Related applications

This application claims the benefit of Indian patent applications No. 1 396/KOL/2010, filed on December 10, 2010 and 1 397/KOL/2010, filed on December 10, 2010 all of which is hereby incorporated by reference.

Field of the Invention

The invention relates to substituted thieno[3,4-b]pyrazine compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds of the invention. The invention also relates to methods for treating, preventing and/or managing diseases, disorders, syndromes or conditions associated with inadequate insulin secretion such as diabetes, related disorders and metabolic syndrome. The invention also relates to methods for treating, preventing and/or managing diseases, disorders, syndromes or conditions which are affected or facilitated by the modulation of GLP- 1 receptor. The invention also relates to processes for the preparation of the compounds of invention. The invention also relates to combination therapy comprising compound or pharmaceutical composition of the invention and one or more therapeutic agent for treating, preventing, managing diseases, disorders, conditions or symptoms associated with inadequate insulin secretion such as diabetes, related disorders and metabolic syndrome. The invention also relates to combination therapy comprising compound or pharmaceutical composition of the invention and one or more therapeutic agent for treating, preventing, managing diseases, disorders, conditions or symptoms which are affected or facilitated by the modulation of GLP- 1 receptor.

Background of the Invention

Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition. Glucose level abnormalities can result in serious long-term complications, such as cardiovascular disease, clironic renal failure, retinal damage, nerve damage, micro-vascular damage and obesity. Type 1 diabetes, also known as Insulin Dependent Diabetes- Mellitus (IDDM), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Type 2 diabetes previously known as adult-onset diabetes or maturity-onset diabetes, or Non- Insulin Dependant Diabetes Mellitus (NIDDM) is due to one or more reason such as defective insulin secretion and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissue to insulin) or increased hepatic glucose output. Therapies for type 2 diabetes are targeted towards increasing insulin sensitivity such as TZDs, hepatic glucose utilization such as biguanides, directly modifying insulin levels such as insulin, insulin analogs, and insulin secretagogues, increasing incretin hormone action such as exenatide and sitagliptin, or inhibiting glucose absorption from the diet such as alpha glucosidase inhibitors (David E. Moller, Nature (2001 ), 414, 821 -827). Some of the therapies involved in current management of the diabetes and related diseases are associated with the risk of hypoglycemia or result in weight gain.

In recent years incretin hormone GLP- 1 , is being used in the clinic to enhance insulin secretion and reduce body weight in patients with type 2 Diabetes Mellitus. For example GLP- 1 analogues such as Exenatide or Liraglutide have been approved for treating diabetes. These GLP- 1 analogues reduce fasting hyperglycemia and results in sustained lowering of hemoglobin glycosylated HbA l C levels. In addition it has been reported that these therapies reduce body weight and have no adverse effects on cardiovascular parameters. However the GLP- 1 analogues are peptide drugs to be administered by injection, limiting clinical utility of these drugs. Several alternative approaches remain to be fully explored with respect to enhancing GLP- 1 activity as well as patient compliance ( nudsen et al ; Proc Natl Acad Sci U S A. (2007) Jan 1 6; 104(3):937-42; Wootten et al, Modulation of the glucagon-like peptide- 1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther. (201 1 ) Feb;336(2):540-50). Orally available small molecule agonists of GLP- 1 R would be a highly valuable contribution to the care for patients. The GLP- 1 receptor is a member of the glucagon-secretin B family of G protein-coupled receptors. GLP- 1 R binds specifically to GLP- 1 in pancreatic β-cells. GLP- 1 R is coupled to Gas, thereby mediating its effects through generation of cAMP, causing cell depolarization and increased cystolic calcium concentration, which results in increased insulin synthesis and release of insulin in β-cells (Drucker et al; Proc Natl Acad Sci U S A. ( 1987) May;84( 10):3434-8). Small molecules that can activate or potentiate GLP- 1 receptor with improved pharmacological properties are therefore of great interest.

Positive allosteric modulators (PAM), is an emerging approach as a small molecule agonists, with the potential to be more specific and produce significant therapeutic advantages over conventional small molecule (orthosteric) or biological drugs. Orthosteric site is the binding site for the endogenous ligand on a receptor. While, a binding site on a receptor that is topographically distinct from the orthosteric site is called as allosteric site (Conn et al ; Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009 Jan;8( 1 ):41 -54). PAM increases the activity of a receptor indirectly via activation of an allosteric site on the protein. In general, most drugs out-compete endogenous ligands in order to bind to the active site. However, allosteric modulators are non-competitive as they bind receptors at a different site even if the endogenous ligand is also binding. Targeting allosteric binding sites represents a powerful mechanism for selectively modulating receptor function (Langmead CJ; Screening for positive allosteric modulators: assessment of modulator concentration- response curves as a screening paradigm. J Biomol Screen. (2007) Aug; 12(5):668-76). Allosteric modulators with limited positive cooperativity would impose a 'ceiling' on the magnitude of their allosteric effect. These properties wi ll allow using a large dose of allosteric modulators with a lower propensity towards target-based toxicity than orthosteric agonists (Conn et al; Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009 Jan;8( l ):41 -54).

Thieno[3,4-b]pyrazine compounds having modulatory activity on GLP- 1 receptor are described herein. Summary of the Invention cordance with one aspect, the invention provides the compounds of Formula (I):

wherein,

L is selected from a bond, (CH ₂ ) _q , -(CH ₂ ) _m CH=CH-(CH ₂ ) _n -, -(CH ₂ ) _m -C≡C-(CH ₂ )„-. - (CH ₂ ) _m -C(0)-(CH ₂ )n-, -(CH ₂ ) _m S(0) _p -(CH ₂ ) _i , -(CH ₂ ) _m NR _a S(0) ₂ -(CH ₂ ) _n -, -(CH ₂ ) _m -0- (CH ₂ )„-, -(CH ₂ ) _m NR _a -(CH ₂ ) _n -, cycloalkyl and heterocyclyl; ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

R is selected from hydrogen, alkyl, haloalkyl, aryl, hydroxyl, alkenyl, alkynyl, alkoxy, halo, cyano, (CR _c R _d ) _n -NR _a COR ₄ , (CR _c R _d ) _n -NR _a R _b , -(CR _c R _<i ) _n -OR4, and (CR _c R _d ) _n -

Ri is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkenyl. alkynyl. alkoxy. halo and cyano;

R ₂ and R ₃ which may be same or different and are independently selected from hydrogen, halo, alkyl, haloalkyl, aryl and -S(0) _P R ₄ ; at each occurrence, R ₄ is selected from alkyl, aryl and heteroaryl;

R _a and R _b , which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, C(0)R4 and S(0) ₂ R4; or R _a and R _b together with the nitrogen atom to which they are attached may form a 3-7 membered heterocyclic ring;

R _c and R _d may be same or different at each occurrence and are independently selected from hydrogen, alkyl and cycloalkyl; or

R _c and R _d together with the carbon atom to which they are attached may form a 3-7 membered carbocyclic or heterocyclic ring;

'q' is an integer ranging from 1 to 4, both inclusive; ^k m ' is an integer ranging from 0 to 4, both inclusive; ν is an integer ranging from 0 to 4, both inclusive;

'ρ' is an integer ranging from 0 to 2, both inclusive; and wherein, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl wherever they occur may optionally be substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, - C(0)OR ^x , -C(0)R\ -C(S)R\ -C(0)NR ^x R ^y , -NR ^x C(0)NR ^y R ^z , -N(R ^x )S(0)R ^y , N(R ^x )S(0) ₂ R ^y , -NR ^x R , -NR C(0)R ^y . -NR ^x C( S)R ^y , -NR C(S)NR ^y R ^z , -S(0 )NR ^x R\ - S(0) ₂ NR ^x R ^y , -OR\ -OC(0)R\ -OC(0)NR ^x R ^y , -R C(0)OR ^y , -R ^x C(0)NR ^y R ^z , - R ^x C(0)R ^y , -SR , -S(0)R ,. and -S(0) ₂ R ^x ; wherein each occurrence of R ^x , R ^y and R ^z are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl; rmaceutically acceptable salt thereof. The below embodiments, which are illustrative in nature only and are not intended to limit the scope of the invention.

According to another embodiment there are provided compounds of Formula (II):

or pharmaceutically acceptable salt thereof; wherein,

L is selected from -(CH ₂ ) _m S(0) _p -(CH ₂ ) _n -, -(CH ₂ ) _m -0-(CH ₂ )n-;

R is selected from hydrogen, alkyl, haloalkyl, aryl, hydroxyl, alkoxy, halo, cyano, (CR _c R _d ) _n - NR _a COR4, -(CR _c R _d ) _n -OR4 and (CR _c R _d ) _n -S(0) _p -R4; R | is selected from hydrogen, alkyl, haloalkyl and cycloalkyl ; and ring A, R , R _c , ¾, m, n and p are as defined herein above.

According to another embodiment there are provided compounds of Formula (III):

(III ) or pharmaceutically acceptable salt thereof; wherein ring A, R, R _\ and 'm' are as defined herein above.

In another aspect the compounds of the invention or pharmaceutically acceptable salts thereof are useful for treating, preventing, managing diseases or disorders associated with inadequate insulin secretion. In another aspect the compounds of the invention or pharmaceutically acceptable salts thereof are useful for treating, preventing, managing diseases or disorders which are affected or facilitated by the modulation of GLP- 1 receptor.

In another aspect of the invention there are provided pharmaceutical compositions of compound of invention of Formula (I) for treating, preventing, managing diseases or disorders associated with inadequate insulin secretion.

In another aspect of the invention there are provided pharmaceutical compositions of compound of invention of Formula (I) for treating, preventing, managing diseases or disorders which are affected or facilitated by the modulation of GLP- 1 receptor.

In another aspect of the invention the compounds of the invention may be used either alone or in combination with one or more therapeutically active agents for treating, preventing, managing diseases or disorders associated with inadequate insulin secretion.

In another aspect of the invention the compounds of the invention may be used either alone or in combination with one or more therapeutically active agents for treating, preventing, managing diseases or disorders which are affected or facilitated by the modulation of GLP- 1 receptor.

In another aspect of the invention there are provided methods for treating, preventing and/or managing diseases, disorders, syndromes or conditions associated with inadequate insulin secretion, comprising administration of an effective therapeutic amount of a compounds of Formula (I) or a pharmaceutically acceptable salt thereof. In another aspect of the invention there are provided methods for treating, preventing and/or managing diseases, disorders, syndromes or conditions which are affected or facilitated by the modulation of GLP- 1 receptor, comprising administration of an effective therapeutic amount of a compounds of Formula (1) or a pharmaceutically acceptable salt thereof. Thus the compounds or pharmaceutical compositions according to the invention are particularly suitable for treating, preventing and/or managing diseases, disorders, syndromes or conditions associated with inadequate insulin secretion, including type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic syndrome and other metabolic disorders. The complications of diabetes include but not limited to diabetes and related complications, infections, microvascular and macrovascular disorders.

In another aspect of the invention there are provided processes for the preparation of compounds of the invention of Formula (I ):

( I )

comprising, a) reacting diaminothiophene compound of formula ( 1 ) with a-ketoester to give compound of formula (5)

b) treating compound of formula (5) with triflic anhydride in presence of DIPEA to give a compound of formula (6) c) converting compounds of formula (6) to give compound of Formula (I) wherein ring A, L, R. R| , R ₂ , R ₃ , and 'm' are as defined above, by using Sonogashira or Suzuki coupling reaction. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

The term "oxo" means C(=0) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention.

The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1 , 1 - dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. The term "alkenyl " refers to a hydrocarbon radical containing from 2 to 1 0 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-l- propenyl, 1 - butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl " refers to a hydrocarbon radical containing at least one carbon- carbon triple bond, and having 2 to about 1 0 carbon atoms. Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of 3 to about 1 2 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 1 2 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted. The term "haloalkyl" refers to an alkyl, as defined herein, that is substituted by one or more halogen groups as defined herein. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine substituent. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen groups. Preferably, a polyhaloalkyl is substituted with up to 12, 10. 8. 6, 4, 3, or 2 halogen groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichloro fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having al l hydrogen atoms replaced with halogen atoms.

The term "aryl " refers to an ^' aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.

The term "arylalkyl " refers to an aryl group as defined above, directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted. A "carbocyclic ring" or "carbocycle" as used herein refers to a 3- to 10- membered saturated or unsaturated, monocyclic, fused bicyclic, spirocyclic or bridged polycyclic ring containing carbon atoms, which may optionally be substituted, for example, carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, aryl, naphthyl, adamantyl etc. Unless set forth or recited to the contrary, all carbocyclic groups or rings described or claimed herein may be aromatic or non aromatic. The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl ", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -C(0)-, S(0)o-2. -C(=N-alkyl)-, or - C(=N-cycloalkyl), etc. Non-limiting examples of heterocyclic rings include azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, benzopyranyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and the like. The heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The tenn "heteroaryl" unless otherwise specified, refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, 0 or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl. thiazolyl, isothiazolyl, pyridyl. pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and die like ^" . Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety. Such substituents include, but are not limited to hydroxy, halo, carboxyl, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, - C(0)OR\ -C(0)R\ -C(S)R\ -C(0)NR R ^y , -NR ^x C(0)NR ^y R ^z , -N(R ^x )S(0)R ^y , - N(R ^x )S(0) ₂ R ^y , -NR ^x R ^y . -NR ^x C(0)R ^y , -NR ^x C(S)R ^y , -NR ^x C(S)NR ^y R ^z , -S(0)NR ^x R ^y , - S(0) ₂ NR ^x R ^y , -OR ^x , -OC(0)R\ -OC(0)NR ^x R ^y , -R ^x C(0)OR ^y , -R ^x C(0)NR ^y R ^z , -R ^x C(0)R ^y , - SR\ -S(0)R\ and -S(0) ₂ R ^x ; wherein each occurrence of R\ R ^y and R ^z are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl. "May optionally be substituted" means that the moiety or group may or may not be substituted. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. The term "treating" or "treatment" of a state, diseases, disorders, syndromes or conditions includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; and/or (c) slowing the progression of a disease, disorder, condition . or syndrome or at least one of its clinical or subclinical symptoms thereof.

The term "subject" includes mammals preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs and non- domestic animals.

The term "modulator", "modulation", "modulate" or "modulating" refers to increase in the activity or function of a receptor directly or indirectly via activation of orthosteric or allosteric site on the receptor; by way of illustration and not limitation, the modulators include agonist, allosteric modulators, Positive allosteric modulators (PAM) and ago- allosteric modulators. As used herein, the term "agonist" refers to any exogenenously administered compound or agent that directly increases the activity of the receptor by binding to the orthosteric site on the receptor.

As used herein, the term "allosteric modulator" refers to any exogenenously administered compound or agent that directly or indirectly increases the activity of the receptor in the presence of the endogenous ligand such as GLP- 1 7-36 amide via binding to an allosteric site on the protein, which is different than the orthosteric site where the endogenous ligand binds.

As used herein, the term "positive allosteric modulator" refers to any exogenenously administered compound or agent that directly increases the activity of the receptor in the presence of the endogenous ligand only via activation of an allosteric site on the protein, which binds at a site different than the endogenous ligand.

As used herein, the term "ago-allosteric agonist" refers to any exogeneously administered compound or agent functions both as an agonist on its own and also it can increase the activity of the receptor by binding to the allosteric GLP- 1 R site of the receptor. A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disease, disorder, condition or syndrome, is sufficient to cause the effect in the subject which is the puipose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

The compounds of the invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non- natural amino acids. With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.

Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the invention.

General Methods of Preparation

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Schemes 1 to 3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art are also within the scope of the present invention. All the isomers of the compounds described are these schemes, unless otherwise specified, are also encompassed within the scope of this invention. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples.

The compound of formula (I) wherein ring A, R, R ₂ , R ₃ and 'm' are as defined herein above, can be prepared by following the procedure as depicted in Scheme- 1 . The appropriately substituted diaminothiophene compound of formula ( 1 ) is treated with diethyl oxalate in a polar solvent for 2- 16 hrs at a temperature ranging from room temperature to reflux temperature to afford compound of formula (2).

Schenie-1

The compound of formula (2) is treated with phosphorous pentachloride in phosphorous oxychloride at a temperature ranging from 0°C to 100°C for about 1 to 6 hr to afford compound of formula (3). The compound of formula (3) is treated with a base such as caesium carbonate and appropriately substituted compound to afford compound of formula (4).

Alternatively the compound of Formula (I) may be prepared by treating compound of formula ( 1 ) with a-ketoester in a polar solvent in presence of acetic acid under suitable reaction conditions to afford compound of formula (5). Further compound of formula (5) is treated with N,N-diisopropylethylamine (DIPEA) and triflic anhydride to afford compound of formula (6).

Compound of formula (4) or (6) is converted to compound of Formula (I) by using any of the coupling reaction such as Sonogashira or Suzuki coupling reaction. Thus compound of Formula (4) or (6) is treated with terminal acetylene compound followed by palladium catalyst, base and Cul in case of Sonogashira reaction. The reaction mixture is then heated at about 100- 120°C under nitrogen for 2 to 12 hr to give corresponding appropriately substituted compound of Formula-I. Alternatively the compounds of Formula (4) or (6) is treated with appropriate substituted boron compound followed by palladium catalyst and base. The reaction mixture is then heated at about 100- 120°C under nitrogen for 2 to 12 hr to give corresponding appropriately substituted compound of Formula-I.

The compounds of invention may also be prepared by treating compound of formula ( 1 ) with a mixture of phenacyl bromide and l ,4-diazabicyclo[2,2,2]octane (DABCO) to afford compound of Formula (7).

Scheme-2

According to Scheme-2, the appropriately substituted 3,4-diaminothiophene ( 1 ) is treated with appropriately substituted diketo ester to afford compound (9), which is further treated with hydrazine to afford compound ( 10). Compound ( 10) may be further derivatized followed by cyclisation to afford compound of Formula (IA).

Scheme-3

Compounds of Formula (IB) can be synthesized using Scheme-3, compound of formula (5 ) is treated with (Benzotriazol- l -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) in the presence of a base such as l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in solvent such as THF under inert atmosphere to give the BOP derivative, which can further be treated with appropriately substituted nucleophile such as morpholine to furnish compound of formula ( 12). This on further treatment with the suitable halogenation reagent such as N-bromosuccinimide (NBS) affords compound of formula ( 1 3). It can be reacted with appropriately substituted boronic acid under Suzuki reaction conditions to afford the compounds of formula (IB).

The compounds of formula (IC) wherein R, R ₂ and m are as defined above, can be prepared by using compound of formula (5), upon treating under halogenation reaction conditions, such as reaction with NBS it can produce the compound of formula ( 14). Compound of formula ( 14) on reaction with sodium methanesulfinate in the presence of copper(I) salt aprotic solvent such as DMF give compound of formula ( 1 5) which on reaction with base such as cesium carbonate in aprotic solvent such as DMF followed by addition of appropriately substituted benzyl bromide gives compound of formula (IC).

Synthesis of appropriate starting materials described in the Examples below can be prepared by techniques known or apparent to those of skill in the art or the starting may be commercially available. One of skill in the art will understand that the synthetic routes can be modified to use different starting materials and/or alternate reagents to accomplish the desired transformations, and that suitable adjustment in the exemplary conditions (e.g. temperatures, solvents, etc.). Additionally, one of skill in the art will recognize that protecting groups may be necessary for the preparation of certain compounds and will be aware of those conditions compatible with a selected protecting group. Accordingly, the methods and reagents described herein are all expressed as non-limiting embodiments.

Some of the representative examples of the invention prepared, by following one or more reaction schemes disclosed above, are given below. These representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention. 2-((5-Methyl- 1 ,3,4-thiadiazol-2-yl)thio)-3-(trifluoromethyl)thieno[3,4-b]p yrazine;

4-(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)mo holine; 2-( 1 H- 1 ,2,4-Triazol- 1 -yl)-3-(trifluoromethyl)thieno[3,4-b]pyrazine;

2-Thiomo holino-3-(trifluoromethyl)thieno[3,4-b]pyrazine; .

N-( l -(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)piperidin-4-y l)acetamide;

4-(Methoxymethyl)- l -(3-(trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)piperidin-4-o l;

2-(( l -Methyl- l H-imidazol-2-yl)thio)-3-(trifluoromethyl)thieno[3,4-b]pyrazi ne;

2-(3-(Trifluoi methyl)thieno[3,4-b]pyrazin-2-yl)isothiazolidine 1 , 1 -dioxide;

2-Methyl-5-(((3-(trifluoiOmethyl)thieno[3,4-b]pyrazin-2-yl)t hio)rnethyl)- l ,3,4-oxadiazole;

4-(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)benzonitr ile;

2-(4-(Methylsulfonyl)phenyl)-3-(trifluorornethyl)thieno[3,4- b]pyrazine;

2-(Pyridin-3-yl)-3-(trifluoromethyl)thieno[3,4-b]pyrazine;

2-([ l , l '-Biphenyl]-4-yl)-3-(trifluoromethyl)thieno[3,4-b]pyrazine;

2-Isopropyl-3-((5-methyl- l ,3,4-thiadiazol-2-yl)thio)thieno[3,4-b]pyrazine;

2-Isopropyl-3-(( l -methyl- l H-imidazol-2-yl)thio)thieno[3,4-b]pyrazine;

4-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)mo holίne;

2-IsoplΌpyl-3-thiomo holinothieno[3,4-b]pyrazine;

4-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)thiomo holine 1 -oxide;

4-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)thiomoφholine 1 , 1 -dioxide;

2-lsopropyl-3-( l H- l ,2,4-triazol- l -yl)thieno[3,4-b]pyrazine;

2-Isopropyl-3-(pyridin-3-ylmethoxy)thieno[3,4-b]pyrazine;

2-Isopropyl-3-(thiophen-2-yl)thieno[3,4-b]pyrazine; 2-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)-5-methyl- l ,3,4-oxadiazole; 2-Isopropyl-3-(5-methyl- 1 ,3,4-thiadiazol-2-yl)thieno[3,4-b]pyrazine; 2-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)-5-(trifluoromethyl) - l ,3,4-oxadiazole; 2-(4-(Methylsulfonyl)phenyl)thieno[3,4-b]pyrazine; 4-(5-(4-FluoiOphenyl)-3-(trifluoromethyl)thieno[3,4-b]pyrazi n-2-yl)morpholine and 2-((4-Fluorobenzyl)oxy)-5-(methylsulfonyl)-3-(trifluoromethy l)thieno[3,4-b]pyrazine or pharmaceutical ly acceptable salt thereof.

The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.

Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds are able to form are included within the scope of the present invention. The compounds of the invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic acids or bases, salts of organic acids or bases, salts of chiral acids or bases, salts of natural amino acids and salts of non-natural amino acids. The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.

Pharmaceutical Compositions The invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient such as a carrier or diluent. Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate GLP- 1 receptor mediated diseases described herein when administered to a subject.

The compounds of the invention may be associated with a pharmaceutically acceptable excipient such as a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agents that do not induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxil iary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, stabilizers, surfactants, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound of Formula (I) can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application. The route of administration may be any route which effectively transports the active compound of the invention, to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subderinal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non- aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions formulation.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation; the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1 0000 mg, according to the potency of the active component or mode of administration.

Suitable doses of the compounds, for use in treating the diseases and disorders described herein, can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must _, be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the dai ly dosage of the GLP- 1 modulator can range from about 0.1 to about 30.0 mg/kg. Mode of administration. dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.

In one embodiment of the invention, the compound of Formula (I) and / or the pharmaceutical compositions of Formula (I) may be used either alone or in combination with one or more additional therapeutic agents for treating, preventing, managing diseases, disorders, syndromes or conditions associated with the modulation of the GLP- 1 receptor. The compounds and compositions of the invention and the additional therapeutic agent as described herein may be administered simultaneously, sequentially or separately. The combination of the compound of Formula (I) with any one or more additional therapeutic agent may be given to the subject in the same or separate dosage formulation. Where separate dosage formulations are used, the compound of Formula (I) and one or more additional therapeutic agents can be administered at essentially the same time i.e., concurrently, or at separately staggered times i.e., sequentially. Combination therapy is understood to include all these regimens. Selection of additional therapeutic agents will, in large part, depend on the desired target therapy. Turner N, et al, Prog. Drug Res. ( 1998) 5 1 : 33-94; Haffner S, Diabetes Care ( 1998) 21 : 160- 178; and DeFronzo R, et al. (eds.), Diabetes Reviews ( 1997) Vol. 5 No. 4. A number of studies have investigated the benefits of combination therapies with oral agents {see, e.g., Mahler R, J. Clin. Endocrinol. Me tab. ( 1 999) 84: 1 165-71 ; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care ( 1 998) 21 :87-92; Bardin CW (ed.), Current Therapy in Endocrinology and Metabolism, 6th Ed. (Mosby - Year Book, Inc., St. Louis, MO 1997); Chiasson J, et al., Ann. Intern. Med. ( 1994) 121 :928-935; Coniff R, et al., Clin. Ther. ( 1997) 1 9: 16-26; Coniff R, et al., Am. J. Med. ( 1995) 98:443-45 1 ; and Iwamoto Y, et al, Diabet. Med. ( 1996) 13 :365-370; Kwiterovich P, Am. J. Cardiol. ( 1998) 82( 12A):3U- 1 7U).

The additional therapeutic agent which can be used in combination with the compounds of invention include, but not limited to, anti-diabetic agents, anti-hypertensive agents, anti- obesity agents, anti-atherosclerotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-metabolic syndrome agents, lipid lowering agents, anti-lipodystrophy agents, appetite suppressants, treatments for heart failure, treatments for peripheral arterial disease and anti-inflammatory agents.

A combination therapy may be used in modulating, including preventing, the onset of the symptoms or complications associated with diabetes or treating, preventing or reducing the risk of developing diabetes and its related symptoms, complications, and disorders, wherein the compounds of the invention can be effectively used in combination with, one or more additional therapeutic agents. One or more additional therapeutic agents for diabetes includes but not limited to insulin and insulin analogs; insulin secretagogues such as sulfonylureas and analogs; meglitinides; insulin sensitizers such as biguanides; thiazolidinediones (PPAR); PPAR alpha/gamma dual agonists; alpha-glucosidase inhibitors; dipeptidyl peptidase-IV (DPP4) inhibitors; glucagon-like peptide- 1 (GLP- 1 ) receptor agonists including glucagon- like peptides and its analogues, amylin agonists; glucagon antagonists; alpha2-antagonists and imidazolines; SGLT2 inhibitors; GPR- 1 19 modulators, insulin signaling agonists, insulin mimetics, aldose reductase inhibitors; 1 1 -beta-hydroxysteroid dehydrogenase Type I inhibitors; RXR agonists; fatty acid oxidation inhibitors; beta-agonists; phosphodiesterase inhibitors, both cAMP and cGMP type; lipoxygenase inhibitors; PTP 1 B inhibitors; gluconeogenesis inhibitors; somatostatin and its analogs and antagonists; antil ipolytic agents; glucose transport stimulating agents; glucose synthase kinase inhibitors; galanin receptor agonists; chemokine receptor antagonist; glucokinase activators; GDIR agonists; GPR40 modulators.

Insulin and its analogs include insulin from animal source and recombinant insulin and its derivatives, for e.g., short acting derivatives Lispro, aspart, glulisine and their protamine solutions and mixtures thereof, or the long acting derivatives, for e.g., glargine, detemir, and their modified formulations, for e.g., inhaled formulations comprising insulin, insulin via buccal route and the like. Sulfonylureas and analogs includes, but not limited to, chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride and the like. Meglitinides such as repaglinide, mitiglinide and the like. Biguanides includes, but not limited to, metformin, phenformin, buformin and the like. Thiazolidinediones for e.g., ciglitazone, pioglitazone, troglitazone, rosiglitazone and the like. PPAR-alpha agonists for e.g., fenofibrate, gemfibrozil and the like. PPAR alpha/gamma dual agonists, for e.g., muraglitazar, peliglitazar, and the like. Dipeptidyl peptidase-IV (DPP4) inhibitors includes saxagliptin, sitagliptin, vildagliptin, denagliptin and the like. Glucagon- like peptide- 1 (GLP- 1 ) receptor agonists, for e.g., Exenatide, Liraglutide, AVE0010, R1583, SUN E7001 , GSK-7161 55 and Exendin-4 (PC-DACTM) and the like. Alpha2-antagonists and imidazolines include, but are not limited to, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan and the like. SGLT2 inhibitors include, but are not limited to, dapagliflozin, sergliflozin, canagliflozin, LX421 1 , BI- 10773, BI-44847, ASP- 1 941 , TS-071 and the like. Alpha-glucosidase inhibitors include, but are not limited to. acarbose, miglitol, voglibose and the like. Amylin analogs such as pramlintide and its derivatives. Other insulin secretagogues, for e.g., linogliride, insulinotropin, exendin-4, N,N-dimethyl-N'-[2-(4- morpholinyl)phenyl]guanidine (E)-2-butenedioate salt (BTS-675820), (-)-N-(trans-4- isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166)) and the like. In another embodiment, the compound of Formula (I) may be used in combination therapy for treating obesity or obesity- related disorders, wherein the compound of Formula (I) can be effectively used in combination with one or more therapeutic agents having synergistic effects such as anti-obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects. Anti-obesity agents include but are not limited to β-3 adrenoceptor agonist agents; gastrointestinal lipase inhibitors, leptins, cannabinoid- 1 ("CB- 1 ") receptor antagonists (such as rimonabant); PPAR delta agonists or partial agonists; dual PPAR alpha, PPAR delta agonists or partial agonists; dual PPAR delta, PPAR gamma agonists or partial agonists; pan PPAR agonists or partial agonists; neuropeptide Y; enterostatin; cholecytokinin; bombesin; amylin; histamine H3 receptors; serotonin 2C receptor agonists (5HT2c), dopamine D2 receptors; melanocyte stimulating hormone; corticotrophin releasing factor; galanin; gamma amino butyric acid (GABA), apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, MCR-4 antagonists; cholescystokinin-A (CCK-A) agonists, serotonin, galanin receptor antagonists; urocortin mimetics, CRF antagonists, CRF binding proteins and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), europeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors (such as ΑΧΟΚΓΝΕ, human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion). Some of the compounds that can be used in combination with the compounds of the invention include, but are not limited to, phenylpropanolamine, phentermine; orlistat, rimonabant. dexamphetamine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, sibutramine, QNEXA (combination of phentermine and topiramate), Lorcaserin, CONTRAVE (combination of naltrexone and bupropion) and the like.

In a further embodiment, the compound of Formula (I) may be used in combination therapy for modulating metabolic syndrome for e.g., treating metabolic syndrome and its related symptoms, complications and disorders, wherein the compound of Formula (I) may be effectively used in combination with, for example, the active agents discussed- above for modulating or treating diabetes, obesity, hyperlipidemia, atherosclerosis, and/or their respective related symptoms, complications and disorders. Metabolic Syndrome or "Syndrome X" is described in Ford et al., J. Am. Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med. Chem.-Imm., Endoc. & Metab. Agents, 1 : 1 -24 (2001 ).

In a further embodiment, the compound of Formula (I) may be used in combination therapy in modulating hyperlipidemia. Examples of suitable lipid lowering agents and anti- atherosclerotic agents, for use in combination with the compounds of Formula (I) include one or more MTP/ApoB secretion inhibitors (e.g., dirlopatide, N-(2,2,2-trifluoroethyl)-9-[4- [4-[[[4'-(trifluoromethyl)[ l , -biphenyl]-2-yl]carbonyl-]amino]- l -piperidinyl]butyl]-9H- fluorene-9-carboxamide methane sulfonate, CP-741 952, SLx-4090; HMG CoA reductase inhibitors (e.g., atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin); squalene synthetase inhibitors, PPAR alpha agonists and fibric acid derivatives (e.g., fenofibrate, gemfibrozil); ACAT inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors (e.g., ezetimibe); Ileal Na+/bile acid cotransporter inhibitors (e.g., compounds as disclosed in Drugs of the Future, 24:425-430 ( 1999); upregulators of LDL receptor activity (e.g., (3R)-3-[( l 3R)- 1 3-hydroxy- 10-oxotetradecyl]-5,7-dimethoxy- l (3H)-isobenzofuranone and (3alpha,4alpha,5alpha)-4-(2-propenyl)-cholestan-3-ol ; bile acid sequestrants (e.g.. WELCHOL, COLESTID, LOCHOLEST and QUESTRAN; and fibric acid derivatives, such as ATROMID, LOPID and TRICOT); cholesterol ester transfer protein inhibitors (e.g., torcetrapib and (2R)-3- { [3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-( 1 , 1 ,2, 2-tetrafluoroeth- o _, xy)phenyl]methyl]amino} - l , l , l -trifluoro-2-piOpanol); nicotinic acid and derivatives thereof (e.g., niacin, acipimox); PCSK9 inhibitors; LXR agonists; lipoxygenase inhibitors as disclosed by Sendobry et al ., "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J. Pharmacology, 120: 1 199- 1206 ( 1997), and Cornicelli et al., " 15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 5 : 1 1 -20 ( 1999)). Preferred hypolipidemic agents are pravastatin, lovastatin, si mvastatin, atorvastatin, fluvastatin, cerivastatin. atavastatin, and rosuvastatin.

Examples of suitable anti-hypertensive agents for use in combination with the compounds of the invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT- 1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists, Dual ET/AI1 antagonist , neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), nitrates, central alpha agonists (e.g., clonidine), alpha 1 blockers (e.g., prazosine), arterial vasodilators (e.g., minoxidil), sympatolytics (e.g., resperine), renin inhibitors (e.g., Aliskiren).

The above other therapeutic agents, when employed in combination with the compounds of the invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, or as otherwise determined by one of ordinary skill in the art.

In one embodiment, the compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic active agents (pharmaceutical combinations) as described above. Where compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary, depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth. In general, compounds of the invention will be administered in therapeutically effective amounts via one or more acceptable modes known in the art, either alone or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.

Method of Use

In one embodiment, the invention provides a compound of Formula (I) and pharmaceutical compositions thereof that are useful in treating diseases, disorders or conditions associated inadequate insulin secretion or which are affected or facilitated by the modulation of GLP- 1 receptor, which includes, but are not limited to, treating, preventing, managing and/or diabetes, slowing the progression of diabetes and related , conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, diabetes related comorbidities, late stage diabetes, obesity, cardiovascular diseases, and metabolic syndrome and its component conditions.

The invention further provides methods of treating diseases, disorders syndromes or conditions associated inadequate insulin secretion or which are affected or facilitated by the modulation of GLP- 1 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof.

In a further embodiment the diseases, disorders or conditions associated inadequate insulin secretion or which are affected or facilitated by the modulation of GLP- 1 receptor, include Type 2 diabetes, Type 1 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, retinopathy, neuropathy, nephropathy, diabetic foot, obesity, Metabolic Syndrome, lipodystrophy including HIV protease associated lipodystrophy, lipid disorders, hypertension, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, vascular restenosis, peripheral arterial disease, and its sequela for example acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication, myocardial ischemia, stroke and heart failure.

Within the context of the invention a metabolic disorder is understood to refer to any disorder associated with the metabolism or resulting from a defect of the metabolism. In another embodiment there are provided methods comprising administering an therapeutically effect amount of a compound of invention to a subject wherein the amount of the compound is effective to a) reduce food intake;

b) lower plasma glucagon;

c) reduce gastric motility or delay gastric emptying; or

d) stimulate insulin release in the subject in need thereof.

In another embodiment of the invention the compound, pharmaceutical composition of the invention and methods for treating, preventing, managing diseases or disorders associated with drug induced obesity. In an embodiment "drug induced obesity" refers to weight gain resulting from a drug regimen wherein the subject taking the drug is considered obese or will be expected to become obese if the drug regimen is continued. In an embodiment the compounds and pharmaceutical composition of the invention may be used for treating, preventing, managing diseases or disorders associated with diabetes related one or more comorbidities of diabetes. A "comorbidity" is a disease condition in addition to diabetes, that adds to the deleterious effects of the diabetes on the subject and/or affects the choice of therapy. Comorbidities can arise secondarily from the diabetes or from other comorbidities, or may arise independently. Among comorbidities commonly occurring in a diabetic subject are illustratively, insulin resistance, chronic kidney disease, hypertension, dyslipidemia, obesity, cardiac insufficiency and sleep apnea. In some embodiments the subject may have more than one such comorbidities. For example, in metabolic syndrome, a subject can exhibit diabetes with insulin resistance, hypertension, dyslipidemia and obesity.

The late stage diabetes includes subjects with type 2 diabetes with a secondary antidiabetic drug failure and having one or more of the hyperglycemia, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, ulcers, macroangiopathies, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart fai lure, oedema, hyperuricaemia, inflammation, asthma, psoriasis, arthritis, rheumatoid arthritis, inflammatory bowel disease, cancer or neurologic disorder.

In an embodiment of the invention there are provided methods for modulating insulin concentration in plasma of a subject, comprising administering therapeutically effective amount of a compound or pharmaceutical composition of the invention to modulate insulin concentration in plasma of the mammal.

In an embodiment of the invention there are provided methods for increasing insulin concentration in plasma of a subject, comprising administering therapeutically effective amount of a compound or pharmaceutical composition of the invention to modulate insulin concentration in plasma of the mammal. The above other therapeutic agents, when employed in combination with the compounds of the invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the references set out above, or as otherwise determined by one of ordinary skill in the art. In an embodiment of the invention the compounds of the invention or the pharmaceutical compositions of the invention can be administered to a subject in need of. The subject as described herein includes mammals including humans, monkeys, dogs, cats etc.

The antidiabetic effects of the compounds provided herein can be demonstrated using a variety of in vitro and in vivo assays including a number of animal models. Some of the assays for measuring insulin release include measurement of insulin release potential of compounds in pancreatic islet cells removed from male C57BL/6 mice or Pancreatic islet cell lines like HIT-T1 5 or INS- I E or RTN-5F: These cell lines are derived from the pancreatic β- cells and can be used to measure the target receptor mediated insulin release by compounds.

Animal models for testing compounds include, for example, mouse strains in which type 2 diabetes characteristics have arisen spontaneously or were produced by selective breeding or non-genetic-based or induced animal models of diabetes are also available, including, for example, animals with diet-induced diabetes induced by a combination of high- fat diet and streptozotocin (STZ) injections or by neonatal STZ injections.

In addition, modulation of secretion from isolated pancreatic cells can be assessed by measuring membrane voltage changes, second messenger activation (e.g., cAMP, IP3 or Ca ²⁺ ) levels, ion flux, phosphorylation levels, transcription levels, and the like. Additional exemplary assays methods described in the literature may also be used.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference.

Nomenclature of the compounds of the invention is according to ChemBioDraw version 12. Structures of the intermediates as well as the final compounds were confirmed by spectral data.

Experimental Details

Some of the representative examples of the present invention were prepared by following one or more reaction schemes as described above.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the relative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference.

Nomenclature of the compounds of the invention is according to ChemBioDraw version 12.

Structures of the intermediates as well as the final compounds were confirmed by spectral data.

Intermediate-l : 3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2( l H)-one To a solution of thiophene-3,4-diamine dihydrochloride (2.0 g, 10.69 mmol) in dry DMF ( 10 mL) was added glacial acetic acid (0.2 niL) and then ethyl-3,3,3-trifluoro-2-oxopropanoate ( 1 .82 g, 10.69 mmol) drop wise for 15 min. at room temperature. The reaction was stirred for 30 min. at room temperature. The solvent was evaporated under reduced pressure and water ( 1 5 mL) was added to the residual mass and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by column chromatography using acetone:hexane (2.5%) to afford the title compound 1 .4g as a yellow semisolid. MS (M+H ⁺ ) m/z 220.9.

Intermediate-2: 3-Isopropylthieno[3,4-b]pyrazin-2( l H)-one

To a solution of thiophene-3,4-diamine dihydrochloride (2.6 g, 1 3.90 mmol) in dry DMF ( 10 mL) was added TEA ( 1 .4 g, 13.9 mmol) at 0°C under N ₂ atmosphere and stirred for 10 min. Then added glacial acetic acid (0.52 mL) followed by ethyl 3-methyl-2-oxobutanoate (2.0 g. 13.9 mmol) drop wise for 1 5 min at room temperature. The reaction was stirred for 30 min at room temperature. Distilled the reaction mixture under reduced pressure and water ( 1 5 mL) was added to the residual mass. It was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using acetone:hexane (5%) to afford 3-isopropylthieno[3,4-b]pyrazin-2( l H )- one 2.1 g as a white solid MS (M+H ⁺ ) m/z 21 3.0.

Intermediate-3: 3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl trifluoromethanesulfonate:

To a solution of 3-(trifluoromethyl)thieno[3,4-b]pyrazin-2( l H)-one (290 mg, 10.69 mmol) in dry DCM (5 mL) was added DIPEA (254 mg, 1 .97 mmol) followed by addition of triflic anhydride (444.2 mg, 1 .57 mmol) at 0°C . The reaction mixture was stirred at 0°C for 40min. The reaction was quenched with water (5 mL) and extracted with dichloromethane ( 10 mL x 3). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using acetone:hexane (5%) to afford the title compound 97.0 mg as a yellow semisolid. ' HNMR (CDC1 ₃ ) : δ 8.437 (d, J=3.6Hz, 1 H), 8. 1 39 (d, J=3.6Hz, 1 H).

Intermediate-4: 2-Chloro-3-(trifluoromethyl)thieno[3,4-b]pyrazine To a solution of 3-(trifluoromethyl)thieno[3,4-b]pyrazin-2( l H)-one (700 mg, 3.18 mmol) in POCl ₃ (5 mL) was added PC1 ₅ (728.83 mg, 3.1 8 mmol) at room temperature. The reaction mixture was stirred at 105°C for l h. Distill the reaction mixture under reduced pressure and quenched the reaction mixture with ice-water ( 1 5 mL). It was basified with solid NaHC0 ₃ till pH is neutral, extracted with ethylacetate ( 10 mL x 4). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S04 and concentrated under reduced pressure to afford the title compound 141 mg as a brown semisolid.

Intermediate-5: 2-Chloro-3-isopropylthieno[3,4-b]pyrazine:

To a solution of 3-isopropylthieno[3,4-b]pyrazin-2( l H)-one (200 mg, 1 .03 mmol) in POCl ₃ ( 5 mL) at room temperature. The reaction mixture was stirred at 70°C for 2h. The solvent was evaporated under reduced pressure. The gummy mass obtained was taken into ice-water ( 15 mL) and was basified with solid NaHC0 ₃ till pH is neutral, extracted with ethylacetate ( 10 mL x 4). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to afford the title compound 1 77 mg as a yellowish solid. ' HNMR (CDC1 ₃ ) : δ 8.330 (d, J=3.2Hz, l H), 8.070 (d, J=3.2Hz, 1 H).

Intermediate-6: Ethyl 3-isopropylthieno[3,4-b]pyrazine-2-carboxylate:

To a solution of thiophene-3,4-diamine dihydrochloride (2.0 g, 10.69 mmol) in dry DMF ( 10 mL) was added glacial acetic acid (0.2 mL) and then ethyl 4-methyl-2,3-dioxopentanoate (2.02 g, 1 1 .76 mmol) drop wise for 15 min. at room temperature. The reaction was stirred for 2h at room temperature. The solvent was evaporated under reduced pressure and to the residual mass water ( 15 mL) was added and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by column chromatography using acetone :hexane (5%) to afford the title compound 391 .0 mg as a yellow semisolid, MS (M+H ⁺ ) m/z 25 1 .1 .

Intermediate-7: 3-Isopropylthieno[3,4-b]pyrazine-2-carbohydrazide

To a solution of Intermediate-6 (2.0 g, 10.69 mmol) in 1 ,4-dioxane (5.0 mL) was added hydrazine hydrate (390.45 mg. 7.79 mmol) at room temperature. The reaction mixture was heated to 45°C for 12h. The solvent was evaporated under reduced pressure to afford the title compound 327.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 237.1 .

Intermediate-8: N'-Acetyl-3-isopropylthieno[3,4-b]pyrazine-2-carbohydrazide

To a solution of lntermediate-7 (3 15.0 mg, 1.33 mmol) in dry DCM ( 10 mL) was added TEA (269.8 mg, 2.66 mmol) at room temperature. Acetic anhydride (204.39 mg, 1 .99 mmol) was added drop wise at 0°C. The reaction was stirred for 30 min at room temperature. Evaporation of solvent under reduced pressure afforded the title compound 300.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 279.1 .

Intermediate-9: 3-Isopropyl-N'-(2,2 _! 2-trifluoroacetyl)thieno[3,4-b]pyrazine-2- carbohydrazide

To a solution of Intermediate-7 (250.0 mg, 1.05 mmol) in dry THF (3.0 niL) was added TEA (269.8 mg, 2.66 mmol) at room temperature followed by trifluoroacetic anhydride (33 1 .0 mg, 1 .59 mmol) was added drop wise at 0°C. The reaction mixture was stirred for 3h at room temperature. Distillation of the solvent under reduced pressure furnished the title compound 3 1 1 .0 mg as a yellow solid, MS (M+H ⁺ ) m/z 333.2.

Intermediate-10: 5-Bromo-3-(trifluoromethyl)thieno[3,4-b]pyrazin-2( 1 H)-one

To a solution of Intermediate- 1 (2.6 g, 1 1 .64 mmol) in dry DMF ( 10 mL) was added N- bromosuccinamide ( 1 .6 g, 8.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 min. The reaction was quenched with water and extracted with ethylacetate (25 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by column chromatography using hexane to afford the title compound 637.0 mg as a yellow solid. Intermediate-11 : 5-(Methylsulfonyl)-3-(trifluoiOmethyl)thieno[3,4-b]pyrazin-2 ( l H)-one

To a solution of intermediate- 10 ( 100 mg, 0.3 mmol) in dry DMF (8.0 mL) was added copper(I)trifluoromethanesulphonate ( 16.9 mg. 0.03 mmol ), sodium methanesulfinate (5 1 .56 mg, 0.50 mmol) and Ν,Ν-dimethyl ethylenediamine ( 1 .6 g, 8.8 mmol) at room temperature. The reaction mixture was stirred at 60°C for 1 h. The reaction was quenched with water and extracted with ethylacetate (25 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using acetone:hexane (20%) to afford the title compound 1 1 .0 mg as a yellow solid, MS (M+) m/z 298.15.

EXAMPLES

Example-1 : 2-((5-Methyl- l ,3,4-thiadiazol-2-yl)thio)-3-(trifluoromethyl)thieno[3,4- bjpyrazine

To a solution of Intermediate-4 in DMF (2 mL) was added KF in alumina (34.2 mg, 0.6 mmol) followed by addition of 5-methyl- l ,3,4-thiadiazole-2-thiol (66.6 mg, 0.5 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate ( 10 mL x 2). The combined organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using ethylacetate:hexane ( 1 5%) to afford the title compound 37.0 mg as yellow solid. MS (M+H ⁺ ) m/z 335.0, ' HNMR (CDC1 ₃ ): δ 8.28 (d, 1 H, J=3.2Hz), 7.93 (d, 1 H, J=3.6Hz), 2.88 (s, 3H). Example-2: 4-(3-(Trifluoromethyl)tHieno[3,4-b]pyrazin-2-yl)mo holine

To a solution of Intermediate- 1 ( 100 mg, 0.45 mmol) in dry THF (5 mL) was added (Benzotriazol- l -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (261 .34 mg, 0.59 mmol) and DBU (103 mg, 0.68 mmol) under N2 atmosphere at room temperature. The resultant mixture was stirred for 20 min and then morpholine ( 1 18.63 mg, 1 .36 mmol) was added. The reaction was stirred overnight at room temperature. Distill the reaction mixture under reduced pressure. The crude mass obtained was purified by column chromatography using acetone :hexane (2.5%) to afford the title compound as a yellow solid. MS (M+H ⁺ ) m/z 290. 1 , Ή NMR (CDCI3): δ 8.13 (d, 1 H, J=3.2Hz), 7.67 (d, 1 H, J=3.2Hz), 3.88 (t, 2H, J=4.4 Hz), 3.36 (t, 2H, J=4.4 Hz).

Example-3: 2-( 1 H- 1 ,2,4-Triazol- 1 -yl)-3-(trifluoromethyl)thieno[3,4-b]pyrazine

The title compound was prepared by following a procedure similar to that described in Example-2 using Intermediate-4. MS (M+H ⁺ ) m/z 272.0. Ή NMR (CDC1 ₃ ):5 8.80 (s, 1 H), 8.46 (d, 1 H, j=3.2 Hz), 8.22-8.21 (m, 2H).

Example-4: 2-Thiomorpholino-3-(trifluoromethyl)thieno[3,4-b]pyrazine The title compound was prepared by following the similar procedure as described in Example-2 using Intermediate-4. MS (M+H ⁺ ) m/z 306.0. Ή NMR (CDC1 ₃ ):5 8.13 (d, I H. J=3.2Hz), 7.69 (d, I H, J=3.2 Hz), 3.58-3.55 (m, 4H), 2.84-2.82 (m, 4H).

Example-5: N-( 1 -(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)piperidin-4-y l)acetamide

Step- 1 : To a solution of Intermediate- 1 (500 mg, 2.3 mmol) in dry THF ( 10 mL) was added BOP reagent ( 1 .3 g, 2.95 mmol) and DBU (51 8.0 mg, 3.4 mmol) under N ₂ atmosphere at room temperature. The resultant mixture was stirred for 20 min and then teri-buiy piperidin- 4-ylcarbamate (909.0 mg, 4.53 mmol) was added. The reaction was stirred overnight at room temperature and then heated to 60°C for 3h. Distilled the reaction mixture under reduced pressure. The product was purified by column chromatography using acetone:hexane (2.5%) to afford the te/Y-butyl ( l -(3-(trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)piperidin-4- yl)carbamate as a yellow solid. MS (M+H ⁺ ) m/z 403.2.

Step-2: To a solution of ter/-butyl ( l -(3-(trifluoromethyl) thieno[3,4-b]pyrazin-2- yl)piperidin-4-yl)carbamate (Step- 1 Intermediate) (200 mg, 0.49 mmol) in dry DC M ( 10 mL) was added TFA ( 1 mL) at 0°C temperature. The resultant mixture was stirred for l h. Distill the reaction mixture under reduced pressure. The TFA salt was then taken in dry DCM ( 10 mL) add TEA ( 140.6 mg, 1 .39 mmol) cool to 0°C and added acetic anhydride (70.98 mg, 0.69 mmol). The reaction was stirred at room temperature for l h. Distill the reaction mixture under reduced pressure. The product was purified by column chromatography using acetone:hexane ( 15%) to afford the title compound N-( l -(3-(trifluoromethyl)thieno[3,4- b]pyrazin-2-yl)piperidin-4-yl)acetamide as yellow solid. MS (M+H ⁺ ) m/z 345.2, Ή NMR

(CDC1 ₃ ): 58.09 (d, I H, J=3.6Hz), 7.62 (d, I H, J=3.2Hz). 4.03-3.97 (m, I H), 3.65-3.61 (m, 2H), 3.03-2.97 (m, 2H), 2.07-2.04(m, 2H), 1 .97 (s, 3H), 1 .64- 1 .58 (m, 2H). Example-6: 4-(Methoxymethyl)- l -(3-(trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)piperidin- 4-ol :

The title compound was prepared by following the similar procedure as described in Example-2 using Intermediate- 1 . MS (M+H ⁺ ) m/z 348.0. Ή NMR (CDC1 ₃ ): δ 8.08 (d, I H, J=3.2Hz), 7.61 (d, I H, J=3.2 Hz), 3.59-3.49 (m, 2H), 3.43 (s, 3H), 3.38-3.3 1 (m, 4H), 2.2 (bs, I H, exchangeable), 1 .79- 1 .76 (m, 4H).

Example-7: 2-(( l -Methyl- l H-imidazol-2-yl)thio)-3-(trifluoromethyl)thieno[3,4-b]pyrazi ne

The title compound was prepared by following the similar procedure as described in Example-2 using Intermediate- 1 . MS (M+H ⁺ ) m/z 317.1. Ή NMR (CDC1 ₃ ): 5 8.18 (d, I H, J=3.6Hz), 7.69 (d, I H, J=3.6 Hz), 7.29 (s, I H), 7.25 (s, I H), 3.72(s, 3H).

Example-8: 2-(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)isothiazolid ine 1 , 1 -dioxide

The title compound was prepared by following the similar procedure as described in Example-2 using Intermediate- 1. MS (M+H ⁺ ) m/z 323.9. Ή NMR (DMSO-d6): δ 8.84 (d, I H, J=3.6 Hz); 8.57 (d, 1 H, J=3.2 Hz); 3.97 (t, 2H, J=6.8Hz); 3.4 (t, 2H, J=7.6Hz), 2.62-2.54 (m, 2H). Example-9: 2-Methyl-5-(((3-(trifluorome

oxadiazole

Step- 1 : To a solution of Intermediate- 1 (200 mg, 0.91 mmol) in dry THF (5 mL) was added BOP reagent (522.61 mg, 1 . 1 8 mmol) and DBU (207.21 mg, 1 .36 mmol) under N ₂ atmosphere at room temperature. The resultant reaction mixture was stirred for 20 min and then ethyl 2-mercaptoacetate ( 163.36 mg, 1 .36 mmol) was added. The reaction was stirred overnight at room temperature. Distill the reaction mixture under reduced pressure. The product was purified by column chromatography using acetone:hexane (5%) to afford the ethyl 2-((3-(trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)thio)acetat e as yellow solid. MS (M+H ⁺ ) m/z 323.1 .

Step-2: To a solution of (E)-N'-hydroxyacetimidamide (68.94 mg, 0.93 mmol) in dry THF (5 mL) was added sodium hydride (22.36 mg, 0.93 mmol) under N ₂ atmosphere at room temperature. The resultant mixture was stirred for 30 min and then ethyl 2-(( 3- (triiluoromethyl)thieno[3,4-b]pyrazin-2-yl)thio)acetate ( 1 50.0 mg, 0.46 mmol) was added. The reaction was refluxed for 5h. The solvent was removed under reduced pressure and the crude product obtained was purified by column cliromatography using acetone :hexane (5%) to afford the title compound as yellow solid. MS (M+H ⁺ ) m/z 333.1 , 1 H NMR (CDC1 ₃ ): 58.02 (d, 1 H, J=3.6Hz), 7.84 (d, 1 H, J=3.6Hz), 4.67 (s, 2H), 2.38 (s, 3H). Example-10: 4-(3-(Trifluoromethyl)thieno[3,4-b]pyrazin-2-yl)benzonitrile

To a solution of Intermediate-3 ( 100 mg, 0.28 mmol), tetrakis(triphenylphosphine)- palladium(O) (62.64 mg, 0.43 mmol), K ₂ C0 ₃ ( 1 17.79 mg, 0.85 mmol) in toluene (3.5 mL), ethanol ( 1 .5 mL), water (0.5 mL) was degassed for 30 min. To this solution 4- cyanophenylboronic acid ( 16.4 mg, 0.014 mmol) was added at room temperature under No atmosphere. The resulting mixture was heated to 85°C for 3h. Distilled the reaction mixture under reduced pressure and the resulting residue was suspended in ethyl acetate (20 mL) and washed with water. The organic phase was dried over anliydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by column chromatography using acetone:hexane (5%) to afford the title compound 17.0 mg as a yellow solid. MS (M+H ⁺ ) m/z 306. 1 , Ή NMR (CDC1 ₃ ): 58.38 (d, 1 H, J=3.2 Hz), 8.21 (d, 1 H, J=3.2 Hz), 7.82 (d, 2H, J=8.4 Hz), 7.71 (d, 2H, J=8.4 Hz).

Example-11 : 2-(4-(Methylsulfonyl)phenyl)-3-(trifluoromethyl)thieno[3,4-b ]pyrazine

The title compound was prepared by following the similar procedure as described in

Example- 10 using Intermediate-3. MS (M+H ⁺ ) m/z 359.1. Ή NMR (CDC1 ₃ ): 58.40 (d, 1 H, J= 3.2 Hz); 8.22 (d, 1 H, J=3.6 Hz); 8.1 1 (d, 2H, J=6.8 Hz); 7.81 (d, 2H, J=8.4 Hz); 3.12 (s,

3H).

Example-12: 2-(Pyridin-3-yl )-3-(trifluoiOmethyl)thieno[3,4-b]pyrazine

The title compound was prepared by following the similar procedure as described in

Example- 10 using Intermediate-3. MS (M+H ⁺ ) m z 282.0. Ή NMR (CDC1 ₃ ): 58.84 (s, 1 H); 8.77 (d, 1 H, J=4.4 Hz); 8.37 (d, 1 H, J=3.6 Hz); 8.21 (d, 2H, J=3.6 Hz); 7.92 (d, 1 H, J=7.6 Hz); 7.68-7.43 (m, 3H).

Example-13: 2-([ l , r-Biphenyl]-4-yl)-3-(trifluoiOmethyl)thieno[3.4-b]pyrazine

The title compound was prepared by following the similar procedure as described in

Example- 10 using Intermediate-3. MS (M+H ⁺ ) m/z 357.2. Ή NMR (DMSO-d ₆ ): δ 8.83 (d, 1 H, J=3.6 Hz), 8.60 (d, 1 H, J=3.2 Hz), 7.84 (d, 2H, J=6.8 Hz), 7.79 (d. 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.0 Hz), 7.53-7.49 (m, 2H), 7.44-7.40 (m, 1 H).

Example-14: 2-Isopropyl-3-((5-methyl- l ,3,4-thiadiazol-2-yl)thio)thieno[3,4-b]pyrazine

To a solution of Intermediate-5 ( 160.0 mg, 0.75 mmol) in DMF (3 mL) was added KF in alumina (99.78 mg, 0.75 mmol) followed by addition of 5-methyl- l ,3,4-thiadiazole-2-ol (52.61 mg, 0.9 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched by adding water (5 mL) and then extracted with ethyl acetate ( 10 mL x 2). The combined organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using ethylacetate:hexane ( 1 5%) to afford the title compound 44.0 mg as a yellow solid. MS (M+H ⁺ ) m/z 309.1 Ή NMR (CDC1 ₃ ): 57.93 (d, 1 H, J=3.2Hz), 7.80 (d, 1 H, J=3.2Hz), 3.41 - 3.38 (m, 1 H), 2.89 (s, 3H), 1 .45 (s, 3H), 1 .44 (s, 3H). Example-15: 2-Isopropyl-3-(( l -methyl- l H-imidazol-2-yl)thio)thieno[3,4-b]pyrazine

The title compound was prepared by following the similar procedure as described iii Example- 14 using Intermediate-5. MS (M+H ⁺ ) m/z 291.1. Ή NMR (CDC1 ₃ ): δ7.79 (d, 1 H, J=3.6 Hz), 7.50 (d, 1 H, J=3.2 Hz), 7.28 (d, 1 H, J= 1 .2 Hz), 7.24 (d, 1 H, J=0.8 Hz), 3.71 (s. 3H), 3.44-3.38 (m, 1 H), 1 .43 (s, 3H), 1 .41 (s, 3H).

Example-16: 4-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)morpholine

The solution of Intermediate-5 ( 150.0 mg, 0.71 mmol) in morpholine (3 mL) was heated at 60°C for 3h. The reaction was quenched by adding water (5 mL) and extract with ethyl acetate ( 10 mL x 2). The combined organic phase was dried over anhydrous Na^SC^ and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using acetone:hexane (2.5%) to afford the title compound 43.0 mg as a pale brown solid. MS (M+H ⁺ ) m/z 264.1 . Ή NMR (CDC1 ₃ ): δ7.74 (d, 1 H, J=3.2Hz), 7.53 (d, l H, J=3.6Hz), 3.90-3.88 (m,4H), 3.42-3.35 (m, 1 H), 3.24-3.21 (m, 4H), 1 .24 (s, 3H), 1.20 (s, 3H).

Example-17: 2-Isopropyl-3-thiomoi holinothieno[3,4-b]pyrazine

The title compound was prepared by following the similar procedure as described in Example- 16 using Intermediate-5, the title compound was obtained as a yellow solid. MS (M+H ⁺ ) mz 280.1 Ή NMR (CDC1 ₃ ): 57.74 (d, IH, J=3.6Hz), 7.53 (d, IH, J=3.4Hz), 3.48- 3.45 (m,4H), 3.34-3.30 (m, IH), 2.85-2.83 (m, 4H), 1.31 (s, 3H), 1.29 (s,3H). Example-18: 4-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)thiomorpholine 1-oxide and

Example-19: 4-(3-isopropylthieno[3,4-b]pyrazin-2-yl)thiomoi holine 1,1 -dioxide

To a solution of 2-isopropyl-3-thiomoipholinothieno[3,4-b]pyrazine (Example-17) (150 mg, 0.54 mmol) in dichloromethane (5.0 mL) was added w-perchlorobenzoic acid (185.55 mg, 1.1 mmol) at 0°C. The resulting mixture was stirred at room temperature for 12h. The reaction mixture was washed with water. The organic phase was dried over anhydrous Na?S0 and concentrated under reduced pressure. The product was purified by column chromatography using acetone: hexane (5%) to afford the title compounds 4-(3- isopropylthieno[3,4-b]pyrazin-2-yl)thiomorpholine 1,1 -dioxide as a yellow solid, MS (M+H ⁺ ) m/z 312.1; Ή NMR (CDCI3): 7.80 (d, IH, J=3.5Hz); 7.57 (d, IH, J=3.6Hz); 3.83- 3.81 (m, 4H); 3.31-3.27 (m, 5H); 1.34 (s, 3H); 1.32 (s, 3H). and further elution using acetone:hexane (20%) afforded 4-(3-isopropylthieno[3,4-b]pyrazin-2-yl)thiomo holine 1- oxide as a yellow solid. MS(M+H ⁺ ) m/z 296.1. Ή NMR (CDC1 ₃ ): 57.77 (d, IH, J=3.6Hz), 7.54 (d. IH, J=3.6Hz), 4.01-3.94 (m, 2H), 3.52-3.47 (m, 2H), 3.34-3.27 (m, IH), 3.12-3.06 (m, 2H), 3.00-2.95 (m,2H), 1.33 (s,3H), 1.32 (s,3H).

Example-20: 2-Isopropyl-3-(lH-l,2,4-triazol-l-yl)thieno[3,4-b]pyrazine

To a solution of Intermediate-5 (150.0mg, 0.71 mmol) in dry DMF (3 mL) added 2CO3 (195.6 mg, 1.41 mmol) and then added lH-l,2,4-triazole (76.23 mg, 1,1 mmol). The reaction mixture was heated at 70°C for 4h. The reaction mixture was quenched by adding water (5 mL) and it was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by column chromatography using acetone:hexane (7.5%) to afford the title compound 27.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 246.1. Ή NMR (CDC1 ₃ ): 88.84 (s, 1H), 8.19 (s, 1H), 8.03 (d, 1H, J=3.6Hz), 7.97 (d, 1H, J=3.6Hz), 3.86-3.83 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H). Example-21 : 2-Isopropyl-3-(pyridin-3-ylmethoxy)thieno[3,4-b]pyrazine

To a solution of pyridin-3-ylmethanol (154.42 mg, 1.41 mmol) in dry DMF (5 mL) was added NaH (84.9 mg, 1.41 mmol) and then added Intermediate-2 (200.0 mg, 0.94 mmol). The reaction mixture was heated at room temperature for 2h. The reaction was quenched by adding water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using acetone: hexane (5%) to afford the title compound 55.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 286.1. Ή NMR (CDCI3): 58.65 (s, 1H), 7.81 (d, lH,J=3.6Hz), 7.77-7.32 (m, 1H), 7.52-7.50 (m, lH), 7.47 (d, lH,J=3.6Hz), 7.28-7.25 (m, 1H), 5.61 (m, 1H), 3.57-3.50 (m, 1H), 1.37 (s, 3H), 1.36 (s, 3H). Example-22: 2-Isopropyl-3-(thiophen-2-yl)thieno[3,4-b]pyrazine

To a solution of Intermediate-5 (200 mg, 0.94 mmol) was added tetrakis(triphenylphosphine)palladium(0) (54.48 mg, 0.047 mmol), K ₂ C0 ₃ (391 .16 mg, 2.82 mmol) in toluene (3.0 raL), ethanol ( 1 .0 mL), water ( 1 .5 mL) and it was degassed for 30 min. To this solution was added thiophen-3-ylboronic acid ( 181 .07 mg, 1 .41 mmol) at room temperature under N ₂ atmosphere. The resulting mixture was heated to 85°C for 3h. Distilling the reaction mixture under reduced pressure provided a residue, which was suspended in ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous Na ₂ SC>4 and concentrated under reduced pressure. The product was purified by column chromatography using acetone :hexane (5%) to afford the title compound 27.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 261 . Ή NMR (CDC1 ₃ ): 57.93 (d, 1 H, J=3.6Hz); 7.90 (d, 1 H, J=3.2Hz); 7.62-7.61 (m, 1 H); 7.46-7.44 (m, 1 H); 7.38-7.37 (m, 1 H); 3.55-3.48 (m, 1 H); 1 .30 (s, 3H); 1 .29 (s, 3H).

Exaitiple-23: 2-(3-IsOpropylthieno[3,4-b]pyrazin-2-yl)-5-methyl- l ,3,4-oxadiazole

To a solution of Intermediate-8 (270.0 mg, 0.81 mmol) in dry pyridine (5.0 mL) was added tosyl chloride (310.1 mg, 1.67 mmol) at room temperature. The reaction was heated to 90°C for 12h. The solvent was evaporated under reduced pressure. The residue was taken into ethylacetate (25 mL). The organic layer was then washed with satd. CuS0 ₄ . The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using acetone:hexane (5%) to afford the title compound 26 mg as a yellow solid, MS (M+H ⁺ ) m/z 261 .1 . ' H NMR (CDCI3): 68.20 (d, l H, J=3.6Hz), 8.00 (d, 1 H, J=3.2Hz), 4.50-4.43 (m, 1 H), 1 .39 (s, 3H), 1 .38 (s, 3H).

Example-24: 2-Isopropyl-3-(5-methyl- l ,3,4-thiadiazol-2-yl)thieno[3,4-b]pyrazine

To a solution of Intermediate-8 (270.0 mg, 0.81 mmol) in dry toluene (5.0 mL) was added Lawesson's reagent (293.9 mg, 0.72 mmol) at room temperature. The reaction was refluxed for 24h. Evaporation of solvent under reduced pressure provided the residue which was taken in ethylacetate (25 mL). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S04 and concentrated under reduced pressure. The product was purified by column chromatography using acetone:hexane (7.5%) to afford the title compound 17.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 277.0. Ή NMR (CDC1 ₃ ): 58.03 (d, 1 H, J=3.2Hz), 7.95 (d, l H, J=3.6Hz), 4.70-4.63 (m, 1 H), 2.85 (s, 3H), 1 .39 (s, 3H). 1 .37 (s, 3H). Example-25: 2-(3-Isopropylthieno[3,4-b]pyrazin-2-yl)-5-(trifluoromethyl) - l ,3,4-oxadiazole

To a solution of Intermediate-9 (300 mg, 0.90 mmol) in dry pyridine (2.0 mL) was added tosyl chloride (344.5 mg, 1 .9 mmol) at room temperature. The reaction was heated to 90 ^Ll C for 12h. Distillation of the reaction mixture under reduced pressure furnished the residue and it was taken in ethylacetate (25 mL). The organic layer was then washed with satd. CuSC^. The combined organic phase was washed with brine and dried over anhydrous Na ₂ S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography using acetone:hexane ( 1 %) to afford the title compound 14 mg as a yellow solid, MS (M+H ⁺ ) m/z 3 1 5.0. Ή NMR (CDC1 ₃ ): δ 8.28 (d, 1 H, J=3.2Hz), 8.05 (d, 1 H, J=3.2Hz), 4.35-4.28 (m, 1 H), 1 .42 (s, 3H), .40 (s, 3H).

Example-26: 2-(4-(Methylsulfonyl)phenyl)thieno[3,4-b]pyrazine

To a solution of 2-bromo- l -(4-methylsulfonyl phenyl) ethanone (364.5mg, 1.31 mmol) in dry THF (2.5 mL) was added DABCO (59.16 mg, 0.52 mmol) and stirred at room temperature for 5 min. Then thiophene-3,4-diamine (200 mg, 1.75 mmol) in THF (2.5 mL) was added at room temperature for 5 min. The reaction mixture was stirred overnight at room temperature. Removal of the solvent under reduced pressure furnished a gummy mass which was taken into water (5 mL) and extracted with ethyl acetate ( 10 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The product was purified by preparative chromatography to afford the title compound 55.0 mg as a pale green solid, MS (M+H ⁺ ) m/z 291.1 . Ή NMR (DMSO-d ₆ ): 59.34 (s, 1 H), 8.53 (d, 2H, J=6.8Hz), 8.48 (d, 1 H, J=3.2Hz), 8.46 (d. 1 H, J=3.2Hz), 8.13 (d. 2H, J=6.8Hz), 3.34 (s, 3H).

Example-27: 4-(5-(4-Fluorophenyl)-3-(trifluoiOmethyl)thieno[3,4-b]pyrazi n-2- yl)morpholine

Step- 1 : To a solution of Example-2 (200.0 mg, 0.7 mmol) in dry DMF (3.0 mL) was added N-bromosuccinamide ( 123.2 mg, 0.69 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 min. and it was quenched by adding water (10 mL) and it was extracted with ethylacetate ( 10 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using hexane to afford 4-(5-Bromo-3- ΐΓίί1ιιθΓοηΊ6ΐΗγ1)ίΗίεηο[3,4-5]ργΓ3ζ ίη-2->Ί)ι ο 1ιοΠη6 124.0 mg as a yellow solid, MS (M+) m/z 368. 16.

Step-2: To a solution of 4-(5-Bromo-3-(trifluoromethyl)thieno[3,4-b]pyrazin-2- yl)morpholine ( 1 15 mg, 0.31 mmol), bis(triphenylphosphine)palladium(II) dichloride (43.84 mg, 0.06 mmol) and Na ₂ C0 ₃ (99.3 1 mg, 0.94 mmol) in 1 ,4-dioxane (5.0 mL), water (0.5 mL) was degassed for 30 min. To this solution then added 4-fluorophenyl boronic acid (99.3 mg, 0.94 mmol) at room temperature under N ₂ atmosphere. The resulting mixture was heated to 80°C for 15 min. Distilled the reaction mixture under reduced pressure and the resulting residue was suspended in ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography using acetone:hexane ( 1 .5%) to afford the title compound 63 mg as a yellow solid, MS (M+H ⁺ ) m/z 384. 1 . Ή NMR (DMSO- d ₆ ): 88.58 (s, 1 H), 8.19-8.1 5 (m, 2H), 7.38-7.33 (m, 2H), 3.80-3.77 (m, 4H).

Example-28: 2-((4-Fluorobenzyl)oxy)-5-(methylsulfonyl)-3-(trifluoromethy l)thieno[3,4-b] pyrazine

To a solution of Intermediate- 1 1 ( 1 10.0 mg, 0.36 mmol) in dry DMF (3.0 mL) was added cesium carbonate ( 179.92 mg, 0.55 mmol) and then added 4-fluorobenzylbromide (76.69 g) at 0°C. The reaction mixture was stirred at 0°C for 5 min. The reaction was quenched by adding water and it was extracted with ethylacetate (25 mL x 2). The combined organic phase was washed with brine and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane to afford the title compound 637.0 mg as a yellow solid, MS (M+H ⁺ ) m/z 407.0. Ή NMR (DMSO-d ₆ ): 57.78 (s, 1 H), 7.49-7.46 (m, 2H), 7.21 -7.16 (m, 2H), 5.29 (s, 2H), 3.50 (s, 3H). Biological Examples Biological Example-1 : Functional cell-based assay

GLP- 1 R-CHO cells were routinely cultivated in Ham's F 12 medium containing 10% Fetal bovine serum (Sigma, USA) and l X-PenStrep. The assay was done using cAMP LANCE Kit Perkin Elmer. The efficacy of GLP- 1 R agonists may be studied in a cAMP production functional assay using CHO cell expressing the cloned GLP- 1 R. GLP- 1 R-expressing cells (3,000 cells per l OmicroL) may be plated in 384-well plates in I X HBSS buffer ( l OmM HEPES, 0.1 % BSA, I mM IBMX at pH7.4). Then 5 μΐ volume of each compound (at concentrations ranging from 0.0001 to 100 μΜ) were incubated with cells followed by addition of GLP- 1 (7-36, in 5 iL, EC20 concentration) for measuring the PAM activity of compounds. The plate was incubated for 30 min at an ambient temperature. For measuring the agonist activity compounds were incubated with cells without GLP- 1 (7-36). After 30 min of incubation the plate was processed for cAMP measurement by addition of LANCE reagents for l h and followed by reading in PheraStar (BMG Laboratories, Australia). The compounds of the present invention were tested at multiple concentrations. For calculation of % cAMP agonist activity, GLP- 1 Receptor activation at E _max was set to 100% and vehicle control cells as 0%. For calculation of % PAM activity, GLP- 1 Receptor activation at EC ₂ o concentration was set to 100%. EC ₅₀ calculations were done using sigmoidal dose-response curve in Graphpad prism version 5.0. The compounds of the invention showed EC50 values in nanomolar to micromolar range.

Thus the in vitro functional cell based assay study indicate that the compounds of the invention modulate the activity of the GLP- 1 receptor indicating the potential for use of the compounds of the invention in the treatment of diseases which are affected or facilitated by the modulation of the GLP- 1 receptor. Biological Example-2: Evaluation of glucose-stimulated insulin secretion (GSIS) potential of compounds INS- I E (rat pancreatic beta cell line) cell line were routinely cultivated and maintained in growth medium {RPMI medium with 9 mM glucose, containing l x penstrep and supplemented with 10% foetal bovine serum (FBS) and 2.5% Heat Inactivated horse serum (Lonza. U.S. A)} . The cells were seeded in T-25 cm ² flask and incubated at 37°C in a 5% CO: in air atmosphere until ready for next passage (usually twice a week) or to be used for assay.

For insulin release assay, cells were trypsinized using 0.05% (w/v) trypsin-0.53mM EDTA, centrifuged and resuspended in a fresh growth medium. 9000- 1 5000 cells/well were seeded in 96 W flat bottom plates (Corning, Cell bind surface plate) and incubated in CO? incubator. Compounds were evaluated for the GSIS potential, post 48 h of seeding in RB buffer (pH, 7.4) containing 0.1 % BSA (Chepurney O.G and Holz G.G. et al., Cell Tissue research 2002, 307 (2): 191 -201 ). Briefly, cells were serum starved for overnight in RPMI medium containing 5 mM glucose, washed thrice on the subsequent day with KRBG buffer before beginning the assay. Cells were then incubated in KRBG buffer without glucose for 30 min. Finally compounds were then incubated with cells for 1 h in presence of supraphysiologic glucose concentrations ( 1 5 mmol/lit) and then measured for the glucose stimulated insulin secretion (GSIS). Briefly, 25 μΐ of supernatant ( 1 :6 diluted in buffer) was mixed with 25 μΐ of HTRF reagents (HTRF assay kit, Cisbio, Germany), incubated for 1 h and read in PHERAstar FS reader (BMG Labtech, Germany) using HTRF settings. Standard insulin concentrations with range of 0.1 to 10 ng/ml. were included in the plate to generate the standard curve for extrapolation of insulin concentration in unknown samples. Calculations were done as fold of insulin release over vehicle (set as 1 ) or comparing the insulin release (ng/ml) of sample wells with vehicle (0.1 % DMSO). Statistics used was one way ANOVA followed by Dunnett's multiple comparison tests in graph pad prism (version, 5.0).

At 3 D M concentration in the presence of EC?o concentration of GLP- 1 . the Examples 1 , 2, 3, 4, 7, 8, 14, 23, 25, 26, potentiated insulin secretion by 3. Ox, 1 .4x, 2.8x, 1 .4x, 3.7x, 3.7x, 1 .6x, 5.8x, l . l x, 37.9x fold. Thus the compounds of the invention have been shown to potentiate glucose stimulated insulin secretion in vitro studies, indicating potential for the use of the compounds of the invention in the treatment of diseases involved with inadequate insulin secretion.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.