0 , filtered and concentrated to obtained crude compound. The crude compound was purified by column chromatography on silica gel (230-400 mesh) using 20-30% of ethyl acetate in pet ether as eluent to afford Compound 1-ld (7.5g) which was taken onto the next step without further purification. LC-MS 2.1 lmins, [M+H] ⁺ 347.

Step-5: Preparation of Compound 1-le:

To a stirred solution of Compound-7 (7.0 g, crude) in methanol (100 mL) was added NaBH ₄ (1.5 g, 39.5 mmol) at 0°C, then the reaction mixture was stirred for lh at RT. The reaction mixture was quenched with aq. NH C1. Aqueous layer was extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution and dried over Na ₂ S0 , filtered and concentrated to afford the crude compound . The crude compound was purified by column chromatography on silica gel (230-400 mesh) using 30-40% of Ethyl acetate in pet ether as an eluent to afford Compound 1-le (1.8 g,). LC-MS: 1.86mins, [M+H] ⁺ 349

Step-6: Preparation of Compound 1-lf:

To a stirred solution of 3-methoxyphenol (15.0 g, 120.83 mmol) in chloroform (120mL) was added a solution of I ₂ (30.66 g, 120.83mmol) in chloroform (600mL) drop wise over a period of 40 min at RT. The reaction mixture was stirred for additional lh. The reaction mixture was then filtered through celite pad and washed with chloroform. The filtrate was washed with 5% Na ₂ S ₂ C>3 aq. solution, 5% aq. NaHCCL solution, water and sat. NaCl solution solution, dried over Na2S04 and concentrated. Crude compound was purified by column chromatography on silica gel (100-200 mesh) using 5-10% of Ethyl acetate in pet ether as an eluent to afford Compound 1- lf (15.76 g, 52.1%). LC-MS: 1.77mins, [M+H] ⁺ 251

Step-7: Preparation of Compound 1-lg:

To a stirred solution of Compound 1-lf (15.76 g, 63.03 mmol) in DMF (120 mL) was added Cs ₂ CC>3 (30.8 g, 94.54 mmol), 2-(chloromethyl)oxirane (8.74 g, 94.54 mmol) and sodium iodide (0.1 eq.). Then the reaction mixture was stirred for 48 h at room temperature. After completion, the reaction mixture was quenched with ice-water and extracted with diethyl ether. The organic layers were washed IN aq. NaOH solution, water and sat. NaCl solution solution and dried over Na ₂ S0 ₄ , filtered and concentrated to afford crude product. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 1-5% of Ethyl acetate in pet ether as an eluent to afford Compound 1-lg (14.7g, 76%). LC-MS: 2.08mins, [M+H] ⁺ 307 Step-8: Preparation of Compound 1-lh

To a stirred solution of Compound 1-lg (14.7 g, 48.03 mmol) in THF(150 mL) was added n- BuLi in 2.5 M THF (21.1mL, 52.84mmol) as dropwise at -78°C, then reaction was stirred for additional lh. After completion of the reaction quenched with IN HC1 and extracted with ethyl acetate. The organic layers were washed with sat. NaCl solution and dried over Na ₂ S0 , and concentrated to obtain crude compound. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 8-10% of ethyl acetate in pet ether as an eluent to afford Compound 1-lh (6.4g, 74%). LC-MS: 1.69mins, [M+H] ⁺ 181

Step-9: Preparation of Compound 1-li:

To a stirred solution of Compound 1-lh (6.4 g, 35.5 mmol) in DCM (64mL) was cooled to 0°C, added PPh ₃ (13.96g, 53.25mmol, 1.5eq.), CBr ₄ (11.77g, 35.5mmol) and stirred atRT for lh. After completion of the reaction quenched with water extracted with DCM. The organic layers were washed with sat. NaCl solution and dried over Na ₂ S0 , concentrated obtained crude compound. Crude compound was purified by column chromatography on silica gel (100-200 mesh) using 0-2% of ethyl acetate in pet ether as an eluent to afford Compound 1-li (6.9g, 80%). LC-MS: 2.15mins, [M+H] ⁺ 243

Step-10: Preparation of Compound 1-lj:

To a stirred solution of Compound 1-li (6.9 g, 28.51mmol) and 2-mercaptobenzothiazole (4.76 g, 28.51 mmol) in DMF(40 mL) was Cs ₂ C0 ₃ at RT, then reaction was stirred for additional 2 h at 80°C. After completion of the reaction quenched ice water and extracted with ethyl acetate. The organic layers were washed with sat. NaCl solution and dried over Na ₂ S0 ₄ , concentrated obtained crude compound. Crude compound was purified by column chromatography on silica gel (100-200 mesh) using 1-5% of Ethyl acetate in pet ether as an eluent to afford Compound 1- lj (6.5g, 69.2%). LC-MS: 2.52mins, [M+H]+ 330

Steps- 11 & 12: Preparation of Compound 1-lk:

To a stirred solution of Compound 1-lj (6.5 g, 20.63 mmol) in DCM (65mL) was added BBr ₃ (1M in DCM) (41.2 mL) dropwise at 0°C. The reaction mixture was stirred at RT for 3h. The reaction was then quenched with NaHC0 ₃ solution and extracted with 10% MeOH in DCM. The organic layers were washed with sat. NaCl solution and dried over Na ₂ S0 ₄ and concentrated to give compound 16 as a mixture (8.0 g). The crude mixture was dissolved in DMF (100 mL) and NaH (1.76 g, 40.92 mmol) was added at 0°C portion wise. The reaction mixture was stirred at RT for 3h. After completion of the reaction quenched sat. NaCl solution solution and extracted with EtOAc. The organic layers were washed with sat. NaCl solution, dried over Na ₂ S0 and concentrated. The crude compound was purified by column chromatography on silica gel (100- 200 mesh) using 10-15% of ethyl acetate in pet ether as an eluent to afford Compound 1-lk (2.3 g, 37%). LC-MS: 2.23mins, [M+H] ⁺ 316

Step-13: Preparation of Compound 1-11:

To a stirred solution of compound 1-lk (630 mg, 2.0 mmol) in THF (145 mL) was added PPh ₃ (1.5 g, 4.1 mmol, 2.0 eq), compound 1-le (697 mg, 2.0 mmol) followed by DIAD (1.1 mL, 4.0 mmol) at 0°C. The reaction mixture was stirred at RT for 1.0 h. The reaction mixture was quenched with aq. NaHC0 ₃ solution, diluted with EtOAc, the layers separated and the aqueous layer further extracted with EtOAc. All the organic layers were combined, washed with water, sat. NaCl solution, dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography on silica gel (230- 400 mesh) using 70% ethyl acetate in pet ether as an eluent to afford compound 1-11 (600 mg) as a mixture. LC-MS: 2.68mins, [M+H] ⁺ 646

Step-13: Preparation of Compound 1-lm:

A homogeneous solution of ammonium molybdate, (NH4) ₆ Mq ₇ q _24. 4H ₂ 0 (226 mg, 0.18 mmol) and 30% H ₂ 0 ₂ (2.3 mL) in EtOH (6 mL) cooled at 0°C was added to a solution of compound 1- 11 (560 mg, 0.91 mmol) in anhydrous EtOH (23 mL) at 0°C. The reaction mixture was stirred gradually allowing it to warm to ambient temperature and stirred further for a period of 18 h. The reaction mixture was then diluted with EtOAc (50 mL) and the organic phase was sequentially washed with aq. sodium sulphite, water, and sat. NaCl solution, dried over anhydrous Na ₂ S0 _4, filtered and concentrated under reduced pressure to furnish the crude product. Purification of the crude residue via flash column chromatography on silica gel (230-400 mesh) using 70% EtOAc/pet ether (v/v) as the eluent afforded compound 1-lm (450 mg, 33% two steps). LC-MS: 2.48mins, [M+H]+ 678

Step-14: Preparation of Compound 1:1: [6-((3-[4-(3-methanesulfonylpropoxy)-2,6- dimethylphenyl]phenyl)methoxy )-2, 3 -dihydro- l-benzofuran-3-yl]methanesulfmic acid To a stirred solution of compound 18 (450 mg, 0.66 mmol) in a mixture of EtOH (18.0 mL) and THF (7.0 mL) was added NaBH (76 mg, 1.99 mmol) at RT. The reaction mixture was stirred for a further 2 h at RT. The reaction mass was then concentrated under reduced pressure to afford crude material which was dissolved in water and washed with EtOAc. The aqueous layer was then lyophilized to afford a solid which was washed with 30% EtOH in n-Hepatane to afford compound 1-1 (150 mg, 40%). LC-MS: 1.78mins, [M+H] ⁺ 545; ¾NMR (400 MHz, d6- DMSO): d 7.46-7.41 (m, 1H), 7.35-7.40 (m, 1H), 7.13 (bs, 1H), 7.07-7.01 (m, 1H), 6.70, (bs, 1H), 6.45-6.40 (m, 1H), 6.39 (bs, 1H), 5.08 (s, 2H), 4.64-4.57 (m 1H), 4.31-4.25 (m, 1H), 4.12- 4.05 (m, 2H), 3.72-3.52 (m, 2H), 3.27-3.23 (m, 2H), 3.03 (s, 3H), 2.27-2.21 (m, 1H), 2.10-2.10

(m 1H), 2.02-1.94 (m, 1H), 1.91 (s, 6H)

Reaction scheme for 6-((3-[2,6-dimethylphenyl]phenyl]methoxy]-2,3-dihydro-1-benz ofuran-3- yljmethanesulfmic acid (Compound 1:2)

Experimental Procedure for Compound 1:2:

Step-1: Preparation of Compound l-2a:

2 -Bromo- 1,3 -dimethyl benzene (20. Og, 108.04 mmol) and 3-formylphenylboronic acid (19.43g, 129.64 mmol) were dissolved in mixture of 1M aqueous solution of sodium carbonate (292 mL), ethanol (100 mL) and toluene (300 mL). The reaction mixture was degassed with argon gas for 10 min and Pd(PPh ₃ ) ₄ (6.24 g, 5.402mmol) was added. Then the reaction was heated to 80°C for 18 h under inert atmosphere. The solution was cooled to RT and filtered through celite. The filtrate was concentrated and the aq. layer extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ , and concentrated. The crude compound was purified by column chromatography on silica gel (230-400 mesh) using 2-4% of ethyl acetate in pet-ether as an eluent to afford Compound l-2a (7.5g, 32.8%). LC-MS: 2.36mins, [M+H] ⁺ 211

Step-2: Preparation of Compound l-2b:

To a stirred solution of Compound l-2a in methanol (7.5 g, 35.68mmol), NaBH (4.06g, 107.4mmol) was added portion-wise at 0°C over a period of 10 min. The reaction temperature was raised to RT and stirred for additional 3 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution, then distilled out methanol completely and diluted with water and extracted with ethyl acetate for 2 times. The organic layer was washed with sat. NaCl solution, dried over Na ₂ S0 ₄ and concentrated to afford the crude product. The crude compound was purified by column chromatography on silica gel (100- 200 mesh) using 8-10% of ethyl acetate in pet ether as an eluent to afford Compound l-2b(1.3g, 17%). ¾ NMR (400 MHz, CDC1 ₃ ): d 7.45-7.40 (m, 1H), 7.38-7.32 (m, 1H), 7.18-7.05 (m, 5H), 4.74 (d, 2H), 2.02 (s, 6H), 1.64 (t, 1H)

Step-3: Preparation of Compound l-2c:

To a stirred solution of Compound l-2b (1.3 g, 6.132 mmol) in DCM (26mL) was added PPh ₃ (2.41g, 9.198 mmol) and CBr ₄ (2.03 g, 6.132 mmol) at 0°C as portion wise for 5 min, then reaction temperature was raised to RT and stirred for additional 1 h. The reaction mixture was quenched with water and extracted with DCM. Then organic layer was washed with sat. NaCl solution solution, dried over Na ₂ S0 and concentrated to give crude compound. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 0-1% of ethyl acetate in pet ether as an eluent to afford Compound l-2c (1.5g, 89.2%). 'H NMR (400 MHz, CDC1 ₃ ): d 7.45-7.35 (m 2H), 7.22-7.12 (m, 2H), 7.12-7.06 (m, 3H), 4.53 (s, 2H), 2.02 (s, 6H) Step-4: Preparation of Compound l-2d:

To a stirred solution of Compound l-2c (1.3 g, 4.761 mmol, 1.5 eq.) and Compound 1-lk (1.0 g, 3.174 mmol) in DMF (5 mL) was added CS ₂ CO ₃ (2.0 g, 6.348 mmol), then reaction mass was heated to 80°C for 3 h. The reaction mixture was quenched with water, and extracted with EtOAc. Then organic layer was washed with sat. NaCl solution solution, dried over Na ₂ S0 ₄ and concentrated obtained crude compound. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 2-5% of ethyl acetate in pet ether as an eluent to afford Compound l-2d (1.3g, 53.8%). LC-MS: 2.39mins, [M+H] ⁺ 510

Step-4: Preparation of Compound l-2e:

To a stirred solution of Compound l-2d (940 mg, 1.846 mmol) in DCM (18mL) was added m- CPBA (60%) (1.3 g, 5.54 mmol) portion wise at 0°C for 5-10min, then the reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with saturated bicarbonate solution and extracted with EtOAc. The organic layer was washed with water, sat. NaCl solution solution and dried over Na ₂ S0 , concentrated to give crude compound. Crude compound was purified by column chromatography on silica gel (230-400 mesh) using 8-10% of Ethyl acetate in pet ether as an eluent to afford Compound l-2e (300mg, 30%). LC-MS: 2.70mins, [M+H] ⁺ 542

Step-5: Preparation of Compound 1:2: [6-((3-[2,6-dimethylphenyl]phenyl)methoxy)-2,3- dihydro-1-benzofuran-3-yl]methanesulfmic acid

To a stirred solution of Compound l-2e (280 mg, 0.517 mmol, l.Oeq.) in ethanol (10 mL) was added NaBH ₄ (38 mg, 1.552 mmol, 3.0 eq.) as portion wise at 0°C. Then the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated, washed with n-Heptane and then with 10% of ethanol and heptane, each time decanting the supernatant. Finally the traces of solvent was removed under vacuum to obtain 1-2 (105 mg, 47.1%). LC-MS: 2.34mins, [M+H] ⁺ 409; ¾NMR (400 MHz, d6-DMSO): d 7.48-7.44 (m, 1H), 7.42-7.38 (m, 1H), 7.17 (bs, 2H), 7.14-7.08 (m, 2H), 7.05-7.01 (m, 2H), 6.45-6.41 (m, 1H), 6.39 (bs, 1H), 5.09 (s, 2H), 4.64-4.58 (m, 1H), 4.31-4.26 (m, 1H), 3.72-3.63 (m, 1H), 2.28-2.23 (m, 1H), 2.02-1.96 (m, 1H), 1.94 (s, 6H)

Reaction scheme for Sodium 2-(4-([2-(cyanomethyl)phenyl]ethylnyl)-2- fluorophenyl)ethnanesulfmate (Compound 8:1) Experimental Procedure for Compound 8:1:

Step-1: Preparation of Compound 8-la:

To a stirred solution of 4-bromo-2-fluorophenylacetic acid (5 g, 21.4 mmol) in THF (50mL) was added BH _3. THF 1.0 M in THF (53.5 ml, 53.5 mmol) at 0°C. The reaction was allowed to stir for 12 h at RT. The reaction mixture was cooled to 0°C, quenched with methanol and concentrated under reduced pressure. Water was added and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 8- la (3.9 g, 84%) which was taken onto the next step without further purification. ¹ H NMR (400 MHz, CDCI ₃ ): d 7.29-7.20 (m, 2H), 7.18-7.10 (m 2H), 3.90- 3.80 (m, 2H), 2.91-2.83 (m, 2H)

Step-2: Preparation of Compound 8-lb:

To a stirred solution of Compound 8-la (12.0 g, 55.32 mmol) in toluene (24 mL) at RT was added 2,6-Lutidine (11.78 g, 110.0 mmol) and then thionyl chloride (13.1 g, 110.0mmol) slowly. Water (1 ml) was added and the reaction mixture heated to 50°C for 12 h. The reaction was cooled to RT, the solvent completely evaporated and water added. The aqueous layer was then extracted with ethyl acetate and the organic layers were washed with saturated aq. NaHCO3 solution. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 8-lb (10.2 g, 79%). ¹ NMR (400 MHz, CDCI ₃ ): d 7.30- 7.22 (m, 2H), 7.18-7.10 (m 2H), 3.75-3.65 (m, 2H), 3.12-3.02 (m, 2H)

Step-3: Preparation of Compound 8-lc:

To a stirred solution of Compound 8-lb (10.2 g, 43.42 mmol) and 2-mercaptobenzothiazole (7.27 g, 43.4 mmol) in DMF (100 mL) was added cesium carbonate (28.21 g, 86.8 mmol) at 0°C. The reaction was then heated at 55°C for 4 h, then cooled to RT, water added and the queous layer extracted with ethyl acetate. The organic layers were washed with water, combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford compound 8-lc (14.1 g, 88%) which was taken onto the next step without further purification. LC-MS: 2.67mins,

[M+H] ⁺ 368, 370

Step-4: Preparation of Compound 8-ld:

To a stirred solution of compound 8-lc (5.0 g, 13.5 mmol, 1.0 eq) in a mixture of TMEDA (25.0 mL) and water (3.0 mL), under inert atmosphere, was added Na ₂ Cl4 (199 mg, 5 mol %) and 2- (di-tert-butylphosphino)-N-phenyl indole (456 mg, 1.35 mmol, 0.1 eq) followed by Cul (257 mg, 10 mol %) at RT. The reaction mixture was heated to 80°C and stirred for 10 min. TMS- acetylene (3.8 mL, 27 mmol, 2 eq) was then added and the temperature was raised to 90°C. After 4h water was added, extracted with EtOAc and the organic phase washed with water, sat. NaCl solution, dried over Na2S0 ₄ , filtered and concentrated under reduced pressure to afford Compound 8- Id (5.2 g) which was taken onto the next step without further purification. LC-MS: 2.32mins, [M+H] ⁺ 386

Step-5: Preparation of Compound 8-le:

To a stirred solution of compound 8-ld (5.2 g, 13.5 mmol) in MeOH (68 mL) was added K2CO3 (3.73 g, 27 mmol) at RT. The reaction mixture was stirred for lh, then filtered through celite, washed with EtOAc and concentrated under vacuum at below 40°C to afford crude compound. The crude compound was purified by column chromatography on neutral alumina using pet ether to 2% Ethyl acetate in pet ether as an eluent to afford Compound 8-le (1.3 g) as a mixture which was taken onto the next step without further purification. LC-MS: 1.33mins, [M+H] ⁺ 314

Step-6: Preparation of Compound 8- If:

To a stirred solution of compound 8-le (1.3 g, 4.15 mmol) in TEA (20.0 mL) was added 2-(2- iodophenyl)acetonitrile (1.15 mL, 8.3 mmol) at RT. The reaction mixture was degassed with argon gas followed by addition of PdCl2(PPh ₃ ) ₂ (583 mg, 083 mmol, 0.2 eq) and Cul (80 mg, 0.41, 0.1 eq) at RT. The reaction mixture was stirred for 1 h, the filtered through celite, washed with EtOAc, and the filtrate concentrated under vacuum below 40°C to afford crude compound. The crude compound was purified by column chromatography on TEA doped silica-gel (230- 400 mesh) using 2 % pet ether to 4% ethyl acetate in pet ether as an eluent to afford Compound 8-lf (535 mg). LC-MS: 1.68mins, [M+H] ⁺ 429

Step-7: Preparation of Compound 8-lg:

To a stirred solution of compound 8-lf (525 mg, 1.23 mmol) in DCM (6.0 mL) was added m- CPBA (1.1 g, 3.7 mmol) at 0°C. The reaction mixture was then warmed to RT and stirred for a further 1 h. The reaction was then quenched with saturated Sodium bisulphite, the aqueous layers separated and the aq. layer extracted with EtOAc. The organic layers were combined, washed with aq. Na ₂ C0 ₃ , water, sat. NaCl solution, dried over Na ₂ S0 , filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica-gel (230-400 mesh) using 10% to 15 % Ethyl acetate in pet ether as an eluent to afford Compound 8- lg (289 mg). LC-MS: 2.42mins, [M+H] ⁺ 461 Step-8: Preparation of Compound 8:1: Sodium 2-(4-([2-(cyanomethyl)phenyl]ethylnyl)-2- fluorophenyl)ethnanesulfmate

+To a stirred solution of compound 8-lg (280 mg, 0.6 mmol, 1 eq) in EtOH (4.0 mL) was added NaBH (46 mg, 1.2 mmol, 3.0 eq) at RT. After 4 h the reaction mixture was concentrated under reduced pressure to afford crude compound which was washed with n-heptane and then 10% EtOH in n-heptane to afford compound 8:1 (130 mg, 67%). LC-MS: 1.86mins, [M-H] ⁺ 326. H NMR (400 MHz, CD ₃ OD): d 7.61-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.30 (m, 4H), 7.30- 7.25 (m, 1H), 3.30 (s, 2H), 3.00-2.94 (m, 2H), 2.54-2.48 (m, 2H)

Reaction Scheme for Sodium 3-(4-([5-fluoro-2-(5- methylthiophenyl)phenyl]methoxy)phenyl)ethane-1-sulfmate (Compound 6:17)

 Experimental Procedure for Compound 6:17:

Step-1: Preparation of Compound 6-17a

To a degassed solution of 2-bromo-5-fluorobenzaldehyde (15.0 g, 74.29 mmol) and 5-methyl-2- thienylboronic acid (11.6 g, 81.72 mmol) in Toluene/H ₂ 0 (150/45 mL) was added, Na ₂ CC>3 (23.62 g, 222.87 mmol), Pd(PPh ₃ ) (4.3 g, 3.74 mmol), under inert gas at RT. The reaction was then stirred at 90°C for 16 h. The reaction mixture was cooled to RT, filtered through celite, washed with water, dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (100-200 mesh) eluted with 2% EtOAc in pet-ether to afford Compound 6-17a (4.0 g, 24%). 'H NMR (400 MHz, CDC1 ₃ ): d 10.13 (d, 1H), 7.67-7.62 (m, 1H), 7.52-7.47 (m, 1H), 7.33-7.26 (m, 1H), 6.83-6.79 (m, 2H), 2.55(s, 3H)

Step-2: Preparation of Compound 6- 17b

To a stirred solution of Compound 6-17a (3.0 g, 13.64 mmol) in methanol (30 mL) was added, NaBH ₄ (518 mg, 13.64 mmol), at 0°C and the reaction was stirred at RT for 2h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford Compound 6-17b (3.0 g, 99%). ¾ NMR (400 MHz, CDC1 ₃ ): d 7.37-7.32 (m, 1H), 7.30- 7.25 (m, 1H), 7.03-6.95 (m, 1H), 6.85-6.83 (m, 1H), 6.74-6.72 (m, 1H), 4.73 (d, 2H), 2.52 (s,

3H), 1.82-1.78 (m, 1H)

Step-3: Preparation of Compound 6- 17c

To a stirred solution of Compound 6-17b (3.0 g, 10.6 mmol) in DCM, was added, PPh ₃ (4.17 g, 15.9 mmol), followed by CBr (5.26 g, 15.9mmol) portion wise at 0°C. The reaction mixture was then stirred for 2h at RT. The DCM was removed under reduced pressure and the residue purified by flash column chromatography using silica-gel (100-200 mesh), eluting with 2% EtOAc in pet-ether to afford Compound 6-17c (3.2 g, 84%). ¹ H NMR (400 MHz, CDCI ₃ ): d 7.35-7.30 (m, 1H), 7.22-7.17 (m, 1H), 7.04-6.97 (m, 2H), 6.76-6.40 (m, 1H), 4.53 (s, 2H), 2.52 (s, 3H)

Step-4: Preparation of Compound 6-17d

To a stirred solution of Compound 6-17c (3.2 g, 11.307 mmol) in DMF (5 mL), was added ethyl 2-(4-hydroxyphenyl)acetate (2.1 g, 11.307 mmol), K ₂ C0 ₃ (3.12 g, 22.614 mmol), at RT and the reaction was stirred for 2h at 80°C. The reaction was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford crude compound. The crude product was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 5% EtOAc in pet-ether to afford a mixture (3.6 g). This mixture (3.6g) was then dissolved in THF (40 mL) and LiAlEfl (5.85 mL, 14.05 mmol) was added at 0°C. After 2h at RT the reaction mixture was quenched with saturated NaS0 ₄ solution, filtered through celite and washed with EtOAc. The filtrate was washed with water, dried over Na2S0 and concentrated under reduced pressure to afford Compound 6-17d (3.0g, 96%). LC-MS: 2.43mins, [M+H] ⁺ 343

Step-5: Preparation of Compound 6-17e

To a stirred solution of Compound 6-17d (3.0 g, 8.77 mmol) in DCM, was added PPh ₃ (3.5 g, 13.15 mmol), followed by the addition of CBr ₄ (4.35 g, 13.5mmol) portion wise at 0°C and the reaction was stirred for 2h at RT. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 2% EtOAc in pet-ether to afford Compound 6-17e(2.1 g, 84%). LC- MS: 2.73mins, [M+H]+ 405

Step-6: Preparation of Compound 6-17f

To a stirred solution of Compound 6-17e (2.1 g, 5.198 mmol) in DMF (10 mL), was added 2- mercaptobenzothiazole (870 mg, 5.198 mmol), CS ₂ CO ₃ (3.378g, 10.396 mmol), atRT and the reaction stirred for 2h at 60°C. The reaction was quenched with ice cold water and extracted with Ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 5% EtOAc in pet-ether to afford Compound 6-17f (2.0 g, 78%). LC-MS: 3.04mins, [M+H] ⁺ 492

Step-7: Preparation of Compound 6-17g

To a stirred solution of Compound 6-17f (1.0 g, 2.036 mmol) in DCM, was added m-CPBA (878 mg, 5.09 mmol) portion wise at 0°C and the reaction was stirred for 6h at RT. The reaction was quenched with saturated NaHC0 ₃ solution and extracted with DCM. The combined organic layers were concentrated under reduced pressure and the residue purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 10% EtOAc in pet-ether to afford Compound 6-17g (650 mg, 84%). LCMS: 1.55mins, [M+H] ⁺ 524 Step-8: Preparation of Compound 6:17: Sodium 3-(4-([5-fluoro-2-(5-methyl-l,3-thiazol-2 - yl)phenyl]methoxy)phenyl)ethane- 1 -sulfmate

To a stirred solution of Compound-6- 17g (200 mg, 0.382 mmol) in ethanol/THF (2 mL/2 mL) was added, NaBH (44 mg, 1.145 mmol) at RT. After 2h the solvent was completely removed, and the residue washed with 10% ethanol/heptane to afford Compound 6-17 (120 mg, 80%). LC- MS: 2.31mins, [M+H] ⁺ 391; ¾NMR (400 MHz, d6-DMSO): d 7.50-7.41 (m, 2H), 2.28-2.23 (m ,1H), 7.09-7.06 (m , 2H), 7.00-6.98 (m, 1H), 6.85-6.81 (m, 3H), 5.02 (s, 2H), 2.65-2.59 (m, 2H), 2.45 (s, 3H), 2.01-1.95 (m, 2H)

Reaction Scheme of Compound 15:4: Sodium 3-(4-([5-fluoro-2-(5-methyl-l,3- thiophenyl)phenyl]methoxy)phenyl)propane- 1 -sulfmate

 Experimental Procedure for Compound 15:4:

Step-1: Preparation of Compound 15-4a

To a stirred solution of Compound 6- 17c (3.0 g, 10.6 mmol) in DMF (5 mL), was added methyl 3-(4-hydroxyphenyl)propionate (1.91 g, 10.6 mmol), K2CO3 (2.93g, 21.2 mmol) at RT and the reaction was stirred at 80°C for 2h. The reaction was quenched with ice cold water and extracted with ethyl acetate. The organic layers were washed with sat. NaCl solution, dried over anhydrous Na2SO 4 and concentrated under reduced pressure to afford crude Compound 15-4a (3.82 g, crude) which was used as such for next step without purification. LC-MS: 2.61mins, [M+H] ⁺

385

Step-2: Preparation of Compound 15-4b

To a stirred solution of Compound 15-4a (3.82 g, 9.88 mmol) in THF (40 mL) was added, LiAlEC (6.17 mL, 14.82 mmol), at 0°C and the reaction was stirred at RT for 2h. The reaction mixture was quenched with saturated Na2S04 solution and filtered through celite and washed with EtOAc. The filtrate was washed with water, dried over Na ₂ S0 and concentrated under reduced pressure to afford Compound 15-4b (3. lg, 87%). ¹ H NMR (400 MHz, CDCI3): d 7.42- 7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.12-7.08 (m, 2H), 7.06-6.99 (m, 1H), 6.86-6.82 (m, 3H), 6.73- 6.68 (m, 1H), 5.05 (s, 2H), 3.37 (t, 2H), 2.71 (t, 2H), 2.50 (s, 3H), 2.12 (qt, 2H)

Step-3: Preparation of Compound 15-4c

To a stirred solution of Compound 15-4b (3.0 g, 8.426 mmol) in DCM, was added PPh ₃ (3.3 g, 12.64 mmol), followed by the addition of CBr (4.18 g, 12.64mmol) portion wise at 0°C and the reaction was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 2% EtOAc in petroleum ether to afford Compound 15-4c (2.6 g, 85%). ¾ NMR (400 MHz, CDC1 ₃ ): d 7.41-7.36 (m, 1H), 7.36-7.31 (m, 1H), 7.12-7.07 (m, 2H), 7.06-6.98 (m, 1H), 6.86-6.81 (m, 3H), 6.73-6.68 (m, 1H), 5.04 (s, 2H), 3.70-3.62 (m, 2H), 2.65 (t, 2H), 2.50 (s, 3H), 1.85 (qt, 2H)

Step-4: Preparation of Compound 15-4d

To a stirred solution of Compound 15-4c (2.6 g, 6.22 mmol) in DMF (lOmL), was added 2- mercaptobenzothiazole (1.04 mg, 6.22 mmol), CS2CO3 (4.403g, 12.44 mmol), at RT and the reaction was stirred at 60°C for 2h. The reaction was quenched with ice cold water and extracted with ethyl acetate. The organic layers were washed with sat. NaCl solution, dried over anhydrous Na ₂ S0 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 5% EtOAc in petroleum ether to afford Compound 15-4d (2.8 g, 90%). LC-MS: 2.46mins, [M+H] ⁺ 506

Step 5: Preparation of Compound 15-4e

To a stirred solution of Compound 15-4d (1.0 g, 1.98 mmol) in DCM, was added m-CPBA (850 mg, 4.95 mmol) portion wise at 0°C and the reaction was stirred at RT for 6h. The reaction was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography using silica-gel (100-200 mesh), eluted with 10% EtOAc in pet-ether to afford Compound 15-4e (600 mg, 61%). LC-MS: 2.61mins, [M+H] ⁺ 538

Step 6: Preparation of Compound 15:4: Sodium 3-(4-([5-fluoro-2-(5- methylthiophenyl)phenyl]methoxy)phenyl)propane- 1 -sulfmate

To a stirred solution of Compound 15-4e (430 mg, 0.799 mmol) in ethanol/THF (25 mL/5 mL) was added, NaBH ₄ (44 mg, 1.145 mmol), at RT. After 2h the reaction mixture was concentrated under reduced pressure and washed with 10% ethanol/heptane to afford Compound 15:4 (130 mg, 40%). LC-MS: 2.39mins, [M+H] ⁺ 405; ¹ H NMR (400 MHz, d6-DMSO): d 7.50-7.42 (m, 2H), 7.29-7.23 (m, 1H), 7.010-7.05 (m, 2H), 7.01-6.98 (m, 1H), 6.88-6.84 (m, 2H), 6.83-6.80 (m, 1H), 5.03 (s, 2H), 2.57-2.50 (m, 2H), 2.45 (s, 3H), 1.79-1.75 (m, 2H), 1.69-1.62 (m, 2H)

'H NMR spectra were obtained on a Agilent 400MR DD2 NMR spectrometer and chemical shifts are given in ppm. HPLC analysis was obtained either using one of two methods, A- Column: Acquity UPLC BEH C-18 (2.1X50 mm) 1.7u, Mobile Phase: A 0.05%FA in Water, B 0.05%FA in Acetonitrile, 0-90% B in A, Flow : 0.55 mL, Diluent : ACN+WATER(70:30) Column temp :35°C; B - Column: Acquity UPLC BEH C-18 (2.1X50 mm) 1.7u, Mobile Phase: A 0.05%FA in Water, B 0.05%FA in Acetonitrile, 0-90% B in A, Flow : 0.4 mL, Diluent : ACN+WATER(70:30) Column temp :35°C Abbreviations: aq. aqueous

DIAD diisopropyl azodi carboxyl ate

DMF N,N'-dimethylformamide

DMSO dimethylsulfoxide

DCM dichloromethane

EtOAc ethyl acetate

EtOH ethanol HPLC high performance liquid chromatography

LC-MS liquid chromatography mass spectroscopy

NMR nuclear magnetic resonance

UV ultraviolet

RT room temperature h hours min minutes b broad bs broad singlet m multiplet s single d doublet t triplet qt quintet

EXAMPLE 2

Biological Assays of Compounds

Dose Response Curves (DRC) and EC50s were generated for GPR40 and GPR120 mediated intracellular Ca ²⁺ efflux using FLIPR Tetra.

Cell lines:

Chemibrite GPR40 receptor cell line (HTS028L; Millipore) and Chemibrite GPR120 receptor stable cell line (HTS225L; Millipore).

Summary of protocol GPR40:

25,000 cells/well were seeded into a 96 well plate and cultured overnight at 37°C. 50mL/well of assay buffer (20mM HEPES+ IX HBSS) were added to the cells and the cells cultured for 20 min at 37°C. The cells were loaded with 50mL/well of Calcium 5 dye and cultured for 45 min at 37°C. Reference and test compounds were added to the GPR40 expressing cells using FLIPRe® Tetra. Intracellular Calcium flux was assessed by use of ScreenWorks 3.1 tool and statistical analysis was carried using GraphPad Prism 4.

Summary of protocol GPR120:

50,000 cells/well were seeded into a 96 well plate and cultured overnight at 37°C. 50mL/well of assay buffer (20mM HEPES+ IX HBSS) were added to the cells and the cells cultured for 20 min at 37 °C. The cells were loaded with 50mL/well of Calcium 5 dye and cultured fir 45 min at 37°C. Reference and test compounds were added to the GPR40 expressing cells using FLIPRe® Tetra. Intracellular Calcium flux was assessed by use of ScreenWorks 3.1 tool and statistical analysis was carried using GraphPad Prism 4.

GPR40 and GPR120 mediated intracellular Ca ²⁺ efflux as mediated by various compounds are shown in Table 1

Table 1

Activity: A <1mM; B l-IOmM; C >10mM; D inactive

The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.