WO2012090219A2 - Thiazole compounds useful as acetyl-coa carboxylase (acc) inhibitors - Google Patents

Abstract

The present invention provides thiazole compounds of Formula I or its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; or combination or mixtures thereof; (I) The present invention further provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor by using compounds of formula (I) or ), its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; or combination or mixtures thereof.

Description

Till Λ/ΟΙ I- COMPOUNDS USEFUL AS ACETYL-COA C A R BOXY L A S E ( A C ) INHIBITORS.

IELD OF THE INVENTION

The present invention relate to thiazole compounds, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxidcs. or prodrugs: pharmaceutical compositions containing them and methods of preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.

The present invention also relates to processes for the preparation of the compounds of the present invention. These compounds are useful for preventing or treating a condition tha responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.

BACKGROUND OF THE INVENTION

Metabolic syndromes are associated with several diseases and disorders, such as obesity, diabetes, and diabesity (typically defined by the occurrence in a single patient of both diabetes and obesity or other overweight conditions, and characterized by elevated blood glucose levels). Metabolic syndromes are typically defined by a clustering of cardiovascular risk factors that increase the risks of coronary heart disease and/or type II diabetes. Such metabolic syndromes are often characterized by elevated insulin concentration, and arc often associated with such conditions as visceral obesity. hypcrlipidemia. atherogenic dyslipidemia, hyperglycemia, hypertension, hyperurceemia and renal dysfunction. Metabolic syndromes, together with insulin resistance, arc increasingly viewed as being major causes of type 11 diabetes and atherosclerosis.

Recent studies have suggested that abnormal fatty aeid metabolism is a contributing cause of metabolic syndrome (see Wakil et al., Fatty acid metabolism: Target for metabolic syndrome, J. Lipid Res.50, S138-S143, Apr.2009; as well as Kusunoki et al., Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome, Endocrine 1, 91-100, Feb.292006).

Abnormal fatty acid synthesis has also been found to be a cause for obesity, as well as nonalcoholic fatty liver disease (NAFLD) and liver dysfunction (such as NAFLD- associated liver dysfunction). Prevalence of NAFLD has markedly increased in the recent years (Cusi K.. Nonalcoholic fatty liver disease in type 2 diabetes mellitus, Curr. Opin. Endocrinol^'. Diabetes Obes.16(2), 141-9. Apr.2009). Acetyl-CoA carboxylase, a member of biotin-dependent carboxylases family, catalyzes the formation of malonyl-CoA, an intermediate that regulates fatty acid biosynthesis and oxidation. ACC exists as two different isoenzymes, ACCl and ACC2. Both forms exhibit high sequence homology except at the N-terminal ends.

There are several differences between ACCl and ACC2. For example, ACC2, a 2458 amino acid peptide, contains a 114 amino acid portion that facilitates anchoring of ACC to the mitochondrial membrane. In contrast, ACCl lacks this targeting sequence and thereby remains cytosolic. In addition, the ACCl and ACC2 isoforms also exhibit divergent tissue expression profiles, providing the basis for different functions. In particular, in oxidative tissues (such as heart and skeletal muscles), ACC2 forms malonyl- CoA which mainly regulates fatty acid oxidation through inhibition of carnityl palmitoyltransferase 1 (CPT-1) inhibition. In the lipogeneic tissues, such as liver and adipose tissues, malonyl-CoA produced by ACCl is utilized as a substrate for fatty acid synthesis and chain elongation.

Accordingly, there remains a need for the development of acetyl-CoA carboxylase (ACC) inhibitors that can be used for the treatment of type 2 diabetes, obesity, diabesity, NAI-LD, liver dysfunction disorders, atherosclerosis, cardiovascular diseases mediated through ACC, and combinations of these diseases and disorders.

^'SUMMARY

The present invention provides thiazole compounds of Formula I or its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs;

(I)

wherein:

Ai i is selected from an arylene or a heteroarylene; wherein said arylene or said heteroarylene are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; Z is Y-A12; wherein

Y is selected from a bond, -0-, -S(0)_n, or -NH;

Ar2 is selected from an optionally substituted aryl, or an optional ly substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R ¹ is a C| -C₆ alkyl;

R² is selected from the group consisting of an optionally substituted l inear or branched C 1 -C2₀ alkyl, an optionally substituted linear or branched heterocyclyl, an optional ly substituted C3-C2₀ cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optional ly substituted heteroaryl, an optional ly substituted heteroarylalkyl, halogen, perlluroalkyl, -N<¾ -OH, -OR3, -CN, -NH₂, -Si(R³)₃, -S(0)_nR^'',-C(0)l i and -C(0)R³; - NR R⁵, and -N(R³)2; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-C20 alkyl, an optionally substituted, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryl, an optional ly substituted arylalkyl, an optional ly substituted heteroaryl. an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R )₃, -S(0)_nR", - C(0)H, -C(0)R⁴, -NR⁴R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C | -C₄ alkyl, perhaloalkyl, or C I -C₄ alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C20 alkyl, an optional ly substituted C3-C2₀ cycloalkyl, an optionally substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃, -N0₂, -Si(R⁸)₃, - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C1 -C₄ alkoxy; R⁵ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C| -C₂o alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl. an optional ly substituted C3-C20 heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -N0₂. - Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said subslituent is independently selected from halogen, hydroxy, Q -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl.

heteroarylene contain one or more heteroatom independently selected from O. N, or

The present invention also provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, using an effective amount of a compound of Formula (1), its pharmaceutically acceptable salts, prodrugs, solvates, N- oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxides, or prodrugs or combination or m ixtures thereof.

The present further provides a pharmaceutical composition comprising at least one compound of Formula (I) and a pharmaceutically acceptable carrier.

The present invention also provides use of compound of Formu la I for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.

These and other features, aspects, and advantages of the present subject matter wi l l become better understood with reference to the following description and appended clai ms. Th is summary is provided to introduce a selection of concepts in a simpl i fied form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to lim it the scope of the claimed subject matter. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides thiazole compounds of Formu la I, its pharmaceutica lly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of ^"N- ox ides, or prodrugs;

(I)

wherein:

An is selected from an arylene or a heteroarylene; wherein said arylene or said hcteroarylene are optional ly substituted with one or more substituents independently selected from halogen, hydroxy, Q -Ci alkyl, perhaloalkyl, or C | -C₄ alkoxy;

Z is Y-Ar₂; wherein

Y is selected from a bond, -0-, -S(0)_n, or -NH ;

Ar₂ is selected from an optionally substituted aryl, or an optional ly substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 al koxy:

R ' is a C, -C₆ alkyl;

R² is selected from the group consisting of an optional ly substituted l inear or branched C | -C₂o alkyl, an optionally substituted linear or branched heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optionally substituted heterocycloalkyi, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, halogen, perfluroalkyl, -NO_Z -OH, -OR₃, -CN, -NH₂, -Si(R³)₃, -S(0)_N R⁴,-C(0)l I , and -C(0)R³; - NR⁴R⁵, and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted C| -C₂o alkyl, an optional ly substituted, an optional ly substituted C3-C20 cycloalkyl, an optionally substituted heterocyclyl. a n optional ly substituted heterocycloalkyl, an optional ly substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R )₃,

- C(0)H, -C(0)R⁴, -NR⁴R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 a lkyl, perhaloalkyl. or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C2₀ alkyl. an opt ional ly substituted C3-C2₀ cycloalkyl, an optionally substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl. an optionally substituted heteroarylalkyl, -CN, -CF3, -N0₂, -Si(R⁸)3, - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy; 3 is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C | -C₂o alkyl, an optiona l ly substituted heterocyclyl, an optionally substituted C3-C2₀ cycloalkyl, an optional ly substituted C3- 0 heterocycloalkyl, an optional ly substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -NO_?,, - S i(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR R⁹, and -OR*; wherein sa id substituent is independently selected from halogen, hydroxy, C ₁ -C4 alkyl. perhaloalkyl, or C 1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S.

An embodiment of the present invention provide the compounds of Formula I , or its pharmaceutically acceptable salts, prodrugs, solvates. N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; wherein:

Z is Y-Ar₂;

Y is selected from a bond, -0-, -S(0)_n, or -NH;

Ar₂ is selected from

wherein, R⁶ is selected from the group consisting of halogen, an optionally substituted linear or branched C | -C₂o alkyl, an optional ly substituted heterocycyl, an optionally substituted C3-C2₀ cycloalkyl. an optionally substituted heterocycloalkyl, an optional ly substituted arylalkyl, an optionally substituted heteroarylalkyl, - N, -Cl \ - O2. -Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -N R⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy. C_\ - C/| alkyl, perhaloalkyl, or C, -G| alkoxy;

A ¹ is a monocyclic heteroaryl ring selected from the group consisting of:

and

each m is 0. 1 or 2:

wherein P, Q, R, and Z are independently selected from -CR⁷- or nitrogen;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C1-C20 alkyl. an optionally substituted heterocyclyl, an optionally substituted C3-C2 cycloalkyl. an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF_3j -NO?, -Si(R^x)₃, - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl. or C -Ci alkoxy;

R is Ci-C₆ alkyl; R² is selected from the group consisting of an optionally substituted linear or branched C|-C₂o alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃- C20 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl. an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF₃, -NO2.-OH, -OR3, -CN. -Si(R³)₃, -C(0)H, and -C(0)R³; - NR'R³, and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy;

R^J is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched CI-C₂Q alkyl, an optionally substituted heterocyclyl, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryl, an optional ly subst ituted arylalkyl, an optionally substituted heteroaryl. an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R⁴)₃, -S(0)_nR⁴, -C(0)H, - C(0)R⁴, - R'^⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optionally substituted liner or branched C1 -C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloal kyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF_3; -N0₂, -S i(R⁸)₃, -S(0)_nR^'\ - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl. or C 1 -C4 alkoxy;

R^ is selected from the group consisting of hydrogen, halogen, an optiona l ly substituted l inear or branched C1 -C20 alkyl, an optional ly substituted l inear or branched C 1 -C20 heteroalkyl, an optionally substituted C₃-C?o cycloalkyl. an optional ly substituted C₃-C₂o heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -NO_?, - Si(R⁸) , -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 a lkyl, perhaloalkyl, or C1 -C4 alkoxy; each R^s and R⁹ is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl ; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heieroarylene contain one or more heteroatom independently selected from O, N, or S.

Another embodiment of the present invention provide the compounds of Form u la I, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; wherein:

An is a phenylene;

Z is Y-Ar₂;

wherein Y is selected from a bond or -O-;

Ar₂ is selected from

wherein A is a monocyclic heteroaryl ring selected from:

R³ is independently selected from halogen or a linear or branched C 1 -C3 alkyi;

R⁴ is selected from hydrogen, a linear or a branched C 1 -C3 alkyi, or -CF₃; R^s is selected from the group consisting of hydrogen and C| -C₂ alkyi, each n is independently 0, 1 , or 2; each m is 0, or 1 ;

R is methyl; and

R² is selected from the group consisting of C|-C₂ alkyi, C3-C4 cycloalkyl, -OCH₃, and - Further embodiment of the present invention provides compounds of Formula I, wherein R' is C1-C4 alkyl, and R² is an optionally substituted linear or branched Ci-C₆ alkyl or -OR⁴, wherein R⁴ is selected from hydrogen, linear or branched C1-C3 alkyl, and - CF₃; and said linear or branched C|-C₆ alkyl is substituted with substituents independently selected from halogen, hydroxy, C|-C₄ alkyl, perhaloalkyl, or C|-C₄ alkoxy.

Still another embodiment of the present invention provides compounds of Formula I, wherein R² is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, and butyl.

Yet another embodiment of the present invention provides compounds of Formula I, wherein said R¹ is methyl.

Further an embodiment of the present invention provides compounds of Formula I, wherein Y is a bond.

Another embodiment of the present invention provides compounds of Formula I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; wherein:

Z is Y-Ar₂;

Y is a bond; and Ar2 is selected from

each R^J is selected from the group consisting of halogen, and an optionally substituted linear or branched Q-C2₀ alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl. or C1-C4 alkoxy;

R⁶ is selected from the group consisting of halogen, an optionally substituted linear or branched Ci-C₂₀ alkyl, an optionally substituted heterocycyi. an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF₃, -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)R - C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, Q -C4 alkyl, perhaloalkyi, or C 1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyi. aryl, heteroaryl, arylalkyl, and heteroarylalkyl ; each m is 0, or 1 ;

wherein P, Q, R, and Z are independently selected from -CR - or nitrogen ;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted l inear or branched C1 -C20 alkyl, an optionally substituted heterocyclyl, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted arylal kyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3j -N0₂, -Si(R⁸)₃, -S(0)_nR^'\ - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloal kyi, or C 1 -C4 alkoxy;

R ' is C , -C₆ alkyl ;

R² is selected from the group consisting of an optional ly substituted l inear or branched C | -C₂o alkyl, an optional ly substituted heterocyclyl, an optional ly substituted C₃- C2₀ cycloalkyl, an optionally substituted heterocycloalkyi, an optionally substituted aryl, an optional ly substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, CF₃, -N0_2j -OH, -OR3, -CN, -Si(R³)₃, -C(0)H, and -C(0)R³; - N R⁴R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, Q -C4 alkyl, perhaloalkyi, or C 1 -C4 alkoxy; '¹ is selected from the group consisting of hydrogen, halogen, -CI-^':, and an optional ly substituted linear or branched C3-C20 alky L and an optional ly substituted C3-C2₀ cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, Q -C4 alky], perhaloalkyl, or Q -C4 alkoxy; R⁵ is selected from the group consisting of hydrogen, halogen, and an optional ly substituted linear or branched C3-C20 alkyl, and an optionally substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 al koxy; each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyi, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, M, or S.

Yet another embod iment of the present invention provides the compounds of Form u la 1. wherein each of P, Q, R, Z is -CR⁷ and R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted l inear or branched C | -C?o a l kyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3> -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, - NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C ₁ -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy. Sti l l another embodiment of the present invention provides the compounds of

Formula I, wherein each of P, Q, R, Z is -CR⁷; R¹ is methyl; R² is -OR³ and R³ is an optional ly substituted linear or branched C3-C2₀ alkyl,- or an optional ly substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C | - C alkyl, perhaloalkyl, or C.1 -C4 alkoxy.

Further an embodiment of the present invention provides the compounds of

Formu la I, wherein Ar2 is

each R^J is independently selected from halogen, or an optionally substituted linear or branched C_rC₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy. C C₄ alkyl, perhaloalkyl, orC_rC4 alkoxy;

R'¹ is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched C|-C₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy, Q-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and

R³ is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched Ci-C₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and each of m and n are, independently, 0, 1, or 2.

Further, in another embodiment R^J is selected from the group consisting of chlorine, bromine, fluorine and methyl; and R⁴ is selected from hydrogen, or methyl.

Still further in another embodiment R⁵ is hydrogen or methyl.

An another embodiment of the present invention provides the compounds of Formula I, wherein Ar² is

each R^J is independently selected from halogen or an optionally substituted linear or branched C|-C₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C_rC₄ alkyl, perhaloalkyl, or C|-C₄ alkoxy; each n is independently 0, 1 or 2, and in is 0.

Further an embodiment of the present invention provides the compounds of Formula I, wherein R³ is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.

Still another embodiment of the present invention provides the compounds of Formula 1, wherein Ar² is

each ³ is selected from halogen or an optionally substituted linear or branched C|- C o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C alkyl, perhaloalkyl, or C1-C4 alkoxy; and each n is independently 0, 1 or 2, and m is 0.

In further embodiment R³ is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.

Still another embodiment of the present invention provides the compounds of Formula I, wherein Ar² is

each R^J is independently selected from halogen or an optionally substituted linear or branched C₁-C2₀ alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and R⁴ is -CF3.

Further an embodiment of the present invention provides the compounds of Formula I, wherein Ar^" is

R³ is independently selected from halogen or an optionally substituted linear or branched C,-C₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy;

A is

; each n is independently 0, 1 or 2, and m is independently 0, or I . Yet another embodiment of the present invention provides the compounds of

2

Formula 1 , wherein Ar is

J is independently selected from halogen or an optionally substituted l inear or branched C 1 -C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C| -C₄ alkyl, perhaloalkyl, or C, -C₄ alkoxy;

A ¹ is

; each n is independently 0, 1 or 2, and m is independently 0, or 1 . Particular embodiments of the present invention are the compounds of formu la 1 its pharmaceutically acceptable salts, prodrugs, solvates, ^"N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of N- ox ides, or prodrugs; which are:







An embodiment of the present invention provides compounds of Formula I, wherein free base forms of the above listed compounds can also be in the form of a pharmaceutically acceptable salt.

Another embodiment of the present invention provides compounds of Formula 1, wherein the free base form of the above listed compounds is in the form of a solvate. Still another embodiment of the present invention provides compounds of Formu la 1, wherein the pharmaceutically acceptable salt of the above listed compounds is in the form of a solvate.

Yet another embodiment of the present invention provides compounds of Formula I, wherein the free base form of the above listed compounds is in the form of an N-oxide.

Further embod iment of the present invention provides compounds of Formula I. wherein the pharmaceutically acceptable salt of the above listed compounds is in the form of an N-oxide.

One of ordinary ski ll in the art will recognize that compounds of Formu la 1 can exist in d ifferent tautomeric and geometrical isomeric forms. All of these compounds, including cw-isomers, /ram'-isomers, ^-isomers, Z-isomers, diastereom ic m ixtures, racemates, nonracem ic mixtures of enantiomers, substantially pure, and pure enantiomers and d iastereomers. are within the scope of the present invention . Substantia l ly pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomcr. preferably no more than 2%, most preferably no more than 1 %.

The optical isomers can be obtained by resolution of the racemic m ixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.

Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric. ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chem ical differences by methods known to those ski lled in the art, for example, by chromatography or fractional crystallization. The optical ly acjive bases or acids are then l iberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral H PLC columns are manufactured by Diacel, e.g., Chiracel OD and Ch iracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formula I can l i kewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization. In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of ²H, 'I f "C. ^{l j}C and/or ^{l 4}C. In one particular embodiment, the compounds are deuterated. Such deuterated forms can be made the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteralion can improve the efficacy and increase the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10) (2000), 1 10 pp.; abalka, George W.; Varma, Rajendcr S., The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron ( 1989), 45(21 ), 6601 -21 ; Evans, E. Anthony, Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981 ), 64(1 -2), 9-32.]

Where applicable, the present invention also relates to useful forms of the compounds as disclosed herein, such as base free forms, and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobrom ic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandel ic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g.. sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skil led in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkal ine earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, DIPEAtes, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopcntanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobrom ides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, n icotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persu l fates, 3- phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates. losylales, mesylates and undecanoates.

For example, the pharmaceutically acceptable salt can be a hydrochloride, a hydrobrom ide, a hydroformate, or a maleate.

Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid add ition salt.

One of ordi nary ski ll in the art wi ll also recognize that some of the compounds of Formu la 1 can exist in different polymorphic forms. As known in the art, polymorphism is an abi l ity of a compound to crystall ize as more than one distinct crystal l ine or "polymorphic'^' species. A polymorph is a sol id crystal line phase of a compound with at least two different arrangements or polymorphic forms of that compound molecu le in the sol id state. Polymorphic forms of any given compound are defined by the same chem ical formula or composition and are as distinct in chemical structure as crystal line structures of two di fferent chem ical compounds.

One of ordinary ski ll in the art will further recognize that compounds of Formu la I can exist in different solvate forms. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystall ine lattice structure of the compound molecule during the crystal lization process.

The present invention also includes prodrugs of compounds of Formula 1 . The term prodrug is intended to represent covalently bonded carriers, wh ich are capable of releasing the active ingredient of Formula I when the prodrug is adm in istered to a mammal ian subject. Release of the active ingred ient occurs in vivo. Prodrugs can be prepared by techniques known to one ski lled in the art. These techniques general ly mod i fy appropriate functional groups in a given compound. These modi fied functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of Formula 1 include compounds wherein a hydroxy, amino. carboxylic, or a similar group is modified. Examples of prodrugs include, but are no limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g.. N,N- dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula 1 ), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula 1 are also within the scope of this invention.

Compounds of Formula I can be prepared according to methods as i l lustrated in Scheme 1, and Scheme 2 as defined below. The compounds of Formula I can also be prepared with the other known processes. The formulas and variables illustrated in the section below are intended only to assist in describing the synthesis of Formula I compounds and are not to be confused with the variables used to define Formula 1 compounds in the claims or in the other sections of the specification.

Scheme 1

Formula 1 Aromatic alcohols, derived from commercially avai lable starting materials through methods known in the art, may be reacted with 2,5-dibromothiazole to render 2-aryloxy-5- bromoth iazoles. Commercially available or modified methoxyarylketones (A) may be subjected to reductive am ination (e.g., with ammonium acetate and sodium cyanoborohydride) to furnish an amine which can be reacted with an appropriate substrate (e.g.. with carboxyl or carboyl halides) using methods known in the art. The methoxy group may be demethylated (e.g., with boron tribromide) under reaction conditions known to one sk i l led in the art to render secondary hydroxyarylalkyalky!am ines. The secondary hydroxyarylalkylam ines can be coupled (e.g., in the presence of copper iodide and an inorganic base) with 2-aryloxy-5-bromothiazoles under reaction cond itions known to one sk i l led in the art. 2-Aryloxy-5-bromothiazoles can be converted to primary am ines and coupled with commercially available or modified hydroxyarylketones (B) followed by reductive amination (e.g., with ammonium acetate and sodium cyanoborohydride), or. alternatively, coupled with commercially available or modified hydroxyaryl brom ides (C). I ntroduction of a carboyl substituent (e.g., with tributy 1( 1 -ethoxyvinyl)tin, pal lad ium acetate, and tri-tert-butyl(methyl)phosphonium tetrafluoroborate in ^"N.N- dimethyl formam ide), and subsequent reductive am ination (e.g., with ammon ium acetate and sodium cyanoborohydride) may yield primary amines. These primary amines can be reacted with an appropriate substrate l ike i) any carboxyl ic acid in the presence o f an am ide coupl ing agent or ii) any acid chloride in the presencs of a base under react ion cond itions known to one ski lled in the art to furnish compounds represented by Form u la I .

Scheme 2

Schemes (2a and 2b) summarize methods for preparing phenyl thiazoyloxy compounds of Formu la I of the present invention. The formulas and variables i llustrated in the section below are intended only to assist in describing the synthesis of Formu la I compounds and are not to be confused with the variables used to define Formula I compounds i n the claims or in the other sections of the specification. Scheme 2a

2-Amino-5-bromothiazole A, which is commercially avai lable as monohydrobromide salt, may be coupled with 4-hydroxyacetophenone under coupling conditions known to the one skilled in the art. Conversion of the amine to a halide substituent may be achieved by means of a Sandmeyer reaction or other coupl ing conditions known to the one skilled in the art. The resulting bromide may be coupled with an appropriately substituted methoxyphenylboronic acid analog under coupling conditions known to the one skilled in the art. Transformation of ketone B to compounds of Formula Ϊ may be carried out via reductive amination under reaction conditions known to the one skilled in the art, followed by reaction with an appropriate ketoyl chloride under reaction conditions known to the one skilled in the art. The methoxy group of compounds of Formula I may be demethylated under reaction conditions known to the one skilled in the art and the resulting aromatic alcohol may be re-alkylated under reaction conditions known to the one skilled in the art.

Scheme 2b

1, %

Commercial ly avai lable 2-bromothiazole may be coupled with an appropriately substi uted inethoxyphenylboronic acid under coupling cond itions known to the one ski l led in the art. which may be fol lowed by bromination of the thiazole under reaction conditions known to the one ski l led in the art to give compound C, whereby all steps may be carried out under reaction conditions known to the one skilled in the art. Compound C may be coupled under reaction conditions known to the one skilled in the art to give compounds of Formu la I . The methoxy group of compounds of Formula I may be demethylated under reaction cond itions known to the one skilled in the art and the resulting aromatic alcohol may be re-alkylated under reaction conditions known to the one skilled in the art. The present invention also provides a pharmaceutical composition comprisi ng at least one compound of Formula 1 and a pharmaceutically acceptable carrier.

An embodiment of the present invention provides a pharmaceutical composition, further comprising at least one second active ingredient.

Another embod iment of the present invention provides a pharmaceutical com position com prising, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current ed ition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, ed itors) current edition, published by Marcel Dekker, Inc., as wel l as Rem ington's Pharmaceutical Sciences (Arthur Osol, editor), 1 553-1593 (current edition).

Adm inistration of the compounds of the present invention may be accompl ished accord ing to patient needs, for example, orally, nasally, parenterally (subciitaneously. intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectal ly, vaginally, topically and by ocular administration.

Various sol id oral dosage forms can be used for administering compounds of the i nvention including such solid forms as tablets, gelcaps, capsu les, caplcts, granu les, lozenges and bulk powders. The compounds of the present invention can be adm in istered alone or combined with various pharmaceutical ly acceptable carriers, di luents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not l im ited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various l iqu id oral dosage forms can also be used for admin istering compounds of the inventions, including aqueous and non-aqueous solutions, emu lsions, suspensions, syrups, and el ixirs. Such dosage forms can also contain suitable inert d i luents known in the art such as water and suitable excipients known in the art such as preservat i ves, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspend ing the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic steri le solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by m ixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, past foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.

For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye. ear or nose. Topical adm inistration may also involve transdermal adm inistration via means such as transdermal patches.

Aerosol formulations suitable for administering via inhalation also can be made. For example, the compounds of Formula 1 can be adm inistered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formu lation can be placed into a pressurized acceptable propel lant. The present invention further provides a method for preventing or treating a cond ition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising adm in istering an effective amount of a compound of formu la (I), its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- ox ides, or prodrugs; or combination or m ixtures thereof;

(I)

wherein:

Aii is selected from an arylene or a heteroarylene; wherein said arylene or said heteroarylene are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;

Z is Y-Ar₂; wherein

Y is selected from a bond, -0-, -S(0)_n, or -NH;

Ar₂ is selected from an optionally substituted aryl, or an optionally substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;

R¹ is a C|-C₆ alkyl;

R² is selected from the group consisting of an optionally substituted linear or branched C|-C₂₀ alkyl, an optionally substituted linear or branched heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted arylalkyi,' an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl. halogen, perfluroalkyl, -N<¾ -OH, -OR3, -CN, -ΝΉ,, -Si(R³)₃, -S(0)_n ^',-C(0)l I, and -C(0)R³; - NR⁴R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optionally substituted C|-C₂o alkyl, an optionally substituted, an optionally substituted C₃-C₂o cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted arylalkyi, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF₃, -N()₂, -Si(R )₃, -S(0)_nR^'V- C(0)H, -C(0)R⁴, -NR R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optionally substituted liner or branched C| -C₂o alkyl, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocyclyl. an optional ly substituted heterocycloalkyl, an optionally substituted aryla lkyl, an optional ly substituted heteroarylalkyl, -CN, -CF3, -N0₂, -Si(R⁸) ,. - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substitucnt is independently selected from halogen, hydroxy, C _rC₄ alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched Q -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted C3-C20 heterocycloalkyl, an optional ly substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF3 -NO?, -

Si(R^s)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl. aryl, heteroaryl, arylalkyl, and heteroarylalkyl; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl. and heteroarylene contain one or more heteroatom independently selected from O, N, or S.

An embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACQ inhibitor, said method comprising administering an effective amount ₍of a compound of Formula I, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; or combination or m ixtures thereof; wherein Z is Y-Ar₂; Y is selected from a bond, -0-, -S(0)_N, or - Ni l; Ar₂ is selected from

wherein, ¹ is selected from the group consisting o f halogen, an optionally substituted linear or branched C | -C₂o alkyl, an optional ly substituted heterocycyl, an optionally substituted C₃-C₂o cycloalkyl, an optionally substituted heterocycloalkyi, an optionally substituted arylalkyi, an optionally substituted heteroarylalkyi, -CN, -CF₃ -NO?, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NRV, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C _r C₄ alkyl, perhaloalkyl, or C1 -C4 alkoxy;

A ¹ is a monocyclic heteroaryl ring selected from the group consisting of:

each m is 0. 1 or 2;

wherein P, Q, R, and Z are independently selected from -CR⁷- or nitrogen;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C|-C₂o alky I, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyi, an optionally substituted heterocycioalkyi, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF3. -N0₂, -Si(R^s)₃. - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substitucnt is independently selected from halogen, hydroxy, C1-C4 alkyl, pcrhaloalkyl, or C|-C/| alkoxy;

R¹ is C-Ce alkyl;

R² is selected from the group consisting of an optionally substituted linear or branched C1-C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃- C20 cycloalkyi, an optionally substituted heterocycioalkyi, an optionally substituted aiyl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF₃, -NO2, -OH, -OR3, -CN, -Si(R³)₃, -C(0)H, and -C(0)R³; - NR R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, pcrhaloalkyl, or C1-C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched Ci-C₂₀ alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyi, an optionally substituted heterocycioalkyi, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R⁴)₃, -S(0)_nR⁴, ~C(0)H, - C(0)R⁴, -NR⁴R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C| -C?o alkyl, an optional ly substituted heterocyclyl, an optional ly substituted C₃-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryla lkyl, an optionally substituted heteroarylalkyl, -CN, -CF_3, -N0₂, -Si(R⁸)₃,

- C(0)H, -C(0)R⁸, -NR⁸R⁹, and ^' -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C, -C₄ alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched Q -C2₀ alkyl, an optionally substituted l inear or branched C | -C₂o heteroalkyl, an optionally substituted C3-C20 cycloalkyl. an optional ly substituted C₃-C2₀ heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -N0₂, -

Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C | -C₄ alkoxy; each R and R is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S. Another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising administering an effective amount of a compound of Formu la I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; or combination or m ixtures thereof; wherein Z is Y-Ar₂;

wherein Y is selected from a bond or-O-;

Ar2 is selected from

wherein A¹ is a monocyclic heteroaryl ring selected from:

R³ is independently selected from halogen or a linear or branched C₁-C₃ alkyl;

R⁴ is selected from hydrogen, a linear or a branched C1-C₃ alkyl. or -Cl^'3; \V is selected from the group consisting of hydrogen and C|-C₂ alkyl. each n is independently 0, 1, or 2; each m is 0, or 1 ; R¹ is methyl; and

R² is selected from the group consisting of C|-C₂ alkyl, C3-C4 cycloalkyl, -OCH₃, and - NH₂

Still another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising administering an effective amount of a compound of Formula I, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxides, or prodrugs; or combination or mixtures thereof; wherein:

Z is Y-Ar₂;

Y is a bond; and Ar2 is selected from

each R³ is selected from the group consisting of halogen, and an optional ly substituted l inear or branched C1 -C20 alkyl; wherei n said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R⁶ is selected from the group consisting of halogen, an optionally substituted l inear or branched C ₁ -C2₀ alkyl, an optionally substituted heterocycyl. an optionally substituted C3-C2₀ cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF₃, -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)1 L - C(0)R^s, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy; each R^s and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl ;

each m is 0, or 1 ; An is wherein P, Q, R, and Z are independently selected from -CR⁷- or nitrogen ;

R ' . is se lected from the group consisting of hydrogen, halogen, ai optional ly substituted l inear or branched C1 -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C2₀ cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3, -N0₂, -Si( ^s)₃, -S(0)_nR⁸, - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C I -C4 alkoxy; R ' is C, -C₆ alkyl;

R² is selected from the group consisting of an optionally substituted linear or branched Ci-C₂₀ alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃- C₂0 cycloalkyl, an optional ly substituted heterocycloalkyl, an optional ly substituted aryl. an optional ly substituted arylalkyl, an optional ly substituted heteroarvL an optiona l ly - substituted heteroarylalkyl, CF₃, -N0_2, -OH, -OR3, -CN, -Si(R³) , -C(0)H_s -C(0)R³; -

4 *ί 3

NR R , and -N(R )₂; wherein said substituent is independently selected from halogen, hydroxy, C | -C alkyl, perhaloalkyi, or Q -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, -CF and an optionally substituted linear or branched C₃-C₂o alkyl, and an optional ly substituted C₃-C?o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C| -C₄ alkyl, perhaloalkyi, or C1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, and an optional ly substituted linear or branched C₃-C₂o alkyl, and an optional ly substituted C₃-C₂o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C1 -C4 al koxy; each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S. An embod iment of the present invention provides a method for preventi ng or treating a condit ion that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, sa id method comprising administering an effective amount of a compound of Formula 1, its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutical ly acceptable salts o f N- oxides, or prodrugs; or combination or mixtures thereof; wherein the Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.

"Effective amount" means the amount of a compound of Formula I that, when adm inistered to a patient (e.g., a mammal) for treating a disease, is sufficient to effect such treatment for the disease to achieve the objectives of the invention. The "effective amount" wi ll vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

Sti l l another, embodiment of the present invention provides a method for preventi ng or treating a cond ition that responds to an Acetyl-CoA Carboxylase (ACC) inh ibitor, said method comprising administering an effective amount of a compound of Formu la I, its pharmaceutically acceptable salts, prodrugs, solvates, N-ox ide thereof: solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N-oxidcs, or prodrugs; or combination or m ixtures thereof; wherein the condition is a metabol ic syndrome.

Yet another embodiment of the present invention provides a method for prevent ing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising adm inistering an effective amount of a compound of F ormula I . its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutical ly acceptable salts of N- oxides, or prodrugs; or combination or mixtures thereof; wherein the condition is selected from type I I d iabetes, obesity, diabesity, atherosclerosis, and cardiovascular d iseases.

An ACC-mediated d isease or cond ition includes but is not l im ited to a disease or cond ition which is, or is related to, cardiovascular disease, dysl ipidem ias (including but not l im ited to disorders of serum levels of triglycerides, hypertriglyceridem ia, V LDL. FI DL, FDL, cholesterol, total cholesterol, hypercholesterolem ia, as wel l as cholesterol d isorders (including disorders characterized by defective reverse cholesterol transport), fam i l ial combined hyperl ipidem ia, coronary artery d isease, atherosclerosis, heart disease, cerebrovascular disease (including, but not limited to stroke, ischemic stroke and transient ischem ic attack (TIA), peripheral vascular disease, and ischemic reti nopathy. In an embodiment, compounds of the invention will, in a patient, increase HDL levels and/or decrease triglyceride levels and/or decrease LDL or non-HDL-cholesterol levels.

An ACC-mediated disease or condition also includes metabol ic syndrome (including but not limited to dyslipidemia, obesity and insul in resistance, hypertension, m icroalbum inem ia, hyperuricaemia, and hypercoagulabi l ity), Syndrome X, d iabetes, prediabetes, insul in resistance, decreased glucose tolerance, non-insulin-dependent diabetes mel l itus, Type I I d iabetes, Type I diabetes, diabetic complications (such as d iabetic retinopathy, neuropathy, and nephropathy), body weight disorders (includ ing but not l i m ited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leplin related diseases. In an embodiment, the compounds of Formula I are useful in the treatment of diabetes mellitus and obesity. In another embodiment, the compounds of Formula I are useful in the treatment of obesity.

As used herein, the term "metabolic syndrome" is a recognized cl inical term used to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insul in resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridem ia, low HDL, hyperuricaemia, hypercoagulabi l ity and/or m icroalbum inemia. Diabestity typically involves a metabolic syndrome (such as insul in resistance syndrome or syndrome X) defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinemia, atherogenic dyslipidem ia, hypertension and hypercoagu labi l ity) that together increase the risk of developing coronary heart disease and type 2 diabetes. Metabol ic syndrome is a clinical disorder where increased insu l in concentration is observed with associated conditions such as visceral obesity, hyperlipidem ia, atherogenic dyslipidemia, hyperglycemia, hypertension, hyperurecem ia and renal dysfunction.

An ACC-mediated disease or condition also includes fatty l iver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcohol ic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto.

An ACC-med iated disease or condition also includes, but is not l im ited to, a d isease or condition which is, or is related to primary hypertriglyceridem ia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperl ipoproteinem ias, fami lial histiocytic reticulosis, lipoprotein lipase deficiency, apol ipoprotein deficiency (such as ApoClI deficiency or ApoE deficiency), and the l ike, or hypertriglyceridemia of unknown or unspecified etiology.

An ACC-med iated disease or condition also includes a disorder of polyunsaturated fatty acid (PUPA) disorder, or a skin disorder, including, but not limited to, eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the l ike.

An ACC-mediated disease or cond ition also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and pre-menstrual syndrome.

An ACC-med iated disease or condition also includes but is not l im ited to a d isease or condition wh ich is, or is related to cancer, neoplasia, mal ignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the l ike.

An ACC-mediated disease or condition also includes a condition where increasi ng lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT .11) are also included herein. Such treatments are useful in humans and in animal husbandry or companion animals, including for adm inistration to canine, feline, bovine, porcine or avian domestic animals or any other an imal to reduce triglyceride production or body weight and/or provide leaner meat products and/or healthier animals.

An ACC-mediated disease or condition also includes a disease or condition wh ich is, or is related to, neurological diseases, psychiatric disorders, mu ltiple sclerosis, eye diseases, and immune d isorders.

An ACC-mediated disease or condition also includes a disease or condition wh ich is. or is related to, viral d iseases or infections including but not l im ited to al l positive strand RNA viruses, coronaviruses, SARS virus, SARS-associated coronavirus, Togaviruses, Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, Filoviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephal itis virus, Sindbis virus, Semliki forest virus, Chikungunya virus, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIR1DAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norvvalk virus, Cal icivirus, Bovine calicivirus, Pig calcivirus, Hepatitis E; CORONAV I R I DA E includ ing Coronavirus, SARS virus, Avian infectious bronch itis virus, Bovine coronavirus, Canine coronavirus, Feline infectious peritonitis virus, Human coronavirus 299E, Human coronavirus OC43, Murine hepatitis virus, Porcine epidemic diarrhea virus. Porcine hemagglutinating encephalomyelitis virus, Porcine transmissible gastroenteritis virus, Rat coronavirus, Turkey coronavirus, Rabbit coronavirus, Berne virus, Breda virus; FLAVIVIRIDAE including Hepatitis C virus, West Nile virus, Yellow Fever virus. St. Louis encephalitis virus, Dengue Group, Hepatitis G virus, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick-borne encephalitis virus. Far Eastern tick-borne encephalitis virus, yasanur forest virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kumilinge virus, Absetarov anzalova hypr virus, llhcus virus, Rocio encephalitis virus, Langat virus, Pestivirus, Bovine viral diarrhea, Hog cholera virus, Rio Bravo Group, Tyuleniy Group, Ntaya Group, Uganda S Group, Modoc Group; PICORNAVIRIDAE including Coxsackie A virus, Rhinovirus. Hepatitis A virus. Encephalomyocarditis virus, engovirus, ME virus, Human poliovims I. Coxsackie B; POTYVIRIDAE including Potyvirus, Rymovirus, Bymovirus. Additionally it can be a disease or infection caused by or linked to Hepatitis viruses, Hepatitis B virus, Hepatitis C virus, human immunodeficiency virus (HIV) and the like. Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses.

In one embodiment, the compounds of the inventions are useful in the treatment of elevated levels of lipids, cardiovascular diseases, diabetes, obesity, and metabolic syndrome.

The term "treating" means to relieve, alleviate, delay, reduce, reverse, improve or prevent at least one symptom of a condition in a subject. The term ''treating" may also mean to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease), manage and/or reduce the risk of developing or worsening a condition.

A subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals ( whether in the wi ld or in a zoological garden), research animals, such as m ice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as ch ickens, turkeys, songbirds, etc., i .e., for veterinary medical use.

Another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, wherein the compounds of the present invention are administered as a mono-therapy.

Yet another embodiment of the present invention provides a method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, wherein the compounds of the present invention are administered as part of a combination therapy. For example, a compound of Formula I may be used in combination with other drugs or therapies that are used in the treatment/prevention/suppression or amel ioration of the diseases or conditions for which compounds of Formula I are useful.

Such other drug(s) may be administered, by a route and in an amount common ly used therefore, contemporaneously or sequentially with a compound of Formula 1. When a compound of Formula 1 is used contemporaneously with one or more _: other drugs, a pharmaceutical Unit dosage form containing such other drugs in addition to the compound o f Formula I may be employed. Accordingly, the pharmaceutical compositions o f the present invention include those that also contain one or more other active ingredients, in add ition to a compound of Formula I.

The present invention also provides the use of compound of Formula 1 for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inh ibitor.

An embodiment of the present invention provides the use of compound of Formu la I, wherein Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.

Another embodiment of the present invention provides the use of compound of

Formu la I as inhibitors of acetyl-CoA carboxylase (ACC) enzymes, for example ACC I and ACC2.

Sti l l another embodiment of the present invention provides the use of compound of Formu la I lor preventing or treating conditions mediated by ACC I and ACC2, or a lternatively, ACC 1 or ACC2 enzymes.

Definitions:

As used herein the term "halogen" means, _^ unless otherwise stated, fluorine, ch lorine, bromine, or iodine atom. As used herein, the suffix "ene" added to any of the described terms means that the substituent is connected to two other parts in the compound. For example, "arylene", means, unless otherwise stated, an aryl moiety that is connected to two other parts in the compound. For example, "heteroarylene" means, unless otherwise stated, a heteroaryl moiety that is connected to two other parts in the compound. Said arylene or heteroarylene can be optional ly substituted by one or more groups that may be the same or different and which can be conceptually formed from an arylene by replacing the hydrogen atom in the aryl or heteroaryl moiety with another atom or substituent group. In some embodiments of the invention, the substituents are alkyl, cycloalkyl, heteroaikyi, heteroaryl, hcterocycloalkyl, -NH₂, -NHR', N(R')₂, OR', or -C(0)OR', wherein each occurrence of • R^! is independently selected from alkyl, heteroaikyi, cycloalkyl, heteroaikyi, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and wherein each R'is optionally substituted by one or two more groups, independently selected from halogen, -R', -OR', -OH. -SI 1, -S ', - N0₂, -CN, -C(0)R\ -OC(0)R',-CON(R')₂, or -OC(0)N(R')_2, -NH₂, -NHR', -N(R'),, - NHCOR', -NHCOH, -NHCONH₂, -NHCONHR', -NHCON(R')₂, -NRCOR', -NRCOI I, - NI ICO2I I, -NHC0₂R', -C0₂R', -C0₂H, -CHO, -CONH₂, -CONHR^,,-COM(R^,)₂, -S(0)₃H_; - S(0)₂R', -SO2N I-I2, -S(0)H, -S(0)R', -S0₂NHR', -S0₂N(R')₂, -NHS(0)₂H, -NR'S(0)₂H, - NHS(())₂R', -NR'S(0)₂R', or -Si(R')₃.

Further, the term "phenylene" in the context of the present invention means a 1 ,2- phenylene, a 1 ,3-phenylene, or 1 ,4- phenylene, most preferably 1 ,4-phenylene.

The term "alkyl" means, unless otherwise stated, a hydrocarbon group that can be conceptually formed from an alkane by removing hydrogen from the structure of a hydrocarbon compound having straight or branched carbon chains, and replacing the hydrogen atom with another atom or substituent group. In some embodiments of the invention, the alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like.

The term "heteroaikyi" means, unless otherwise stated, an alkyl group consisting of one to fourteen carbon atoms and having one to six heteroatoms selected from oxygen, nitrogen, sulfur, and silicon, and wherein the nitrogen, sulfur and silicon atoms may optional ly be oxidized and the nitrogen atom may optionally be quatemized. The heteroatoms O, N and S may be placed at any interior position of the heteroaikyi group. The hclcroatom Si may be placed at any position of the heteroaikyi group, including the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples i ncl ude, but are not limited to 2-methoxyethyl, 2-(methylamino)ethyl, 2- (dimethylam ino)ethyl, 2-(ethylthio)methyl, 2-(methylsulfmyl)ethyl, 2-

(methylsulfonyl)ethyl, 2-methoxyvinyl, trimethylsi lyl, dimethyl(vinyl)si lyl, 2- (cyclopropylthio)ethyl, and 2-(methoxyimino)ethyl. Up to two heteroatoms may be consecutive, such as, for example, (methoxyamino)methyl and trimethylsilyloxy.

The term "substituted alkyl" and "substituted heteroalkyl" denote that the alky I and the heteroal kyl group is substituted by one or more substitutents, such as halogen, hydroxy, aikoxy. alkoxy-alkyl, oxo, cycloalkyl, napthyl, amino, (monosubstitutcd) am ino, (disubstituted)am ino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamide, N- (alkyl)carboxamide, cyano, trifluoromethyl, methylsulfonylamino, thiol, alkylthio or alkylsu lfonyl .The substituted alkyl groups may be substituted once or more, with the same or different substitutents.

In some embodiments of the invention, the substituent groups include hydroxy. fluorine, chlorine, brom ine, CF₃, NH₂, N HCH_3> N(CH₃)₂, C0₂CH₃, SEt, SC i l₃, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

The terms "cycloalkyl", "heterocycloalkyl" means, unless otherwise stated, cyc l ic versions of "alkyl", and "heteroalkyl", respectively. Additionally, for heterocycloa lkyl, a hclcroatom can occupy the position at which the heterocycle is attached to the remai nder o f the molecule. Examples of cycloalkyl include, but are not l im ited to cyclopropyl. cyclopentyl, cyclohexyl, cyclohex- l -enyl, cyclohex-3-enyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamant- l -yl, adamant-2-yl, bicyc lo| 2.1 .() |pentyl. bicyclo| 3.1 .0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1 .0]octyl, spiro( 2.6 |nonyl, bicyclo| 2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl, and the like. Examples of heterocycloalkyl include, but are not limited to piperidinyl, piperidin-2- yl, piperidin-3-yl, morpholin-4-yl, morpholin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, piperazinyl, piperazin-2-yl, and the l ike.

The term "aikoxy" refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom. Su itable examples of aikoxy groups include, but are not l i m ited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, and the like.

The term " lower alkoxy" refers to "C I to C7 alkoxy" such as methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, tert-butoxy, and the like. "C I to C7 alkoxy" can be optional ly substituted, meaning that the alkyl portion of the alkoxy can be substituted to form, for example, branched alkoxy, and the l ike.

The term "aryl" means, unless otherwise stated, a polyunsaturated, typical ly aromatic, hydrocarbon substituent which can be a monocycl ic system or polycyclic ring system (with up to three rings) which are fused together or l inked covalently. The monocycl ic or polycycl ic ring system comprises about 5 to about 1 6 carbon atoms. Suitable examples of aryl groups include, but are not limited to phenyl, naphlhyl, anthracenyl, and the like.

The term "heteroaryl" means, unless otherwise stated, "aryl" groups that contain from one to four heteroatoms selected from nitrogen, oxygen, and su l fur, wherein the n itrogen and sulfur atoms are optionally oxidized, and one or several nitrogen atom arc optional ly quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-iimiting examples of aryl and heteroaryl groups include phenyl, 1 -naphlhyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl. 3- pyrazolyl, 2-im idazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl -4- oxazolyl, 5-oxazoIyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazoIyI, 2-thiazolyl, 4-th iazolyl. 5- th iazolyl, 2-furyl. 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrim idyl, 4-pyrim idyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 - isoqui nolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-qu inolyl .

T he term "substituted aryl" and "substituted heteroaryl" means, unless otherwise staled, that the aryl and the heteroaryl group is substituted by one or more substitutents, such as halogen, hydroxy, alkoxy, alkoxy-alkyl, oxo, cycloalkyl, napthyl, am ino, (monosubstituted) amino, (disubstituted)amino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxam ide, N-(alkyl)carboxamide, cyano, trifluoromethyl, methylsulfonylam ino, thiol, alkylthio or alkylsulfonyl .The substituted alkyl groups may be substituted once or more, with the same or different substitutents. The terms "arylalkyl" and "heteroarylalkyl " means, unless otherwise stated, those rad ica ls in wh ich an aryl group is attached to an alkyl group (e.g.. benzyl, phcnethyl, pyridylmethyl, and the l ike) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth- l -yloxy)propyl, and the like).

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sul fur (S).

"Substituted" herein refers to a substituted moiety, such as a hydrocarbon, e.g., substituted alkyl or aryl wherein at least one element or rad ical, e.g., hydrogen is replaced by another, e.g., hydrogen is replaced by a halogen as in chlorobenzyl .

"Optional" or "optionally" means that the subsequently described event or ci rcumstance may or may not occur, and that the description i ncludes instances where said event or circumstance occurs and instances where it does not. For example, the phrase 'optional ly substitued aryl" means that the aryl group may or may not be substituted and that the description included both unsubstituted and aryls where there is substitution .

The phrases "independently selected", "independently" and their variants, when used in reference to two or more of the same substituent group (e.g., two or more R^J groups within the same compound), are used herein to mean that that two or more groups can be the same or different. For example, the compound of Formula 1 can comprise two R ' groups, wherein one R³ group is hydrogen and the other R³ group is a halogen. Moreover, the compound of Formula 1 can comprise two R³ groups, wherein both ^J groups are -CN.

Exam les

The invention is further illustrated by the fol lowing examples which in no way should be construed as being further l imiting. One ski lled in the art wi ll readi ly appreciate that the speci fic methods and results described are merely i l l ustrative. Structures of the intermediates as wel l as the final compounds were confirmed by nuclear magnetic resonance spectra for proton (Ή NMR) and/or LCMS.^■ Intermediate la

l -Iso ropoxy-2,3-dimethyl-benzcne

1 -lsopropoxy-2,3-dimethyl-benzene 2,3-dimethyl-phenol was converted into l -Isopropoxy-2,3-dimethyl-benzene using the synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779.

I H-NM (400 MHz, CDC13 ) δ (ppm):7.040-7.000 (t, I H, J=8), 6.766-6.720 (m, 2H)_; 4.503-4.442 (m, I H), 2.265 (s, 3H), 2.141 (s, 3H), 1 .340-1 .324 (d, 6H, .1=6.4).

Intermediate lb

4-Is hydc

4-Isopropoxy-2,3-dimethyl-benzaldehyde

l -lsopropoxy-2,3-dimethyl-benzene (intermediate la )was converted into 4-Isopropoxy- 2,3-dimethyl-benzaldehyde using the synthetic procedure reported in JOC, 60, 23, 1 995. 7479-7490. The crude material was taken for next step. LC/MS [M+H]=l 93.1 .

Intermediate I

4-Isopropoxy-2,3-dimethyl-phenol

4-lsopropoxy-2,3-dimethyl-phenol 4-Isopi poxy-2,3-dimethyl-benzaldehyde (intermediate lb) was converted into 4- lsopropoxy-2,3-dimethyI-phenol using the synthetic procedure reported in BP 1040102 H I .

¹ H-N R (400 MHz, CDCI₃ ) δ (ppm): 6.647-6.625 (d, I H, J=8.8), 6.575-6.554 (d, I H. .1 8,1). 4.378 (s I H), 4.330-4.270 (m, I H), 2.161 (s, 6H), 1 .302- 1 .287 (d, 6H, .1=6).

Intermediate II

-isopropoxyphcnol

4-isopropoxyphenol

I lydroquinone was converted into 4-isopropoxyphenol using the synthetic procedure reported in J.Med.Chem. 2006, 49, 3770-3779.

Intermediate III

2-Chloro-4-isopropoxy-phenol

2-Chloro-4-isopi opoxy-phenol

4-lsopropoxy-phenol (intermediate) was converted into 2-Chloro-4-isopropoxy-phenol using the synthetic procedure reported in Bioorg. Med. Chem. Lett., 2005, 15(14), 3347- 335.1.

¹ H-N (400 MHz, DMSO-d6 ) δ (ppm): 9.51 (s, I H), 6.83-6.88 (m, 2H), 6.697-6.725 (dd, I H, J = 1 1 .2, 2.4 Hz), 4.388-4.448 (m, I H), 1 .1 82-1 .198 (d, 6H, J = 6.4 Hz).

Intermediate IV

-Cyclopropylmethoxy-phenol

4-Cyclopropylmethoxy -phenol

Hydroquinone was converted into 4-cyclopropylmethoxy-phenol using the synthetic procedure reported in J.Med.Chem. 2006, 49, 3770-3779. Intermediate V

2-Chloro-4-cyclopropylmethoxy-phenol

2-Chloro-4-cyclopropylmethoxy-phenol

4-cyclopi pylmelhyloxyphenoI (intermediate IV) was converted into 2-chloro-4- cyclopropylmethyloxyphenol using the synthetic procedure reported in Bioorg. Med.Chem. Led., 2005.15(14), 3347-3351

LC/MS [M-H] + 197, ¹ H-N R (400 MHz, CDC1₃ ) δ (ppm): 6.929-6.879 (m, 211), 6.773- 6.751 (m, IH), 5.161 (s, IH), 3.738-3.721 (d, 2H, J=6.8 Hz), 1.257-1.223 (m, IH), 0.639- 0.629 (m, 211), 0.331-0.320 (m, 2H)

Intermediate Via

4-propoxy-phenoI

4-propoxy-phenol

Hydroquinone was converted into 4-propoxyphenol using the synthetic procedure reported in J. Med.Chem., 2006, 49, 3770-3779.

Ή-MMR (400 MHz. DMSO-d6 ) δ (ppm): 8.814 (s, IH), 6.7-6.722 (d 21-1, .1 = 8.81-1/,), 6.627-6.649 (d, 211..1 = 8.8 Hz), 3.766-3.798 (t, 2H, .1 = 6.4 Hz), 1.609-1.661 (q, 211..1 - 6.8 Hz), 0.857-0.914 (t, 3H, J = 6.4 Hz)^'.

Intermediate VI

3-Chloro-4-propoxy-phenol

3-Chloro-4-propoxy-p enol 4-propoxyphenol (intermediate Via) was converted into 3-chloro-4-propoxyphenol using modification of the synthetic procedure outlined in WO 200416621 Al by using N- chlorosuccinimide instead of N-bromosuccinimide.

Ί-1-NMR (400 MHz, DMSO d6 ) δ (ppm): 9.28(s,1 H), 6.92-6.94(d, 1 H, J=8.8 Hz), 6.78 (s, 1 H), 6.64-6.66(d, H I, J=9.2 Hz), 3.88-3.85(t, 2H,J=5.6Hz) l .70- 1 .66(m,2H),0.97-0.94 (t,3HJ=6.8 Hz).

Intermediate VII

3-Chloro-4-isopropoxy-phenol

3-Chloro-4-isopropoxy-phenol

4-isopropoxyphenol (intermediate II) was converted into 3-chloro-4-isopropoxyphenol using modification of the synthetic procedure outlined in WO 200416621 Al by using N- chlorosuccinimide instead of N-bromosuccinimide.

Ή-NMR (400 MHz, DMSO d6 ) 5 (ppm): 9.33(s, 1 H), 6.93-6.96(d, l H,J=8.8Hz),6.77 (s, 1 H,), 6.63-6.66 (d, 1 H,J=8.8Hz),4.34-4.37 (m, 1 H).1 .21 - 1 .25 (d, 6H, J=5.6Hz )

Intermediate Villa

l- ene

l - ethoxymethoxy-3-trifluoiOmethoxy-benzene

To a solution of 3-Trifluoromethoxy phenol (5.0 g, 28.08 mmol,) in dry Ti l l- (20m L)was added 4A molecular sieves (10 g) and the reaction mixture was cooled to -5 ⁰ C. Then Potassium tert -butoxide (12.5 g, 1 12 mmol,) was added to this cold reaction mixture which was then warmed to RT and stirred for 30 min. Again the reaction mass was cooled to -5 C and MOMC1 (4.5 ml, 56.0 mmol, 2.0 eqv) was added drop wise. After the addition the reaction was continued for another 2h at RT. Reaction mixture was diluted with water ( 1 50ml) and extracted with diethylether (200ml X 2), washed with water, brine. dried over Na2S04 and evaporated the solvent. The yellow oily crude was purified by column chromatography (Neutral AI203, Hexane) to afford l-(Methoxymethoxy)-3- (tritluoromethoxy) benzene in 60% yield.

LC/ S [ -l-l] + 221.2, Ή-NMR (400 MHz, DMSO d₆) δ (ppm): 7.383-7.424(1,1 H,J=8.0 I Iz); 7.040-7.058(d,lH,J=7.2 Hz );6.954-6.977 (d,2H,J=9.2 Hz) ; 5.214 (s,2H,); 3.336

Intermediate VHIb

2-Chlor -l-methoxymethoxy-3-trifluoromethoxy-benzene

2-Chloro-l-rnethoxymethoxy-3-trinuoromethoxy-benzene

Sec -Butyl lithium (16.8 ml, 31.52 mmol, 2.0 eqv, 12% in cyclohexanc) was added dropwise to a solution of 1 -Methoxymethoxy-3-trifluoiOmethoxy-benzene (intermediate VII lb) (3.5 g, 15.76 mmol) in THF (70 niL) at -78 °C. The reaction mixture was stirred for 2h at -78 °C before 1,1,2-frichloi trifluoroethane (3.5 ml) was added and the same temperature was maintained for another lh. The reaction was quenched by addition of satd. NH4CI solution and extracted with ethyl acetate. The combined organic extract was -washed with water and dried over sodium sulphate and evaporated. The crude was purified by column chromatography (Silica gel 100-200 mesh, EtOAc-Hexane (0.2: 9.8)) to afford 2- Chloro-l-(methoxymethoxy)-3-(trifluoromethoxy) benzene in 55% yield.

Ή-NMR (400 MHz, DMSO d₆) δ (ppm): 7 90-7.430(t,l H,J=8.4 Hz); 7.276- 7.297(d,l H,J=8.4 Hz );7.170-7.190 (d,lH,J=8.0 Hz) ; 5.336 (s,2H,); 3.406 (s3H,);

Intermediate VIII

2- ol

2-Chloro-3-trifluoromethoxy-phenol

2-Chloi -l-methoxymethoxy-3-trifluoromethoxy-benzene (intermediate Vlllb) (1.0 g, 3.98 mmol) was taken in 4 N methanolic hydrochloric acid at 0 °C and stirred at room temperature for 30 min. Then the solvent was evaporated under nitrogen atmosphere to afford 2-Chloro-3-trifluoromethoxy-phenol in 97 % yield.

MS |M-H] 211.1, ¹ H-NMR (400 MHz, DMSO d₆) δ (ppm): 10.776 (s,lli,); 7.215- 7.257(1, 1H,J=8.4 Hz);6.986-7.007 (d,lH,J=8.4 Hz) ; 6.924-6.945 (d,lH.J=8.4 Hz):

Intermediate IX

3-Bromo-4-cyclopropylmethoxy-phenol

3-Bromo-4-cyclopropylmethoxy-phenol 4-cyclopropylmethoxyphenol (intermediate IV) was converted into 3-bromo-4- cyclopropylmethoxyphenol using the synthetic procedure outlined in WO 200416621 Λ1 ¹ H-NMR (400 MHz, CDC\₃ ) δ (ppm): 7.067 (s, IH), 6.821-6.800 (d, 114, .1-8.4), 6.733- 6.713 (d, 111, .1-8 Hz), 3.822-3.806 (d, 2H, J=6.4), 1.278-1.263 (m, IH), 0.628-0.610 (m. 211), 0.370-0.355 (m, 2H).

Intermediate X

4-cthoxy-phenol

4-ethoxy-phenol Hydroquinone was converted into 4-ethoxyphenol using the reported synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779.

¹ H-NMR (400 MHz, DMSO-d6 ) δ (ppm): 8.813 (s, IH), 6.695-6.717 (d, 211, J = 8.8 Hz), 6.626-6.648 (d, 2H, J = 8.8 Hz), 3.855-3.906 (q, 2H, J = 7.2 Hz), 1.236-1.270 (t, 3H, J = 6.8 Hz) Intermediate XI

2-ChIoro-4-ethoxy-phenol

2-Chloro-4-ethoxy-phenol

4-elhoxyphcno! (intermediate X) was converted into 2-chloro-4-cthoxyphenol using the synthetic procedure outlined in Biorg. Med. Chem. Lett., 2005, 3347-335 J.

Intermediate XII

-Ethoxy-2-methyl-phenol

4-Ethoxy-2-methyl-phenol

Methyl hydroquinone was converted into 4-ethoxy-2-methyl-phenol using the synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779

Ί ΐ-NMR (400 MHz, CDC1₃ ) δ (ppm): 6.696-6.602 (m, 31 1), 4.320 (s, 1 1 1), 3.987-3.935 (q, 21 1. .1=6.8), 2.224 (s, 3H), 1 .390-1 .355 (t, 3H, J=6.8).

Intermediate XIII

2-Methyl-4-propoxy-phenol

2- ethyl-4-propoxy-phenol

Methyl hydroquinone was converted into 2-methyl-4-propoxyphenol using the synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779.

Ί-1-NMR (400 MHz, CDC 13 ) δ (ppm): 6.726-6.748 (bd, 2H, J = 8.8 Hz), 6.660-6.681 (bd, I I I, J - 8.4 Hz), 3.861 -3.876 (m, 3H), 2.226 (s, 3H), 1 .760-1 .832 (sep, 2H, .1 - 7.6 Hz), 1 .0 1 5- 1 .072 0, 3H, J = 7.6 Hz) Intermediate XIV

-Bromo-4-isopropoxy-phenol

2-Bromo-4-isopropoxy-phenol

4-isopropoxyphenoi (intermediate II) was converted into 2-bromo-4-isopropoxyphenol using the synthetic procedure reported in Bioorg. Med.Chem. Lett., 2007, 17(7), 1961- 1965.

Ί l-N R (400 MHz, DMSO-d6 ) δ (ppm): 9.594 (s, 1H), 7.011 (s, 1 H).6.821-6.843 (d, III, J - 8.8 Hz), 6.745-6.766 (d, 1H, J = 8.4 Hz), 4.393-4.423 (sep, 111, .1 - 6.4 Hz). 1.177-1.221 (d,3H, J = 6 Hz)

Intermediate XV

-Isopropoxy-2-methyl-phenol

4-Isopropoxy-2-methyl-phenol

Methyl hydroquinone was converted into 2-methyl-4-isopropoxyphenol using synthetic procedure reported in J.Med.Chem., 2006, 49, 3770-3779

11 -l- M (400 MHz, DMSO-d6 ) δ (ppm): 8.678 (s, 1H), 6.616-6.638 (m, 2H), 6.512- 6.533 (d, lH, J = 8.4 Hz), 4.316-4.376 (m, 1H), 2.058 (s, 3H), 1.169-1.183 (d, 611, .1 = Hz)

Intermediate XVI

-CyclopentyloxyphenoI

4-Cyclopentyloxyphenol

Hydroquinone was converted into 4-cyclopentyloxyphenol using the synthetic procedu reported in J.Med.Chem., 2006, 49, 3770-3779 I l-N R (400 Hz. DMSO-d6) δ (ppm): 8.866 (s, IH), 6.683-6.705 (d, 211, J - 8.8 Hz), 6.626-6.649 (d, 211, J = 9.2 Hz), 4.624-4.652 (m, IH), 1.796-1.987 (m, 2H), 1.535-1.669 (m, 6H)

Intermediate XVII

2-Bromo-4-cyclopentyloxy-phenol

2-Bromo-4-cyclopentyloxy-phenol

4-Cyclopentyloxyphenol (intermediate XVI) was converted into 2-bromo-4 Cyclopentyloxyphenol using the synthetic procedure reported in Bioorg. Med.Chem. Leil. 2007, 17(7), 1961-1965

Intermediate XVIII

l-(4-Methoxy-phenyl)-cthylamine

1 -(4-Methoxy-phenyl)-ethylamine . l-(4-Methoxy-phenyl)-ethanone was reacted with ammonium acetate and sodium cyanoborohydride similar to the procedure employed for intermediate XXV to afford crude l-(4-Methoxy-phenyl)-ethylamine which was taken to the next step without any purifi cation.

LCMS-IM+H] 135.1 (fragmented mass), H'NMR(DMSO-d6): 7.360-7.382 (d, 2H, J= 8.8 Hz), 6.956-6.977 (d, 211, J=8.4 Hz), 4.311-4.328 (m, IH), 3.743 (s, 311), 1.429-1.447 (d. 311, .1-7.2 Hz).

Intermediate XIX

N-| i -(4-Mcthoxy-phenyl)-ethyl]-acetamide

N-[l-(4- ethoxy-phenyl)-ethyl]-acetamide I -(4-Methoxy-phenyl)-ethylamine (intermediate XVIII) was reacted with acetyl chloride similar to the procedure employed for Example 3 to afford N-|l -(4-Methoxy-phenyl)- ethyl |-acetamide in 44% yield.

I.CMS-[M-i-H]= 194.1, H'NMR(DMSO-d6): 8.127-8.145 (d, IH, J-7.2 Hz), 7.179-7.200 (d, 2H, .1= 8.4 Hz), 6.836-6.858 (d, 2H, J=8.8 Hz), 4.813-4.849 (m, IH), 3.706 (s, 3H), 1.794 (s, 3H), 1.273- 1.290 (d, 3H, J= 6.8 Hz).

Intermediate XX

N-[l ide

N-[l-(4-Hydroxy-phenyl)-ethyl]-acetamide

A solution of Boron tribromide (0.1178 ml, 1.242 mmol) in DCM (15 ml) was added to a stirred solution of N-| l-(4-Methoxy-phenyl)-ethyl]-acetamide ( (200 mg, 1.0350 mmol) in DCM (15 ml) at 0°C over a period of 25 min and stirred for 16 hrs at room temperature. The reaction mixture was quenched with ice cold water and evaporated the solvent, compound was extracted with ethyl acetate (100 ml *2), Total organic layer was washed with water and brine, dried over anhydrous Na2S04, evaporated the solvent. The crude material was purified by column chromatography, compound was collected with 40 to 50 % ethyl acetate-hexane to afford N-| l-(4-Hydroxy-phenyl)-ethyr|-acetamide in 81% yield. LCMS-IM+H] 180.3, H'NMR (DMSO-d6): 8.072-8.086 (d, IH, J=5.6 Hz), 7.054-7.074 (d, 211, .1= 8.0 Hz), 6.656-6.677 (d, 2H, J=8.4 Hz), 4.770-4.805 (m, IH), 1.785 (s, 311).

1.253-1.269 (d, 3H, J= 6.4 Hz).

Intermediate XXI

5-Bro -2-(4-isopropoxy-2,3-dimethyl-phenoxy)-thiazole

5-l3romo-2-(4-isopropoxy-2,3-dimethyl-phenoxy)-thiazole Potassium carbonate (1 .99 g, 1 5.53 mmol) was added to a mixture of 4-Isopropoxy-2,3- dimethyl-phenol (intermediate 1) ( 1 .38 g, 7.66 mmol) and 2,5-dibromothiazole ( 1 .86 g, 7.66 mmol) in 20 ml of N,lM-dimethylformamide. The reaction mixture was heated 130 °C for 3 hours. Then the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was puri lied by column chromatography over si lica using hexane-ethyl acetate system to afford 5-l3romo-2-(4-isopropoxy-2,3-dimethyl-phenoxy)-thiazole in 68 % yield.

MS [M i-I-I] 342.2, Ή-NMR (400 MHz, CDCL3) δ (ppm): 7.132 (s, I H), 6.959-6.981 (d, 1 I I, J=8.8 Hz), 6.724-6.746 (d, I H, J=8.8 Hz), 4.458-4.488 (m, I H), 2.167 (s, 311), 2.1 52 (s, 3 H), 1 .333- 1 .349 (d, 611, J=6.4 Hz).

Intermediate XXII

5-Bromo-2-(4-isopropoxy-phenoxy)-thiazole

4-Isopropoxy-phenol (intermediate 11) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(4-isopropoxy- phcnoxy)-thiazole in 52% yield.

Ή-NMR (400 M Hz, CDCL3 ) δ (ppm): 7.144-7.167 (m, 3H), 6.878-6.910 (m, 21 1), 4.496- 4.526 (m, 1 H), 1 .333- 1 .349 (d, 6H, J=6.4 Hz).

Intermediate XXIII

5-(4 iazole

5-(4-Bronio-phenoxy)-2-(4-isopropoxy-phenoxy)-thiazole

Λ mixture of 5-Bromo-2-(4-isopropoxy-phenoxy)-thiazole (intermediate XXI I) ( 1 .5 g. 4.7 mmol), 4-bromo-phenql (0.99 g, 5.7 mmol), cesium carbonate (4.66g. 14.32 mmol), copper iodide (0.9 g, 4.7 mmol) in 25 ml of Ν,Ν-dimethylformamide was heated at 120 °C for 5 hour. Then the reaction mixture was cooled to room temperature, di luted with water and filtered through celite and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column over silica using hexane-ethyl acetate system to afford 5-(4-Bromo-phenoxy)-2-(4-isopropoxy-phenoxy)-thiazole in 36 % yield.

MS M+l-1] 406.2, Ή-NMR (400 MHz, CDCL3) δ (ppm): 7.408-7.447 (m, 2H), 7. 163- 7. 1 86 (m, 2H), 6.947-6.978 (m, 2H), 6.905-6.882 (m, 21 1), 6.856 (s, 1 H), 4.486-4. 16 (m. 1 1 1). 1 .326- 1 .341 (d, 6H, .1=6 Hz).

Intermediate XXIV

l -{4-|2- -Isopropoxy-phenoxy)-thiazol-5-y!oxy]-phenyl}-ethanone

1 - {^/l-[ 2-(4-lsopiOpoxy-p enoxy)-thiazol-5-yloxy]-pheiiyl} -ethaiione

5-(4-Bromo-phenoxy)-2-(4-isopropoxy-phenoxy)-thiazole (intermediate XXI II) (0.5 g, 1 .23 mmol), Tributyl( I -ethoxyvinyl)tin (.533 g, 1 .477 mmol) were dissolved in 5 ml of N.N-dimethylformamide and the mixture was degasified by bubbling nitrogen gas for 1 0 m inutes. Then palladium (II) acetate ( 13.81 mg, 0.062 mmol) and tri-tcrt-butyl phosphonium tetrafluoroborate (35.7 mg, 0.123 mmol) were added and heated at 100 °C for 1 5 hour. Then the reaction mixture was cooled to room temperature, diluted with water and filtered through celite and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column over silica using hexane-ethyl acetate system to afford l -{4-[2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}- ethanone in 80 % yield.

MS I 1 1 1 1 370.3, Ή-NMR (400 MHz, CDCL3) δ (ppm): 7.944-7.966 (m, 21 1), 7. 1 81 - 7.204 (m, 2H), 7.1 1 7-7. 1 39 (m, 2H), 6.892-6.914 (m, 3H), 4.476-4.536 (m, 1 H), 2.571 (s, 31 1), 1 .329-1 .343 (d, 6H, .1=5.6 Hz). Intermediate XXV

l-{4-|2-(4 hyIaminc

l - i 4-[₂-(4-Isopropoxy-phenoxy)-tliiazol-5-yloxy]-plienyl ) -ethylamine

I -{4-| 2-(4-lsopropoxy-phenoxy)-thiazol-5-yloxy]-phenyI} -ethanone (intermediate XXIV) (375 mg, 1 .016 mmol), ammonium acetate (939 mg, 12.19 mmol) and molecular sieves powder 4 A (2g) were taken in methanol ( 10ml) and stirred at room temperature for 20 m in after which sodium cyanoborohydride (95.7 mg, 1 .524 mmol) was added. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and filtered through celite. The solvent was evaporated under vacuum to obtain crude which was dissolved in water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and evaporated to aflbrd crude l -{4-| 2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken into the next step without any purification.

MS [M+H] 371 .3.

Intermediate XXVI

5-Bromo-2-(2-chIoro-4-isopropoxy-phenoxy)-thiazole

5-Bromo-2-(2-chloro-4-isopropoxy-phenoxy)-thiazole

2-Chloro-4-isopropoxy-phenol (intermediate 111) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(2- chloro-4-isopropoxy-phenoxy)-thiazole in 52% yield. MS [M i l l] 348.1, Ή-NMR (400 MHz, CDCL3) δ (ppm): 7.204-7.226 (d, 1 H, .1=8.8 II/). 7.121 (s, III), 6.979-6.986 (d, lH, J-2.8 Hz), 6.798-6.828 (dd, 1H, J=I2 Hz, 3.2 Hz). 4.482-4.513 (m_s 11-1), 1.337-1.351 (d, 6H, J=5.6 Hz).

Intermediate XXVII

5-Bromo-2-(4-cyclopropylmethoxy-phenoxy)-thiazole

5-Bromo-2-(4-cyclopropylmethoxy-phenoxy)-thiazole

4-Cyclopropylmethoxy-phenol (intermediate IV) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(4- cyclopropylmethoxy -phenoxy)-thiazole in 59% yield.

'll-NMR (400 MHz, CDCL3) δ (ppm): 7.138-7.174 (m, 3H), 6.898-6.930 (m.21-1), 3.7.91- 3.807 (d, 2H. J=6.4 Hz), 1.234-1.308 (m, 1H).0.629-0.675 (m, 2H), 0.332-0.370 (m 211).

Intermediate XXVIII

l-{4-[2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone

!-{4-[2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy]-phenyl j-ctlianone

A mixture of 5-Bromo-2-(4-cyclopropylmethoxy -phenoxy)-thiazole (intermediate XXVII) (1.5 g, 4.6mmol), 4-hydroxy-acetophenone (750 mg, 5.5 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in 10 ml of N,N-dimethylformamide was heated at 150 °C for 15 hour. Then the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column chromatography over silica using hexane-ethyl acetate system to afford 1 -{4-|2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy ]-phenyl}-ethanone in 8 % yield.

Intermediate XXIX

l-{4-|2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine

l-i -|2-(4-CyclopiOpylinethoxy-pheiioxy)-thiazol-5-yloxy]-plienyl}-etliylaminc

l-{4-|2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone

(intermediate XXVIII) was treated with ammonium acetate and sodium cyanoborohydride similar to the procedure employed for the intermediate XXV to afford crude l-{4-|2-(4- CycIopropylmethoxy-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethylamine which was taken into the next step without any purification. MS [M+H] 383.3

Intermediate XXX

5-Bromo-2-(3-chIoro-4-isopropoxy-phenoxy)-thiazolc

I g 5-Bromo-2-(3-chloiO-4-isopiOpoxy-phenoxy)-thiazole

3-Chloro-4-isopropoxy-phenol (intermediate VII) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(3- chloro-4-isopropoxy-phenoxy)-thiazole in 76.6% yield.

LCMS-[M+2]= 350.1, H'NMR(DMSO-d6): 7.552-7.558 (d, 1H, J=2.4 Hz), 7.406 (s, I I I), 0 7.291-7.321 (dd, I I I, J= 12 Hz, 2.8 Hz), 7.221-7.243 (d, H, J=8.8 Hz), 4.461-4.670 (m_s I I I), 1.277-1.291 (d, 6H, .1=5.6 Hz). Intermediate XXXI

5-Bromo-2-(3-chIoro-4-propoxy-phenoxy)-thiazole

5-Biomo-2-(3-chloiO-4-propoxy-phenoxy)-t iazole

3-Chloro-4-propoxy-phenol (intermediate VI) was reacted with 2,5-dibromothiazoIe similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(3- chloro-4-propoxy-phenoxy)-thiazole in 52% yield.

LCMS-[M+2]= 350.1, H'NMR(CDC13): 7.311-7.319 (d, 1H, J= 3.2 Hz), 7.106-7.137 (m_f 2H), 6.913-6.935 (d, 111, J= 8.8 Hz),3.975-4.007 (t, 2H, J= 12.8 Hz), 1.821-1.908 (m, 211). 1.054-1.092 (1.3H, J= 7.6 Hz).

Intermediate XXXII

5-Bromo-2-(2-chloro-3-trifluoromethoxy-phenoxy)-thiazole

5-BroiTH)-2-(2-chloro-3-lriniioromcllioxy-p enoxy)-lhicizolc 2-Chloro-3-trifluoromethoxy-phenol (intermediate VIII) was reacted with 2,5- dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5- Bi ino-2-(2-chloro-3-trifluoromethoxy-phenoxy)-thiazole in 27% yield.

MS [M+H] 413.4, ¹ H-NMR (400 MHz, DMSO d₆) δ (ppm): 7.638-7.652(1, 311,), 7.582- 7.596 (d, 2H, J=5.6 Hz), 7.420 (s, 1H). Intermediate XXXIII

5-Bromo-2-(3-bromo-4-cyclopropylmethoxy-phenoxy)-thiazole

5-Bromo-2-(3- romo-4-cyclopropylmethoxy-phenoxy)-thiazole

3-lkomo-4-cyclopropylmethoxy-phenol (intermediate IX) was reacted with 2,5- dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5- Bromo-2-(4-isopropoxy-2,3-dimethyl-phenoxy)-thiazole in 31 % yield.

LC/ S M+H] + 406.1. Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.141-7.173 (dd, 2H, J-7.2 Hz); 6.937 (s,IH,); 6.905 (s,lH,); 3.789-3.806 (d,2H, .1=6.8 Hz); 1.269-1.286 (m, 1 H);0.612-0.661 (m,2H);0.342-0.369(m,2H).

Intermediate XXXIV

5-Bromo-2-(2-chloro-4-cyclopropylmethoxy-phenoxy)-thiazole

5 - Brum 0-2 -(2-cliloro- -c clop ro y tin clhoxy-phenoxy)-tlii_<izolc

2-Chloro-4-cyclopropylmethoxy-phenol (intermediate V) was reacted with 2,5- dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5- Bromo-2-(2-chloro-4-cyclopropylmethoxy-phenoxy)-thiazole in x % yield.

Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.213-7.235 (d, 1H, J=8.8 Hz), 7.116 (s, IH), 6.998 (s, 1H)_: 6.830-6.860 (dd, IH, J=12 Hz, 3.2 Hz), 3.784-3.801 (d, 2H, J=6.8), 1.242-1.295 (m, I H), 0.621 -0.684 (m, 2H), 0.322-0.37 (m, 2H). Intermediate XXXV

5-Bromo-2-(2-chloro-4-ethoxy-phenoxy)-thiazole

5-B rom o-2-(2-ch loro-4-ethoxy-plienoxy )-th iazo le

2-ChIoro-4-ethoxy-phenol (intermediate XI) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(2-chloro-4- ethoxy-phenoxy)-thiazole in 90% yield.

Ί-1- R (400MHz, DMSO-d6) δ (ppm): 7.937 (s, 1H), 7.7478-7.455 (d, 1H, .1 9.211/). 7.381 (s, 1 H,), 7.199-7.192 (d, ΓΗ, J=2.8Hz), 4.088-4.037 (m, 2H), 1.332-1.297 (1.311. .1 7.2Hz) .

Intermediate XXXVI

5-(4-Bromo-phenoxy)-2-(2-chloro-4-ethoxy-phenoxy)-thiazole

5-(4-Bromo-phenoxy)-2-(2-chloro-4-ethoxy-phenoxy)-thiazole

5- i mo-2-(4-ethoxy-2-methyl-phenoxy)-thiazole (intermediate XXXV) was reacted with 4-bromo-phenol similar to the procedure employed for the intermediate XXIII to afford 5- (4-Bromo-phcnoxy)-2-(2-chIoro-4-ethoxy-phenoxy)-thiazole in 22% yield.

LC/MS [M+H^'J +428.1 Intermediate XXXVII

l-{4-f2-(2-Chloro-4-ethoxy-phenoxy)-thiazol-5-yloxy]-phenyI}-cthaHonc

I - !4-|2-(2-Chloro-4-ethoxy-plienoxy)-thiazol-5-yloxy]-phenyl ) -ethanone 5-(4-Bromo-phenoxy)-2-(2-chloro-4-ethoxy-phenoxy)-thiazole (intermediate XXXVI) was reacted with Tributyl(l-ethoxyvinyl)tin similar to the procedure employed for the intermediate XXIV to afford l-{4-[2-(2-Chloro-4-ethoxy-phenoxy)-thiazol-5-yIoxy|- phcnyl}-ethanone in 43% yield.

LC/MS [M+ll] +390.2, Ή-NMR (400MHz, DMSO-d6) δ (ppm) 8.037-8.005 (m, 2H,),. 7.490-7.467 (d, 1H, J=9.2Hz), 7.236-7.214 (d, 2H, J=8.8Hz), 7.183-7.169 (d, 111. J 5.6H ), 7.146 (s, 1H), 6.989-6.967 (m, 1H), 4.081-4.013 (m, 21-1), 2.533 (s,31I).0.877- 0.839 (t, 3H, J=8Hz) .

Intermediate XXXVIII

]-{4-[2-(2-Chl I}-ethylamine

l-J4-|2-(2-Chloro-4-ctlioxy-plienoxy)-lhiazol-5-yloxy]-phenyl)-ethylaminc l-{4-|2-(2-Chloi -4-ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate XXXV11) was reacted with ammonium acetate and sodium cyanoborohydridc similar to the procedure employed for intermediate XXV to afford crude l-{4-|2-(2-Chloro-4- ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken to the next step without any purification. MS [M+H] 391.1. Intermediate XXXIX

5-B zolc

5-B omo-2-(2-methyl-4-piOpoxy-phenoxy)-thiazole

4-propxy-2-methyl-phenol (intermediate XIII) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(2- methyl-4-propxy-phenoxy)-thiazole in 92% yield.

LC/MS |\MI| +330.2

Intermediate XXXX

5-B zolc

5-Bi'omo-2-(4-ethoxy-2-methyl-phenoxy)-lhiazole

4-Ethoxy-2-methyl-phenol (intermediate XII) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(4- ethoxy-2-methyl-phenoxy)-thiazole in 72% yield.

LC/MS M+H] +316.1, Ή-NMR (400MHz, DMSO-d6) δ (ppm): 7.935 (s, IH), 7.220- 7.198 (d, III, J=8.8Hz), 6.908 (s, IH,), 6.779 (s, IH), 6.823-6.802 (d, IH, .1-8.41 Iz). 4.037-4.985 (m, 2H), 2.133 (s,3H), 1.992 (s, 3H), 1.349 -1.290 (m, 3H) . Intermediate XXXXI

5-Brom -2-(2-chloro-4-methoxy-phenoxy)-thiazole

5- romo-2-(2-c loro-4-methoxy-phenoxy)-thiazole

2-Chloro-4-methoxy-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(4-ethoxy-2-methyl- phenoxy)-thiazole in 72% yield.

LC/MS [M+H] 320.3, Ή-NMR (400MHz, CDC13) δ (ppm): 7.228-7.250 (d, I I I, .1 8.8 Hz), 7.1 14 (s, 1 H), 7.003 (s, 1 H), 6.832-6.862 (dd, l H, J=12 Hz, 3.2), 3.81 1 (s, 31 1).

Intermediate XXXXII

5-liro -2-(2-bromo-4-isopropoxy-phenoxy)-thiazole

5-Bromo-2-(2-bromo-4-isopropoxy-phenoxy)-thia ole

2-bromo-4-isopropoxy-phenol (intermediate XIV) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford 5-Bromo-2-(2- bromo-4-isopropoxy-phenoxy)-thiazole.

LC/MS [M+H] 320.3, Ή- MR (400MHz, CDC13) δ (ppm): 7.203-7.226 (d, 1 H, .1=9.2), 7. 127-7.149 (m, 2H), 6.846-6.876 (dd, 1H, J=12 Hz, 2.8 Hz), 4.468-4.529 (m, M l), 1 .335- 1 .351 (d, 6H, J=6.4 Hz). Intermediate XXXXIII

5-Bro hiazo!c

5-Bromo-2-(4-isopropoxy-2-methyl-^'phenoxy)-tliiazole

4-Isopropoxy-2-methyl-phenol (intermediate XV) was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate XXI to afford crude 5-Bromo-2-(4- isopropoxy-2-melhyl-phenoxy)-thiazole which was taken into the next step without any purification.

MS I M i H] 330.4.

Intermediate XXXXIV

5-Bromo-2-(4-cyclopentyloxy-phenoxy)-thiazolc

5-Bromo-2-(4-cyclopenty!oxy-phenoxy)-thiazole

4-lsopropoxy-2-methyl-phenol (intermediate XVI) was reacted with 2,5-dibromothiazolc sim i lar to the procedure employed for the intermediate XXI to afford crude 5-Bromo-2-(4- cyclopentyloxy-phenoxy)-thiazole.

LC/MS [M+H]-l-341 Ή-NMR (400 MHz, CDC1₃ ) δ (ppm):7.141 -7. l 58(d,2H,J - 6.8 l lz),7.141 (s, 1 H),6.87 I - 6.893 (d, 2H, J = 8.8 Hz), 4.729 - 4.792 (m, I H), l .805- 1 .898(m. 6I 1)J .552 - 1 .627(m, 2H).

Intermediate XXXXV

5-(4-Bromo-phenoxy)-2-(4-cyclopentyloxy-phenoxy)-thiazole

5-(4-l3romo-phenoxy)-2-(4-cyclopentyloxy-phenoxy)-lliiazole 5-13romo-2-(4-cyclopenlyloxy-phenoxy)-lhiazole (intermediate XXXXIV) was reacted with 4-bromo-phenol similar to the procedure employed for the intermediate XXIII to afford 5-(4-Bromo-phenoxy)-2-(4-cyclopentyloxy-phenoxy)-thiazole in 22% yield.

LC/MS |M+2H]+434 Ή-NMR (400 MHz, CDC13 ) 5 (ppm):7.415-7.438(d,2HJ=9.2 Hz),7.176-7.154(d,2H,J=8.8 Hz),6.954-6.976 (d,2H,J=8.8 Hz),6.887(s,lH),6.855- 6.864(d,2H,J=3.6 Hz),4.707-4.728 (m,lH),l .817-1.94I(m,4H),l .799-1.863(m,2H),l .599- 1.612(m,2H).

Intermediate XXXXVI

l-{4-f2-(4-Cyclopcntyloxy-phenoxy)-thiazol-5-yloxy]-phenyl}-cthanonc

l ^l4-[2-(4-Cyclopentyloxy-phenoxy)-thiazol-₅-yloxy]-plienyl)-etliaiione 5-(4-Bromo-phenoxy)-2-(4-cyclopentyloxy-phenoxy)-thiazole (intermediate XXXXV) was reacted with Tribiityl(l-ethoxyvinyl)tin similar to the procedure employed for the intermediate XXIV to afford l-{4-[2-(2-Chloro-4-ethoxy-phenoxy)-thiazol-5-yloxy|- phenyl}-ethanone in 43% yield.

IX/MS [M+HI+396.4 ¹ H-NMR (400 MHz, CDCI3 ) δ (ppm):7.942-7.964(d,2HJ=8.8 Hz), 7.176-7.189(d,2H,J=5.2 Hz),7.115-7.137 (d,2H,J=8.8 Hz),6.887(s,l H),6.896- 6.9()8(d,2H,J=4.8 Hz), 6.891 (s,lH),2.570(s,3H)4.707-4.728 (mJH), 1.817- 1.941 (m,4H), 1.799-1.863(m,2H), 1.599-1.612(m,2H)

Intermediate XXXXVH

l -{4-|2-(4-Cyclopentyloxy-phenoxy)-thiazoi-5-yloxy]-phenyl}-ct ylamine

I - | 4-[2-(4-Cyclopentyloxy-phenoxy)-thiazol-5-yloxy]-phenyl j -ethyl am ine

1 -{4-| 2-(4-Cyclopentyloxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate XXXXVI) was reacted with ammonium acetate and sodium cyanoborohydi ide similar to the procedure employed for intermediate XXV to afford crude l -{4-[2-(4-Cyclopentyloxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken to the next step without any purification.

Intermediate XXXXVIII

N-(l -{4-[2-(2-Chloro-4-hydroxy-phenoxy)-thiazoI-5-yIoxyl-phenyl}-ethyl)-acetamide

N-( 1 - ( 4-|2-(2-Chloro-4-hydroxy-phenoxy) hiazol-5-yloxy]-phenyl ) -ethyl)-acetamide

A solution of Borontribromide (1 .17ml, 1 1.8mmol) in 50 ml of dichloromethane was - added dropwise to a solution of N-(l-{4-[2-(2-Chloro-4-isopropoxy-phenoxy)-thiazol-5- yloxy]-phenyl}-ethyl)-acetamide (2.6g, 5.9mmol) in 20 ml of dichloromethane at -78 °C and stirred at same temperature for 30 minutes. The reaction mass was quenched with methanol and diluted with water, pH was adjusted with saturated sodium bicarbonate and the extracted with DCM.The combined organic extract was washed with brine, dried over anhydrous sodium sulphate and evaporated to afford N-( l -{4-[2 -(2-Chloro-4-hydroxy- phenoxy)-thiazol-5-yloxy^'|-phenyl} -ethyl)-acetamide.

LC/ S I VI 1 11 +403.5. Intermediate XXXXIX

2 l

ι-4-cyclopent loxy-phenol

Intermediate L

5-Brom -2-(2-chloro-4-cyclopentyloxy-phenoxy)-thiazole

5-Bromo-2-(2-chloro-4-cyclopentyloxy-p enoxy)-thiazolc

2-Chloro-4-cyclopentyloxy-phenol (intermediate XXXXIX) was reacted with 2,5- dibromothiazole similar to the procedure employed for the intermediate XXI to afford crude 5-Bromo-2-(2-chloro-4-cyclopentyloxy-phenoxy)-thiazole.

Intermediate LI

-CyclopentyIoxy-phenol

4-Cyclopentyloxy-phenol

Hydroquinone was converted into 4-cyclopentyloxyphenol using the synthetic procedure reported in J.Med. Chem, 2006, 49, 3770-3779.

Ή NM R (400 MHz, DMSO-d6) δ (ppm): 8.866 (s, I H), 6.683-6.705 (d, 2H, J = 8.8 Hz), 6.626-6.649 (d, 2H, J = 9.2 Hz), 4.624-4.652 (in, I H), 1 .796-1 .987 (m, 21 1), 1 .535- 1 .669 (m, 6H) Intermediate LII

2-Bromo-4-cyclopentyloxy-phenol

2-Bromo-4-cyclopentyloxy-phenol

4-Cyclopentyloxyphenol (intermediate LI) was converted into 2-bromo-4- Cyclopentyloxyphenol using the synthetic procedure reported in Bioorg. Med. Chem. Le.lt... 2007. 17(7), 1961 - 1965.

Intermediate LIII

5-Brom -thiazole

5-Bromo-2-(2-bromo-4-cyClopenlyloxy-phenoxy)-thiazole

A mixture of 2-bromo-4- Cyclo pentyloxy-phenol (intermediate LI I) ( 1 .00 g, 3.89 mmol) and 2,5-dibromothiazole (0.942 mg, 3.89 mmol) and Potassium carbonate ( 1 .6 g, 1 1 .6 mmol) in 20 m l of N,N-dimethyl formamide was heated 1 30 °C for 3 hours. Then the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined .organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column chromatography (silica gel 100-200 mesh, 5:95 ethylacetate: hexane) to afford 5-13romo-2- (2-bromo~4-cyclopentyloxy-phenoxy)-thiazole in 68 % yield.

LC/ S: [M+H] 422.4.

Intermediate LIV

4-Propoxy-phenol

4-Pro poxy-phenol I lydroquinone was converted into 4-propoxyphenol using the synthetic procedure reported in J. ed.Chem., 2006, 49, 3770-3779.

Ή NMR (400 MHz, DMSO-d6 ) δ (ppm): 8.814 (s, 1H), 6.7-6.722 (d, 2H, J = 8.8 Hz), 6.627-6.649 (d, 2H, J<= 8.8 Hz), 3.766-3.798 (t, 2H, J = 6.4 Hz), 1.609-1.661 (q, 2H, J= 6.8 Hz), 0.857-0.914 (t, 3H, J= 6.4 Hz).

Intermediate LV

-Bromo-4-propoxy-phcnol

2-BiOmo-4-propoxy-phenol

4-propoxyphenol (intermediate L1V) was converted into 2-bromo-4-propoxyphenol using the synthetic procedure reported in Bioorg. Med.Chem. Lett., 2007, 17(7), 1961-1965. Ή NMR (400 MHz, CDCL₃) δ (ppm): 7.012-7.019 (d, lH, J=2.8 Hz), 6.917-6.939 (d, H I, .1=8.8 Hz), 6.779-6.809 (dd, HI, J =12 Hz, 3.2 Hz), 5.111 (s, 1H ), 3.829-3.863 (t, 2H, .1-6.8 Hz), 1.556-1.817 (m, 2H), 1.000-1.036 (t, 3H, J = 7.6 Hz).

Intermediate LVI

5-Br zole

5-I3romo-2-(2-bromo-4-propoxy-phenoxy)-lhiazolc 2-bromo-4-propoxyphenol (intermediate LV) was reacted with 2,5-DibromothiazoIe similar to the procedure employed for the intermediate LIII to afford 5-Bromo-2-(2- bromo-4-propoxy-phenoxy)-thiazole in 68 % yield.

LC/MS:394.5, Ή NMR (400 MHz, CDCL3) δ (ppm): 7.122-7.259 (m, 3H), 6.870-6.898 (dd, 111, J=1.2 Hz, 2.4 Hz), 3.923-3.891 (t, 2H, J=6.4 Hz), 1.764-1.866 (m, 2H), 1.018- 1.054 (t, 3H, J=7.2 Hz). Intermediate LVII

5-Ii olc

5-Bromo-2-(2-ethy]-phenoxy)-thiazole

2-elhyl phenol was reacted with 2,5-Dibromothiazole similar to the procedure employed for the intermediate LHI to afford 5-Bromo-2-(2-ethyl-phenoxy)-thiazole in 68 % yield. LCMS:[M+H] 286.4, H 'NMR (400 MHz, CDCL3) δ (ppm): 7.380 (bs, 2H) 7.263-7.325 (m, 3 H), 2.529-2.585 (q, 2H, J=7.6 Hz), 1 .096- 1 .1 34 (t, 3H, J=7.6 Hz).

Intermediate LVIII

-Bromo-2-(3-mcthoxy-phenoxy)-thia/olc

5-BroiTio-2-(3-methoxy-phenoxy)-thiazole

3-methoxy-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LIII to afford crude 5-Bromo-2-(3- methoxy-phenoxy)- thiazole which was taken for next step without any further purification.

Ί-Ι NMR (400MHz, DMSO-d6) δ (ppm): 7.433 (s, 1 H), 7.395-7.354 (t, l H, J=8.4 Hz), 6.958-6.898 (m, 3H), 6.338-6.298 (m, 1 H), 3.761 (s, 3H).

Intermediate LIX

-Uromo-2-(3-ethoxy-phcnoxy)-thiazole

5-Bromo-2-(3-ethoxy-phenoxy)-1hiazo le

3-cthoxy-phcnol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LI I I to afford crude 5-Bromo-2-(3- ethoxy-phenoxy)-thiazole which was taken for next step without any further purification. Ί-l N R (400MHz_; D SO-d6) 5 (ppm): 7.430 (s, IH), 7.379-7.338 (1, IH, .1=8.4 I Iz). 6.988-6.884 (m, 3H), 6.321-6.275 (m, IH), 4.038-3.950 (q, 2H), 1.321-1.293 (t, 3H_; .1=6.8 Hz).

Intermediate LX

5- lc

-Bromo-2-(3-trifluoromethoxy-phenoxy)-thiazole

3-Trifluoromethoxy-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LI II to afford crude 5-Bromo-2-(3- trifluoromethoxy- phenoxy)-thiazole which was taken for next step without any further purification.

Intermediate LXI

5-Bromo-2-(2-chloro-phcnoxy)-thiazolc

S-Brom o-2-(2-chloro-phenox )-thiazole

2-Chloro-phenol was reacted with 2,^'5-dibromothiazole similar to the procedure employed for the intermediate Llll to afford crude 5-Bromo-2-(2- chloro-phenoxy)-thiazole which was taken for next step without any further purification.

Intermediate LXII

5-Bro -2-(2-isopropyl-phenoxy)-thiazolc

5-Broino-2-(2-iso rop l-phenoxy)-thiazole

2-isopropyl-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LIU to afford crude 5-Bromo-2-(2- isopropyl-phcnoxy)-hiazole which was taken for next step without any further purification.

LC/MS |M ll| +298.7 Intermediate LXIII

5-Bromo-2-(2-fluoro-4-methoxy-phenoxy)-thiazole

5-B ramo-2-(2-fluoro-4-niellioxy-|>heiioxy)-thiazole

2-fluoro-4-methoxy-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LII1 to afford crude 5-Bromo-2-(2- fluoro-4-methoxy- phenoxy)-lhiazole which was taken for next step without any further purification.

LC/MS [ -i-H] +306.2, Ή NMR (400MHz, CDC13-d6) δ (ppm):7.228-7.206 (d, 1R J=8.8 ll/)_r 7.105 (s, 1H), 6.780-6.686 (

m, 2H), 3.806 (s,3H).

Intermediate LXIV

N-(l-{4-|2-(2-FIuoro-4-hydroxy-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethyl)-acetamide

N-( I - 14-|^'2-(2-Fluoro-4-hydroxy-phcnoxy)-thiazol-5-yloxy]-phcnyl! -clh l) -acelam ide

A solution of Borontribromide (0.8ml, 8.4 mmol) in 10 ml of dichloromethane was added dropwise to a solution of N-(l-{4-[2-(2-Fluoro-4-methoxy-phenoxy)-thiazol-5-yIoxy|- phenyl}-ethyl)-acetamide (1.7 g, 4.2 mmol) in 25 ml of dichloromethane at -78 °C and then stirred at room temperature for 15 hour. The reaction mass was quenched with bicarbonate solution and diluted with water and the extracted with dichloromethane. The combined organic extract was washed with brine, dried over anhydrous sodium sulphate and evaporated to afford crude N-(l-{4-[2-(2-Fluoro-4-hydroxy-phenoxy)-thiazol-5- yloxy |-phenyl}-ethyl)-acetamide which was used for next step without any purification. Intermediate LXV

l-Isopropoxy-2-methyl-benzenc

I -Jsopropoxy-2-nrethy l-benzene

2-methyl-phenol was converted into 1 -Isopropoxy-2-methyl-benzene using the synthetic procedure reported in J.Med.Chem, 2006, 49, 3770-3779.

Ί 1 NMR (400 MHz. CDC 13 ) δ (ppm): 7.110-7.148 (t, 2H, J=7.2 Hz), 6.821-6.855 (t.211. .1 7.211/).4.504-4.549 (m ,111).2.217 (s, 3H), 1.338-1.353 (d, 6H, .1 6.0 Hz).

Intermediate LXVI

4-Isopropoxy-3-mcthyl-benzaldehydc

4-Isopi poxy-3-melhyl-benzaldehyde

I -lsopropoxy-2-methyl-benzene (intermediate LXV) was converted into 4-lsopropoxy-3- methyl-benzaldehyde using the synthetic procedure reported in JOC, 60, 23, 1995, 7479- 7490. The crude material was taken for next step.

Intermediate LXVIl

-Lsopropoxy-3-methyl-phenol

4-Isopropoxy-3-mcthyl-phenol

4-Isopropoxy-3-methyl-benzaldehyde (intermediate LXVI) was converted into 4- lsopropoxy-3-methyl-phenol using the synthetic procedure reported in EP 1040102 Bl. Ή NMR (400, MHz, CDC!₃ ) δ (ppm): 6.715-6.736 (d, IH, J=8.4 Hz), 6.634-6.641 (d. IH. .1-2.8 Hz), 6.563-6.591 (m ,1H), 4.442 (s, IH), 4.318-4.348 (m , IH), 2.172 (s, 311), 1.289- 1.303 (d, 6H, .1=5.6 Hz). Intermediate LXVIII

5-Brom -2-(4-isopropoxy-3-methyl-phenoxy)-thiazole

5-Bromo-2-(4-isopropoxy-3-methyl-phenoxy)-thiazole

4-lsopropoxy-3-methyl-phenol (intermediate LXVII) was reacted with 2,5 dibromothiazole similar to the procedure employed for the intermediate LI II to afford 5 l3romo-2-(4-isopropoxy-3-methyl-phenoxy)-thiazole in 63.9 % yield.

Ή N R (400 M Hz, CDC1₃ ) δ (ppm): 7.141 (s, 1 H), 6.990-7.026 (m, 2H), 6.812-6.833 (d I I I. .1 8,1 Hz), 4.477-4.507 (m, 1 H), 2.207 (s, 3H), 1 .338- 1 .353 (d, 61 1, .1=6.0 Hz).

Intermediate LXIX

l-Methoxy-2,3-dimethyl-benzene

l - eLhoxy-2.3-di methyl-benzene

2.3-dimethyl-phenol was converted into l -methoxy-2,3-dimethyI-benzene using the synthetic procedure reported in .I.Med.Chem., 2006, 49, 3770-3779.

Intermediate LXX

4-Me chydc

4- ethoxy-2,3 -d im ethy l-benzaldehyde

l -Methoxy-2,3-dimethyl-benzene (intermediate LXIX) was converted into 4-Methoxy- 2,3-dimethyl-benzaldehyde using the synthetic procedure reported in JOC, 60, 23, 1 995, 7479-7490. The crude material was purified by column chromatography (silica gel 100- 200 mesh, 5:95 Ethyl acetate: hexane) to afford 4-Methoxy-2,3-dimethyl-benzaldehyde in 39.86 % yield. LC/MS [M+I I] 165.2, Ή NMR (400 MHz, CDCi₃ ) δ (ppm): 1 0.1 53 (s, 1 H), 7.662-7.683 (d, H I. J=8.4 Hz), 6.824-6.846 (d, 1 H, J=8.8 Hz), 3.899 (s, 3H), 2.602 (s, 2H), 2. 1 87 (s, 31 1).

Intermediate LXX1

4- ol

4-Methoxy-2,3 -dimethyl-phenol

4-Methoxy-2,3-dimethyI-benzaIdehyde (intermediate LXX) was converted into 4- Methoxy-2,3~dimethyl-phenol using the synthetic procedure reported in EP 1040102 B 1 . Ή NMR (400 MHz, CDC1₃ ) δ (ppm): 6.598 (s, 2H), 4.340 (s, 1 H), 3.765 (s , 3 H), 2.163- 2.1 76 (d, 61 1. .1=5.2 Hz).

Intermediate LXX 11

5-Iiromo-2- -methoxy-2,3-dimethyl-phenoxy)-thiaz le

5-Bronio-2-(4-metlioxy-2,3-dimelhyl-phenoxy)-lliiazole

4- ethoxy-2,3-dimethyl-phenol (intermediate LXXI) was reacted with 2,5- dibromothiazole similar to the procedure employed for the intermediate LI 11 to afford 5- Bromo-2-(4-methoxy-2,3-dimethyl-phenoxy)-thiazole in 74.62 % yield.

Ή NM R (400 MHz, CDC1₃ ) δ (ppm): 7.127 (s, 1 H), 6.998-7.020 (d, 1 H, J=8.8 Hz), 6.71 7-6.739 (d, 1 H, .1=8.8 Hz), 3.828 (s, 3H), 2.1 62-2.179 (d, 6H, J=6.8 Hz).

Intermediate LXXIII

-2-phcnoxy-thiazol

5-Bromo-2-phenoxy-thiazole Phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermed iate LI I I to afford 5-Bromo-2-phenoxy-thiazole.

Intermediate LXXIV

-Bromo-2-o-toIyloxy-thiazolc

5-Bromo-2-o-tolyloxy-thiazole

2-Methyl-Phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LIII to afford 5-Bromo-2-o-tolyloxy-thiazole.

Intermediate LXXV

5-Bro -2-(2-trifluoromethoxy-phenoxy)-thiazole

5-Bromo-2-(2-tri nuoromethoxy-phenoxy)-thiazole

2-tri lluoi mcthoxy-phenol was reacted with 2,5-dibromothiazole sim i lar to the procedure employed for the intermediate LI I I to afford crude 5-Bromo-2-(2-tri fluoiOmcthoxy- phenoxy)-th iazolc which was taken as such for next step without any puri fication.

I C M S [M i I I] 342.2.

Intermediate LXXVI

l-[4-(2-Amino-thiazol-5-yloxy)-phenyl]-ethanone

l -|4-(2-Amino-thiazol-5-yloxy)-phenyl]-ethanone

A m ixture of 2-Am ino-5-bromothiazole monohydrobrom ide ( 1 0 g, 0.0384 mol), 4- hydroxyacetophenone (5.24 g, 0.0384 mol), potassium carbonate ( 1 3.3 g. 0.0962 mol) in 1 00 m l of N.lM-dimethylformamide was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column chromatography (silica gel 100- 200 mesh, 40:60 ethylacetate:hexane) to afford 1-[4-(2-Amino-thiazol-5-yloxy)-phenyl|- 5 ethanone in 24.4 % yield.

LCMS-[ +H] 235.4, Ή NMR (400 MHz, CDC1₃): 7.960-7.982_. (d, 2H, J=8.8 Hz), 7.149- 7.170 (d, 211, 8.4 Hz), 6.897 (s, 2H), 6.772 (s, lH), 2.485 (s, 1H).

Intermediate LXXVTI

l-|4-(2 hanonc

I Q l-[4-(2-Bromo-thiazol-5-yloxy)-pheny!]-ethanone

tert-Butylnitrite (1.21 g, 0.0117 mol) was added dropwise to a stirred solution of copper(l[)bromide (2.1 g, 0.0064 mol) in 30 ml acetonitrile at -10 °C and stirred for 5 min. Then a solution of l-|4-(2-Amino-thiazol-5-yloxy)-phenyl]-ethanone (intermediate I, X VI) (2.2 g, 0.0094 mol) in 20 ml acetonitrile was added dropwise at -10 °C and 1 stirred for two hours at -10 °C. Then the reaction mixture was filtered through celite and evaporated the solvent. The crude material was purified by column chromatography (silica gel 100-200 mesh, 10:90 ethylacetaterhexane) to afford l-[4-(2-Bromo-thiazol-5-yloxy)~ phcnylj-ethanone in 14.3 % yield.

LCMS-IM+2] 300.5, Ή NMR (400 MHz, CDCl₃):7.972-7.994 (d, 2H, .1=8.8 Hz), 7.248 0 (s, 1 H), 7.130-7.152 (d, 2H, J=8.8 Hz), 2.589 (s, 3H).

Intermediate LXXVIII

l-{4- -(2-Allyl-phenoxy)-thiazol-5-yloxy]-phenyI}-ethanone

l-{4-|^'2-(2-Allyl-phenoxy)-tliiazol-5-yloxy]-phenyl J -ethanone Λ mixture of 1 -|4-(2-Bromo-thiazol-5-yloxy)-phenyl]-ethanone (intermediate LX VI I) (0.2 g, 0.671 mmol), 2-allylphenol (0.089 g, 0.671 mmol) and potassium carbonate (0.1 85 g, 1 .34 mmol) in 2 ml of Ν,Ν-dimethylformamide was heated at 120 °C for 1 5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by column chromatography (silica gel 100-200 mesh, 1 5:85 ethylacetate:hexane) to afford l -{4-| 2-(2- A l lyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone in 65 % yield. LCMS-[M+H] 352.5.

Intermediate LXXIX

l -{4-[ -(2-Allyl-phenoxy)-thiazoI-5-yIoxy]-phenyl}-ethylamine

l - (4-[2-(2-Allyl-plienoxy)-thiazol-5-yloxy]-phenyl }-et ylamine l -{4-| 2-(2-Allyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate LXXV11 I) ( 1 55mg, 0.438 mmol), ammonium acetate (405 mg, 5.26 mmmol) and molecular sieves powder 4A ( I g) were taken in 10 ml of methanol and stirred at room temperature for 20 m inutes after which sodium cyanoborohydride (41 mg, 0.658 mmol) was added. The reaction m ixture was heated at 75 °C for 15 hours. The reaction mixture was cooled to room temperature and filtered through celite. The solvent was evaporated under vacuum to obtain crude which was dissolved in water and extracted with ethyl acetate. The combined organic extract was washed with brine and dried over anhydrous sodium sulphate and evaporated to afford crude l -{4-[2-(2-Allyl-phenoxy)-thiazol-5-yloxy |-phenyl}- ethylamine which was taken into the next step without any purification.

LCMS-[M+H] 353.6. Intermediate LXXX

l -{4-f2-(2-Ethyl-4-fluoro-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanonc

l -| 4-(2-Bromo-thiazol-5-yloxy)-phenyl]-ethanone (intermediate LXXVII) was reacted with 2-ethyl-4-fluorophenoI similar to the procedure employed for the intermediate I XVI I I to afford I -{4-| 2-(2-Ethyl-4-fluoro-phenoxy)-thiazol-5-yloxy]-phenyl} -ethanone in 83 % yield.

LCMS-I M+H] 358.2, Ή NMR (400 MHz, CDC 13): 7.953-7.975 (d, 1 H, .1=8.8 Hz), 7.192- 7.225 (m, I H), 7. 1 1 8-7.139 (d, 8.4 Hz), 7.002-7.032 (dd, J= 12.0 Hz, 2.8 Hz), 6.895-6.962 (in, 21 1), 2.642-2.669 (q, 2H, J=7.2 Hz), 2.575 (s, 3H), 1 .214- 1 .256 (t, 3H, J=7.2 Hz).

Intermediate LXXXI

l-{4-[2-(2-Ethyl-4-fluoro-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyIaminc

1 - j4-|2-(2-Eiliyl-4-fluoiO-phenoxy)-thiazol-5-yloxy]-plienyl ) -ethylainine l -{4-| 2-(2-Ethyl-4-fluoro-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate LXXX) was reacted with sodiumcyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate LXXIX to afford crude l -{4-| 2-(2-Ethyl-4- nuoro-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken as such for next step without any purification. Intermediate LXXXII

2-(l-Hyd l,4-diol

2-( I -Hydroxy-ethyl)-benzene- 1 ,4-diol

Sodiumborohydride (1 8.25 g, 493 mmol) was added portion wise to a stirred solution of 2- acctylhydroquinone (25.0 g, 164 mmol) in 500 ml of methanol at 0 °C over 30 minutes. The reaction mixture was stirred at room temperature for 1 5 hours. Then the reaction mixture was quenched with acetone and solvent was evaporated. The residue was taken in water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated to afford crude 2-( l - Hydroxy-ethyl)-benzene- 1 ,4-diol which was taken for next step without any puri fication. LC S-| M-I 1] 1 53.3.

Intermediate I. XXXIII

2-Ethyl-benzene-l ,4-diol

2-Ethyl-benzene-l ,4-diol

Trifluoroaceticacid ( 120 ml, 1623 mmol) was added dropwise to a solution of 2-( I - Hydroxy-ethyl)-benzene- l ,4-diol (intermediate LXXXII) (25 g, 162 mmol), triethylsi lane (26 ml, 162 mmol) in 250 ml of dichloromethane at 0 °C. The reaction mixture was stirred at room temperature for 1 5 hour. Then the reaction mixture was quenched with ice-cold water and evaporated the solvent. The residue was taken in water and extarcted with ethyl acetate. The comboned organic extract was washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified using column chromatography (si lica gel 100-200 mesh, 10:90 ethylacetate:hexane) to afford 2-Ethyl- benzene- l , 4-diol in 89 % yield. Intermediate LXXXIV

2-Ethyl-4-isopropoxy-phenol

2-Ethyl-4-isopropoxy-p enol

2-Ethyl-benzene-l,4-diol (LXXXII1) was converted into 2-Ethyl-4-isopropoxy-phenol using the reported synthetic procedure reported in J.Med. Chem., 2006, 49, 3770-3779. Ή NMR (400 MHz, CDC13): 8.672 (s, 1H), 6.593-6.639 (m, 2H), 6.470-6.535 (m, 1H), 4.326-4.370 (m, 1H), 2.435-2.488 (m, 2H), 1.172-1.187 (d, 6H, J=6.0 Hz), 1.062-1.099 (t, 311, J=7.2 Hz).

Intermediate LXXXV

l-{4-|2-(2-Et yl}-ethanonc

I - ( 4-[2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl J -ethanone l-|4-(2-Bromo-thiazol-5-yloxy)-phenyl]-ethanone (intermediate LXXVH) was reacted with 2-Ethyl-4-isopropoxy-phenol (intermediate LXXXIV) similar to the procedure employed for the intermediate LXXVIII to afford l-{4-[2-(2-Ethyl-4-isopropoxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone in 66% yield.

LCMS-IM+H] 398.6, Ή NMR (400 MHz, CDC13): 7.941-7.963 (d, 2H, J=8.8 Hz), 7.105- 7.133 (m, 3H), 6.905 (s, IH), 6.806-6.812 (d, 1H, J=2.4 Hz), 6.718-6.747 (dd, IH, .1=11.6 II/.2.4 Hz), 4.493-4.522 (m, IH), 2.602-2.659 (q, 2H, J=7.6 Hz), 2.569 (s, 111), 1.327- 1.342 (d, 6H, .1=6.0 Hz), 1.199.-1

.236 (t, 3H, .1=7.2 Hz). Intermediate LXXXVI

l -{4-|2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine

I -{4-| 2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate LXXXV) was reacted with sodiumcyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate LXXIX to afford crude l -{4-[2-(2-Ethyl-4- isopiOpoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken as such for next step without any purification.

Intermediate LXXXVII

l- ne

1 -Methoxy-4-methyl-benzene

Methyl iodide (8.6m l, 138 mmol) was added dropwise to a mixture of p-cresol ( 1 0 g. 92.47 mmol) and potassium carbonate (25.5 g, 1 84.94 mmol) in 1 00 m l of M.N- Dimethylformamide at 0 °C. Then the reaction mixture was stirred at room temperature for 1 5 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over anhydrous sodium sulphate and evaporated to afford 1 -Methoxy-4-methyl-benzene in 88% yield.

Ή NMR (400 MHz, CDC13): 7.078-7.099 (d, 2H, J=8.4 Hz), 6.798-6.819 (d, 21 1, .1=8.4 Hz), 3.785 (s, 3H), 2.291 (s, 3H). Intermediate LXXXVIII

l-(2-Metho l)-ethanone

I -(2-M elhoxy-5-methy]-pheny])-ethanonc

Λ solution of acetyl chloride (6.79 ml, 95.1 mmol). l-Methoxy-4-methyl-benzene (intermediate LXXXVII) (9.69 g, 79.4 mmol) in 50 ml of dichloromethane was added dropwise to a suspension of aluminium chloride (12.69 g, 95.1 mmol) in 50 ml of dichloromethane at 0 °C. ^rPhen the reaction mixture was stirred at room temperature for 3 hours. Then the reaction mixture was quenched with 1.5 N hydrochloric acid solution and extracted with dichloromethane. The combined organic extract was washed with water. brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified using column chromatography (silica gel 100-200 mesh, 15:85 ethylacetate:hexane) to afford l-(2-Methoxy-5-methyl-phenyl)-ethanone in 69 % yield. Ί-Ι NMR (400 MHz, CDCI3): 7.528 (s, JH), 7.247 (bs, lH), 6.852-6.873 (d, 111, J=8.4 Hz), 3.881 (s, 3H), 2.601 (s, 3H), 2.299 (s, 3H).

Intermediate LXXXIX

l-(2-Meth yl)-cthanol

l-(2-Methoxy-5-methyl-phenyl)-ethanol

1 -(2-Methoxy-5-methyI-phenyl)-ethanone (LXXXVIII) was reacted with sodiumborohydride similar to the procedure employed for the intermediate LXXXII to afford l-(2-Methoxy-5-methyl-phenyl)-ethanol which was taken as such for next step. Ή NMR (400 MHz, CDC13): 7.140 (s, 1H), 7.024-7.045 (d, I H, J=8.4 Hz), 6.768-6.788 (d, 1 If . J=8.0 Hz), 5.062 (m, 1H), 3.838 (s, 3H), 2.296 (s, 3H), 1.492-1.508 (d, 311, J=6.4 Intermediate LXXXX

2-Ethyl-l-methoxy-4-methyl-benzene

2-Ethyl-l -methoxy-4-methyl-benzene

I -(2-Methoxy-5-methyl-phenyl)-ethanol (intermediate LXXXIX) was reacted with Trifluoroaceticacid and triethylsilane. similar to the procedure employed for the intermediate LXXX II I to afford 2-Ethyl-l -methoxy-4-methyl-benzene in 88% yield. Ί-Ι NMR (400 MHz, CDC13): 6.950-6.985 (m, 2H), 6.728-6.750 (d, 1 I I, .1=8.8 Hz), 3.800 (s. 3 H), 2.578-2.634 (q, 2H, J=7.2 Hz), 2.277 (s, 3 H), 1 .1 64- 1 .202 (t, 31 .1=7.8 I I/.).

Intermediate LXXXXI

l

2-Ethyl-4-methyl-phenol

A solution of Borontri bromide (4.5 ml, 39.94mmol) in 50 ml of dichloromethane was added dropwise to a solution of 2-Ethyl- 1 -methoxy-4-methyl-benzene (intermediate LX XX X) (4.0 g, 26.62 mmol) in 50 ml of dichloromethane at 0 °C and stirred at same temperature for 60 minutes. The reaction mass was quenched with bicarbonate solution and di luted with water and the extracted with dichloromethane. The combined organic extract was washed with brine, dried over anhydrous sodium sulphate and evaporated to a fford crude 2-Ethyl-4-methyl-phenol which was used for next step w ithout any puri fication .

LCMS-ΓΜ-Η] 1 35.3 Intermediate LXXXXII

l -{4-[2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone

1 - !4-| 2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5-yloxy]-phenyl) -elhanone l -| 4-(2-BiOmo-thiazol-5-yloxy)-phenyl]-ethanone (intermediate LXXVI1) was reacted with 2-Ethyl-4-methyl-phenol (intermediate LXXXXI) simi lar to the procedure employed for the intermediate LXXVIII to afford l -{4-[2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5- yloxy |-phenyI }-elhanone in 36% yield.

LC S-[M+H] 354.6, Ή NMR (400 MHz, DMSO-d₆): 7.968-7.990 (d, 21 1, .1=8.8 Hz), 7. 1 30-7.225 (m, 5H), 7.070-7.089 (d, I H, J=7.6 Hz), 2.517-2.555 (m, 5H), 2.282 (s, 3 H), 1 . 1 06- 1 . 144 (m, 3H).

Intermediate LXXXXIII

l-{4-|2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine

1 - J4-[2-(2-lit yl-4-methyl-phenoxy)-thiazol-5-yioxy]-phenyl j -etliylamine l -{4-[2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5-yloxy]-phenyl} -ethanone (intermediate LXXXXII) was reacted with sodiumcyanoborohydnde and ammonium acetate similar to the procedure employed for the Intermediate LXXIX to afford crude l -{4-[2-(2-Ethyl-4- methyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken as such for next step without any purification.

LCMS-[M+H] 355.2. Intermediate LXXXXIV

2-Chloro-6-ethyl-phcnol

2-Chloro-6-etliyl-phenol

2-Ethyl-pheno_.l was converted into 2-chloro-6-ethyl-phenol using the synthetic procedure outl ined in Biorg. Med. Chem. Lett., 2005, 3347-3351.

LCMS:|M-H] 155.2, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.152-7.1 72 ( d, I H, .1=8.0 Hz), 7.042-7.061 (d, I H, J=7.6 Hz), 6.780-6.819 (t, I H, J=8.0 Hz), 5.574 (s, I H) 2.663- 2.719 ( q, 2H, J=7.2 Hz ), 1 .209-1 .280 (m, 3H).

Intermediate LXXXXV

] -{4-|2-(2-Chloro-6-cthyl-phenoxy)-thiazol-5-yloxy]-phenyl}-et anonc

I - ! 4-[2-(2-Cliloro-6-ethyl-phenoxy)-thiazo]-5-yloxy]-phenyl } -el anone

I -| 4-(2-Bromo-thiazoI-5-yloxy)-phenyl]-ethanone (intermediate LXXVI I) was reacted with 2-chloro-6-ethyl-phenol (intermediate LXXXXIV) similar to the procedure employed for the intermediate LXXVIII to afford l -{4-[2-(2-Chloro-6-ethyl-phenoxy)-thiazol-5- yloxy]-phenyl}-ethanone in 40% yield.

LCMS:[M+H] 374.6, ' H MR (400 MHz, CDCI₃) δ (ppm): 7.961 -7.983 (d, 2H, .1=8.8 Hz), 7.321 -7.344 (dd, I H, J=9.2 Hz, 1 .6 Hz), 7.175-7.259 (m, 2H) 7.1 25-7.146 (d, 21 1. .1=8.4 Hz), 6.866 (s, I H), 2.676-2.733 (q, 2H, J=7.6 Hz), 2.578 (s, 3H). 1 .222- 1 .259 (m, 31 1). Intermediate LXXXXVI

l-{4-[2-(2-C }-ethyl

l - | 4-|2-(2-Chloro-6-et yl-phenoxy)-thiazol-5-yloxy]-phenyl) -et ylamine l -{4-| 2-(2-Chloro-6-ethyl-phenoxy)-thiazol-5-yloxy]-phenyi} -ethanone (intermediate LXXXXV) was reacted with sodiumcyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate LXXIX to afford crude 1 -{4-[2-(2-Chloro-6- ethyl-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethylamine which was taken as such for next step without any purification.

LCMS:| M+H] 375.6

Intermediate LXXXXVII

i-{4-[2-(2-Methoxy-phenoxy)-thiazoI-5-yIoxy]-phenyl}-ctha

l - {4-|^'2-(2-Methoxy-phenoxy)-thiazol-5-yloxy |-phenyl j -ethan nc l -| 4-(2-Bromo-thiazol-5-yloxy)-phenyl]-ethanone (intermediate LXXVI I) was reacted with 2-methoxy-phenol similar to the procedure employed for the intermediate LXXVII1 to afford 1 -{4-[2-(2-Methoxy-phenoxy)-thiazoI-5-yloxy]-phenyl}-ethanone.

Ή NMR (400 MHz, DMSO-d₆): 7.980-8.001 (d, 2H, J= 8.4 Hz), 7.286-7.362 (m, 2H), 7.1 99-7.221 (d, 3H, .1=8.8 Hz), 7.1 13 (s, I H), 6.985-7.004 (m, I H), 3.795 (s, 3H), 2.532 (s, Intermediate LXXXXVIH

l-{4-[2-(2-Methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylaminc

1 - )4-[2-(2-Methoxy-phenoxy)-thiazol-5-yloxy]-phenyl J -ethylamine I -{4-|2-(2-Methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate LXXXXVIl) was reacted with sodiumcyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate LXX1X to afford crude l-^'{4-|2-(2-Methoxy- phcnoxy) hiazol-5-yloxy|-phenyl}-ethylamine which was taken as such for next step without any purification.

LCM-S [M+H] 343.1

Intermediate LXXXXIX

3-Chloro-5-methoxy-phenol

3-Chloro-5-methoxy-phenol

Sodium methanelhiolate (3.04 g, 43.37 mmol), was added to a solution of l-chloro-3.5- dimethoxy benzene (5.0 g, 28.96 mmol) in 20 ml of l-Methyl-2-Pyrrolidone and the reaction mixture was heated at 140 °C for 2.5 h then stirred at room temperature over night. l-Methyl-2-pyrrolidone was removed under reduced pressure and the material partitioned between ethyl acetate/water/lN hydrochloric acid. The organic layer was washed twice with IN hydrochloric acid, brine, dried over sodium sulfate and solvent removed under reduced pressure to give a yellowish solid. The solid was purified by column chromatography (silica gel 60-120 mesh, 10:90 ethylacetate:hexane) to afford 3- Chloro-5-methoxy-phenol in 76.4 % yield.

MS [M-H] 157.2, Ή NMR (400 MHz, CDCI₃) δ (ppm): 6.455-6.500 (d, 2H, J=I8.0 Hz), 6.291 (s, 1H), 4,978 (s, III), 3.767 (s, 3H). Intermediate D

l-{4-|2-(3-Cliloro-5-methoxy-phenoxy)-thiazoI-5-yIoxy]-phenyI}-etlianone

l-i4-[2-(3-Chloi -5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone 1 -|4-(2-Bromo-tliiazol-5-yloxy)-phenyi]-ethanone (intermediate LXXVll) was reacted with 3-Chloro-5-methoxy-phenol (intermediate LXXXXIX) similar to the procedure employed for the intermediate LXXVIII to afford l-{4-[2-(3-Chloro-5-methoxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone.

Intermediate DI

l-{4-[2-(3-Chloro-5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyI miiic

l-{4-|2-(3-Chloro-5-metlioxy-phenoxy)-thiazol-5-yloxy]-p enyl) -eth lamine l-{4-|2-(3-Chloro-5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethanone (intermediate D) was reacted with sodiumcyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate LXXIX to afford crude l-{4-|2-(3-Chloro-5- methoxy-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethylamine which was taken as such for next step without any purification.

Intermediate DII

N-(l-{4-[2-(3-C ethyl)-acetamide

N-( I- J -[2-(3-Chlor -5-hydroxy-phenoxy)-thiazol-5-yloxy]-plienyr]-etliyl)-acelamidc M-( l -{4-|^'2-(3-Chloro-5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl }-ethyl)-acetam ide (Example 23) was reacted with borontribromide similar to the procedure employed for the intermediate LXIV to afford N-(l -{4-[2-(3-Chloro-5-hydroxy-phenoxy)-thiazol-5-yloxy |- phcnyl }-cthyl)-acetamide, which was taken for the next step without any purification.

Intermediate Dili

-Bromo-2-m-tolyloxy-thiazole

5-Bromo-2-m-tolyloxy-thiazole

3-Met^'hyl-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate LI 1I to afford crude 5-Bromo-2-m-tolyjoxy-thiazole which was taken as such for next step without any purification.

Intermediate DIV

5-Bromo-2-(2-chloro-4-propoxy-phenoxy)-thiazolc

5-Bromo-2-(2-chloro-4-propoxy-phenoxy)-thiazole

2-Chloro-4-propoxy-phenol was reacted with 2,5-dibromothiazole similar to the procedure employed for the intermediate L1I1 to afford crude 5-Bromo-2-(2-chloro-4-propoxy- phenoxy)-thiazole which was taken as such for next step without any purification

Intermediate DV

5-Brom -2-(4-cyclopentyloxy-2-methyl-phenoxy)-thiazole

5-Bromo-2-(4-cyclopentyloxy-2-methyl-phenoxy)-thiazole 2-Chloro-4-cyclopentyloxy-phenol was reacted with 2,5-dibromothiazole to afford crude 5-Bromo-2-(4-cyclopentyloxy-2-methyl-phenoxy)-thiazole which was taken as such for next step without any purification.

Intermediate DVI

N-(l -{4-[ -(4-IIydroxy-phenyl)-thiazoI-5-yloxy]-phenyl}-ethyl)-aceta

H-( l - ,^,4-[2-(4-Hydroxy-p enyl)-thiazol-5-yloxy]-phenyl } -ethyl)-acetamide

A solution of Borontribromide (0.07 ml, 0.733 mmol) in 5 ml of dichloromethane was added dropwise to a solution of the synthesized intermediate N-( l -{4-[2-(4-Methoxy- phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (90 mg, 0.2442 mmol) in 1 5 m l dichloromethane at -78 °C. Then the reaction mixture was stirred at room temperature for 1 5 hours. The reaction mass was quenched with bicarbonate solution and di luted with water and the extracted with dichloromethane. The combined organic extract was washed with bri ne, dried over anhydrous sodium sulphate and evaporated to afford crude N-( l -{4- | 2-(4-[ lydi xy-phenyl)-thiazol-5-yloxy |-phenyl}-ethyl)-acetamide which was used for next step without any purification.

LCMS-[M+H |- 355.2, H 'NMR (400 MHz, DMSO-d6): 9.939 (s, 1 H), 8.230-8.249 (d, 1 I I. .1=7.6 Hz), 7.648-7.669 (d, 2H, J=8.4 Hz), 7.498 (s, I H), 7.308-7.329 (d, 2H, .1= 8.4 Hz), 7.1 1 7-7.1 38 (d, 2H, J= 8.4 Hz), 6.816-6.837 (d, 2H, J=8.4 Hz), 4.859-4.896 (m_s I H), 1 .81 0 (s, 3H), 1 .298- 1 .3 16 (d, 3H, J=7.6 Hz).

Intermediate DVII

l -{4-[2-(3-Isopropoxy-phenyl)-thiazol-5-yIoxy]-phenylj-ethylamine

I -!4-[2-(3-Isopropoxy-phcnyl)-thiazol-5-yloxy]-p eny!J-etliylaminc

The synthesized intermediate ]-{4-[2-(3-Isopropoxy-phenyl)-thiazol-5-yloxy ]-phenyl}- cthanone was reacted with sodium cyanoborohydride and ammonium acetate similar to the procedure employed for the Intermediate I to afford crude l-{4-|2-(3-lsopropoxy- phcnyl)-thiazol-5-yloxy] phenyl} ethylamine which was taken as such for next step without any purification.

Intermediate DVIII

l-{4-|2-(4 thylamine

I - 1 -|2-( -Isopropoxy-2-melhyI-phenyl)-tliiazol-5-yloxy]-p enyl ] -ethylamine

The synthesized intermediate I -{4-[2-(4-Isopropoxy-2-methyl-phenyl)-thiazol-5-yloxy |- phenyl}-ethanone was reacted with ammonium acetate and sodium cyanoborohydrdidc similar to the procedure employed for the Intermediate I to afford 1 -{4-|2-(4-Isopropoxy- 2-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-ethylamine which was taken directly for next step without any purification.

Example 1

N-(l-{4-f2-(4-Isopropoxy-2,3-dimethyl-phenoxy)-thiazol-5-yloxy]-phenyl}-i

acetamidc

A mixture of 5 3romo-2-(4-isopropoxy-2,3-dimethyl-phenoxy)-thiazole (intermediate XXI) (300 mg, 0.877 mmol), lM-[] -(4-Hydroxy-phenyl)-ethyI]-acetamide (intermediate XX) ( 1 57 mg. 0.877 mmol), cesium carbonate (570 mg, 1 .75 mmol), copper iodide ( 1 66 mg, 0.877 mmol) in 3 ml of Ν,Ν-dimethylformamide was heated at 120 °C for 1 5 hour. I hen the reaction mixture was cooled to room temperature, diluted with water and fi ltered through celite and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by preparative HPLC to afford N-( l -{4-| 2-(4- lsopi poxy-2,3-dimethyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 1 0 % yield.

MS | M+H] 441 .2, Ή-NMR (400 MHz, DMSO d₆) δ (ppm): 8.196-8.21 5 (d, I H, .1-7.8 Hz), 7.270-7.291 (d, 2H, J=8.4 Hz), 7.017-7.078 (m, 4H), 6.851 -6.873 (d, I H, .1=8.8 Hz), 4.830-4.883 (m, 1 H), 4.484-4.544 (m, I H), 2.085 (s, 6H), 1 .795 (s, 3 H), 1 .275- 1 .293 (d. 31 1. J--7.2 Hz), 1 .238-1 .253 (d, 6H, J=6 Hz).

The compound showed IC50 for hACC2 and hACC l of 1.84uM and >40uM respectively.

·

Example 2

N-(l -{4-[2-(4-Isopropoxy-phcnoxy)-thiaz0l-5-yloxy]-phenyl}-ethyl)-acetamidc

l -{4-|2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyI}-ethylamine (intermediate

XXV) (350 mg, 0.945 mmol) was taken in 10ml THF to which diisopropyl ethyl amine (0.32 ml, 1 .89 mmol) was added at 0°C. The mixture was stirred at this temperature after which acetyl chloride (0.073 ml, 1.03 mmol) was added slowly. The reaction mixture was warmed to room temperature and maintained for Ih. To the reaction mass was added water and extracted with ethyl acetate twice. The organic extracts were washed with saturated ammonium chloride, water and brine and dried over anhydrous sodium sulphate. The material was purification by preparative TLC to afford N-(l-{4-[2-(4-Isopropoxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 12 % yield.

MS [M+H] 413.4, ¹ H-NMR (400 MHz, DMSO d₆) δ (ppm): 8.201-8.220 (d, IH, J=7.6 Hz);7.236-7.298(q, 4H,J=8.8 Hz); 7.042-7.083(t,3H,J=8.8 Hz );6.943-6.965 (d,2H,J=8.8 Hz) ; 4.854-4.878 (t,lH,); 4.558-4.588 (q,l H,);l .798 (s,3H,);l .279-1.297(d, 1 H,J=7.2 Hz); 1.235- 1.251 (d,6H,J=6.4Hz).

The compound showed IC50 for hACC2 and hACCI of 0.429 uM and 2.2uM respectively.

Example 3

(l-{4-[2-(4-Isopropoxy-phenoxy)-thiazoI-5-yloxy]-phenyl}-ethyl)-carbam

methyl ester

I - {4-|2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine (intermediate

XXV) (150 mg, 0.405 mmol) was taken in 3ml THF to which triethylamine (67 mg, 0.67 mmol) was added at 0°C. The mixture was stirred at this temperature after which methyl chloiOformate (0.031 ml, 0.0.405 mmol) was added slowly. The reaction mixture was warmed to room temperature and maintained for Ih. To the reaction mass was added water and extracted with ethyl acetate twice. The organic extracts were washed with brine and dried over anhydrous sodium sulphate. The material was purification by preparative TLC to afford (l-{4-[2-(4-Isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-carbamic acid methyl ester in 19 % yield.

MS M HI] 429.4, H-NMR (400 MHz, DMSO d ) δ (ppm): 7.611-7.630 (IH, J 7.8 Hz), 7.284-7.305 (d, 2H, J=8.4 Hz), 7.237-7.259 (d, 2H, J-8.8 Hz), 7.043-7.081 (m, 311), 6.932-6.965 (m, 2H), 4.541-4.630 (m, 2H), 3.476 (s, 3H), 1.279-1.297 (d, 3H, J=7.2 Hz), 1.235-1.250 (d,6H,J=6 Hz)

The compound showed 1C₅₀ for hACC2 and hACCI of 8.8uM and 9.01 uM respectively. Example 4

N-(l-{4-[2-(2-Chloro-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyI}-ethyl)-

5-Bromo-2-(2-chloro-4-isopropoxy-phenoxy)-thiazole (intermediate XXVI) was reacted with N-| l-(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(l-{4-[2-(2-Chloro-4-isopropoxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 12% yield.

MS [Mi-11] 447.1, 'll-NMR (400 MHz, DMSO d₆) δ (ppm): 8.250-8.268 (d, 111.1=7.2 Hz), 7.342-7.363 (d, 2H, J=8.4 Hz), 7.241-7.263 (d, 2H, J=8.8 Hz), 7.103-7.109 (d. 1 H, .1=2.4 Hz), 7.018 (s, 111), 6.886-6.916 (dd, lH, J=12 Hz, 2.4 Hz), 4.877-4.913 (m. Ill), 4.572-4.602 (m, IH), 1.816 (s, 3H), 1.305-1.322 (d, 3H, J=6.8 Hz), 1.218-1.233 (d.611. .1 -6 Hz).

The compound showed IC50 for hACC2 and liACCl of 1.33uM and >50uM respectively.

Example 5

N-(l-{4-[2-(2-Chloro-4-ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-cthyl)

-acetamide

I -{4-[2-(2-Ghloro-4-ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine (intermediate XXXVIll) was reacted with acetyl chloride similar to the procedure employed for

Example 3 to afford N-(l-{4-[2-(2-Chloro-4-ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}- cthyl)-acetamide in 7% yield LC/MS [M+H] +433.3, Ή-NMR (400MHz, CDC1₃) δ (ppm): 7.269-7.244 (m, 2H,), 7.233 (s, 1 H), 7.087-7.060 (d, 2H, J=10.8Hz), 6.995-6.989 (d, 1 H, J = 2.4Hz), 6.843-6.81 3 (m, 2H), 5.639-5.624 (d, 1 H, J=6Hz), 5.123-5.086 (m, 1 H,), 4.042-3.989 (m, 2H)_S 1 .989 (s,3H), 1 .500-1 .482 (d, 3H, J=7.2), 1.413-1.398 (t, 3H, J=2.4Hz) .

The compound showed IC₅₀ for hACC2 and hACC l of 0.245uM and 0.57u respectively.

Example 6

4-[2-(4-Cyclopropylmcthoxy-phcnoxy)-thiazol-5-yloxy]-phenyl}-elhyl)- acetamide

To the solution of l -{4-[2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}- ethylamine (intermediate XXIX) in DCM was reacted with acetic acid, in DC and al lowed to stirr at RT overnight . To the reaction mass was added water and extracted with ethyl acetate twice. The organic extracts were washed with brine and dried over anhydrous sodium sulphate and evaporated. The crude material was purified by preparative FLC to afford N-( l -{4-| 2-(4-Cyclopropylmethoxy-phenoxy)-thiazol-5-yloxy|-phenyl} -ethyl)- acetamide in 20% yield.

MS [M+H] 425.3, Ή-NMR (400 MHz. DMSO d₆) δ (ppm): 8.200-8.219 (d, 1 1 1. .1-7.8 Hz), 7.243-7.296 (m, 4H), 7.039-7.081 (m, 21 1), 6.953-6.975 (d, 2R .1=8.8 Hz), 4.834- 4.870 (m, 1 IT), 3.789-3.806 (d, 2H, J=6.8 Hz), 1 .797 (s, 3H), 1 .278- 1 .296 (d, 3H, J-7.2 Hz), 1 . 162-1 .212 (m, 1 H), 0.526-0.570 (m, 2H), 0.280-0.3 17 (m, 2H).

The compound showed 1C₅₀ for hACC2 and hACCl of 0.629uM and 0.577uM respectively. Example 7

N-(l -{4-[2-(4-Cyclopcntyloxy-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethyI)-acetamide

1 -{4-|2-(4-Cyclopentyioxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine (intermediate XXXXVII) was reacted with acetyl chloride similar to the procedure employed for

Example 3 to afford N-(l-{4-[2-(4-Cyclopentyloxy-phenoxy)-thiazol-5-yloxy |-phenyl}- ethyl)-acetamide.

LC/MS [M+ITJ+439.4 ¹ H-NMR (400 MHz, CDC 13 ) δ (ppm):7.260(s,1 H),7.155-7.177 (d_;2H,J=8.8 Hz),7.032-7.053(d,2H, J=8.4 Hz),6.845-6.885(t,3H,J=7.2 Hz),7.009-7.025 (d,2II,.I=6.4 Hz),5.598 (bs, 1 H),5.082-5.134(m,l H),4.720-4.910(m, 1 H), 1.979(s,3H) 1.799- l.862(m,6H),l.460-1.477(d,3H,J=6.8 Hz), 1.293-1.352(m,2H)

The compound showed IC₅₀ for hACC2 and hACCl of 0.519uM and 0.605uM respectively.

Example 8

N-(I-{4-[2-(2-Methyl-4-propoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-cthyl)-acetamidc

5-Bi mo-2-(2-methyl-4-propoxy-phenoxy)-thiazole (intermediate XXXIX) was reacted with N-| I -(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(1 -{4-|2-(2-Methyl-4-propoxy- phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 9% yield

LC/MS [ VI tllj +427.4, ¹ H-NMR (400MHz, CDC1₃) δ (ppm): 7.279-7.259 (d, 111. .1 8ll/)_r 7.116-7.094 (d, 1H, J=8.8Hz), 7.044-7.023 (d, 2H, J=8.4Hz), 6.837 (s, I1L). 6.749 (s, 1H), 6.743-6.727 (m, 2H), 5.641-5.625 (d, 1H, J=6.4Hz), 5.135-5.064 (m, 111), 3.907-3.875 (t, 2H, J=6Hz), 2.252 (s,3H), 1.898 (s, 3H), 1.818-1.766 (m, 2H), 1.479- 1.461 (d, 3H, J=7.2Hz), 1.044-1.088 (t, 2H, J=6.8Hz) .

The compound showed IC50 for hACC2 and hACCl of 0.17uM and 0.26uM respectively.

Example 9

-(l-{4-[2-(4-Cyclopentyloxy-2-methyl-phenoxy)-thiazol-5-yloxy]-phcnyl}-cthyl)- acetamide

5-13romo-2-(4-cyclopentyloxy-2-methyl-phenoxy)-thiazole (intermediate DIV) was reacted with N-| 1 -(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) to afford N-(l- {4-|2-(4-Cyclopcntyloxy-2-methyl-phenoxy)-thiazol-5-yloxy]-phenyI}-ethyl)-acetamide. Ή NMR (400 MHz, DMSO-d₆): 8.197-8.217 (d, 1H, J=8.0 Hz), 7.276-7.297 (d, 2H, .1=8.4 Hz), 7.163-7.185 (d, IH, .1=8.8 Hz) 7.020-7.070 (m, 3H), 6.847 (s, 1H), 6.747-6.776 (dd, III, .1-3.2 Hz, 11.6 Hz), 4.835-4.872 (m, 1H), 4.759-4.787 (m, 1H), 2.153 (s, 3H), 1.881- 1.892 (m, 211), 1.799 (s, 3H), 1.669-1.680 (m, 4H), 1.557 (m, 2H), ! .279-1.297 (d, 311. .1 7.2 I Iz).

Example 10

N-(l-{4-[2-(2-Bromo-4-cycIopentyIoxy-phenoxy)-thiazoI-5-yIoxy|-phenyI}-cthyl)- acctamide

Λ mixture of 5-Bromo-2-(2-bromo-4-cyclopentyloxy-phenoxy)-thiazole (intermediate Llll) (300 mg, 0.7159 mmol), ^"N-| l-(4-Hydroxy-phenyl)-ethyl]-acetamidc (intermediate XX) (140 mg, 0.7875 mmol), cesium carbonate (465.3 mg, 1.4318 mmol) and copper iodide (0.068 mg, 0.3579 mmol) in 5 ml of Ν,Ν-dimethylformamide was heated at 120 °C for 15h. Then the reaction mixture was cooled to room temperature, diluted with water and filtered through celite. The filtrate was extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by preparative HPLC to afford N-(l -{4-|2-(2- Bromo-4-cyclopentyloxy-phenoxy)-thiazol-5-yloxy]-Phenyl ethyl) acetamide in 8.9 % yield.

LCMS:[ M+H] 519.5, Ή_. NMR (400 MHz, CDC1₃) δ (ppm): 7.336-7.356 (d, 2H, J=8.0 Hz), 7.205-7.226 (d, 2H, J=8.4 Hz), 7.034-7.123 (m, 2H), 6.761-6.828 (m, 211) 5.715- 5.731 (d, HI, .1-6.4 Hz), 5.103-5.173 (m.lH), 4.670-4.696 (m, 1H), 1.983 (s, 3H), 1.739- 1.933 (m.61-1), 1.476-1.493 (d, 3H, .1=6.8 Hz), 1.256-1.290 (d, 211, J=13.6 Hz).

Example 11

N-(l-{4-[2-(4-Ethoxy-2-methyl-phenoxy)-thiazol-5-yloxy]-phenyI}-ethyI)-acctamide

5-Bromo-2-(4-ethoxy-2-methyl-phenoxy)-thiazole (intermediate XXXX) was reacted with N-|^'l -(4-Hydroxy-phenyl)-ethyr|-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(l-{4-[2-(2-Methyl-4-propoxy-phenoxy)-thiazol- 5-yloxy |-phenyl}-ethyl)-acetamide in 6% yield.

LC/MS I M · 111 -1413.3, Ή-NMR (400 VI Hz, CDC1₃) δ (ppm): 7.279-7.259 (d. 111. .1 811/). 7.118-7.096 (d, III, J==8.8Hz), 7.045-7.023 (d, 2H, J 8.811/). 6.839 (s, III.). 6.779 (s, III), 6.746-6.717 (m, 2H), 5.669-5.653 (d, IH, J=6.4Hz), 5.117-5.081 (m, 111), 4.030-3.977 (m, 2H), 2.253 (s,3H), 1.992 (s, 3H), 1.480-1.462 (d, 3H, J=7.2Hz), 1.350- 1.301 (t,2H,J=6.4Hz) .

The compound showed IC₅₀ for hACC2 and hACCl of 0.306 uM and 0.88 uM respectively. -

Example 12

N-(l-{4-[2-(4-lsopropoxy-2-methyl-phenoxy)-thiazol-5-yloxy]-phenyl}-cMiyl)-

5-BiOmo-2-(4-isopropoxy-2-methyl-phenoxy)-thiazole (intermediate XXX XI 11) was reacted with N-| l-(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(l-{4-[2-(4-Isopropoxy-2-methyl- phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 5% yield. LC/MS [M+H] +427.6, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.260-7.281 (d, 111, J=8.4 Hz);7.088-7.110 (d, 111, J=8.8 Hz,); 7.023-7.044 (d,2H,J=8.4 Hz );6.841 (s,lll,) ; 6.770 (s.l 11.): 6.684-6.734 (dd,lH,J=6.4 Hz); 5.612-5.627 (d,IH, J=6.0 Hz);5.080-5.115(1.111, .1-6.8 Hz);4.458-4.519(m,l H,);2.247 (s,3H);1.983 (s,3H,);l .460-1.478(d,311,1-7.2 I Iz); 1.317- 1.331 (d,6H, .1=5.6 Hz)

The compound showed 1C₅₀ for hACC2 and hACCl of 0.25 uM and 0.813 uM respectively.

Example 13

N-(l-{4-[2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acctamide

l-{4-|2-(2-Bthyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine

(intermediate LXXXVI) was reacted with acetyl chloride similar to the procedure employed for the Example 39 to afford crude material, which was purified by preparative TEC to afford N-(l -{4-[2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy |-phenyl}- cthyl)-acetamide in 54 % yield.

LCMS-IM+H] 441.7, Ή NMR (400 MHz, DMSO-d₆): 8.197-8.216 (d, 111, T-7.6 Hz), 7.276-7.297 (d, 2H, J=8.4 Hz), 7.173-7.195 (d, IH, J=8.8 Hz), 7.024-7.065 (m, 3H), 6.855 (s, IH), 6.775-6.804 (dd, IH, J=l 1.6 Hz, 2.4 Hz),4.835-4.871 (m, IH), 4.546-4.606 (m, IH), 2.485-2.545 (m, 2H), 1.798 (s, 3H), 1.278-1.296 (d, 3H, J=7.2 Hz), 1.250-1.264 (d, 6H, J=5.6 Hz), 1.093-1.130 (t, 3H, 7.2 Hz).

TM-(l-{4-|2-(2-Ethyl-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide was further purified by chiral HPLC using Chiralpak IA (250mm*4.6mm) column and was eluted at 50:50 heptane: ethyl acetate. The first isomer (Isomer A) was eluted at retention time (R₍) of 11.269 min and the second isomer (Isomer B) was eluted at retention time (R_t) of 16.734 min. Once the column was completed the solvent was evaporated to afford the respective isomers as gummy material.

Isomer A: LCMS-[M+H] 441.7, Ή NMR (400 MHz, CDC1₃): 7.260-7.280 (m, 211), 7.097-7.119 (d, IH, .1=8.8 Hz), 7.022-7.043 (d, 2H, .1=8.4 Hz), 6.840 (s, IH), 6.802 (s. Ill), 6.708-6.737 (dd, IH, J=l 1.6 Hz, 2.8Hz), 5.574-5.588 (d, IH, J=7.6 Hz), 5.062-5.133 (m, IH), 4.473-4.533 (m, 1H), 2.593-2.650 (q, 2H, J=7.6 Hz), 1.979 (s, 3H), 1.459-1.477 (d, 311, J=7.2 Hz), 1.324-1.340 (d, 6H, J=6.4 Hz), 1.190-1.227 (t, 3H, 7.2 Hz),

isomer B: LCMS-[M+H] 441.7, Ή NMR (400 MHz, CDCI₃): 7.260-7.281 (m, 2H)_S 7.097-7.119 (d, IH, J=8.8 Hz), 7.021-7.043 (d, 2H, J=8.8 Hz), 6.840 (s, IH), 6.802 (s, IH), 6.708-6.737 (dd, 1 H, J=11.6 Hz, 2.8Hz), 5.574 (bs, IH), 5.062-5.133 (m, IH), 4.473- 4.533 (m, IH),^' 2.593-2.650 (q, 2H, J=7.6 Hz), 1.979 (s, 3H), 1.459-1.477 (d, 3H, .1=7.2 11/.), 1.324-1.340 (d, 611, J=6.4 Hz), 1.190-1.227 (t, 311, 7.2 Hz).

Example 14

N-(l-{4-[2-(3-Ethoxy-phenoxy)-thiazoI-5-yloxy]-phenyI}-ethyl)-acetamide

5-Bromo-2-(3- ethoxy-phenoxy)-thiazole (intermediate LIX) was reacted with N-| l-(4- I lydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for Example 10 to affbrd N-(l-{4-|2-(3-Ethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)- acetamide in 10 % yield.

LC/MS I I · 111399.6, Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.286-8.266 (d, 111, .1=8 Hz), 7.372-7.350 (d, 2H, J=8.8 Hz), 7.313-7.247 (m, 3H), 7.101-7.073 (m, 1 H), 6.897- 6.837 (m, IH), 6.726-6.672 (m, 2H), 4.917-4.838 (m, IH), 4.048-3.972 (m.1 II), 1.81 (s. 311), 1.326-1.316 (d, 311, J=4 Hz).

{Example 15

N-(l-{4-[2-(2-Chloro-4-p henyI}-ethyl)-acetamide

5-Bromo-2-(2-chloro-4-propoxy-phenoxy)-thiazole (intermediate DV) was reacted with N-| l-(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 10 to afford N-(l-{4-[2-(2-Chloro-4-propoxy-phenoxy)- thiazol-5-yloxy]-phenyl}-ethyl)-acetamide.

LC S-IM+HJ 447.6, Ή NMR (400 MHz, DMSO-d₆): 8.250-8.270 (d, IH, J=8.0 Hz), 7.343-7.365 (d, 2H, .1=8.8 Hz), 7.224-7.263 (m, 3H) 7.121-7.129 (d, IH, J=3.2 Hz), 7.013 (s, III), 6.905-6.935 (dd, 1H, J=2.8 Hz, 12.0 Hz), 4.879-4.915 (m, IH), 3.898-3.931 (t, 2H, J=6.8 Hz), 1.818 (s, 3H), 1.661-1.713 (m, 2H), 1.307-1.325 (d, 3H, J=7.2 Hz), 0.924- 0.961 (t, 3H, J=7.6 Hz). Example 16

N-(1-{4-f2-(2-EthyI-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamidc

5-Bi iTio-2-(2-ethyl-phenoxy)-thiazole (intermediate LV11) was reacted with N-| I -(4- Hydroxy-phenyl)-ethyl]-acetarnide (intermediate XX) similar to the procedure employed for the Example 10 to afford N-(l-{4-[2-(2-Ethyl-phenoxy)-thiazol-5-yloxy]-phenyl}- ethyl)-acetamide in 5 % yield.

LCMS:[ M+H] 383.6, Ή N R (400 MHz, DMSO-d₆) δ (ppm): 8.203-8.223 (d, 111, J=8 Hz), 7.239-7.305 (m, 6H), 7.042-7.085 (t, 3H, .1=8.4 Hz), 4.839-4.893 (m, IH).2.561- 2.654 (m, 2H), 1.800 (s, 3H), 1.282-1.299 (d, 3H, J=6.8 Hz), 1.116-1.154 (t, 3H_: J=7.6 11z).

N-( I -{4-|2-(2-Ethyl-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (Example 16) was further purified by chiral HPLC using Chiralpak 1A (250mm*4.6mm) column and was eluted at 100 % ethyl acetate. The first isomer (Isomer A) was eluted at retention time (R,) of 10.658 minute and the second isomer (Isomer B) was eluted at retention time (R,) of 13.910 min. Once the column was completed the solvent was evaporated to afford the respective isomers as gummy material.

isomer A: LCMS:[ M+H] 383.6, Ή NMR (400 MHz, CDCi₃) δ (ppm): 7.157-7.309 (m, 6H), 7.027-7.050 (d, 2H, J=9.2 Hz), 6.841(s,IH), 5.076-5.112 (t, 1H, J=7.2 Hz), 2.655- 2.713 (q_;2H, J=7.6 Hz), 1.973 (s, 3H), 1.455-1.472 (d, 3H, J=6.8 Hz), 1.245-1.257 (d, 3H, .1=4.8 Hz).

Isomer B: LCMS:f M+H] 383.6, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.146-7.309 (m, 6H), 7.026-7.048 (d, 2H, J=8.8 Hz), 6.839 (s, IH), 5.710-50725 (d, IH, J=6 Hz), 5.075- 5.111 (t, IH, .1=7.2 Hz), 2.655-2.712 (q, 2H, J=7.6 Hz), 1.971 (s, 3H), 1.454-1.470 (d, 311. J-6.4 Hz), 1.245-1.257 (d, 3H, J=4.8 Hz). Example 17

N-(l -{4-[2-(2-Ethyl-4-methyl-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethyl)-acetamidc

To a solution of Acetic acid (27 mg, 0.423 mmol), triethylamine (0.1 77 ml. 1 .27 mmol) in 2 m l dichloromethane at 0 °C was added EDC.HCl ( 121 mg, 0.64 mmol), N-hydroxy benzcnetriazole (HOBt) (57 mg, 0.423 mmol) and the mixture was allowed to stirr for 1 5 minutes at same temperature and then added a solution of l -{4-| 2-(2-Ethyl-4-methyl- phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine (intermediate LXXXXIll) ( 1 50 mg, 0.423 mmol) in 3 ml of dichloromethane and allowed to stirr at RT overnight. To the reaction mass was added water and extracted with dichloromethane. The organic extracts were washed with brine and dried over anhydrous sodium sulphate and evaporated. The crude material was purified by preparative TLC to afford N-( l -{4-| 2-(2-Ethyl-4-mcthyl- phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 30% yield.

LCMS-I M+H] 397.7, Ή NMR (400 MHz, CDC1₃): 7.256-7.279 (m, 2H), 7.077-7.096 (d, 21 1, . 7.6 Hz), 7.023-7.077 (m, 3H), 6.831 (s, I H), 5.566-5.582 (d, I H, J=6.4 Hz), 5.061 - 5. 1 32 (m, I H), 2.601 -2.659 (q, 2H, J=7.6 Hz), 2.331 (s, 3H), 1 .975 (s, 3H), 1 .457- 1 .474 (d, 31 1, J-6.8 Hz), 1 .1 88- 1 .225 (t, 3H, J=7.6 Hz).

Example 18

N-(l-{4-|2-(2- romo-4-propoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetaniide

5-Bromo-2-(2-biOmo-4-propoxy-phenoxy)-thiazole (intermediate LVI) was reacted with N-| l -(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 10 to afford N-(l -{4-[2-(2-Bromo-4-propoxy-phenoxy)- thiazol-5-yloxy]-Phenyl} - ethyl)acetamide in 8 % yield.

LCMS:[ M+H] 493.6, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.340-7.360 (d, 2H, J=8 Hz), 7.213-7.260 (t, 2H, J=l 0.8 Hz), 7.1 15-7.121 (d, I H, J=2.4 Hz), 7.050-7.072 (d, HI, J-8.8 Hz), 6.796-6.873 (m, 2H), 5.722 (s, l H), 5.107-5.160 (m, I H), 3.863-3.895 (t, 2H, J=6.8 llz), 1.992 (s, 3H), 1.746-1.833 (m, 2H), 1.482-1.499 (d, 3H, 3=6.8 Hz), 1.007-1.044 (t. 11, J- 7.6 Hz).

N-( 1 -{4-|2-(2-BiOmo-4-piOpoxy-phenoxy)-lhiazol-5-y)oxy |-Phenyl} - ethyl)acctamidc (Example 18) was further purified by chiral HPLC using Chiralpak IA (250mm*4.6mm) column and was eluted at 100 % ethyl acetate. The first isomer (Isomer A) was eluted at retention time (R,) of 10.658 minute and the second isomer (Isomer B) was eluted at retention time (R_t) of 13.910 min. Once the column was completed the solvent was evaporated to afford the respective isomers as gummy material.

Isomer A: LCMS:[ M+H] 493.6, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.341-7.362 (d, 211. .1=8.4 Hz), 7.212-7.259 (t, 2H, J=10.4 Hz), 7.Π6-7.122 (d, 1H, .1=2.4 Hz), 7.051- 7.074 (d, H I, J=9.2 Hz), 6.800-6.826 (m, 2H), 5.609-5.626 (d, IH, J=6.8 Hz), 5.107-5.179 (m. IH), 3.864-3.896 (t, 2H, J=6.8 Hz), 1.984 (s, 3.H), 1.747-1.818 (m, 2H), 1.499-1.564 (d.311, .1-7.2 Hz), 1.008-1.045 (t, 3H, J=7.6 Hz).

Isomer B: LCMS:| M+H] 493.6, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.341-7.362 (d. 2H, J=8.4 Hz), 7.211-7.260 (t, 2H, .1=10.8 Hz), 7.116-7.122 (d, IH, .1-2.4 Hz), 7.051- 7.074 (d. Ill, .1=9.2 Hz), 6.800-6.824 (m, 211), 5.614-5.629 (d, HI, .1-6 Hz).5.107-5.179 (m, III), 3.864-3.896 (t, 211, .1=6.8 Hz), 1.984 (s, 31-1), 1.765-1.818 (m, 211). 1.481-1.498 (d, 3H, .1=6.8 Hz), 1.008-1.045 (t, 3H, 1=7.6 Hz).

Example 19

N-(l-{4-[2-(2-Fluoro-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-

N-(l -{4-[2-(2-Fluoro-4-hydroxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate LXIV) was reacted with Isopropyl iodide to afford N-(1-{4-|2-(2-FILIOIO-4- isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 30% yield.

LC/MS [M+H] 431.4, Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.275-8.256 (d, IH..1=7.6 llz), 7.364-7.343 (d, 2H, .1=8.4 Hz), 7.290-7.231 (m, 3H), 7.024-6.967 (m, 211), 6.742- 6.719 (m, 2H), 4.917-4.880 (m, 1 H), 4.601-4.541 (m, I H), 1.819 (s, 311), 1.325-1.307 (d, 311, J=7.2 Hz), 1.236-1.221 (d, 6H, J=6 Hz). N-( l - {4-|^"2-(2-Fluoro-4-isopropoxy-phenoxy)-thiazol-5-yloxy]-phenyl} -ethyl)-acetamide (Example 19) was further purified by chiral HPLC using Chiraipak I A (250mm *4.6mm) column and was eluted at 100 % ethanol. The first isomer (Isomer A) was eluted at retention time (R_t) of 8.996 minute and the second isomer (Isomer B) was eluted at retention lime (R_t) of 10.357 min. Once the column was completed the solvent was evaporated to afford the respective isomers as white solid.

Isomer A: Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.272-8.254 (d, 1 H, J=7.2 Hz), 7.365-7.344 (d, 2H, J=8.4 Hz), 7.290-7.242 (m, 3H), 7.026-6.964 (m, 2H), 6.743-6.721 (m, 1 1 1), 4.915-4.861 (m, 1 H), 4.604-4.544 (m, l H), 1 .819 (s, 3H), 1 .326- 1 .308 (d, 311, y -7.2 Hz), 1 .238- 1 .223 (d, 6H, J=6 Hz).

Isomer B: Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.276-8.261 (d, 1 H, J=7.2 Hz), 7.365- 7.345 (d, 21 1 J=8 Hz), 7.263-7.244 (m, 3H), 6.998-6.970 (m, 2H), 6.744-6.723 (d, 1 H, .1 8.4 Hz), 4.91 7-4.882 (m, 1 H), 4.590-4.561 (m, 1 H), 1 .821 (s, 311), 1 .326- 1 .309 (d, 3 H, .1-6.8 Hz), 1 .238- 1 .224 (d, 6H, J=5.6 Hz).

Example 20

N-(1 -{4-|2-(2-Fluoro- -propoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide

N-( l -{4-| 2-(2-Fluoro-4-hydroxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate LXIV) was reacted with n-propyl iodide to afford N÷(1 -{4-[ 2-(2-Fluoro-4- propoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 30% yield.

LC/MS [M+H] 431 .1 , Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.270-8.25 1 (d, 1 11, J=7.6 Hz), 7.363-7.342 (d, 2H, J=8.4 Hz), 7.297-7.237 (m, 3H), 7.056-6.986 (m, 2H), 6.763- 6.740 (m, 2H), 4.91 5-4.879 (m, 1 H), 3.937-3.885 (m, 2H), 1 .819 (s, 3 H), 1 .733-1 .646 (m, 21 1), 1 .307- 1 .286 (d, 3H, J=8.4 Hz), 0.960-0.923 (t, 3H, J=7.2 Hz).

N-( l -{4-| 2-(2-Fluoro-4-propoxy-phenoxy)-thiazol-5-yloxy]-phenyl} -ethyl)-aeetamide

(Example 20) was further purified by chiral HPLC using Chiraipak IA (250mm*4.6mm) column and was eluted at 100 % ethanol. The first isomer (Isomer A) was eluted at retention time (R_t) of 8.996 minute and the second isomer (Isomer B) was eluted at retention time (R_t) of 10.357 min. Once the column was completed the solvent was evaporated to afford the respective isomers as white solid. Isomer Λ: Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.271-8.251 (d, 1H, J=8 Hz), 7.363- 7.343 (d, 211, .1=8.4 Hz), 7.312-7.241 (m, 3H), 7.070-6.989 (m, 2H), 6.798-6.762 (m, 1 H), 4.915-4.861 (m, 1H), 3.939-3.887 (m, 2H), 1.820 (s, 3H), 1.735-1.647 (m, 211), 1.326- 1.308 (d, 3H, J=7.2 Hz), 0.975-0.944 (t, 3H, J=4.8 Hz).

Isomer B: Ή NMR (400MHz, DMSO-d6) δ (ppm): 8.272-8.254 (d, 1 H, J=7.2 Hz).7.363- 7.342 (d, 2H, J=8.4 Hz), 7.298-7.239 (m, 3H), 7.013-6.976 (m, 2H), 6.763-6.741 (m, 1 H), 4.915-4.879 (m, 1H), 3.918-3.885 (m, 2H), 1.819 (s, 3H), 1.733-1.663 (m, 2H), 1.323- 1.307(d, 3H, .1-6.4 Hz), 0.960-0.924 (t, 3H, .1=7.2 Hz). Example 21

N-[l-(4-{2-[2-MethyI-4-(thiazoI-2-yIoxy)-phenoxy]-thiazoI-5-yloxy}-phenyl)-ethyI]-

A mixture of N-(l-{4-|2-(

-5-yloxy]-phenyl}-ethyl) -acetamide (intermediate XXXXVlll) (0.5 g, 1.23 mmol), 2-bromo-thiazol (0.243 g, 1.47 mmol), potassium carbonate (0.5 lg, 3.6 mmol), in 20 ml of Ν,Ν-dimethylformamide was heated at 140 °C for over night. Then the reaction mixture was cooled to room temperature, diluted with water and filtered through celite and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude material was purified by preparative HPLC to afford N-[l-(4-{2-[2-Methyl-4-(thiazol-2- phenoxy]-thiazoI-5- yloxy}-phenyl)-ethyl]-acetamide in 5% yield.

LC/MS [M+H] 4473.6, Ή-NMR (400MHz, CDC13-d6) δ (ppm): 7.428-7.422 (d, 1H, .1 7.411/ ).7.379-7.358 (d, 2H, J=8.4Hz), 7263-7.257 (d, 3H, J=2.4Hz), 7.236 (s, III,), 7.188-7.171 (m, lH), 6.894 (s, 1H), 6.872-6.863 (m, lH), 5.850 (s, 1H), 5.171-5.136 (m, 1 H), 2.018 (s,3H), 1.462-1.442 (d, 3H, J=8Hz)

The compound showed IC50 for hACC2 and hACCl of>50uM and >50uM respectively.

Example 22

N-[l-(4-{2-|2-ChIoro-4-(pyrazin-2-yIoxy)-phenoxy]-thiazol-5-yloxy}-phcnyl)-ethyl|- acetamide

N-(l-{4- 2-(2-Chloro-4-hydroxy-phenoxy)-thiazol-5-yloxy]-phenyl} -ethyl)

-acetamide (intermediate XXXXVllI) was treated with 2-chloro pvrazine similar to the procedure employed for the Example 21 to afford N-[l-(4-{2-[2-Chloro-4-(pyrazin-2- yloxy)-phenoxy |-thiazol-5-yloxy}-phenyl)-ethyl]-acetamide in 5% yield.

LC/MS |M+H] +483.5, Ή- MR (400MHz, CDCI3-d6) δ (ppm): 8.467 (s, 1 H,), 8.307- 8.302 (d, IH,), 8.100 (s, IH), 7.383-7.361 (d, 2H,J=8.8Hz ), 7.292-7.259 (d, IH, .1=2.8Hz), 7.208 (s, IH), 7.166 (s, IH), 7.150 (s, IH), 7.079-7.049 (m, 1 H), 5.632-5.615 (d,IH, .1 -6.8Hz),5.172-5.136(m, 111) , 1.930 (s, 3H), 1.471 -1.415 (d, 3H, J=6.8Hz).

Example 23

N-(l-{4-[2-(3-ChIoro-5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acctamidc

l-{4-|2-(3-Chloro-5-methoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethylamine

(intermediate Dl) was reacted with acetyl chloride to afford crude material, which was purified by preparative TLC to afford N-(l-{4-[2-(3-Chloro-5-methoxy-phenoxy)-thiaz.ol- 5-yloxy|-phenyl}-ethyl)-acetamide.

LCMS-[M+Hj 419.6, Ή NMR (400 MHz, DMSO-d₆): 8.220-8.239 (d, IH, .1=7.6 Hz), 7.296-7.318 ^'(d, 2H, J=8.8 Hz), 7.077-7.127 (m, 3H), 6.946-6.970 (m, 2H), 4.848-4.885 (m, I H), 3.783 (s, 3H), 1.805 (s, 3H), 1.289-1.306 (d, 3H, J=6.8 Hz).

Example 24

N-(l-{4-[2-(2-Isopropyl-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethyl)-acctamide

5-Bromo-2-(2-isopropyl-phenoxy)-thiazole (intermediate LX1I) was reacted with N-| l-(4- 1 lydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 10 to afford N-(l-{4-[2-(2-isopropyl-phenoxy)-thiazol-5-yloxy|-phenyl}- cihyl)-acetamide in 15% yield.

LC/MS I I ; 111397.6, Ή NMR (400MHz, CDCI3-d6) δ (ppm): 7.367-7.345 (d, 211 J=8.8 Hz), 7.298-7.267 (m, 3H), 7.178-7.088 (m, 2H), 7.041-7.021 (d, IH, J=8 Hz), 6.798 (s, 111), 5.703-5.636 (m, IH), 5.180-5.110 (m, IH), 3.386-3.352 (m, IH), 1.984 (s, 3H). 1.499-1.482 (d, 3H, J=6.8 Hz), 1.271-1.254 (d, 2H, J=6.8 Hz).

Example 25

N-(l-{4-f2-(3-Chloro-4-isopropoxy-phenoxy)-thiazoI-5-yIoxy]-phenyl}-ethyl)- acctamidc

5-Mromo-2-(3-chloi -4-isopropoxy-phenoxy)-thiazole (intermediate XXX) was reacted with N-| l-(4-I IydiOxy-phenyl)-ethyr|-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(l-{4-[2-(3-Chloro-4-isopropoxy-p henoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide.

LCMS-|M+H]= 447.1,H'NMR(CDC13):7.354-7.375 (d, 2H, J= 8.4 Hz), 7.237-7.258 (d, 211, .1=8.4 Hz), 7.136-7.142 (d, IH, .1=2.4 Hz), 6.891-6.957 (m, 2H), 6.833 (s. III), 5.670- 5.687 (d, IH, J=6.8 Hz), 5.134-5.170 (m, IH), 4.444-4.475 (m, IH), 2.004 (s, 3H), 1.491- 1.509 (d, 3H, J=7.2 Hz), 1.350-1.365 (d, 6H, J=6 Hz).

The compound showed IC₅₀ for hACC2 and hACCl of >50uM and >50uM respectively.

Example 26

N-(l-{4-[2-(2-Chloro-3-triiluoromethoxy-phenoxy)-thiazol-5-yIoxy]-phenyl}-ethyl)-

5-Bromo-2-(2-chloi -3-trifluoromethoxy-phenoxy)-thiazole (intermediate XXXII) was reacted with N-[ l-(4-Hydroxy-phenyl)-ethyl]-acetamide (intermediate XX) similar to the procedure employed for the Example 1 to afford N-(1-{4-|2-(2-CIIIOI -3- trilluoromethoxy-phenoxy)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 2 % yield.

IX/MS M+H] + 473.2, Ή NMR (400 MHz, CDC!₃) δ (ppm): 7.361-7.383 (d, 211, .1=8.8 llz):7.282 (s,1H,); 7.242-7.263 (d,2H,I=7.6 Hz ); 7.121 -7.142 (d,l l-|J=8.4 Hz) ; 7.072 - 7.093 (d,IH,J=8.4 Hz); 6.919 (s,lH,); 5.748-5.765 (d,lH,J=6.8 llz);5.1 I6- 5.187(m,1 H,);2.006 (s,3H,);l .491-1.509 (d,3 H,J=7.2 Hz).

Example 27

N-(l-{4-[2-(4-Isopropoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide

Isopropyl iodide (0.13 ml, 1.

of N-(l-{4-|2-(4-Hydroxy- phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate DV11) (300 mg, 0.86 mmol) and potassium carbonate (237 mg, 1.72 mmol) in 5 ml of N,N-dimethylformamide and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and evaporated. The crude product was first purified by preparative TLC and further purified by preparative HPIX to afford N-(l-{4-[2-(4-Isopropoxy-phenyl)-thiazol-5-yloxy|-phenyl}-ethyl)- acetamide in 34 % yield.

LCMS-[M+HJ- 397.6, H'NMR (400 MHz, DMSO-d6): 8.232-8.251 (d, 1H, J= 7.6 Hz), 7.7 1-7.751 (d, 211, J = 8.0 Hz), 7.350 (s, IH), 7.313-7.334 (d, 2H, J= 8.4 Hz), 7.127-7.148 (d, 211, J= 8.4 Hz), 6.974-6.996 (d, 2H, J= 8.8 Hz), 4.864-4.900 (m, 1 H), 4.656-4.686 (m, H I), 1.812 (s, 3H), 1.300-1.319 (d, 3H, J= 7.6 Hz), 1.264-1.279 (d, 6H, .1= 6Hz).

The compound showed 1C₅₀ for hACC2 of 0.169 uM.

Example 28

N-(l-{4-[2-(4-Ethoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acctamidc (JBF-527)

-( l-{4-|2-(4-Hydroxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate DVll) was reacted with ethyl iodide similar to the procedure employed for the Kxamplc 27 to afford crude material which was purified by Preparative HPIX to afford N-(l-{4-|2- (4-Elhoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 46 % yield.

LCMS-[M+H]- 383.7, H'NMR (400 MHz, DMSO-d6): 8.230-8.250 (d, 1H, J=8.0 Hz), 7.745-7.766 (d, 2H, J=8.4 Hz), 7.533 (s, 1H), 7.313-7.334 (d, 2H, J= 8.4 Hz), 7.129-7.150 (d, 211, J=8.4 Hz), 6.987-7.008 (d, 2H, J=8.4 Hz), 4.862-4.899 (m, H I), 4.046-4.098 (q, 2H, J= 8.8 Hz), 1.812 (s,3H), 1.300-1.346 (m,6H).

The compound showed IC₅₀ for hACC2 of 0.32 uM and hACCl of 33.4 uM.

Example 29

N-(l-{4-[2-(3-Isopropoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamidc

I -{4-|2-(3-Isopropoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethylamine (intermediate DVlll) was reacted with acetic acid to afford crude material which was purified by preparative HPLC to afford N-(l-{4-[2-(3-lsopropoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)- acetamide in 26.8 % yield.

LCMS-I M+H] 397.7, Ή NMR (400 MHz, DMSO-d6) δ (ppm): 8.234-8.254 (d, 1 H, .1=8.0 Hz), 7.595 (s, IH), 7.317-7.353 (m, 5H), 7.143-7.164 (d;2H, J=8.4 Hz), 6.980-7.010 (m, IH), 4,862-4.898 (m, 111), 4.635-4.695 (m, 1H), 1.808 (s, 3H), 1.296-1.314 (d, 311, J=7.2 Hz), 1.255-1.270 (d, 6H, .1=6.0 Hz). Example 30

N-(l-{4-[2-(4-Isopropoxy-2-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-ethyJ)-acctamidc

l-{4-|2-(4-lsopropoxy-2-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-elhylamine

(intermediate DVlll) was reacted with acetic acid to afford N-(l-{4-|2-(4-lsopropoxy-2- mcthyl-phenyl)-thiazol-5-yloxy|-phenyl}-ethyl)-acetamide as pale yellow gum with 8 % yield.

LC/MS [M-l-H] 411.5, Ή NMR (400 MHz, DMSO-d₆) δ (ppm): 7.547-7.568 (d, 1 H, .1=8.4 Hz), 7.404 (S, IH), 7.255-7.311 (m, 2H), 7.091-7.112 (d, 2H, .1=8.4 Hz), 6.745-6.780 (m, 211), 5.102-5.137 (m, IH), 4.576-4.606 (m, IH), 2.554 (s, 3H), 1.985 (s.3H), 1.474-1.491 (d, 3H, .1=6.8 Hz), 1.340-1.355 (d, 6H, J=6 Hz).

Example 31

JN-(l-{4-|2-(4-Isopropoxy-3-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamidc

I -{4-|2-(4-Isopi poxy-3-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-ethylamine

(intermediate DVlll) was reacted with acetic acid to afford to afford N-(l-{4-|2-(4- lsopropoxy-3-methyl-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 3.1 % yield.

LCMS-I M+H] 411.5, Ή NMR (400 MHz, CDC1₃) δ (ppm): 7.588-7.630 (m, 2H), 7.352 (s, 111), 7.257-7.303 (m, 2H), 7.079-7.101 (d, 2H, J=8.8 Hz), 6.831-6.852 (d, 111, J=8.4 Hz), 5.602 (s, IH), 5.097-5.134 (m, IH), 4.568-4.597 (m, IH), 2.231 (s, 3J-I), 1.988 (s, IH), 1.473-1.490 (d, 3 H, J=6.8 Hz), 1.301-1.367 (m, 6H). Example 32

N-(l-{4-[2-(4-Propoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acctamide

N-(l-{4-|2-(4-Hydroxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate DVII) was reacted with n-propyliodide similar to the procedure employed for the Example 27 to afford crude material which was purified by Preparative I1PLC to afford N-(l-{4-[2-(4-Propoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide in 39 % yield. I S-I +H]- 397.6, H'NMR (400 MHz, DMSO-d6):8.238-8.257 (d, 111, .1-7.6 Hz). 7.743-7.765 (d, 2H, .1= 8.8 Hz), 7.535 (s, 1H), 7.312-7.333 (d, 2H, .1= 8.4 Hz), 7.129- 7.l50(d, 211, J-8.4 II/.), 6.993-7.014 (d, 2H, J=8.4 Hz), 4.861-4.898 (m. Ill), 3.954-3.987 (L 211, .1=6.8 Hz), 1.811 (s, 3H), 1.703-1.755 (m, 2H), 1.299-1.317 (d, 311, .1= 7.2 Hz), 0.950-0.988 (t, 3H, J^~ 7.6 Hz).

The compound showed IC₅₀ for hACC2 of 0.096 uM. Example 33

N-(l-{4-|2-(2-Chloro-4-methoxy-phenyI)-thiazol-5-yloxy]-phenyl}-ethyl)-acctamidc

The synthesized intermediate 1 -{4-|2-(2-Chloro-4-methoxy-phenyl)-lhiazol-5-yloxy ] phenyl}-ethylaminc was reacted with acetyl chloride to afford M-(I-{4-|2-(2-Chloro-4 methoxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide.

MS |M+H] 403.6, 'i l-NMR (400 MHz, DMSO-d6) δ (ppm): 8.260-8.241 (d, 1R .1=7.6 Hz), 8.089-8.067 (d, 1H, J=8.8 Hz), 7.662 (s, lH), 7.343-7.322 (d, 211, J=8.4 Hz), 7.169- 7.148 (d, 3H , J=8.4 Hz), 7.086-7.062 (d, 1H, J=8.8 Hz), 4.903-4.868 (m, 1H), 3.832 (s, 311), 1.813 (s, 3H), 1.320-1.304 (d, 3H, J=6.4 Hz).

The compound showed IC50 for hACC2 of 0.169 uM. Example 34

-( l -{4-[2-(4-Cyclopropylmethoxy-phenyI)-thiazol-5-yloxy|-phcnyl}-cthyl)-acctamidc

N-( l -{4-| 2-(4-Hydroxy-phenyl)-thiazol-5-yloxy]-phenyl}-ethyl)-acetamide (intermediate DV1 I ) was reacted with cyclopropylmethylbromide similar to the procedure employed for the Example 27 to afford crude material which was purified by Preparative HPLC to afford N-(l -{4-| 2-(4rCyclopropylmethoxy-phenyl)-thiazol-5-yloxy]-phenyl }-ethyl)- acetam ide in 55 % yield.

I .( ^'MS-| \H I I |- 409.6, H 'N MR (400 MHz, DMSO-d6): 8.233-8.252 (d, I H, J- 7.6 Hz), 7.736-7.758 (d 2H, J 8.8 Hz), 7.532 (s, 1 H), 7.3 1 2-7.333 (d, 2H, J- 8.4 Hz), 7. 1 29-7. 1 0 (d, 21 1, .1- 8.4 Hz), 6.987-7.008 (d, 2H, J= 8.4 Hz), 4.862-4.899 (m, 1 1 1), 3.854-3.870 (d. 21 1. J= 6.4 Hz), 1 .81 1 (s, 3H), 1.299- 1 .317 (d, 3H, J= 7.2 Hz), 1.222 (m, 1 H), 0.542-0.587 (q, 21-1, J= 5.2 Hz), 0.31 7-0.340 (q, 2H, J= 4.8 Hz).

The compound showed IC50 for hACC2 of 0.131 uM.

Measurement of ACC Inhibition

The procedures for measuring ACC 1 inhibition and ACC2 inhibition are identical except for the source of the enzyme, and is based upon standard procedure as described by Harwood et al. (J. Biol. Chem. 2006; 28:37099-371 1 1), the contents of which are incorporated herein by reference. For measurement of ACC activity and assessment of ACC inhibition, the compounds of formula (I) of present invention was dissolved in dimethylsulfoxide (DMSO) in polypropylene tubes. The reaction was set up in the 96-well plates with the respective positioning of control compounds, reference standards and the compounds of present invention. 88μ1 of the substrate mix carrying 25 μΜ acetyl CoA (ACA) and 4mM ATP in a assay buffer (containing 50mM HEPES, 2mM MgCL₂, 2mM D l l . l OmM fri-potassium citrate, 12mM HCO₃ and 0.75mg/ml BSA) was added to the respective wells of the assay plate, already carrying 12μ1 of the test compound or reference standard in the wells. The m in wells meant for the background carried 120μ I o 5N Hydrochloric acid. This was followed by the addition of Ι ΟμΙ of the radioactive l igand I '''C-NaHCOs; Amersham Biosciences; specific activity: 56mCi/mmol] to al l wel ls of the assay plate. The reaction was initiated by the addition of 500ng of citrate-activated enzyme to al l the wells. The plate was incubated at 37°C for 60 minutes. After incubation, the reaction was term inated by adding 1 20μ 1 of 5N Hydrochloric acid in al l wel ls except min wel ls. The plate was transferred to a 70°C vacuum oven (fitted with an elaborate system of acid trap and charcoal traps) and was kept for overnight. The residue in the dried wel ls was re-suspended with 30μ1 of the distilled water followed by the addition of 200μΙ of icroscint20 to each well. The plate was sealed with plate sealer and was kept on a plate shaker with vigorous shaking for 4-5 hours (or til l the counts stabi l ize). Subsequently, counting of the plates was carried out using M icroBeta Tri lux (Counting time 30sec/wel l).

The IC50 of the compound to inhibit ACC 1 and ACC2 activity was determ ined by the concentration of the compound required to inhibit 50% of the total activity of the : enzyme (measured in the absence of any compound/inhibitor). The selectivity of the compounds for ACC2 over ACC 1 was determined by divid ing IC50 of the compound for ACC 1 by IC50 of the compound for ACC2.

Table 1 : Activity Value for ACQ and ACC2 activity

Speci fic embodiments depicting non-limiting examples of Formula I with their respective ACC 1 and ACC2 inhibitory activity profiles and their target selectivity data are provided in the fol lowing Table 1 :

Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein.

Claims

WE CLAIM:

1 . A thiazole compound of formula 1 or its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N- ox ides: pharmaceutically acceptable salts of N-oxides, or prodrugs;

(I)

wherein :

An is selected from an arylene or a heteroarylene; wherein said arylene or said heteroarylene are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C | -C₄ alkyl, perhaloalkyl, or C1 -C4 alkoxy;

Z is Y-Ar₂; wherein

Y is selected from a bond, -0-, -S(0)_n, or -NH ;

Ar₂ is selected from an optionally substituted aryl, or an optionally substituted heteroaryl; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R ¹ is a C | -C_fi alkyl;

R² is selected from the group consisting of an optional ly substituted l inear or branched C 1 -C20 alkyl, an optional ly substituted linear or branched heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted aryl, an optionally substituted arylalkyi, an optional ly substituted heteroaryl, an optionally substituted heteroarylalkyl, halogen, perfluroalkyl, -N0₂, -OH, -OR₃, -CN, -NH₂, -Si(R³)₃, -S(0)_nR⁴,-C(0)H, and -C(0)R³; - NR⁴R⁵, and -N(R )₂; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted C] -C₂o alkyl, an optionally substituted, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocyclyl. an optionally substituted heterocycloalkyl, an optional ly substituted aryl, an optional ly substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R⁴)₃, -S(0)_nR'⁴, - C(0)H, -C(0)R⁴, -NR⁴R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C20 al kyl, an optionally substituted C3-C20 cycloalkyl, an optionally substituted heterocyclyl, an optional ly substituted heterocycloalkyl, an optional ly substituted aryla lky l, an optional ly substituted heteroarylalkyl, -CN, -CF₃, -N0₂, -Si(R⁸) . - S(0)_nR , -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C | -C₄ alkyl. perhaloalkyl. or C1 -C4 alkoxy;

R⁼ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C1 -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C₃-C₂o cycloalkyl, an optionally substituted C₃-C₂o heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -C F₃ -NO2. - Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, Ci -C₄ a lkyl, perhaloalkyl, or C 1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl ; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heleroarylene contain one or more heteroatom independently selected from O, N, or S.

2. The compound of Formula 1 as claimed in Claim 1 , its pharmaceutical ly acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutical ly acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; wherein:

Z is Y-Ar₂;

Y is selected from a bond, -0-, -S(0)_n, or -NH;

Ar₂ is selected from

wherein, R⁶ is selected from the group consisting of halogen, an optionally substituted linear or branched C1 -C20 alkyl, an optionally substituted heterocycyl, an optionally substituted C₃-C₂o cycloalkyl. an optionally substituted heterocycloalkyi, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C| - Ci alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

A ¹ is a monocyclic heteroaryl ring selected from the group consisting of: .

each m is 0, 1 or 2;

wherein P, Q. R, and Z are independently selected from -CR^;- or nitrogen;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched Ci-C₂₀ alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyi. an optionally substituted heterocycloaikyi, an optionally substituted aryialkyl. an optionally substituted heteroarylalkyl, -CN, -CF3. -NO2, -Si(R )₃. - S(0)_NR⁸, -C(0)H, -C(0)R⁸, -NRV, and -OR⁸; wherein said subslitucnl is independently selected from halogen, hydroxy, C1-C4 alkyl, pc haloalkyl. or Ci-C/i alkoxy;

R¹ is Ci-C₆ alkyl;

R² is selected from the group consisting of an optionally substituted linear or branched C1-C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃- C20 cycloalkyi, an optionally substituted heterocycloaikyi, an optionally substituted aryl, an optionally substituted aryialkyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, -CF₃, -N0₂,-OH, -OR3, -CN, -Si(R³)₃, -C(0)H, and -C(0)R³; - NR R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C1-C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted aryl, an optional ly substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -S i(R )₃, -S(0)_nR⁴, -C(0)l-l, - C(0)R⁴, -NR R\ and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C_.1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted l iner or branched C 1 -C20 alkyl, an optional ly substituted heterocyclyl, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3, -N0₂, -Si(R⁸)₃, -S(0)„R^s, - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C1 -C20 alkyl, an optional ly substituted l inear or branched C | -C₂₀ heteroalkyl, an optionally substituted C₃-C2o cycloa lkyl, an optional ly substituted C₃-C2o heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF₃ -N0₂, - Si(R⁸)₃, -S(0)„R⁸, -C(0)H, -C(0)R⁸, -N R⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl. perha loalkyl, or C1 -C4 alkoxy;

8 9

each R and R is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heleroarylene contain one or more heteroatom independently selected from O, N, or S.

3. The compound of Formula 1 as claimed in claim 1, its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; wherein:

An is a phenylene;

5 Z is Y-Ar₂;

wherein Y is selected from a bond or-O-;

Ar₂ is selected from

R is independently selected from halogen or a linear or branched C1-C3 alkyl;

4 is selected from hydrogen, a linear or a branched C1-C3 alkyl, or -CF₃; I 5 ⁵ is selected from the group consisting of hydrogen and C|-C₂ alkyl, each n is independently 0, 1, or 2;

each m is 0, or 1 ;

R¹ is methyl; and

R² is selected from the group consisting of C]-C₂ alkyl, C₃-C₄ cycloalkyl, -OCH3, and -

4. The compound as claimed in claim 1, wherein R¹ is C1-C4 alkyl, and R² is an optionally substituted linear or branched Ci-C₆ alkyl or -OR⁴, wherein R⁴ is selected from hydrogen, l inear or branched C| -C₃ alkyl, and -CF₃; and said linear or branched C | -C, al kyl is substituted with substituents independently selected from halogen, hydroxy. C | -C. alkyl, perhaloalkyl, or C 1 -C4 alkoxy.

5. The compound as claimed in claim 1 , wherein R is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, and butyl.

6. The compound as claimed in 1 , wherein said R¹ is methyl .

7. The compound as claimed in any of the claims 1 to 6, wherei n Y is a bond.

8. The compound as claimed in claim 2, its pharmaceutical ly acceptable salts prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; wherein:

Z is Y-Ar₂;

Y is a bond; and Ar₂ is selected from

each R ' is selected from the group consisting of halogen, and an optional ly substituted linear or branched C] -C₂o alkyl; wherein said substitucnt is independently selected from halogen, hydroxy, C1 -C4 alkyl. perhaloalkyl, or C | -C| alkoxy;

R⁶ i s selected from the group consisting of halogen, an optional ly substituted l inear or branched C1 -C20 alkyl, an optionally substituted heterocycyl, an optional ly substituted C₃-C₂o cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3i -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, - C(0)R^s, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently- selected from halogen, hydroxy, C1 -C4 alky 1, perhaloalkyi, or C 1 -C4 al koxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloal kyl, aryl. heteroaryl, arylalkyl, and heteroarylalkyl ; each m is 0, or 1 ;

wherein P, Q, R, and Z are independently selected from -CR - or n itrogen;

R⁷ is selected from the group consisting of hydrogen, halogen, an optional ly substituted l inear or branched C1 -C20 alkyl, an optional ly substituted heterocyclyl, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl. an optional ly substituted heteroarylalkyl, -CN, -CF_3> -N0₂, -Si(R⁸)₃, -S(())„R^'\ - C(0)l-l_s -C(0)R^s, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyi. or

C I -C4 alkoxy;

R ¹ is C | -C₆ alkyl;

R² is selected from the group consisting of an optionally substituted linear or branched C 1 -C20 alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃- C20 cycloalkyl, an optionally substituted heterocycloalkyl, an optional ly substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, CF₃, -N0_2, -OH, -OR3, -CN, -Si(R³)₃, -C(0)I I, -C(0) R³; - N R⁴R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C 1 -C4 alkoxy; R⁴ is selected from the group consisting of hydrogen, halogen, -CF₃ and an optional ly substituted l inear or branched C₃-C₂₀ alkyl, and an optional ly substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy;

R⁵ is selected from the group consisting of hydrogen, halogen, and an optionally substituted linear or branched C3-C20 alkyl, and an optionally substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy; each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S. 9. The compound as claimed in claim 8, wherein each of P, Q, R, Z is -CR^;' and R is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C|-C₂<> alkyl, an optionally substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalky!, an optionally substituted heteroarylalkyl, -CN, -CF₃. -N0₂, -Si(R^B)₃, -S(0)_NR^S. - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 alkoxy.

10. The compound as claimed in claim 8, wherein each of P, Q, R. Z is -CR⁷: and R' is hydrogen; R¹ is methyl; R² is -OR³ and R^J is an optionally substituted linear or branched C3-C20 alkyl, or an optionally substituted C3-C20 cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C|-C₄ alkyl, perhaloalkyi, or C1-C4 alkoxy.

11. The compound as claimed in claim 8, wherein Ar₂ is

each R^J is independently selected from halogen, or an optionally substituted linear or branched C|-C₂₀ alkyl; wherein said substituent is independently selected from halogen, hydroxy. C_rC₄ alkyl, perhaloalkyi, or C1-C4 alkoxy; R⁴ is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched C|-C₂o alkyl; wherein said substituent is independently selected from halogen, hydroxy, Q-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and

R^~ is selected from the group consisting of hydrogen, halogen and an optionally substituted linear or branched C1-C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; and each of m and n are, independently, 0, 1, or 2.

12. The compound as claimed in claim 11, wherein R³ is selected from the group consisting of chlorine, bromine, fluorine and methyl; and R⁴ is selected from hydrogen, or methyl.

13. The compound as claimed in claim 11 , wherein R⁵ is hydrogen or methyl.

2 *

14. The compound as claimed in claim 2, wherein Ar is

each R is independently selected from halogen or an optionally substituted linear or branched C1-C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyl, or C1-C4 alkoxy; each n is independently 0, 1 or 2, and m is 0.

15. The compound as claimed in claim 14, wherein R³ is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.

16. The compound as claimed in claim 2, wherein Ar² is

each R³ is selected from halogen or an optionally substituted linear or branched C_r C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy. C _rQ al kyl, perhaloalkyl, or C1 -C4 alkoxy; and each n is independently 0, 1 or 2, and m is 0.

1 7. The compound as claimed in claim 16, wherein R³ is independently selected from the group consisting of chlorine, bromine, fluorine and methyl.

1 8. The compound as claimed in claim 2, wherein Ar is

each R³ is independently selected from halogen or an optional ly substituted linear or branched C 1 -C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, Q -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy; and R⁴ is -CF3.

1 9. The compound as clai wherein Ar² is

R³ is independently selected from halogen or an optionally substituted l inear or branched C1 -C20 alkyl ; wherein said substituent is independently selected from halogen, hydroxy. C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

A is

; each n is independently 0, 1 or 2, and m is independently 0, or 1 .

2

20. The compound as clai herein Ar is

R³ is independently selected from halogen or an optionally substituted linear or branched C|-C₂₀ alky 1 : wherein said substituent is independently selected from halogen, hydroxy, CrC, alky I, perhaloalkyl, or C|-C alkoxy;

each n is independently 0, 1 or 2, and m is independently 0, or 1.

21. The compound as claimed in any of the claims 1 to 3, wherein the compound is selected from the group consisting of:

136

137

138

its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs.

22. A pharmaceutical composition comprising at least one compound as claimed in any one of the claim 1 to 21 , or its pharmaceutically acceptable salts, prodrugs, solvates. N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N-oxides, or prodrugs; or combination or mixtures thereof; and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition as claimed in claim 22, further comprising at least one second active ingredient.

24. Λ method for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor, said method comprising administering an effective amount o f a compound of formula (1), its pharmaceutical ly acceptable salts, prodrugs, sol vates, N- ox ide thereof; solvates of pharmaceutically acceptable salts and N-ox idcs; pharmaceutically acceptable salts of N-oxides. or prodrugs; or combination or m ixtures thereof;

( 1 )

wherein:

An is selected from an arylene or a heteroarylene; wherein said arylenc or said heteroarylene are optional ly substituted with one or more substituents independently selected from halogen, hydroxy, C | -C₄ alkyl, perhaloalkyl, or C | -C al koxy:

7. is Y-Ar₂; wherein

Y is selected from a bond, -0-, -S(0)_n, or -NH;

Ai-2 is selected from an optionally substituted aryl, or an optional ly substituted heteroaryl ; wherein said substituent is independently selected from halogen, hydroxy, C | -C₄ alkyl, perhaloalkyl, or C 1 -C4 alkoxy;

R ¹ is a C i -C_f, alkyl;

R² isi selected from the group consisting of an optionally substituted l inear or branched C 1 -C20 alkyl, an optionally substituted linear or branched heterocyclyl. an optional ly substituted C3-C20 cycloalkyl, an optionally substituted heterocycloalkyi, an optionally substituted aryl, an optionally substituted arylalkyi, an optional ly substituted heteroaryl, an optional ly substituted heteroarylalkyl. halogen, perfluroalkyl, -N0_2, -OH, -OR₃, -CN, -NH₂, -Si(R³)₃, -S(0)_nR^'',-C(0)H, and -C(0)R³: - NR⁴R⁵, and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy; R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted C | -C₂o alkyl, an optionally substituted, an optional ly substituted C3-C20 cycloalkyl, an optional ly substituted heterocyclyl, an optional ly substituted heterocycloalkyi, an optional ly substituted aryl. an optional ly substituted arylalkyl, an optional ly substituted hetcroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R⁴)₃,

- C(0)l l, -C(6)R⁴, -NR R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C1 -C4 alkyl, perhaloalkyi, or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optional ly substituted liner or branched C1 -C20 alkyl, an optional ly substituted C3-C20 cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyi, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF₃, -N0₂, -Si( R^s)_3; - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyi. or C 1 -C4 alkoxy;

R⁵ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C1 -C20 a lkyl, an optional ly- substituted heterocyclyl, an optionally substituted C₃-C20 cycloalkyl, an optional ly substituted C3-C20 heterocycloalkyi, an optional ly substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF₃ -N0₂, - Si(R⁸)₃, -S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyi, or C1 -C4 alkoxy; each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyi, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; wherein each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyi, heteroaryl, heteroarylalkyl. and heleroarylcne contain one or more heteroatom independently selected from O, N, or S. method as claimed in claim 24, . wherein Z is Y-Ar₂;

Y is selected from a bond, -0-, -S(0)_n, or -NH;

A r2 is selected from

wherein, R⁶ is selected from the group consisting of halogen, an optionally substituted linear or branched C1 -C20 alky 1, an optional ly substituted heterocycyl, an optional ly substituted C3-C20 cycloalkyl. an optionally substituted heterocycloalkyl, an optional ly substituted arylalky , an optional ly substituted heteroarylalkyl, -CN. -CI-₃ -NO?. -Si(R^s)₃, -S(0)„R⁸, -C(0)H, -C(0)R⁸, -N R^SR⁹, and -OR⁸; wherei n said substituent is independently selected from halogen, hydroxy, C ; - C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;

A ¹ is a monocyclic heteroaryl ring selected from the group consisting of:

each m is 0, 1 or 2;

wherein P, Q, R, and Z are independently selected from -CR - or n itrogen ;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally substituted linear or branched C1 -C20 alkyl, an optional ly substituted heterocyclyl, an optionally substituted C3-C20 cycloalkyl, an optional ly substituted heterocycloalkyi, an optionally substituted arylalkyi, an optionally substituted heteroarylalkyl, -CN, -CF3 -NO2, -Si(R⁸)₃, - S(0)_nR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituenl is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C 1 -C4 alkoxy; 1 is C C_f, alkyl ;

R² is selected from the group consisting of an optional ly substituted l inear or branched C | -C₂o alkyl, an optionally substituted heterocyclyl, an optionally substituted C3- C?o cycloalkyl, an optionally substituted heterocycloalkyi, an optional ly substituted aryl, an optional ly substituted arylalkyi, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0_2, -OH, -OR3, -CN, -Si(R³)₃, -C(0)H, and -C(0)R³; - NR⁴R\ and -N(R³)₂; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C1 -C4 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C1 -C20 alkyl, an optionally substituted heterocyclyl, an optional ly substituted C3-C₂₀ cycloalkyi, an optional ly substituted heterocycloalkyl, an optionally substituted aryl. an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, -CF₃, -N0₂, -Si(R⁴)₃, -S(0)_NR⁴, -C(0)H, - C(0)R⁴, -NR⁴R⁵, and -OR⁴; wherein said substituent is independently selected from halogen, hydroxy, C₁ -C4 alkyl, perhaloallcyl, or C1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, an optionally substituted liner or branched Ci-C₂o alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃-C₂o cycloalkyi, an optional ly substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF_3, -N0₂, -Si(R⁸)₃, -S(0)„R⁸. - C(0)H, -C(0)R⁸, -NRV, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C-C₄ alkyl, perhaloalkyl, or C | -C| alkoxy; R³ is selected from the group consisting of hydrogen, halogen, an optional ly substituted linear or branched C| -C₂o alkyl, an optionally substituted linear or branched Q -C₂₀ heteroalkyl, an optionally substituted C3-C20 cycloalkyi, an optionally substituted C₃-C₂o heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF₃ -N0₂. - Si(R⁸)₃, -S(0)_NR⁸, -C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaloalkyl, or C₁ -C4 alkoxy; each R⁸ and R⁹ is, independently, selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyi, heterocycloalkyl. aryl, heteroaryl, arylalkyl, and heteroarylalkyl; each n is, independently, 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylene contain one or more heteroatom independently selected from O, N, or S.

26. The method as claimed in claim 24, wherein An is a phenylene

Z is Y-Ar,; wherein Y is selected from a bond or -0-;

Ai"2 is selected from

wherein A is a monocyclic heteroaryl ring selected from:

R is independently selected from halogen or a linear or branched C C₃ alkyl;

R⁴ is selected from hydrogen, a linear or a branched C 1 -C3 alkyl, or -CP;,; R^S is selected from the group consisting of hydrogen and C1 -C2 alkyl. each n is independently 0, 1 , or 2; each m is 0, or 1 ; ' is methyl; and

R² is selected from the group consisting of C| -C₂ alkyl, C3-C4 cycloalkyl. -OCH3, and - N H₂

27. The method as claimed in claim 24, wherein Z is Y-Ar₂;

Y is a bond; and A12 is selected from

each R³ is selected from the group consisting of halogen, and an optionally substituted linear or branched C1-C20 alkyl; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi. or C1-C4 aikoxy;

R⁶ is selected from the group consisting of halogen, an optionally substituted linear or branched C1-C20 alkyl, an optionally substituted heterocycyl, an optionally substituted C₃-C₂o cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, -CN, -CF_3j -N0₂, -Si(R⁸)₃, -SiO^R⁸, -C(0)M, - C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C1-C4 alkyl, perhaloalkyi, or C1-C4 aikoxy, each R⁸ and R⁹ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl ; each m is 0, or 1 ;

wherein P, Q, R, and Z are independently selected from -CR - or nitrogen;

R⁷ is selected from the group consisting of hydrogen, halogen, an optionally ^ substituted linear or branched C|-C₂o alkyl, an optionally substituted heterocyclyl, an optionally substituted C₃-C₂o cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted arylalkyl, an optional ly substituted heteroarylalkyl, -CN, -CF_3, -N0₂, -Si(R⁸)₃, -S(0)_nR⁸, - C(0)H, -C(0)R⁸, -NR⁸R⁹, and -OR⁸; wherein said substituent is independently selected from halogen, hydroxy, C | -C₄ alkyl, perhaioalkyi, or C1 -C4 alkoxy; 1 is C | -C₆ alkyl ;

R² is selected from the group consisting of an optional ly substituted l inear or branched C | -C₂o alkyl, an optional ly substituted heterocyclyl, an optional ly substituted C3- ( .(, cycloalkyl. an optionally substituted heterocycloalkyl, an optional ly substituted aryl. an opt ionally substituted arylalkyl, an optionally substituted heteroaryl, an optional ly substituted heteroarylalkyl, CF₃, -N0_2, -OH, -OR3, -CN, -Si(R³)₃, -C(0)H, -C(0)R³: - N R⁴ R\ and - (R³)2; wherein said substituent is independently selected from halogen, hydroxy. C 1 -C4 alkyl, perhaioalkyi, or C 1 -C4 alkoxy;

R⁴ is selected from the group consisting of hydrogen, halogen, -CI' ;, and an optional ly substituted linear or branched C₃-C?o alkyl, and an optional ly substituted C₃-C₂o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaioalkyi, or C 1 -C4 alkoxy:

R^" is selected from the group consisting of hydrogen, halogen, and an optional ly substituted linear or branched C₃-C₂o alkyl, and an optionally substituted C₃-C₂o cycloalkyl; wherein said substituent is independently selected from halogen, hydroxy, C 1 -C4 alkyl, perhaioalkyi, or C 1 -C4 alkoxy; each n is independently 0, 1 , or 2; and wherein heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl. and heteroarylene contain one or more heteroatom independently selected from O, N, or S.

28. The method as claimed in any of the claims 24 to 27, wherein the Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.

29. The method as claimed in any of the claims 24 to 27, wherein the cond ition is a metabol ic syndrome.

30. The method as claimed in claim 29, wherein the condition is selected from type I I diabetes, obesity, diabesity, atherosclerosis, and cardiovascular diseases.

3 1 . Use of compound as claimed in any one of the claims 1 to 21 , or its pharmaceutically acceptable salts, prodrugs, solvates, N-oxide thereof; solvates of pharmaceutically acceptable salts and N-oxides; pharmaceutically acceptable salts of N- oxides, or prodrugs; or combination or mixtures thereof; for preventing or treating a condition that responds to an Acetyl-CoA Carboxylase (ACC) inhibitor.

32. Use of compound as claimed in claim 31 wherein said Acetyl-CoA Carboxylase (ACC) is ACC- 1 or ACC-2.