WO2011151434A1

WO2011151434A1 - Novel compounds, pharmaceutical composition and methods for use in treating metabolic disorders

Info

Publication number: WO2011151434A1
Application number: PCT/EP2011/059179
Authority: WO
Inventors: Hamid Hoveyda; Guillaume Dutheuil; Mohamed El Bousmaqui; Jérôme BERNARD
Original assignee: Euroscreen S.A.
Priority date: 2010-06-04
Filing date: 2011-06-03
Publication date: 2011-12-08

Abstract

The present invention is directed to novel compounds of formula (I) and their use in treating metabolic diseases.

Description

NOVEL COMPOUNDS, PHARMACEUTICAL C OMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERS

The present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates and prodrugs, which are useful as therapeutic compounds, particularly in the treatment and/or prevention of type 2 diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

[BACKGROUND OF THE INVENTION]

Type 2 diabetes mellitus (T2D) is an increasing, worldwide public health problem associated with devastating pathologies such as lipid disorders including dyslipidemia, hypertension, obesity, and atherosclerosis (Wild et al, Diabetes Care 27, pp 1047-1053, 2004). T2D is primarily characterized by insulin resistance and hyperglycemia. Insulin resistance is defined as a decreased response of peripheral tissues to insulin action. Insulin resistance has been recognized as an integral feature of metabolic syndrome, a condition encompassing glucose intolerance, obesity, dyslipidemia and atherosclerosis. Hyperinsulinemia and delayed clearance of glucose in an oral glucose tolerance test (OGTT) are hallmarks of insulin resistance in patients. Dyslipidemia is characterized by high levels of triglycerides and/or LDL (bad cholesterol) or low levels of HDL (good cholesterol). Dyslipidemia is a key risk factor for cardiovascular diseases.

Drug therapies are available to address both T2D and dyslipidemia. Specifically, statins, fibrates and nicotinic acid or combinations thereof are often considered as a first line therapy in dyslipidemia whereas metformin, sulphonylureas and thiazolidinediones are three, widely-used classes of oral anti-diabetic drugs (Tenenbaum et al., Cardiovascular Diabetology, 5, pp20-23, 2006). Although theses therapies are widespread in their use, the common appearance of adverse effects or lack of efficacy after long-term use causes concern. Moreover, the growing patient population suffering from T2D, dyslipidemia and associated metabolic diseases creates a demand for new entrants able to overcome the limitations of the current therapeutics. Patients having T2D have a resistance to the effects of insulin in stimulating glucose and lipid metabolisms in the main insulin-sensitive tissues, which are muscle, liver and adipose tissue. Therefore the compounds of the invention showing benefit in both glucose and lipid metabolisms, represent a real advantage and an added value for the treatment of T2D and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

[SUMMARY OF THE INVENTION]

The invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions. The compounds of the invention are generally disclosed by the application WO 2010/066682 but none is specifically exemplified therein.

In a general aspect, the invention provides compounds of general formula

I:

I wherein: W is C or N; X is CH or N;

Y is CH, or Y is N under the condition that X is CH; R¹ is C3-C4 alkyl or C3-C6 cycloalkyl; R¹ is H or methyl;

R² is C₁-C4 alkyl or C3-C5 cycloalkyl; R³ is H, methyl, or methoxy;

R⁴ is selected from (i) -OR⁷, (ii) dimethylamino, (iii) 5-membered heterocyclyl, (iv) 5- membered heteroaryl, each of said heterocyclyl or heteroaryl ring may be further substituted by: a) one or two methyl group(s), and/or

b) one oxo moiety, and/or

c) one or two fluorine atom(s), or

R⁴ forms together with R³ a 5 to 6-membered heterocyclyl or 5-membered heteroaryl ring fused to the heteroaryl moiety they are attached to, each of said 5 to 6-membered heterocyclyl or 5-membered heteroaryl ring may be further substituted by: d) one, two or three methyl group(s), and/or

e) one oxo moiety;

R⁵ is H or fluoro when W is C or R⁵ is absent when W is N;

R⁶ is H, fluoro, chloro, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ alkoxy or C₁-C₂ haloalkoxy;

R⁷ is methyl, C₁-C3 alkyloxyethyl optionally substituted by one methyl group.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

The invention further provides methods of treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt, solvate or prodrug of formula (I), to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, , metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

In a preferred embodiment the disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.

[DETAILED DESCRIPTION OF THE INVENTION]

As noted above, the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts, solvates and prodrugs.

Preferred compounds of formula I and pharmaceutically acceptable salts, solvates, and prodrugs thereof are those wherein:

W is C; and/or Y is CH; and/or

R¹ is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl or cyclopentyl, preferably R¹ is propan-l-yl, propan-2-yl or cyclopentyl; and/or

R¹ is H; and/or

R² is cyclopropyl; and/or

R³ forms together with R⁴ a pyrrolidinyl, oxazolidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl or triazolyl moiety fused to the heteroaryl ring they are attached to, each of said moieties being optionally substituted by one oxo group and/or up to three methyl groups, or R³ is methyl and R⁴ is methoxy, or R³ is H and R⁴ is methoxy, (2- methoxyethyl)oxy optionally substituted by one methyl group, (2-isopropoxyethyl)oxy, dimethylamino, 2-oxopyrrolidin-l-yl optionally substituted by one methyl or one or two fluoro group(s), pyrazol-l-yl, 3,5-dimethylpyrazol-l-yl, preferably R³ forms together with R⁴ a 2-oxopyrrolidinyl, 2-oxo-oxazolidinyl, N-methylpyrrolyl, 1- methylpyrazolyl moiety fused to the heteroaryl ring they are attached to, or R³ is methyl and R⁴ is methoxy, or R³ is H and R⁴ is methoxy, (2-methoxyethyl)oxy optionally substituted by one methyl group, 2-oxopyrrolidin-l-yl optionally substituted by one methyl group at position 3 of the pyrrolidine ring, 3,5-dimethylpyrazol-l-yl, more preferably R³ is H and R⁴ is methoxy, (2-methoxyethyl)oxy, 2-oxopyrrolidin-l-yl optionally substituted by one methyl group at position 3 of the pyrrolidine ring; and/or

R⁵ is H or fluoro, and/or

R⁶ is H, fluoro, chloro, methoxy, -OCHF₂, -OCF₃, preferably R⁶ is H or chloro, more preferably R⁶ is H.

In one embodiment, preferred compounds of Formula I are those of formula la:

la, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein

X and Y are as defined above in respect to formula I;

W is as defined above in respect to formula I, preferably W is C;

R¹ is as defined above in respect to formula I, preferably R¹ is propan-l-yl, propan-2-yl, cyclopropyl, eye lo butyl or cyclopentyl, more preferably R¹ is propan-l-yl, propan-2-yl or cyclopentyl;

R³ and R⁴ are as defined above in respect to formula I, preferably R³ forms together with R⁴ a 1 ,3 , 3-trimethyl-2-oxopyrrolidinyl, N-methyl-2-oxo-oxazolidinyl, 1 ,4-dimethyl-2- oxopiperazinyl, 4-methyl-3-oxomorpholinyl, N-methylpyrrolyl, 1-methylpyrazolyl or 1- methyltriazolyl moiety fused to the heteroaryl ring they are attached to, or R³ is methyl and R⁴ is methoxy, or R³ is H and R⁴ is methoxy, (2-methoxyethyl)oxy, (S)-2- methoxypropoxy, ((R)- ¹ -methoxypropan-2-yl)oxy, (2-isopropoxyethyl)oxy, dimethylamino, 2-oxopyrrolidin-l-yl, 3-methyl-2-oxopyrrolidin-l-yl, 3-fluoro-2- oxopyrrolidin-l-yl, pyrazol-l-yl, 3,5-dimethylpyrazol-l-yl, more preferably

R³ forms together with R⁴ a l,3,3-trimethyl-2-oxopyrrolidinyl, N-methyl-2-oxo- oxazo lidinyl , 1 , 4-dimethyl-2-oxopiperazinyl, 4-methyl-3-oxomorpholinyl, N- methylpyrrolyl when X is N, 1-methylpyrazolyl or 1-methyltriazolyl moiety fused to the heteroaryl ring they are attached to; or R³ is methyl and R⁴ is methoxy; or

R³ is H and R⁴ is methoxy when R¹ is propan-l-yl, propan-2-yl, cyclopropyl, eye lo butyl, or when one of X or Y is N,

R³ is H and R⁴ is (2-methoxyethyl)oxy, (S)-2-methoxypropoxy, ((R)-l-methoxypropan-2- yl)oxy, (2-isopropoxyethyl)oxy; or

R³ is H and R⁴ is dimethylamino when X is N; or

R³ is H and R⁴ is 2-oxopyrrolidin-l-yl when R¹ is propan-2-yl or cyclobutyl or when R¹ is cyclopentyl and X is N; or

R³ is H and R⁴ is 3-methyl-2-oxopyrrolidin-l-yl, 3-fluoro-2-oxopyrrolidin-l-yl, pyrazol-1- yl, 3,5-dimethylpyrazol-l-yl; still more preferably R³ forms together with R⁴ a N-methyl-2-oxo-oxazolidinyl, N- methylpyrrolyl when X is N, 1-methylpyrazolyl moiety fused to the heteroaryl ring they are attached to, or

R³ is methyl and R⁴ is methoxy, or

R³ is H and R⁴ is methoxy when R¹ is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl, or when one of X or Y is N; or

R³ is H and R⁴ is (2-methoxyethyl)oxy, (S)-2-methoxypropoxy, ((R)-l-methoxypropan-2- yl)oxy, 2-oxopyrrolidin-l-yl, 3,5-dimethylpyrazol-l-yl, even more preferably R³ forms together with R⁴ a N-methylpyrrolyl moiety fused to the heteroaryl ring it is attached to when X is N, or

R³ is H and R⁴ is dimethylamino when X is N; or

R³ is H and R⁴ is methoxy when R¹ is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl, or when one of X or Y is N; or R³ is H and R⁴ is (2-methoxyethyl)oxy or 2-oxopyrrolidin-l-yl;

R⁵ is as defined above in respect to formula I, preferably R⁵ is H;

Other preferred compounds of formula la are those wherein the

moiety is selected from the group consisting of

and wherein the dotted lines indicate the attachment point to the phenyl group of formula la.

Preferred compounds of formula la are those of formulae Ia-1, Ia-2, Ib-1 and Ib-2

lb-1 lb-2 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein W, X, Y, R³, R⁴, R⁵ and R⁶ are as defined above in respect to formula la and L is methylene or ethylene.

Preferred compounds of formulae Ia-1, and Ia-2are those wherein one of X or Y is N and the other one is CH.

Preferred compounds of formulae Ib-1, and Ib-2 are those wherein both X and Y are CH.

Other preferred compounds of formulae Ia-1, Ia-2, Ib-1 and Ib-2 are those of formulae Ia-3, Ia-4, Ib-3 and Ib-4 respectively

and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein L,W, X, Y, R³, R⁴ and R⁵ are as defined above in respect to formulae Ia-1, Ia-2, Ib-1 and Ib-2.

Preferred compounds of formulae Ia-3 and Ia-4 are those wherein one of X or Y is N and the other one is CH.

Preferred compounds of formulae Ib-3, and Ib-4 are those wherein both X and Y are CH.

Other preferred compounds of formulae Ia-3, Ia-4, Ib-3 and Ib-4 are those of formulae Ia-5, Ia-6, Ib-5 and Ib-6 respectively

and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein L, X, Y, R³ and R⁴ are as defined above in respect to formulae Ia-3, Ia-4, Ib-3 and Ib-4.

Preferred compounds of formulae Ia-5 and Ia-6 are those wherein one of X or Y is N and the other one is CH.

Preferred compounds of formulae Ib-5 and Ib-6 are those wherein both X and Y are CH.

Other preferred compounds of Formula la are those of formula Ia-7:

la-7 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein W, X, Y, R¹, R³, R⁴ and R⁵ are as defined above in respect to formula la.

Preferred compounds of formula Ia-7 are those wherein W is C and R⁵ is H, preferably those wherein W is C and R⁵ is H and one of X or Y is N and the other one is CH.

Other preferred compounds of formula Ia-7 are those wherein W is C, both R³ and R⁵ are H, and both X and Y are CH.

Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

Table 1 :

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(5-(2-

11 methoxyethoxy)pyrazin-2- 551.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

/

(3R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-(3 -methyl -

12 2-oxopyrrolidin- 1 -yl)pyridin-3 - 573.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3-(cyclopropyl(4-(2-(6- methoxypyridin-3 -

13 yl)phenyl)thiazol-2- 480.6 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3 -

14 yl)phenyl)thiazol-2- 533.7 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(5-methyl-5H-

15 pyrrolo[2,3 -b]pyrazin-2- 530.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4-

(cyclopropyl(4-(2-(5-

16 (dimethylamino)pyrazin-2- 520.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid ( )-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-( 1 -methyl- 1 H-

17 pyrazolo [ 3 ,4-b]pyridin- 5 - 530.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-( 1 -methyl- 1 H-

18 [ 1 ,2,3]triazolo[4,5-b]pyridin-6- 531.6 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(4-methyl-3 - oxo-3,4-dihydro-2H-pyrido[3,2-

19 b][l,4]oxazin-7- 561.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-((S)-2-

20 methoxypropoxy)pyridin-3- 564.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4-

(cyclopropyl(4-(2-(6-(2-

21 isopropoxyethoxy)pyridin-3 - 578.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

-< (R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-(((R)- 1 -

22 methoxypropan-2-yl)oxy)pyridin- 564.7

3-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid

/

(R)-3 -(cyclopentylmethyl)-4-

(cyclopropyl(4-(2-(5-(2-

23 oxopyrrolidin- 1 -yl)pyrazin-2- 560.7 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid

(3R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-(3-fluoro-2-

24 oxopyrrolidin- 1 -yl)pyridin-3 - 577.7 yl)phenyl)thiazol-2-yl)amino)-4-

I /— ⁿ oxobutanoic acid

(R)-4-((4-(2-(6-(l H-pyrazol- 1 - yl)pyridin-3-yl)phenyl)thiazol-2-

25 yl)(cyclopropyl)amino)-3 - 542.7

(cyclopentylmethyl)-4-

^■ oxobutanoic acid

(R)-3 -(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-

26 methoxypyridazin-3 - 507.6 yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid (R)-3-(cyclopropyl(4-(2-(5- methoxypyrazin-2-

27 yl)phenyl)thiazol-2- 481.6 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3-(cyclopropyl(4-(2-(5-(2- oxopyrrolidin- 1 -yl)pyrazin-2-

28 yl)phenyl)thiazol-2- 534.6 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3-((4-(2-(6-(lH-pyrazol-l- yl)pyridin-3-yl)phenyl)thiazol-2-

29 yl)(cyclopropyl)carbamoyl)-5- 516.6 methylhexanoic acid

(R)-3-(cyclopropyl(4-(2-(l- methyl- 1 H-pyrazolo[3 ,4-

30 b]pyridin-5-yl)phenyl)thiazol-2- 504.6 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3-(cyclopropyl(4-(2-(3- methyl-2-oxo-2,3- dihydrooxazolo[4,5-b]pyridin-6-

31 yl)phenyl)thiazol-2- 521.6 yl)carbamoyl)-5-methylhexanoic

acid

(R)-3-(cyclopropyl(4-(2-(5- (dimethylamino)pyrazin-2-

32 yl)phenyl)thiazol-2- 494.6

K yl)carbamoyl)-5-methylhexanoic

acid

harmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of table 1 were named using ChemDraw Ultra 12 purchased from CambridgeSoft (Cambridge, MA, USA).

The compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.

[APPLICATIONS]

The compounds of the invention are therefore useful in the prevention and/or treatment of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

In a particular preferred embodiment the diseases are type II diabetes and a lipid disorder such as dyslipidemia.

The invention also provides for a method for delaying in patient the onset of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt, solvate, and prodrug thereof to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating a patient and/or preventing a patient from developing a disease selected from the group consisting of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

In a particular preferred embodiment the disease are type II diabetes and a lipid disorder such as dyslipidemia.

Preferably, the patient is a warm-blooded animal, more preferably a human.

According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts, solvates, or prodrugs may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate, or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH). The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which may necessitate the use of active agents in addition to the compounds of Formula I or their pharmaceutical acceptable salts, solvates or prodrugs, there may be additional rationales which compel or highly recommend the use of combinations of drugs involving active ingredients which represent adjunct therapy, i.e. which complement and supplement the function performed by the compounds of the present invention.

Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts, solvates, or prodrugs in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates, or prodrugs are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.

Examples of other active ingredients that may be administered in combination with a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and either administered separately or in the same pharmaceutical composition, include but are not limited to:

(a) PPARy agonists and partial agonists, including both glitazones and non- glitazones (e. g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512 and LY-818;

(b) Biguanides such as metformin and phenformin;

(c) Protein tyrosine phosphatase- IB (PTP-1B) inhibitors,

(d) Dipeptidyl peptidase IV (DP-IV) inhibitor, such as MK-0431 and LAF-237;

(e) Insulin or insulin mimetics;

(f) Sulfonylureas such as tolbutamide and glipizide or related materials;

(g) a-glucosidase inhibitors (such as acarbose);

(h) agents which improve a patient's lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) cholesterol absorption inhibitors such as for example ezetimibe, (vi) acyl CoAxholesterol acyltransferase (ACAT)inhibitors such as avasimibe, (vii) CETP inhibitors such as torcetrapib and (viii) phenolic anti-oxidants such as probucol;

(i) PPARa/γ dual agonists such as muraglitazar, tesaglitazar, farglitazar and JT-501; (j) PPAR5 agonists such those disclosed in W097/28149;

(k) Antiobesity compounds such as fenfluramine, dextenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, MC4R agonists, cannabinoid receptor 1 antagonists/inverse agonists and β3 adrenergic receptor agonists;

(1) Ileal bile acid transporter inhibitors;

(m)Agents intended for use in inflammatory conditions such as aspirin, nonsteroidal, anti-inflammatory drugs, glucocorticoids, azulfidine and cyclo- oxygenase 2 selective inhibitors;

(n) Glucagon receptor antagonists;

(o) GLP-1; (p) GIP-1;

(q) GLP-1 analogs, such as exendins, for example exenitide, and

(r) Hydro xysterol dehydrogenase- 1 (HSD-1) inhibitors.

The above combinations include combinations of a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof not only with one other active compound but also with two or more active compounds. Non limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and anti-obesity compounds.

In the above-described embodiment combinations of the present invention, the compound of Formula I, a pharmaceutically acceptable salt, solvate, or prodrug thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).

The invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate, or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.

Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as active ingredient.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament. Preferably, the medicament is used for treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

As set forth above, the compounds of the invention, their pharmaceutically acceptable salts, solvates or prodrugs may be used in monotherapy or in combination therapy. Thus, according to one embodiment, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warm-blooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient. The benefits and advantages of such a multiple drug regimen, possible administration regimens as well as suitable additional therapeutic agents and/or active ingredients are those described above.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, micro crystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 0,05 and 1000 mg, and usually between 1 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

Usually, depending on the condition to be prevented or treated and the route of administration, the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[DEFINITIONS]

The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

Where groups may be substituted, such groups may be substituted with one or more substituent(s), and preferably with one, two or three substituents. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as "alkyl, aryl, or cycloalkyl, each being optionally substituted with..." or "alkyl, aryl, or cycloalkyl, optionally substituted with..." encompasses "alkyl optionally substituted with. "aryl optionally substituted with..." and "cycloalkyl optionally substituted with...".

The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C_nH2_n+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms,. Alkyl groups may be linear or branched and may be substituted as indicated herein.

Suitable alkyl groups include methyl, ethyl, n-propyl which comprises propan-l-yl and propan-2-yl, /-propyl, n-butyl, /-butyl, s-butyl and /-butyl, pentyl and its isomers (e.g. n-pentyl, /so-pentyl), and hexyl and its isomers (e.g. n-hexyl, /so-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and /-butyl.

When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.

The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 , 1 , 1- trifluoroethyl and the like.

The term "cycloalkyl" as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".

The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2- imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro- 2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3 ,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4- dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-l-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3- dioxolanyl, 1 ,4-oxathianyl, 1 H-pyrrolizinyl, tetrahydro-l,l-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

The ring atoms of heterocyclyl moieties are numbered based on scheme below

pyrrolidinyl tetrahydrofuranyl imidazolinyl oxazolidinyl

piperidinyl tetrahydropyranyl piperazinyl morpholinyl

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2- yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- o r 5-indanyl, 5-, 6-, 7- o r 8-tetrahydronaphthyl, 1,2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno [3, 2-b] furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3- benzo thiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin- l(6H)-yl , 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

The ring atoms of heteroaryl moieties are numbered on scheme below:

X is selected from: X is selected from: X is selected from: Y is selected from:

N. O or S N, O or S N. O or S C, N

Examples: Examples: Examples: Examples:

pyrrolyl imidazolyl pyrazolyl pyridyl

furanyl oxazolyl isooxazolyl pyrimidinyl

thiophenyl thiazolyl isothiazolyl

X is selected from: X is selected from:

N, O or S N. O or S

Examples: Examples:

indolyl benzimidazolyl

benzofuranyl benzoxazolyl

benzothiophenyl benzothiazolyl

The term "biaryl" as used herein designates two aryl moieties as defined herein linked via a single bond. Non-limiting examples of such biaryl moieties include biphenyl.

biphenyl

The term "heterobiaryl" as used herein designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moity as defined herein linked via a single bond. Non-limiting examples of such heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.

(2-pyridinyl)phenyl (3-pyridinyl)phenyl (4-pyridinyl)phenyl

bipyridinyl

The term "alkylamino" as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.

The compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms . Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.

The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line (^■ww ), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.

The compounds of the invention may also contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.

The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoro acetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH, OH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:

(i) by reacting the compound of Formula I with the desired acid;

(ii) by reacting the compound of Formula I with the desired base;

(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

(iv) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

All references to compounds of formula I include references to salts, solvates, multi- component complexes and liquid crystals thereof.

The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I.

In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereo isomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.

The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.

The term "prodrug" as used herein means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which the COOH moiety is replaced by a substituent Z selected from table 2 below. Table 2

The term "predrug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.

The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.

The term "human" refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).

The terms "treat", "treating" and "treatment, as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.

The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease. The term "therapeutically effective amount" (or more simply an "effective amount") as used herein means the amount of active agent or active ingredient which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.

The term "administration", or a variant thereof (e.g. 'administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.

By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

The term "pharmaceutical vehicle" as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

The term "lipid disorder" as used herein means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.

The present invention will be better understood with reference to the following examples. These examples are intended to represent pecific embodiments of the invention, and are not intended to limit the scope of the invention.

CHEMISTRY EXAMPLES

All temperatures are expressed in °C and all reactions were carried out at room temperature (RT) unless otherwise stated.

Analytical thin layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminium sheet silica gel 60 F₂₅₄ purchased from VWR International. TLC plates were revealed using ultraviolet irradiation (wavelength=254nm) at room temperature or bromocresol green spray reagent at 0.1% in propan-2-ol purchased from VWR International upon heating at 160°C or KMn0₄ revelator upon heating at 160°C. The KMn0₄ revelator was prepared by dissolving 3g of potassium permanganate, 20g of sodium carbonate, 0.5g of sodium hydroxide in lOOmL of distilled water.

HPLC-MS spectra were obtained on Agilent LCMS using Electropsray ionization (ESI). The Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad. The column used was an XBridge CI 8, 4.6 x 50 mm, 3.5 μιη.

Eluent was a mixture of solution A (0.1% TFA in H₂0) and solution B (0.1% TFA in MeCN). Gradient was applied at a flow rate of 2 mL min^-1 as follows: gradient A: held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B: held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min.

Determination of ee was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:

- Hexane and Ethano 1 (0.1 % TFA)

- Hexane and Propanol (0.1% TFA)

- Hexane and Ethyl acetate (0.1% TFA)

- Hexane and Dichloromethane (0.1% TFA)

- Hexane and tert-butyl methyl ether (0.1% TFA)

Selected specific methods A, B and C are reported below. Method A: compound was characterized on a CHIRALPAK I A column (isocratic mode) using a mixture of hexane and dichloromethane (65/35) acidified by 0.4% of TFA at a flow rate of 1.2 mL/min, and confirmed on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and Ethyl acetate (75/25) acidified by 0.1% of TFA at lmL/min. Method B: compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethyl acetate (70/30) acidified by 0.1% of TFA at a flow rate of lmL/min. Method C: compound was characterized on a CHIRALPAK IC column (isocratic mode) using a mixture of heptane and ethanol (95/5) acidified by 0.1% of TFA at a flow rate of 1.5mL/min.

Preparative HPLC purifications were carried out on Fractionlynx instrument, from Waters. This instrument consists of a Fraction Collector, a 2767 Sample Manager, a pump control a module II, a 515 HPLC Pump, a 2525 Binary Gradient Module, a Switching Valve, a 2996 Photodiode Array Detector and a Micromass ZQ. The column used was a Waters Sunfire CI 8 Eluent was a mixture of solution A (0.1 % TFA in H₂0) and solution B (0.1 % TFA in MeCN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.

1H and ¹³C NMR spectra were recorded on a Bruker ARX 300MHz. Chemical shifts are expressed in parts per million, (ppm, δ units). Coupling constants are expressed in Hertz units (Hz). Splitting patterns describe apparent multiplicities and are described as s (singlet), d (doublet), t (triplet), q (quintet), m (multiplet), or br (broad).

Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, and the following abbreviations are used:

Ac: Acetyl,

BuLi: butyllithium,

DCM: Dichloromethane,

DIEA: N,N-diisopropylethylamine,

DMAP: 4,4-dimethylaminopyridine,

DMF: N,N-dimethylformamide,

DPP: Diphenylphosphino, eq: Equivalent(s),

ee: Enantiomeric excess,

EtOAc: Ethyl acetate,

EtOH: Ethanol,

H A T U : 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tretramethyluronium hexafluorophosphate ,

g: Gram(s),

h: Hour(s),

L: Liter(s),

MeCN: Acetonitrile,

MeOH: Methanol,

Me: Methyl,

μΕ: Micro liter(s),

μW: Microwave,

mg: Milligram(s),

mL: Milliliter(s),

mmol: Millimole(s),

min: Minute(s),

mol: Mole(s),

MW: Molecular weight,

NFSI: N-fluorobenzenesulfonimide,

NaHMDS: Sodium hexamethyldisilazane,

P: UV purity at 254nm determined by HPLC-MS,

PE: Petroleum ether,

RM: Reaction mixture,

rt: retention time,

RT: Room temperature,

tBu: tert-Butyl

TFA: Trifluoroacetic acid,

THF: Tetrahydrofuran,

TLC: Thin layer chromatography,

Y: Yield. General Synthetic Scheme

Compounds of the invention were synthesized according to Scheme 1.

I

Scheme 1: General synthetic route for the compounds in the present invention

Amide coupling between intermediates 1.1 and 1.2 using HATU provided intermediate 1.3 which was deprotected to the acid compound of the invention I under acidic conditions.

Synthesis of intermediates 1.1

Chiral syntheses of intermediates 1.1 were carried out using Evans' chiral auxiliary approach (Evans et al. J. Org. Chem. 1999, 64, 6411-6417; Tararov et al. J. Chem. Soc. Perkin Trans. 1, 1997, 3101-3106) (Scheme 2).

Scheme 2: General scheme for the preparation of intermediates 1.1 using Evans' chiral auxiliary approach

(S)-4-benzyloxazolidin-2-one 2.2 was acylated using mixed anhydride 2.1 to furnish intermediate 2.3. Diastereo selective alkylation of 2.3 with tert-butylbromoacetate yielded intermediates 2.4 which upon auxiliary cleavage provided intermediates 1.1.

Synthesis o f intermediates 1.2

Biaryl- or heterobiaryl-thiazole amine intermediates were synthesized using Suzuki approach as shown in schemes 3 and 4.

General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 1.2 using Suzuki approach (Scheme 3):

Scheme 3: General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 1.2 using Suzuki approach

Alternative general scheme for the preparation of biaryl- or heterobiaryl-thiazole amine

Scheme 4: Alternative general scheme for the preparation of biaryl- or heterobiaryl- thiazole amine intermediates 1.2 using Suzuki approach

Intermediates 3.1 can be made using Hantzsch-type synthetic methodology as shown in Scheme 5. Thus, halogenation of substituted acetophenones 5.1 (Larock, R. C. Comprehensive Org Transf 2^nd Ed., Wiley, 1999, pp 709-719; White et al. J. Med. Chem. 1996, 39, 4382-95) and subsequent condensation with thiourea 5.3 (Swain et al. J. Med. Chem. 1991, 34, 140-151; Bartoli et al. J. Med. Chem. 1998, 41, 1855-68) will furnish amino -thiazole intermediates.

use of microwave

5.1 5.2 _{3 1}

Scheme 5: General scheme for the preparation of intermediates 3.1 using

Hantzsch-type synthetic approach

Alternatively, synthesis of intermediates 3.1 can be achieved through the method described by Rudolph (Rudolph, J. Tetrahedron 2000, 56, 3161):

Scheme 6: General scheme for the preparation of intermediates 3.1 using

Rudolph's synthetic approach

Acetophenone intermediates 5.1 can be prepared as described in Scheme 7.

General synthetic scheme for the preparation of substituted acetophenone intermediates 5.1 through Weinreb amide approach (Scheme 7):

7.1 7.2 5.1

Scheme 7: General synthetic scheme for the preparation of substituted acetophenone intermediates 5.1 through Weinreb amide approach

Thiourea intermediates 5.3 can be prepared as described in Scheme 8.

General synthetic scheme for the preparation of substituted thiourea intermediates 5.3

(Scheme 8):

Scheme 8: General synthetic scheme for the preparation of substituted thiourea intermediates 5.3

2-amino-4-aryl-5-fluorothiazole intermediates can be prepared from 2-amino-4- aryl-thiazole intermediates using the conditions described in Chem. Res. Toxicol. 2007, 1954-1965.

5-amino-3-(hetero)biarylthiadiazole may be synthesized as was done for the 2- amino-4-(hetero)biarylthiazole using Suzuki coupling approach from 5-amino-3- bromothiadiazole which may be obtained using the methodology suggested in Scheme 9.

9.8

Scheme 9: General synthetic scheme for the preparation of 5-amino-3-bromothiadiazole intermediates

General Method A: synthesis of intermediate la (R)-4-tert-butoxy-2- (cyclopentylmethyl)-4-oxobutanoic acid

Step 1 : synthesis of (S)-4-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one

Solution A: Trimethylacetylchloride (41 mL, 0.33 mol) was added dropwise over 15 min to a stirred solution of 3-cyclopentylpropionic acid (46.6 g, 0.33 mol) and triethylamine (52 mL, 0.38 mol) in anhydrous THF (1.2 L) at -78°C under a nitrogen atmosphere. The thick white precipitate which formed was allowed to warm to ~0°C and stirred for 1 h.

Solution B: n-Butyllithium (2.5M/hexane, 134 mL, 0.33 mol) was added dropwise over 20 min to a stirred solution of (S)-4-benzyl-2-oxazolidinone (59.2 g, 0.33 mol) in dry THF (600 mL) at -78°C under a nitrogen atmosphere. The yellow solution was allowed to warm to ~0°C and stirred for 1 hour, after which time a white gelatinous precipitate had formed.

Solution A was re-cooled to -78°C and solution B added via cannula over 2.5 hours. Extra THF (200 mL) was added to solution B to aid cannula transfer of the more viscous final portion. The resulting white suspension was allowed to warm to RT slowly overnight. The mixture was cooled in an ice bath and saturated aqueous ammonium chloride (500 mL) added slowly, followed by water (400 mL) to dissolve any precipitated salts, and Et₂0 (500 mL). The separated organic layer was dried (Na₂S0₄) and evaporated in vacuo to leave a yellow oil (1 10 g). Crude was purified by column chromatography using an increasing gradient from 5-20% EtOAc in petroleum ether) to give the product as a pale yellow oil which solidifies to a white solid on standing. Y: 91 g (91%), P=100%, rt= 4.38 min (gradient A), (M+H)⁺ = 302.2.

Step 2: synthesis of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3- (cyclopentylmethyl)-4-oxobutanoate

NaHMDS (1M/THF, 410 mL, 0.41 mol) was added dropwise over 1 h to a stirred solution of (S)-4-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (95 g, 0.315 mol) in dry THF (1.5 L) at -78°C under a nitrogen atmosphere. After 1 hour at low temperature t-butyl bromoacetate (70 mL, 0.41 mol) was added dropwise over 30 min. The resulting solution was then allowed to warm to RT slowly overnight. The mixture was cooled in an ice bath and saturated aqueous ammonium chloride (300 mL) added slowly, followed by water (100 mL) and EtOAc (500 mL). The separated aqueous layer was extracted with EtOAc (200 mL) and the combined organics dried (Na₂S0₄) and evaporated in vacuo to leave an off-white sticky solid. This solid was washed with PE several times to give the desired product as a colorless solid (63 g) which was pure by NMR. The petroleum ether filtrates were evaporated and the crude material was purified by column chromatography using an increasing gradient (PE/EtOAc = 95/5 -> 70/30) to give a colorless solid, which was washed with petroleum ether to give a further 10 g of pure product. Y: 73 g (56%>), P>95%>, rt=4.86 min (gradient A), (M+H)⁺ = 416.2. Step 3: synthesis of intermediate la (R)-4-tert-butoxy-2-(cyclopentylmethyl)-4- oxobutanoic acid

Hydrogen peroxide (35% in water, 68 mL, 0.7 mol) was added dropwise over 15 mins to a stirred solution of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3- (cyclopentylmethyl)-4-oxobutanoate (73 g, 0.18 mol) in THF/water (4/1, 750 mL) at 0°C under a nitrogen atmosphere. A thick precipitate formed so further THF/water (4/1, 500 mL) was added. Stirring was continued for 10 mins then a solution of LiOH (15 g, 0.35 mol) in water (300 mL) was added dropwise over 15 mins. The mixture was allowed to warm to RT slowly overnight. The mixture was cooled in ice and a solution of sodium sulfite (225 g, 1.8 mol) in water (1 L) was added dropwise over 1 h, causing a small exo therm. The mixture was evaporated in vacuo to dryness to leave a colorless solid. This was partitioned between water (1.5 L) and Et₂0 (1 L) and stirred overnight to dissolve all solids. The separated aqueous layer was washed with Et₂0 (9 x 500 mL). The aqueous layer was then cooled in ice and acidified to pH = 1-2 with 6M HC1, extracted with DCM (3 x 500 mL), dried (Na₂S0₄) and evaporated in vacuo to leave a yellow oil, 30.2 g (batch 1). NMR showed the desired product along with -20% of the di-acid by-product resulting from hydrolysis of the t-Bu ester.

The Et₂0 washings were extracted with 1M NaOH, which was then acidified with cone. HC1 to pH = 1-2, extracted with DCM and evaporated in vacuo to give batch 2.

Batch 1 was combined with the separated oil from batch 2 and purified by column chromatography using an increasing gradient (PE/EtOAc = 9/1 -> 7/3) to give the title product as a pale yellow oil. Y: 30 g (65%), P>95%, rt=2.91 min (gradient A), (M+H)⁺ = 255.5, ee > 99%. ^!HNMR (CDC1₃): 5=2.8 (q, 1H), 2.58 (dd, 1H), 2.37 (dd, 1H), 1.56- 1.82 (m, 4H), 1.41-1.55 (m, 5H), 1.4 (s, 9H), 1.05 (m, 2H).

The following intermediates were synthesized using general method A adapting the starting materials to targeted intermediate:

intermediate lb: (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-methylpentanoic acid, intermediate lc: (R)-4-(tert-butoxy)-2-(cyclobutylmethyl)-4-oxobutanoic acid, intermediates Id: (R)-4-(tert-butoxy)-2-(cyclopropylmethyl)-4-oxobutanoic acid and le: (R)-2-(2-(tert-butoxy)-2-oxoethyl)hexanoic acid, were synthesized using general method A (step 2 and 3 ) from a mixture of (S)-4-benzyl-3-(3- cyclopropylpropanoyl)oxazolidin-2-one and (S)-4-benzyl-3-hexanoyloxazolidin- 2-one which was synthesized as follows:

To a solution of (S)-4-benzyl-3-(3-cyclopropylacryloyl)oxazolidin-2-one (1.5 g, 5.53 mmol) (synthesized from (E)-3-cyclopropylacrylic acid using general method A, step 1) in EtOAc (25 mL), Pd/C (137 mg, 39 μιηοΐ) was added under stirring. The reaction flask was placed under vacuum and back-filled with hydrogen (Pressure = 3 bars). When the reaction was complete, reaction mixture was filtered on a short Celite pad, washed with EtOAc. (2 x 20ml) and filtrate was concentrated under vacuum to afford desired title mixture of intermediates and opened cyclopropyl side product. Mixture was used as such without further purification in the next step.

General Method B: synthesis of intermediate 2a N-cyclopropyl-4-(2-(6-(2- methoxyethoxy)pyridin-3 -yl)phenyl)thiazo 1-2-amine

Synthesis of 1-cyclopropylthiourea

A solution of cyclopropylamine (43 mL, 0.621 mol) in dry chloroform (1.1 L) was stirred and cooled to 0°C under nitrogen. Benzoylisothiocyante (83.5 mL, 0.621 mol) was added drop wise to the solution, then after complete addition the mixture allowed to reach RT. After 30min at RT the mixture was concentrated to give a yellow solid. This solid was suspended in methanol (1 L), 4N NaOH (155 mL, 0.621mol) was added and the solution warmed to 60°C for 1.5 h. The solution was cooled to RT then concentrated to remove the methanol. The residue was dissolved in water (400 mL) and the sides of the flask scratched with a spatula to produce a precipitate. This suspension was stirred for 20 min with an overhead stirrer then the solution was filtered and the solid washed with water (200 mL). This white solid was dried in the vacuum oven at 50°C to give 25.95g of title product.

The aqueous filtrate was concentrated to dryness then 200 mL of water was added to yield another solid suspension which was treated as above to yield a further 15.96 g of product. The aqueous filtrate was concentrated to dryness then 150mL of water added and the solution cooled to 5°C to yield another solid suspension which was treated as above to yield a further 7.85g of title product. Y: 49.8 g (69%), P>95%, ^!HNMR (MeOH-d⁴): 5=3.3 (s, 2H), 2.45 (br s, 1H), 1.77 (m, 2H), 1.58 (m, 2H).

Synthesis of 4-(2-bromophenyl)-N-cyclopropylthiazol-2-amine

A solution of 2'-bromoacetophenone (100 g, 0.502 mol) in dry THF (100 mL) was stirred and cooled to 0°C. Solid aluminium chloride (3.37 g, 0.025 mol) was added, then bromine (28.3 mL, 0.552 mol) was added dropwise over 1.25 h. The mixture was allowed to reach RT and stirred for 2h. The solution was quenched with water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were washed with brine (2 x 400 mL) and dried over sodium sulfate. Filtration and concentration gave 2- bromo-l-(2-bromophenyl)ethanone as a yellow oil (215.4 g).

A solution of 2-bromo-l-(2-bromophenyl)ethanone (176.9g, 0.414mol) was stirred in ethanol (1.8 L) and 1-cyclopropylthiourea (48 g, 0.414 mol) was added. The mixture was heated to reflux for 2h then cooled to RT and most of the ethanol removed by evaporation. The residue was stirred rapidly whilst diethyl ether (2.2 L) was added, thus resulting in a precipitate. The cream solid was filtered from the solution and air dried on the filter funnel, this was analysed as the HBr salt of the title product (145 g). This material was suspended in DCM (1.1 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (2 x 900 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give title product as an off white solid. Y: 101 g (83%), P>95%, rt=3.29 min (gradient A), (M+H)⁺ = 295.2.

Synthesis of 5-bromo-2-(2-methoxyethoxy)pyridine

To a solution of 5-bromopyridin-2-ol (5.75 mmol, lg), triphenylphosphine (8.62mmol, 2.26 g), and 2-methoxyethanol (7.2 mmol, 0.55 g) in THF (25 mL), was added slowly diisopropyl azodicarboxylate (8.62 mmol, 1.7 mL) at RT. The mixture was stirred at RT overnight. The reaction was quenched with MeOH, diluted with water and extracted with DCM (25 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Crude was purified by flash chromatography (cyclohexane/EtOAc = 9/2 -> 7/3) to yield title product. Y: 1.05 g (79%), P>80%, rt=3.9 min (gradient A), (M+H)⁺ = 233.

Synthesis of 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yPpyridine

A solution of 5-bromo-2-(2-methoxyethoxy)pyridine (4.52mmol, 1.05g) in DMSO (20 mL) was degassed with Ar. 4,4,4^*,4^*,5,5,5^*,5^*-octamethyl-2,2^,-bi(l,3,2- dioxaborolane) (4.97mmol, 1.26 g), potassium acetate (13.55 mmol, 1 .33 g) and tetrakis(triphenyl-phosphine)palladium(0) (0.45 mmol, 0.522 g) were then added and the mixture was heated at 80°C for 2 days. The RM was cooled down to RT, quenched with a saturated aqueous solution of NH₄C1 and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over soldium sulfate and concentrated to dryness . Crude was purified by flash chromato graphy (cyclohexane/EtOAc = 9/1 -> 1/1) to yield title product. Y: 1.26 g (79%), P>95%, rt=l min (gradient A), (M+H)⁺ = 280.

Synthesis of intermediate 2a N-cyclopropyl-4-(2-(6-(2-methoxyethoxy)pyridin- 3 -yl)phenyl)thiazo 1-2-amine

A solution of 4-(2-bromophenyl)-N-cyclopropylthiazol-2-amine (1.77 mmol, 523 mg), a 2M solution of potassium carbonate in water (5.32 mmol, 2.66 mL), 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.55 mmol, 990 mg) in toluene (15 mL) was degassed (3 vacuum/N₂ cycles). Tetrakis(triphenyl-phosphine)palladium(0) (0.177 mmol, 0.205 g) was then added and the RM was heated under reflux for 5 days. The RM was cooled down and concentrated in vacuo. Crude was purified by flash chromatography (cyclohexane/EtOAc = 9/1 -> 4/6) to yield title product. Y: 0.46 g (74%), P>95%, rt=3.4 min (gradient A), (M+H)⁺ = 368.

The following intermediates were synthesized from the appropriate bromoketone using general method B:

intermediate 2i : N-cyclopropyl-4-(2-(6-methoxypyridin-3 -yl)phenyl)thiazo 1-2- amine from (6-methoxypyridin-3-yl)boronic acid. General Method C: synthesis of intermediate 2b N-cyclopropyl-4-(2-(5- methoxypyrazin-2-yl)phenyl)thiazol-2-amine

Synthesis of 2-(2-(cyclopropylamino)thiazol-4-yl)phenylboronic acid

To a stirred solution of 4-(2-bromophenyl)-N-cyclopropylthiazol-2-amine (16.72 mmol, 4.94 g) in THF (40 mL) at -78°C was added dropwise a 2.5M solution of nBuLi in hexanes (33.4 mmol, 13.4 mL). After 15 min, triisopropyl borate (50.4 mmol, 9.3 g) was rapidly added. After a further hour at -78°C, the RM was warmed to RT and stirred for lh. The reaction mixture was evaporated to dryness and residue analyzed by LCMS showing title product to be 40% pure (rt=3.2 min, gradient A). The residue was dissolved in toluene (50 mL) thus obtaining a 0.2M solution of title product to be used as such in next step.

Synthesis of intermediate 2b N-cyclopropyl-4-(2-(5-methoxypyrazin-2- vDphenyDthiazo 1-2-amine

A solution of 2-(2-(cyclopropylamino)thiazol-4-yl)phenylboronic acid (1.06 mmol), 2M solution of potassium carbonate in water (1.59 mmol, 0.79 mL) and 2-bromo-5- methoxypyrazine (0.53mmol, 0.1 g) in toluene (5 mL) was degassed (3 vacuum/N₂ cycles and then Ar bubbling). Tetrakis(triphenyl-phosphine)palladium(0) (0.053 mmol, 0.061 g) was then added and the RM was heated under reflux ovemight.The reaction mixture was cooled down, diluted with EtOAc, washed with water and concentrated in vacuo. Crude was purified by flash chromatography (cyclohexane/EtOAc = 95/5 -> 90/20) to yield title product. Y: 0.17 g (99%), P>75%, rt=3.3 min (gradient A), (M+H)+ = 328.

The following intermediates were synthesized from the appropriate bromoketone using general method C:

intermediate 2c: N-cyclopropyl-4-(2-(6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-3- yl)phenyl)thiazol-2-amine from 5-bromo-2-(furan-2-yl)pyridine,

intermediate 2d: 5-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)-l,3,3-trimethyl- lH-pyrrolo[2,3-b]pyridin-2(3H)-o n e f r o m 5-bromo-l,3,3-trimethyl-lH- pyrrolo[2,3-b]pyridin-2(3H)-one which was synthesized from 5-bromo-lH- pyrrolo[2,3-b]pyridin-2(3H)-one as follows:

To a solution of 5-bromo-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (1.96 mmol, 420 mg) in dry DMF (2.5 mL) under N₂ at -40°C was added sodium hydride (7.9 mmol, 314 mg). The RM was stirred for lh at -40°C and then iodomethane (19.6 mmol, 1.23 mL) was added dropwise. The RM was stirred at -40°C for 2h and then allowed to warm slowly to RT. The mixture was quenched (cooling bath ~ 0°C) by addition of a saturated aqueous solution of NH₄C1. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine (2 x), dried and concentrated in vacuo. Crude was used as such in the next Suzuki coupling step.

intermediate 2e: 6-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)-3- methyloxazolo[4,5-b]pyridin-2(3H)-one from 6-bromo-3-methyloxazolo[4,5- b]pyridin-2(3H)-one which was synthesize d from 6-bromooxazolo[4,5- b]pyridin-2(3H)-one using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2f: N-cyclopropyl-4-(2-(6-methoxy-5-methylpyridin-3- yl)phenyl)thiazol-2-amine from 5 -bromo-2-methoxy-3 -methylpyridine, intermediate 2g: 7-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)- 1 ,4-dimethyl- 3 ,4-dihydropyrido [2,3 -b]pyrazin-2( lH)-one from 7-bromo- 1 ,4-dimethyl-3 ,4- dihydropyrido[3,2-b]pyrazin-2(lH)-one which was synthesized from 7-bromo- 3,4-dihydropyrido[3,2-b]pyrazin-2(lH)-one using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2h: l-(5-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)pyridin-2- yl)pyrrolidin-2-one from l-(5-bromopyridin-2-yl)pyrrolidin-2-one which was synthesized from 5-bromopyridin-2-amine as follows:

In a 250 mL round bottom flask were introduced successively under Ar: 5- bromopyridin-2-amine (10 g, 57.8 mmol), K₂C0₃ (32.0 g, 231 mmol) and dry MeCN ( 1 15 mL). To this suspension was added at once 4-bromobutanoyl chloride (10 mL, 86.7 mmol) and the RM was stirred at RT overnight.The RM was filtered and the solid washed with MeCN. The filtrate was concentrated and the residue taken up in EtOAc and diluted with water. The organic layer was then washed with aqueous HC1 0.5M, dried and concentrated in vacuo to give 8.67g (62%) of title product as a white solid,

intermediate 2j : N-cyclopropyl-4-(2-(5-(2-methoxyethoxy)pyrazin-2- yl)phenyl)thiazol-2-amine from 2-bromo-5-(2-methoxyethoxy)pyrazine which was synthesized from 5-bromopyrazin-2-ol as described above for the synthesis of 5-bromo-2-(2-methoxyethoxy)pyridine,

intermediate 2k: 1 -(5-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)pyridin-2-yl)- 3-methylpyrrolidin-2-one from 1 -(5-bromopyridin-2-yl)-3-methylpyrrolidin-2- one which was synthesized from l-(5-bromopyridin-2-yl)pyrrolidin-2-one as follows:

To a solution of l-(5-bromopyridin-2-yl)pyrrolidin-2-one (1.66mmol, 400 mg) in anhydrous THF (4 mL) at -78°C under Ar, was added a 1M solution of LiHMDS in anhydrous THF (1.99 mmol, 1.99 mL). The RM was stirred for 15min at -78°C and then iodomethane (3.32 mmol, 0.2 mL) was added dropwise. The RM was stirred at -78°C for 10 min. 5 mL of a saturated aqueous solution of NH₄C1 was added and the organic layer was washed with brine, dried aver magnesium sulfate and evaporated to dryness. Crude was purified by flash chromatography (cyclohexane/EtOAc=95/5 -> 9 0 / 1 0 ) t o y i e l d l-(5-bromopyridin-2-yl)-3- methylpyrrolidin-2-one. Y: 0.42 g (55%), P>95%.

intermediate 21: N-cyclopropyl-4-(2-(5-methyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)phenyl)thiazol-2-amine from 2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine, intermediate 2m : N-cyclopropyl-4-(2-(5 -(dimethylamino)pyrazin-2- yl)phenyl)thiazol-2-amine from 5-bromo-N,N-dimethylpyrazin-2-amine which was synthesized from 5-bromopyrazin-2-amine using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2n : N-cyclopropyl-4-(2-( 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin-5 - yl)phenyl)thiazol-2-amine from 5-bromo-l -methyl- lH-pyrazolo[3,4-b]pyridine which was synthesized from 5-bromo-lH-pyrazolo[3,4-b]pyridine using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2o: N-cyclopropyl-4-(2-(l -methyl- 1 H-[ 1 ,2,3]triazolo[4,5- b]pyridin-6-yl)phenyl)thiazol-2-a m i n e f r o m 6-bromo- 1 -methyl- 1H-

[l,2,3]triazolo[4,5-b]pyridine which was synthesized from 6-bromo-lH- [l,2,3]triazolo[4,5-b]pyridine using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2 : 7-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)-4-methyl-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one from 7-bromo-4-methyl-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one which was synthesized from 7-bromo-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one using iodomethane and sodium hydride as described for intermediate 2d,

intermediate 2q: (S)-N-cyclopropyl-4-(2-(6-(2-methoxypropoxy)pyridin-3- yl)phenyl)thiazol-2-amine from (S)-5-bromo-2-(2-methoxypropoxy)pyridine which was synthesized from 5-bromopyridin-2-ol and (S)-2-methoxypropan-l-ol using the Mitsunobu chemistry as described above for the synthesis of 5-bromo- 2-(2-methoxyethoxy)pyridine,

intermediate 2r: N-cyclopropyl-4-(2-(6-(2-isopropoxyethoxy)pyridin-3- yl)phenyl)thiazol-2-amine from 5-bromo-2-(2-isopropoxyethoxy)pyridine which was synthesized from 5-bromopyridin-2-ol and 2-isopropoxyethanol using the Mitsunobu chemistry as described above for the synthesis of 5-bromo-2-(2- methoxyethoxy)pyridine,

intermediate 2s: (R)-N-cyclopropyl-4-(2-(6-((l-methoxypropan-2- yl)oxy)pyridin-3-yl)phenyl)thiazol-2-a m i n e f r o m (R)-5-bromo-2-(l- methoxypropan-2-yloxy)pyridine which was synthesized from 5-bromopyridin- 2-ol and (S)-l-methoxypropan-2-ol using the Mitsunobu chemistry as described above for the synthesis of 5-bromo-2-(2-methoxyethoxy)pyridine,

intermediate 2t: 1 -(5-(2-(2-(cyclopropylamino)thiazol-4-yl)phenyl)pyrazin-2- yl)pyrrolidin-2-one from l-(5-bromopyrazin-2-yl)pyrrolidin-2-one which was synthesized from 5-bromopyrazin-2-amine and 4-bromobutanoyl chloride using the conditions described above for the synthesis of l-(5-bromopyridin-2- yl)pyrrolidin-2-one,

intermediate 2u : 1 -(5 -(2-(2-(cyclopropylamino)thiazo l-4-yl)phenyl)pyridin-2- yl)-3-fluoropyrrolidin-2-one from 1 -(5-bromopyridin-2-yl)-3-fluoropyrrolidin-2- one which was synthesized from l-(5-bromopyridin-2-yl)pyrrolidin-2-one as follows: To a solution of l-(5-bromopyridin-2-yl)pyrrolidin-2-one (1.52 mmol, 0.37 g) in 7 mL of THF at -78°C and under Ar, was added slowly a 1M solution of LiHMDS (3.34 mmol, 3.34 mL). The RM was stirred for 30 min at -78°C and then a solution of NFSI (3.49 mmol, 1.1 g) in THF (5 mL) was added dropwise. The RM was stirred at -78°C for 30 min and allowed to warm up to RT. EtOAc (20 mL) and 5 mL of a saturated aqueous solution of NH₄C1 was added and organic layer was wached with brine, dried over magnesium sulfate and evaporated to dryness to yield l-(5-bromopyridin-2-yl)-3-fluoropyrrolidin-2-one as a yellow oil to be used as such in the next step. Y:400 mg (quantitative),

intermediate 2v: 4-(2-(6-( 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)-N- cyclopropylthiazol-2-amine from 5 -bromo-2-( 1 H-pyrazol- 1 -yl)pyridine, intermediate 2w: N-cyclopropyl-4-(2-(6-methoxypyridazin-3-yl)phenyl)thiazol- 2-amine from 3-bromo-6-methoxypyridazine.

General Method D: synthesis of Example 1: compound n°l : (R)-3- (cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2-methoxyethoxy)pyridin-3- yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid

Step 1 : synthesis of (R)-tert-butyl 3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- (2-methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoate

To a solution of (R)-4-tert-butoxy-2-(cyclopentylmethyl)-4-oxobutanoic acid la (0.46 mmol, 117 mg) in anhydrous MeCN (4 mL) was added HATU (0.5 mmol, 190 mg) . After 5 min was added N-cyclopropyl-4-(2-(6-(2-methoxyethoxy)pyridin-3- yl)phenyl)thiazol-2-amine 2a (0.42 mmol, 143 mg) and DIEA (0.5 mmol, 87 μί). Reaction mixture was stirred overnight at RT. TLC indicated reaction was complete. The RM was diluted with EtOAc and washed with sat. aq. NaHC0₃ and water. The organic phase was dried over MgS 0₄ and evaporated. Crude was purified by flash chromatography (PE/EtOAc= 9/1 -> 7/3) to yield title compound. Y: 139 mg (44 %), P>80%, rt=5.3 min (gradient A), (M+H)⁺ =606.

Step 2: synthesis of Example 1: compound n°l : (R)-3-(cyclopentylmethyl)-4- (cyclopropyl(4-(2-(6-(2-methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid To a solution of (R)-tert-butyl 3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoate (0.18 mmol, 139 mg) in DCM (2 mL) was added TFA (1 mL). RM was stirred at RT for 3h. TLC (DCM/EtOAc=95/5) indicated reaction was complete. Reaction mixture was then diluted with EtOAc and the organic layer was washed (5 x 25 mL) with an aqueous NaHS0₃ solution (10%), brine (2 x 25 mL) and water (2x 25 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Crude was purified by flash chromatography (cyclohexane/EtOAc: 7/3) to yield a solid which was further re- dissolved and lyophilized. Y: 71 mg (70%), P=93% rt=6.66 min (gradient B), (M+H)⁺ =550.7. 1H NMR (CDC1₃): 5=8.04 (br s, 1H), 7.72 (m, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 6.75 (d, 1H), 6.67 (s, 1H), 4.49 (dt, 2H), 3.77 (dt, 2H), 3.45 (s, 3H), 3.01 (q, 1H), 2.81 (m, 1H), 2.64 (m, 1H), 1.80 (m, 3H), 1.57 (m, 7H), 1.04 (m, 6H), 0.62 (m, 2H).

Examples 2 to 27 were synthesized using general method D and intermediates described above.

Example 2: compound n°2 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- methoxypyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2b.

Example 3: compound n°3 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3,5- dimethyl- 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2c.

Example 4: compound n°4 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,3,3- trimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)- 4-oxobutanoic acid was synthesized from intermediates la and 2d.

Example 5: compound n°5 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-2- oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2e.

Example 6: compound n°6 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methoxy- 5-methylpyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2f using general method E and further preparative HPLC purification.

Example 7: compound n°7 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,4- dimethyl-2-oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2g.

Example 8: compound n°8 (R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lc and 2h.

Example 9: compound n° 9 (R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates lc and 2i.

Example 10: compound n°l l (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- methoxyethoxy)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2j.

Example 11: compound n° 12 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- methyl-2-oxopyrrolidin- 1 -yl)pyridin-3 -yl)phenyl)thiazo l-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2k.

Example 12: compound n° 1 3 (R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2i.

Example 13: compound n°14 (R)-3-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin-l-yl)pyridin- 3-yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2h.

Example 14: compound n° 15 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 21.

Example 15: compound n°16 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- (dimethylamino)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2m.

Example 16: compound n°17 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2n.

Example 17: compound n°18 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l- methyl- 1 H-[ 1 ,2,3]triazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2o.

Example 18: compound n° 19 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(4- methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2p.

Example 19: compound n°20 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-((S)-2- methoxypropoxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2q.

Example 20: compound n°21 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- isopropoxyethoxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2r.

Example 21: compound n°22 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(((R)- 1 -methoxypropan-2-yl)oxy)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2s.

Example 22: compound n°23 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- oxopyrrolidin- 1 -yl)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2t.

Example 23: compound n°24 (3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3- fluoro-2-oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2u.

Example 24: compound n°25 (R)-4-((4-(2-(6-(lH-pyrazol-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid was synthesized from intermediates la and 2v. Example 25: compound n°26 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridazin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid was synthesized from intermediates la and 2w.

Example 26: compound n°27 (R)-3-(cyclopropyl(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2b.

Example 27: compound n°33: (R)-3-(cyclopropyl(4-(2-(6-methoxypyridazin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2w.

Example 28: compound n°29 : (R)-3-((4-(2-(6-(lH-pyrazol-l-yl)pyridin-3- yl)phenyl)thiazol-2-yl)(cyclopropyl)carbamoyl)-5-methylhexanoic acid was synthesized from intermediates lb and 2w.

Example 29: compound n°37: (R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)amino)-3 -(cyclopropylmethyl)-4-oxobutanoic acid and compound n° 38 : (R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2- yl)carbamoyl)heptanoic acid were synthesized from a mixture of intermediates le/ld and 2i and further preparative HPLC purification.

BIOLOGY EXAMPLES

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the inhibition of in-vivo lipolysis following the injection of compounds 13 and 15 in mice.

Oral Glucose Tolerance Test (OGTT)

Lean male C57BL/6J mice (7 weeks of age) were kept in a 12/12h light-dark cycle (light from 0600-1800 h) with controlled temperature conditions (22-24°C). At day -1 food was removed from all mice. The acute experiment was performed 17 hours later (day 1). Mice (n=6) were dosed per oral with vehicle (cyclodextin/NaCl 0.9%) or compounds of the invention (50 mg/kg). At time points -15 and 0 min, baseline blood glucose was measured through a tail bleeding (using a glucometer). Then glucose was administered by oral gavage (2g/kg glucose) and blood glucose was then measured at time points 15, 30, 60 and 120 minutes. The blood glucose area under the curve (AUC) between time t-15 min and time tl20 min was calculated (GraphPad Prism software). The percentages of AUC inhibition induced by the compounds of the invention were calculated following the formula: % of AUC inhibition = [1- (AUC compound / AUC vehicle)] * 100 and are reported in Table 3.

Table 3

Compound n° % of AUC inhibition

1 19

2 11

3 11

4 8

5 25

6 17

7 19

8 23

9 9

11 13

13 22

14 14

15 18

16 13

17 11

18 7

19 7

20 6

21 13

22 18

23 23

25 25

26 18

27 18 33 10

37 8

38 23

When tested in the above-described assay, preferred compounds of the invention showed a % of AUC inhibition > 11%, indicating that the compounds of invention are able to significantly reduce the level of blood glucose.

In vivo assay to assess compound anti-lipolytic activity in rodent model

Male C57BL/6N wild-type are housed one per cage in a room maintained on a 12h light/dark cycle under constant temperature (22-25°C) with ad libitum access to food and water. The anti-lipolytic effects of the compounds of the invention are studied in awake mice. Animals are fasted overnight before experimental use. On the day of the experiment, animals are put in metabolic cages and left undisturbed to acclimate to the environment for l-2h. Blood samples are taken at indicated time points from the intraorbital retrobulbar plexus. A 1% sodium citrate saline solution is used to flush the lines. A pre-treatment blood sample is obtained from each animal to determine baseline values for free fatty acids (FFA) and triglycerides (TG). Compounds of the invention are given via oral gavage, sc injection, iv injection or ip injection for each different series of experiments. Blood samples are collected into pre-cooled tubes pre-coated with heparin (200μ1 blood, Li-heparin, Sarstedt) for determination triglycerides and glycerol and in tri-potassium EDTA added sodium fluoride (200 μΐ blood, K₃-EDTA, 1.6 mg/mL + 1% NaF, Sarstedt) for determination of plasma free fatty acids. The tubes are placed on wet ice pending processing. Blood samples will be centrifuged at 4000 x g, at 4°C, 15 min the resulting plasma will be transferred into non-coated tubes and stored at - 80°C until analyses. The plasma is thawed at 4°C for determinations of FFA and TG using commercial kits (Wako Chemicals).

According to the method described above and by way of illustration the compounds n° 13 and 15 administered orally, inhibit, 15 minutes following the dosing, in vivo FFA baseline at the concentration of 50mg/kg from normal diet fed mice in comparison to the vehicle (Figure 1).

CYP 450 Profilling Assay

P450-Glo™ Screening assay (Promega) are used to evaluate the potential of the compounds of the invention to inhibit cytochrome P450 isoforms (CYP 1 A2 # V9770, 2C9 # V9790, 2C19 # V9880, 2D6 # V9890, 3A4 # V9910). These assays employ luminogenic CYP450 probe substrates that are derivatives of beetle luciferin, a substrate for luciferase enzymes. The derivatives are converted by P450s cytochrome to luciferin, which in turn reacts with luciferase to produce an amount of light that is directly proportional to the activity of the P450.

P450- Glo™ assays are performed in two steps, the P450- Glo™ subtrates are first converted by cytochrome P450 enzyme to a luciferin product which is then detected as a luminescent signal from a luciferase reaction. To perform the assay, the cytochrome P450 mixture with cytochrome P450 enzyme and a P450- Glo™ substrate is prepared at pH 7.4 in a P04 buffer at the optimal concentration for each cytochrome P450 isoform. The compounds of the invention (Dose response curve from ΙΟΟμΜ to 30nM) are added to the mixture in duplicates. Luciferin- Free water+0.1% DMSO is used as negative control and known inhibitor as positive control. The reactions are initiated by adding the NADPH regeneration system and are performed at 37°C (incubation time as describe in the table below). Luciferin detection reagent is added to stop cytochrome P450 activity and initiate the D-luciferin detection reaction. The IC₅₀ value (compound concentration required to inhibit cytochrome activity by 50%) of the compound of the invention were then determined.

When tested in the above-described assay, preferred compounds of the invention showed an IC₅₀≥ ΙΟμΜ on all five cytochrome P450 iso forms, indicating no or a weak CYP450 activity inhibition by the compounds of the invention.

While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation ant it is understood that various changes may be made without departing from the spirit and scope of the invention.

Claims

1. A compound having formula la:

W is C or N;

X is CH or N;

Y is CH, or Y is N under the condition that X is CH;

R¹ is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl or cyclopentyl;

R³ forms together with R⁴ a 1 , 3 , 3-trimethyl-2-oxopyrrolidinyl, N-methyl-2-oxo- oxazo lidinyl , 1 , 4-dimethyl-2-oxopiperazinyl, 4-methyl-3-oxomorpho linyl , N- methylpyrrolyl when X is N, 1-methylpyrazolyl or 1-methyltriazolyl moiety fused to the heteroaryl ring they are attached to; or

R³ is methyl and R⁴ is methoxy; or

R³ is H and R⁴ is methoxy when R¹ is propan-l-yl, propan-2-yl, cyclopropyl, cyclobutyl or when one of X or Y is N,

R³ is H and R⁴ is (2-methoxyethyl)oxy, (S)-2-methoxypropoxy, ((R)-l-methoxypropan-2- yl)oxy, (2-isopropoxyethyl)oxy; or R³ is H and R⁴ is dimethylamino when X is N; or

R³ is H and R⁴ is 2-oxopyrrolidin-l-yl when R¹ is propan-2-yl or eye lo butyl or when R¹ is cyclopentyl and X is N; or

R³ is H and R⁴ is 3-methyl-2-oxopyrrolidin-l-yl, 3-fluoro-2-oxopyrrolidin-l-yl, pyrazol-1- yl, 3,5-dimethylpyrazol-l-yl;

R⁵ is H; R⁶ is H.

2. The compound of claim 1 having formula Ia-1

la-1 and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein W, X, Y, R³, R⁴, R⁵ and R⁶ are as defined in claim 1.

3. The compound of claim 1 having formula Ia-2

la-2 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein W, X, Y, R³, R⁴, R⁵ and R⁶ are as defined in claim 1.

4. The compound of claim 1 having formula lb- 1

lb-1 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein W, X, Y, R³, R⁴, R⁵ and R⁶ are as defined in claim 1.

5. The compound of claim 1 having formula Ib-2

lb-2 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein W, X, Y, R³, R⁴, R⁵ and R⁶ are as defined in claim 1 and L is methylene or ethylene.

6. The compound of claim 2 having formula Ia-5

la-5 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein X, Y, R³ and R⁴ are as defined in claim 2.

7. The compound of claim 3 having formula Ia-6

la-6 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein X, Y, R³ and R⁴ are as defined in claim 3.

8. The compound of claim 4 having formula Ib-5

lb-5 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein X, Y, R³ and R⁴ are as defined in claim 4.

9. The compound of claim 5 having formula Ib-6

lb-6 and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein L, X, Y, R³ and R⁴ are as defined in claim 5.

10. The compound according to claim 1 selected from the group consisting of:

1 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- methoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

2 (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- methoxypyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid; (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3,5-dimethyl- 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3 -(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 ,3 ,3 -trimethyl- 2-0X0-2, 3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(3-methyl-2-oxo- 2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-methoxy-5- methylpyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(l,4-dimethyl-2- oxo-l,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)phenyl)thiazol- 2-yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclobutylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridin-3-yl)phenyl)thiazol-2-yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- methoxyethoxy)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-methyl-2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)carbamoyl)-5-methylhexanoic acid;

(R)-3-(cyclopropyl(4-(2-(6-(2-oxopyrrolidin- 1 -yl)pyridin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5 -methylhexanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-methyl-5H- pyrrolo[2,3-b]pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5- (dimethylamino)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid; (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 -methyl- 1 H- pyrazolo[3,4-b]pyridin-5-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-( 1 -methyl- 1 H- [l,2,3]triazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(4-methyl-3-oxo- 3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-7-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid; (R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-((S)-2- methoxypropoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(2- isopropoxyethoxy)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(((R)-l- methoxypropan-2-yl)oxy)pyridin-3-yl)phenyl)thiazol-2- yl)amino)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(5-(2- oxopyrrolidin- 1 -yl)pyrazin-2-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(3R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6-(3-fluoro-2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-4-((4-(2-(6-( 1 H-pyrazol- 1 -yl)pyridin-3 -yl)phenyl)thiazol-2- yl)(cyclopropyl)amino)-3-(cyclopentylmethyl)-4-oxobutanoic acid;

(R)-3-(cyclopentylmethyl)-4-(cyclopropyl(4-(2-(6- methoxypyridazin-3-yl)phenyl)thiazol-2-yl)amino)-4- oxobutanoic acid;

(R)-3-(cyclopropyl(4-(2-(5-methoxypyrazin-2-yl)phenyl)thiazol- 2-yl)carbamoyl)-5-methylhexanoic acid; (R)-3-(cyclopropyl(4-(2-(5-(2-oxopyrrolidin- 1 -yl)pyrazin-2- yl)phenyl)thiazol-2-yl)carbamoyl)-5 -methylhexanoic acid; (R)-3-((4-(2-(6-(l H-pyrazol- l-yl)pyridin-3 -yl)phenyl)thiazol-2- yl)(cyclopropyl)carbamoyl)-5 -methylhexanoic acid; 30 (R)-3-(cyclopropyl(4-(2-(l-methyl-lH-pyrazolo[3,4-b]pyridin-5- yl)phenyl)thiazol-2-yl)carbamoyl)-5 -methylhexanoic acid;

31 (R)-3-(cyclopropyl(4-(2-(3-methyl-2-oxo-2,3- dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)thiazol-2- yl)carbamoyl)-5 -methylhexanoic acid;

32 (R)-3-(cyclopropyl(4-(2-(5-(dimethylamino)pyrazin-2- yl)phenyl)thiazol-2-yl)carbamoyl)-5 -methylhexanoic acid;

33 (R)-3-(cyclopropyl(4-(2-(6-methoxypyridazin-3- yl)phenyl)thiazol-2-yl)carbamoyl)-5 -methylhexanoic acid;

35 (R)-3-(cyclopropyl(3-(2-(5-methoxypyrazin-2-yl)phenyl)- 1 ,2,4- thiadiazol-5-yl)carbamoyl)-5 -methylhexanoic acid; and

36 (R)-3-(cyclopropyl(4-(2-(5-methyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)phenyl)thiazol-2-yl)carbamoyl)-5-methylhexanoic acid.

37

(R)-4-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)amino)-3-(cyclopropylmethyl)-4-oxobutanoic acid

38

(R)-3-(cyclopropyl(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)carbamoyl)heptanoic acid and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

11. A pharmaceutical composition comprising a compound according to any of Claims 1 to 10 or a pharmaceutically acceptable salt, solvate, or prodrug thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

12. Medicament comprising a compound according to any of Claims 1 to 10 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a composition according to claim 11.

13. A compound according to any of Claims 1 to 10 or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating and/or preventing type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steato hepatitis (NASH).