KR20010052570A - Cell adhesion-inhibiting antiinflammatory compounds - Google Patents

Abstract

The present invention relates to compounds of formula (I), which are useful for treating inflammation. The present invention also relates to pharmaceutical compositions comprising a compound of formula I and to a method of inhibiting / treating inflammatory diseases in mammals.

Formula I

Description

Cell adhesion-inhibiting antiinflammatory compounds < RTI ID = 0.0 >

Inflammation occurs from a series of events involving vasodilation with increased vascular permeability and exudation of fluids and plasma proteins, and such collapse of vascular integrity precedes or precedes infiltration of inflammatory cells. The inflammatory mediators that occur at the site of the initial lesion act to call inflammatory cells to the injured area. These mediators (chemokines, complement fragments and lipid mediators such as IL-8, MCP-1, MIP-1 and RANTES) have chemotactic activity on leukocytes and attract inflammatory cells to inflamed lesions. Thus, a chemotactic factor that induces circulating leukocytes to localize at the site of inflammation requires that the leukocytes pass from the correct site to the vascular endothelial cells. The recruitment of such white blood cells is carried out by a process called cell adhesion.

Cell adhesion occurs through a series of harmonically controlled steps that first adhere leukocytes to specific areas of vascular endothelial cells, then move them through the endothelial barrier to the inflamed tissue (Springer, TA, 1994, Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm, Cell 76: 301-314; Lawrence, MB, and Springer, TA, 1991, Leukocytes' Roll on a Selection of Physiologic Flow Rates: Distinction from and Prerequisite for Adhesion Through Integrins, Cell 65 Endothelial Cell Interactions in Inflammation, Proc. Natl., Pp. 859-873; von Adrian, U., Chambers, JD, McEnvoy, LM, Bargatze, RF, Arfos, KEand Butcher, Like Cell Adhesion Molecule 1 Mediates Rolling, L. and Rosen, SD, 1991. Lactic-Like Cell Adhesion Molecule 1 in Mesenteric Venules in vivo, Blood 77: 2553-2555). These steps are mediated by integrin, Ig colostrum members, and adhesion molecule systems such as selectin, which is expressed on blood circulating leukocyte surfaces and endothelial cells. The first step consists of leukocytes rolling along the endothelial cell lining in the inflamed area. The rolling step is mediated by the interaction between selectin molecules expressed on the surface of endothelial cells in the inflammatory area and leukocyte surface oligosaccharides (e.g., the sialylated Lewis-X antigen (Slex)). This selectin molecule is not normally expressed on the surface of endothelial cells but is induced by the action of inflammatory mediators such as TNF-a and interleukin-1. Rolling reduces the rate of circulating white blood cells in the area of inflammation, making leukocytes more firmly attached to endothelial cells. The firm adhesion is carried out by interaction between the integrin molecules present on the surface of the rolling white blood cells and the corresponding receptors (Ig phase and molecules) present on the surface of the endothelial cells. Ig-phase and molecules or CAM (cell adhesion molecules) are not expressed or expressed in small amounts on normal endothelial cells. CAM, such as selectin, is induced by the action of inflammatory mediators such as TNF-a and IL-1. The final event during the adhesion process is leukocyte migration through the endothelial cell barrier and leukocyte migration to the inflammatory site in response to the chemotactic gradient. This transition is mediated by the conversion of leukocyte integrins, which change from a low to a high fusing state. The adhesion process depends on the induction of selectin and CAM on the surface of vascular endothelial cells mediating the rolling and firm adhesion of leukocytes to the vascular endothelium.

Induction expression of e-selectin and CAM is mediated by the transcription factor NFkB. NFkB is a group of dimeric transcription factors made up of monomers containing the 300 amino acid Rel domain. This factor binds to DNA and interacts with each other and binds to an inhibitor molecule called IkB (Vermaa, IM, Stevenson, JK, Schwarz, EM, Antwerp, DV, and Miyamoto, S., 1995, Rel / NFlB / IkB Family: Intimate Tales of Association and Dissociation, Genes Dev. 9: 2723-2735; and Baldwin, AS 1996, The NFKB and IkB proteins: New Discoveries and Insights, Annu. Rev. Immunol. 14: 649-681). NFkB is found in cytoplasm forming a complex with IkB. Activation of NFkB occurs in response to inflammatory mediators such as TNF-α, IL-1 and lipopolysaccharides. Activation of NFkB requires phosphorylation of IkB followed by ubiquitination of the IkB molecule and subsequent degradation by proteasomes. The release of NFkB from the bound IkB translocates the dimer to the nucleus, where it can bind to a particular DNA sequence. The e-selectin gene and CAM contain the NFkB recognition sequence upstream of the coding region. DNA-linked NFkB, which works in conjunction with other proteins in the transcriptional complex, induces the expression of e-selectin and CAM genes among the various genes regulated by this transcription factor.

The present invention discloses compounds that inhibit the expression of e-selectin and ICAM-1 relative to VCAM-1. This compound is useful for the treatment or prevention of diseases caused by the expression of the adhesion molecule. Diseases include those with leukocyte induction, in particular acute and chronic inflammatory diseases, autoimmune diseases, tumor metastasis, allograft rejection and reperfusion injury.

The present invention relates to compounds useful for treating inflammatory diseases, pharmaceutical compositions comprising the compounds, and methods of inhibiting inflammation in mammals.

Summary of the Invention

The present invention relates, in one aspect, to a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:

In the formula (I)

--- represents a single bond or a double bond, provided that when only one bond is a double bond, the adjacent bond is a single bond,

E, F and G are

(1) carbon,

(2) nitrogen, and

(3) N ⁺ -O ^- to be selected from,

However, E, F and G are at least one of the nitrogen or N ⁺ -O ^-, and at least one of E, F and G are carbon atoms, and

Y and Z are each

(1) carbon,

(2) nitrogen,

(3) oxygen, and

(4) S (O) _t (wherein t is an integer of 0 to 2)

Provided that at least one of Y and Z is other than carbon,

L _A is

(1) covalent bonding,

(2) -O-,

(3) -S (O) _t- ,

(4) -NR ₆ -

(Wherein R < ₆ > is

(a) hydrogen,

(b) C1 to C10 alkyl optionally substituted with one or two substituents each independently selected from (i) aryl, and (ii) C3 to C10 cycloalkyl,

(c) alkanoyl having an alkyl moiety of C1 to C10, and

(d) cycloalkyl of C3 to C10,

(5) -C (W) -, wherein W is selected from (a) O and (b) S, and

(6) alkenylene,

X _A is

(1) halo,

(2) (a)

(b) C3 to C10 cycloalkyl,

(c) from -CO ₂ R ₇ (where, R ₇ is (i) hydrogen and (ii) aryl, and C3 to optionally alkyl-substituted C1 to C10 with one or two substituents selected from among cycloalkyl, each of C10 Selected),

(d) -NR ₈ R ₉ wherein R ₈ and R ₉ are each (i) hydrogen, (ii) -OH, aryl, heterocycle, C3 to C10 cycloalkyl and -NR _A R _B , , R _A and R _B are each selected from the group consisting of hydrogen and C 1 to C 6 alkyl optionally substituted with one or two OH), (iii) a C 1 to C 6 alkyl optionally substituted with one or two substituents each independently selected from (Vi) a heterocycle, and (vii) an aryl, wherein (vi) and (vii) are independently selected from the group consisting of C1 to C10 alkyl, alkenyl having an alkyl moiety of C1 to C10, (iv) cycloalkyl of C3 to C10, (v) alkoxy, C6 alkyl < / RTI > and halo, each of which is optionally substituted with one or two substituents each independently selected from halogen,

(e) -C (W) R ₁₀ wherein W is as defined above and R ₁₀ is (i) hydrogen, (ii) one or two substituents each selected from aryl and C3 to C10 cycloalkyl Optionally substituted C 1 to C 10 alkyl, (iii) -NR ₈ R ₉ and (iv) -OR ₇ ),

(f) -OH,

(g) aryl, and

(h) from the heterocycle (here, (g) and (h) are (i) C1 to C20 _{alkyl, (ii) -NR 8 R 9} , (iii) alkoxy of C1 to C10, (iv) C1 to C10 (Vi) C1 to C3 perfluoroalkyl, (vii) C2 to C10 alkenyl, (viii) C1 to C10 alkoxy and -OH, each of which is optionally substituted with one or two optionally substituted C1 to C10 alkyl with a _{substituent, (ix) -CO 2 R 7} , (x) aryl, and (xi) optionally substituted with 1, 2, 3, 4, or 5 substituents respectively selected from -CHO C 1 -C 10 alkyl, which may be optionally substituted with one, two or three substituents each selected from halogen,

(3) C3 to C10 cycloalkyl,

(4) aryl,

(5) Heterocycles [wherein, (4) and (5)

(a) a C1 to C20 alkyl,

(b) (i) from -OR ₁₁ {Here, R ₁₁ is hydrogen, -C (W) R ₁₂ (where, R ₁₂ is C1 to alkyl, cycloalkyl, aryl and heterocyclyl of C3 to C10 in the C10 And optionally substituted with one, two, three or four substituents each independently selected from C1-C6 alkyl and-OH optionally substituted with one or two OH, (ii) alkoxy (Iii) spiroalkyl of C3 to C10, and (iv) halo, each of which is optionally substituted with one or two substituents each independently selected from lower alkyl, lower alkoxy and alkoxyalkoxy, Gt; C1-C10 < / RTI > alkyl,

(c) a C1 to C10 alkoxy optionally substituted with one or two substituents each independently selected from (i) alkoxy, and (ii) alkoxyalkoxy,

(d) C1 to C10 thioalkoxy,

(e) halo,

(f) perfluoroalkyl of C1 to C3,

(g) (i) -C ( W) R 10 , and (ii) -C (W) R 12 of any substituted C2 to C10 with one or two substituents each selected from alkenylene,

(h) -CO ₂ R _7,

(i) -NR < ₈ > R < ₉ &

(j) aryl,

(k) -C (W) R ₁₂ ,

(1) -CHO,

(m) -C (O) NR < ₈ > R < ₉ &

(n) -CN,

(o) a heterocycle optionally substituted with one or two substituents each independently selected from (i) C1 to C10 alkyl and (ii) C1 to C3 perfluoroalkyl,

(p) -C (W) R 10,

(q) ethylene dioxy, and

2, 3, 4 or 5 substituents each independently selected from (r) -OCF ₃ ,

(6) -OR ₇ ,

(7) hydrogen and

(8) -NR < ₈ > R < _{9 &} gt ;;

L _B is

(1) covalent bonding,

(2) -O-,

(3) -S (O) _t- ,

(4) -NR ₆ -,

(5) -C (W) - and

_{(6) -C (= NR 13} ) - [ where, R ₁₃ is

(a) hydrogen,

(b) -NO _2,

(c) -CN, and

(d) -OR ₁₄ wherein R ₁₄ is selected from the group consisting of (i) hydrogen, (ii) aryl and (iii) aryl and -C (O) R ₁₅ wherein R ₁₅ is hydrogen, -OH, alkoxy and NR _{≪ /} RTI > R < _B >), each of which is optionally substituted with one or two substituents each independently selected from C1-C10 alkyl;

X _B is

(1) hydrogen,

_{(2) (a) -CO 2} R 7,

(b) -NR ₈ R ₉ ,

(c) -C (W) NR 8 R 9,

(d) heterocycle,

(e) (i) C1 to C10 alkyl, (ii) -NO _2, and (iii) aryl optionally substituted with one or two substituents each selected from among -NR _A R _B,

(f) -OR ₁₆ wherein R ₁₆ is selected from (i) hydrogen and (ii) -C (W) NR _A R _B ; and

(g) -NR _A C (W) NR < ₈ > R < ₉ &

(3) (a) -C (W) NR _A R _B ,

(b) -CO ₂ R _7, and

(c) C2-C6 alkenyl optionally substituted with one or two substituents each independently selected from a heterocycle,

(4) -NR ₁₇ R ₁₈ [where, R ₁₇ and R ₁₈ are each

(a) hydrogen,

(b) (i) -OH, (ii) -C (W) R 10, (iii) -NR A C (= NR 13) NR B R 19 ( Here, R _A, R _B and R ₁₃ are described above (Iv) heterocycle, (v) aryl, (vi) halo, and (vii) -NR _A R _B , wherein R ₁₉ is selected from hydrogen, C 1 to C 10 alkyl and -NO ₂ C1 to C10 alkyl optionally substituted with one, two or three substituents selected from < RTI ID = 0.0 >

(c) alkoxy,

(d) optionally substituted with 1, 2 or 3 substituents each independently selected from (i) halo, (ii) C1 to C10 alkyl, (iii) C1 to C10 alkoxy, (iv) C1 to C3 perfluoroalkyl Substituted aryl,

(e) heterocycle,

(f) -NR _A R _B ,

(g) -C (O) R ₂₀ wherein R ₂₀ is selected from (i) hydrogen, (ii) C 1 to C 10 alkyl, (iii) -OR ₁₂ and (iv) -NR _A R _B ) , (h) C3 to C10 cycloalkyl, and (i) -OH,

(5) alkoxy,

(6) -OH,

_{(7) -NR A C (=} NR 13) NR B R 19,

(8) -C (W) NR 8 R 19,

(9) aryl,

(10) Heterocycles [wherein, (9) and (10)

(a) halo,

(b) (i) halo, (ii) C1 to C10 alkoxy, (iii) -NR _A R _B , (iv) -OH, (v) -CO ₂ R ₇ , _A R _B, and (vii) aryl, each of which is optionally substituted with 1, 2, or 3 substituents each selected from C1-

(c) -NR _A R _B ,

(d) C1 to C10 alkoxy,

(e) C1 to C10 thioalkoxy,

(f) perfluoroalkyl of C1 to C3,

(g) -OH,

(h) -C (W) NR 8 R 9,

(i) -CO ₂ R _7,

(j) -NR _A C (W) OR ₂₁ wherein R _A is as defined above and R ₂₁ is (i) optionally substituted with one or two substituents selected from aryl and C 3 to C 10 cycloalkyl C1 to C10 alkyl, (ii) aryl and (iii) C3 to C10 cycloalkyl),

(k) C2 to C10 alkenyl,

(l) heterocycle,

(m) aryl, and

(n) -NO _2] , or a pharmaceutically acceptable salt thereof,

(11) -CN,

(12) -CHO,

(13) halo, and

(14) -B (OR _A ) (OR _B )

With the proviso that when R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are hydrogen or absent, -L _A - is a covalent bond and -L _B - is a covalent bond, one of X _A and X _B is Other than hydrogen,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are absent,

(1) hydrogen,

(2) (a) -OC (O) R ₂₂ wherein R ₂₂ is selected from (i) alkyl, (ii) alkoxy and (iii) NR _a R _b )

(b) alkoxy,

(c) -OH,

(d) -NR _A R _B ,

(e) heterocycle, and

(f) C1 to C6 alkyl optionally substituted with one or two substituents each independently selected from aryl,

(3) -CO ₂ R _7,

(4) -C (O) NR _A R _B ,

(5) -SR < ₂₃ > wherein R < _{23 &}

(a) hydrogen,

(b) C1 to C6 alkyl,

(c) (i) aryl optionally substituted with one or two substituents selected from C1 to C6 alkyl and (ii) halo,

(6) -NR _A R _B ,

(7) halo,

(8) alkoxy,

(9) perfluoroalkyl of C1 to C3,

(10) -OH and

(11) heterocycle,

Provided that when E, F and Y are carbon, G is nitrogen, Z is sulfur, -L _A - is a covalent bond, and X _A is halo, then R ₁ is other than -CO ₂ R ₇ .

In another aspect, the present invention relates to a method of treating a disease, including administering an effective amount of a compound represented by formula (I).

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Term Definition

The term " alkanoyl ", as used herein, refers to an alkyl group attached to the carbon atom through a carbonyl group.

As used herein, the term " alkenyl " means a C2 to C12 monovalent straight or branched chain group containing at least one C-C double bond derived from an alkene by one hydrogen atom elimination.

As used herein, the term " alkenylene " means a C2 to C10 bivalent straight or branched chain group comprising a C-C double bond derived from an alkene by two hydrogen atom elimination.

The term " alkoxy ", as used herein, refers to an alkyl group attached to the parent atom through an oxygen atom.

The term " alkoxyalkoxy ", as used herein, refers to an alkoxy group bonded morphologically through another alkoxy group.

The term " alkoxycarbonyloxy " as used herein refers to an alkoxy group as defined herein attached to a parent molecular moiety through a carbonyloxy group as defined herein.

The term " alkoxycarbonyloxymethylene " as used herein refers to an alkoxycarbonyloxy group as defined herein attached to the parent molecular moiety through a methylene group as defined herein.

As used herein, the term " alkyl " means a saturated straight or branched chain C1 to C20 derived from an alkane by the removal of one hydrogen atom.

The term " alkylcarbonyl ", as used herein, refers to an alkyl group as defined herein appended to the parent molecular moiety through a carbonyl group.

The term " alkylcarbonyloxy ", as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyloxy group as defined herein.

The term " alkylcarbonyloxymethylene " as used herein refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.

The term " alkylene " means a divalent group derived from a linear or branched hydrocarbon group of C1 to C10. Representative examples of alkylene include -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH (CH ₃ ) CH ₂ - And the like, but are not limited thereto.

The term " amino ", as used herein, refers to the group -NR ₈₀ R ₈₁ wherein R ₈₀ and R ₈₁ are each selected from hydrogen and alkyl.

The term " aminocarbonyl ", as used herein, refers to an amino group, as defined herein, attached to a parent molecular moiety through a carbonyl group, as defined herein.

The term " aminocarbonyloxy ", as used herein, refers to an aminocarbonyl group, as defined herein, attached to a parent molecular moiety through an oxy group, as defined herein.

The term " aminocarbonyloxymethylene " as used herein refers to an aminocarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.

The term " aryl " means a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group may also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl group of the present invention may be optionally substituted.

As used herein, the term " carbonyl " means a -C (O) - group.

The term " carbonyloxy ", as used herein, refers to a carbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group as defined herein.

As used herein, the term " cycloalkyl " means a C3 to C12 monovalent saturated cyclic hydrocarbon group derived from a cycloalkane by the removal of one hydrogen atom.

As used herein, the term " ethylene dioxy " means that the oxygen atom of the ethylene dioxy group is bonded to the parent molecular moiety through one carbon to form a five-membered ring, or the oxygen atom of the ethylene dioxy group forms a six- (CH ₂ ) ₂ O- group bonded to the parent moiety through two adjacent carbon atoms.

The term " halo " or " halogen ", as used herein, means F, Cl, Br or I.

The term "heterocycle" refers to a 4-membered, 5-membered, 6-membered or 7-membered ring containing one, two or three heteroatoms each selected from the group consisting of nitrogen, oxygen and sulfur. The 4-membered and 5-membered rings have 0 to 2 double bonds, and the 6-membered and 7-membered rings have 0 to 3 double bonds. The term " heterocycle " also refers to a heterocyclic ring in which any ring of the heterocyclic ring is optionally substituted with 1, 2 or 3 groups selected from an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring or other 1 cyclic heterocyclic ring, Or bicyclic, tricyclic and tetracyclic groups fused to two rings. Heterocyclo is selected from the group consisting of acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzodienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, di Wherein said heterocyclic ring is selected from the group consisting of pyridyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, Pyrimidinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxadiazolyl, piperazinyl, piperidinyl, Pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroquinolyl, tetrazolyl, thia Thiazolyl, thiazolyl, thiazolyl, thiazolyl, thienyl, Thiomorpholinyl, triazolyl, and the like.

Also, as the heterocyclic compound, a monocyclic heterocyclic group may be substituted with an alkylene group (e.g., , , And the like).

Also, as the heterocyclic compound, there is a compound represented by the following formula.

In this formula,

X ^* is -CH ₂ - is selected from, -CH ₂ O and -O-,

Y ^* is selected from -C (O) - and - (C (R ") ₂ ) _v- wherein R" is hydrogen or C1 to C4 alkyl and v is 1 to 3.

Such heterocyclo includes 1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like. The heterocyclic group of the present invention may be optionally substituted.

As used herein, the term " oxo " means ═O.

As used herein, the term " oxy " means -O-.

The "methylene" is the term used herein is -CH ₂ - means a group.

The term " perfluoroalkyl ", as used herein, refers to an alkyl group in which all hydrogen atoms are replaced by fluoride atoms.

The term " phenyl ", as used herein, refers to a monocyclic carbocyclic ring system having one aromatic ring. The aryl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl group of the present invention may be optionally substituted.

The term " pharmaceutically acceptable prodrug " as used herein is intended to be suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, etc. within the scope of sound medical judgment, Quot; refers to the prodrugs of the compounds disclosed in the present invention, which are suitable for their intended use at risk ratios, as well as where possible, zwitterionic forms of the compounds described in the present invention.

As used herein, the term " prodrug " refers to a compound that is rapidly modified in vivo, for example, by hydrolysis in blood, to the parent compound represented by the above formula. A more detailed description of this is given in T. Higuchi and V.Stella, Prodrugs as Novel Delivery Systems, Vol. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

The term " spiroalkyl ", as used herein, refers to an alkylene group in which two carbon atoms in the alkylene group are joined by one carbon atom of the parent molecular group to form a C3 to C7 carbocyclic ring.

As used herein, the term " tautomeric " means that one atom of one molecule is protonated to another atom of the same molecule, with the two or more structurally distinct compounds being in parallel with each other.

The term " thioalkoxy " as used herein refers to an alkyl group attached to the moiety through a sulfur atom.

The compounds of the present invention may exist as stereoisomers with asymmetric or chiral centers. This compound is designated by the symbol " R " or " S " depending on the arrangement of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. As stereoisomers, there are enantiomers and diastereoisomers, and mixtures of enantiomers or diastereomers . Each of the stereoisomers of the compounds disclosed herein may be synthesized from commercially available starting materials comprising an asymmetric or chiral center or may be prepared via resolution known to one skilled in the art after preparation of the racemic mixture. (1) attachment of an enantiomeric mixture to the chiral auxiliary, separation of the resulting diastereomeric mixture by recrystallization or chromatography, and free of the optically pure product from the preparation, or (2) chromatography on chiral chromatographic columns There is direct separation of the optical enantiomer mixture.

The geometric isomers may also be present in the compounds of the present invention. The present invention also contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around the C-C double bond or the arrangement of substituents around the carbocyclic ring. "Z" indicates the presence of a substituent on the same side of the CC double bond, and "E" indicates the presence of a substituent on the opposite side of the CC double bond . The arrangement of the substituents around the carbocyclic ring is represented by cis or trans. Here, " sheath " means that a substituent is present on the same side of the ring surface, and " trans " means that a substituent is present on the opposite side of the ring surface. A mixture of compounds in which the substituents are both located on the same and opposite surfaces of the ring surface is referred to as cis / trans.

In addition, the compounds of the present invention may exist in tautomeric forms. The present invention includes tautomers as one atom of a molecule proton transfers to another atom of the same molecule, producing two different compounds in equilibrium with each other.

The compounds of the present invention include, but are not limited to, the following.

Methyl 2 - [(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate,

6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine,

6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine,

6-ethyl-4 - [(2-methylethyl) thio] thieno [2,3-d] pyrimidine,

6-ethyl-4 - [(phenylmethyl) thio] thieno [2,3-d] pyrimidine,

6-ethyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3-d] pyrimidine,

Ethyl 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine-

6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidin-

Thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine,

Thiadiazol-2-yl) thio] -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine,

4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine,

Thiadiazol-2-yl) thio] -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine,

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine,

Methyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [3,2-d] pyrimidine,

Methyl-4 - [[5- (methylthio) -1,3,4-thiadiazol-2-yl] thio] thieno [3,2-d] pyrimidine,

4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -7-methylthieno [3,2-d] pyrimidine,

7-methyl-N - [(4- (methylthio) phenyl] thieno [3,2- d] pyrimidin-

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine-

Methyl 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4- (2-pyridinylthio) thieno [2,3-c] pyridine-2- carboxamide,

4 - [(4-chlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

Methoxy-N-methyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide,

Methoxy-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

(4-chlorophenyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide,

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde,

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O-

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- (phenylmethyl) oxime,

2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid, <

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O-

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, oxime,

2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide, 2- [

(E) -3 - [(4-methylphenyl) thio] thieno [2,3-c] pyridin-

2,3-c] pyridin-2-yl] ethanone, 2-

Benzoyl-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine,

2-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine,

2,3-c] pyridin-2-yl] ethanone, oxime, thiophene,

(2,3-dihydroxypropyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide,

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxylic acid, hydrazide,

N ² -4 - [(4- methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] carbonyl] -N ⁶ - [(nitro) methyl-imino] -L- lysine, methyl ester,

(Aminoiminomethyl) -4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine,

Methyl 4 - [(2-methoxy-2-oxoethyl) thio] thieno [2,3- c] pyridine-

4 - [(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(4-bromophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide,

4 - [[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(2-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(3-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(2,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(2-methyl-3-furanyl) thio] thieno [2,3- c] pyridine- 2- carboxamide,

4 - [[(4-chlorophenyl) methyl] thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(3,4-dichlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4 - [(4-methoxyphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide,

4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide,

Thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl acetate salt, 4-methylphenylsulfonyl chloride,

4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 2- carboxamide,

Methyl 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine-

4- (4-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxylate,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate,

4 - [(4-trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-octylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- [4- (1-methylethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

4- (2-bromo-4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-ethynylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,2-dihydroxyethyl)

4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [2- (2,3-dihydroxypropyl)

Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 1-oxide,

4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

4- (4-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

(4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

(4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Ethyl 3 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate,

4-phenoxy-ethyno [2,3-c] pyridine-2-carboxamide,

4- (3-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-carboxamide,

4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-iodophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4-methoxymethyl)

2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridinium, iodide,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid,

Thieno [2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate,

Thieno [2,3-c] pyridine-2-methanol, 4- (4-chlorophenoxy)

(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde,

(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

4-bromothieno [2,3-c] pyridine-2-carboxamide,

Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylate,

4-chlorothieno [2,3-c] pyridine-2-carboxamide,

4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide,

Methyl 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxylate,

Methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine- 2- carboxamide,

4-phenylthieno [2,3-c] pyridine-2-carboxamide,

Methyl 4-phenylthieno [2,3-c] pyridine-2-carboxylate,

4 - ([1,1'-biphenyl] -4-ylthio) thieno [2,3-c] pyridine- 2- carboxamide,

(5-formyl-2-furanyl) thieno [2,3-c] pyridine-2- carboxamide,

Ethyl 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate,

4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4- yl] oxy] benzoic acid,

4- (1-phenylethenyl) thieno [2,3-c] pyridine-2- carboxamide,

Methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxalate,

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide,

N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy)

N, N-diethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy)

4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyridine- 2- carboxamide,

Thieno [2,3-c] pyridin-2-yl] carbonyl] pyrrolidine,

Thieno [2,3-c] pyridin-2-yl] carbonyl] piperidine,

Thieno [2,3-c] pyridin-2-yl] carbonyl] morpholine,

Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine,

Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine,

2,3-c] pyridin-2-yl] carbonyl] -4- (phenylmethyl) -piperazine,

2,3-c] pyridin-2-yl] carbonyl] -4- (2-pyridinyl) -piperazine,

(4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide,

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -N- Lt; / RTI >

2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thieno [

(4-chlorophenoxy) -N- [l, l-bis (hydroxymethyl) ethyl] thieno [2,3- c] pyridine- 2- carboxamide,

(D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl) thieno [2,3- c] pyridine- 2- carboxamide,

Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2-

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide,

4 - [(4-methylphenyl) methyl] thieno [2,3-c] pyridine-

Methyl 4 - [(4-methylphenyl) methyl] thieno [2,3-c] pyridine-

4- (4-morpholinyl) thieno [2,3-c] pyridine-2- carboxamide,

Thieno [2,3-c] pyridine-2-carboxylic acid, N-oxide,

Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, N-

(4-chlorophenoxy) -2- (2-methoxyphenyl) thieno [2,3-c] pyridine,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine,

4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide,

Methyl 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylate,

2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy)

Methyl 4- (4-chlorophenoxy) 3-hydroxyt enone [2,3-c] pyridine-

(4-chlorophenoxy) -3- (1-methylethoxy) thieno [2,3-c] pyridine- 2- carboxamide,

3-Bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine,

Thieno [2,3-c] pyridine-3-carboxylic acid, 4- (4-chlorophenoxy)

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3-carboxamide,

Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-

Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid,

4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine,

4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- 2- carboxamide,

4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-

Ethyl 4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3- b] pyridine-5-

7 - [(4-methylphenyl) thio] thieno [3,2-b] pyridine- 2- carboxamide,

Methyl 6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-

Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate,

6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- 2- carboxamide,

2-bromo-4 - [(4-methylphenyl) thio] thieno [3,2- c] pyridine,

4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine- 2- carboxamide,

4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine-

4- (4-methylphenoxy) thieno [3,2-c] pyridine-2- carboxamide,

4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonitrile,

7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2- carboxamide,

Methyl 7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2-carboxylate,

7- (4-methylphenoxy) [l, 3] thiazolo [5,4- c] pyridine- 2- carboxamide,

Methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-

7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine- 2- carboxamide,

Methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2- carboxamide,

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carboxylic acid,

7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carbamide,

7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboethioamide,

4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2- carboxamide,

2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl)

2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3- dihydroxypropyl)

(2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

(4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide,

(2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3- c] pyridine- 2- carboxamide,

(2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide,

4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide,

4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide,

2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-

2,3-c] pyridin-2-yl] carbonyl} amino) acetic acid,

(2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno [2,3- c] pyridine- 2- carboxamide,

(2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine- 2- carboxamide,

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid,

Thieno [2,3-c] pyridine-2-carboxamide (100 mg) was obtained in the same manner as in Example 1, ,

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid,

(2R) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid,

2,3-c] pyridine-2-carboxamide, 2,3-dimethyl-lH-

(2S) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid,

2,3-c] pyridine-2-carboxamide, 2,3-c] pyridine-2-carboxamide,

Thieno [2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide,

2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide,

4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy)

N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide,

(4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

(4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

(4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide,

4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide,

4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide,

Methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (2,3,4-Trifluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide,

Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-aminophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

Methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (hydroxymethyl)

Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (methoxymethyl)

4- {4 - [(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-c] pyridine- 2- carboxamide,

Methyl} phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [

Ethoxy] methyl} phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4 - {[

Methyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [

Pyridin-2-yloxymethyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide,

Methyl-4- {4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3- c] pyridine-

2,3-c] pyridin-4-yl] oxy} benzyl 2-furoate, 4 - {[2- (aminocarbonyl) thieno [

2-yl] oxy} methyl) phenoxy) -2,3-dihydroxy-6- (hydroxymethyl) ] -N-methylthieno [2,3-c] pyridine-2-carboxamide,

4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Carboxyphenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4-fluorophenyl)

Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- ({[2- (4-morpholinyl) ethyl]

Phenoxy} thieno [2,3-c] pyridine-2-carboxamide, 4- {4 - [(E) -3- (4-morpholinyl)

3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine Carboxamide,

Methyl-4- [4 - ((E) -3 - {[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3 -c] pyridine-2-carboxamide,

Thieno [2,3-c] pyridin-2 (1 H) -quinolin-2- - carboxamide,

Amino] -3-oxo-1-propenyl} phenoxy) -N-methylthieno [2,3-c] quinolin-2- ] Pyridine-2-carboxamide,

Amino] -3-oxo-1-propenyl) phenoxy] -N-methyl thieno [3, 2,3-c] pyridine-2-carboxamide,

Amino] ethyl} -3-oxo-1-propenyl] phenoxy} -N-methylthieno [ [2,3-c] pyridine-2-carboxamide,

Amino] -3-oxo-1-propenyl] phenoxy} thieno [2,3-b] -c] pyridine-2-carboxamide,

[4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide,

Thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-

2-yl] phenoxy} thieno [2,3-c] pyridine-2-carbaldehyde Vox amide,

Methyl-thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4,5-dihydro-1H-imidazol-

Methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

4 - ([1,1'-biphenyl] -4-yloxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

Methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl]

Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxaldehyde amides,

Methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

2,3-c] pyridin-2-yl} - (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] thieno [ 1,3,4-oxadiazole-2-amine,

Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,1-difluoro-2-

2,3-c] pyridine-1-carboxylic acid ethyl ester was used in place of 4- (4- {2- [2- (2- ethoxyethoxy) ethoxy] -1,1- difluoroethyl} phenoxy) 2-carboxamide,

2,3-c] pyridine-1-carboxylic acid ethyl ester, which was prepared in accordance with the general method of example 1 from 2- 6-Ium,

Methyl] carbonyl] thieno [2,3-c] pyridine prepared in Step 1 was added to a solution of 4- (4-bromophenoxy) -6 - {[(2,2- dimethylpropanoyl) oxy] 6-ium,

2,3-c] pyridin-6-ynyl) -2, 3-dihydro-

4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide,

4 - [(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

N ⁴ - (4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide,

Thieno [2,3-c] pyridin-2-yl] methanol,

4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime,

Thieno [2,3-c] pyridine-2-carbaldehyde O-Methyloxime,

2,3-c] pyridin-2-yl] -1-ethanone O-Methyloxime,

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

Thiophene [2,3-c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide,

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile,

2,3-c] pyridine-2-carboximidamide, 4- (4-chlorophenoxy) -N'-

C] pyridin-2-carboximidamide, 4- (4-chlorophenoxy) -N'-cyanothieno [2,3- c]

2,3-c] pyridin-2-yl] (2-nitrophenyl) methanol,

Thieno [2,3-c] pyridin-2-yl] (2-nitrophenyl) methanone,

(2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

(2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

2,3-c] pyridin-2-yl] (3-nitrophenyl) methanol,

(3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

(3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine,

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

L- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl]

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methanamine,

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methyl carbamate,

2,3-c] pyridin-2-yl] methyl} urea, N - {[4- (4-chlorophenoxy)

(E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-

(E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-

2,3-c] pyridin-2-yl] -2,3-dihydroxy-N-methylpropanamide,

Thieno [2,3-c] pyridin-2-yl] -2,3-dihydroxypropanamide, 3- [4- (4-bromophenoxy)

4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine,

4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylformamide,

2,3-c] pyridin-2-yl] urea, N- [4- (4-chlorophenoxy)

Thiophene [2,3-c] pyridin-2-yl] -N'-methylthiourea,

4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-sulfonamide,

Thieno [2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl)

(4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2-sulfonamide,

Thieno [2,3-c] pyridin-2-yl] phenol,

Thieno [2,3-c] pyridin-2-yl] aniline,

Thieno [2,3-c] pyridin-2-yl] aniline,

Thieno [2,3-c] pyridine, 2,4-dihydro-2H-pyridin-

Thieno [2,3-c] pyridin-2-yl] -3-pyridineamine,

Thieno [2,3-c] pyridin-2-yl] -2-pyridinamine,

Thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazole-2-amine,

Thiophene [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-2-ylamine,

2,3-c] pyridin-2-yl] -4H-1,2,4-triazole-3-amine,

2,3-c] pyridin-2-yl] -1,3,4-thiadiazole-2-amine,

2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c]

2,3-c] pyridin-2-yl} -1,3,4-oxadiazole-2-amine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [

2-yl] thieno [2,3-c] pyridine, which was obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl)

2,3-c] pyridine, 2,3-dicarboxylic acid ethyl ester, 2-

2,3- c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazole-3-amine,

3-yl] thieno [2,3-c] pyridine, which is obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl)

Thiophene [2,3-c] pyridin-2-yl] -1,2,4-oxadiazole-3-amine,

2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazole-2-amine,

2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c]

2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine,

2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine,

2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine,

Methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-

2,3- c] pyridin-2-yl] -1,3-thiazole-4-carboxamide, 2- [4- (4-chlorophenoxy)

2,3-c] pyridin-2-yl] -1,3-thiazol-4-ylcarbamate,

Thieno [4,3-c] pyridin-2-yl] -1,3-thiazol-4-

2,3-c] pyridine, 2,4-dihydro-2H-pyran-2-

2- (1H-imidazol-2-yl) thieno [2,3-c] pyridine,

4-chloro-3-methylthieno [2,3-c] pyridine-2- carboxamide,

Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide,

N- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine- 2- carboxamide,

4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide,

7- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide,

2,3-c] pyridine-3-carboxylate, 3-tert-butyl 2- (aminocarbonyl) -4- (4- chlorophenoxy)

N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

(4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamide,

7- chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide,

7-chloro-4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide,

7- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide,

7- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide,

7- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide,

4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2- carboxamide,

4- (4-bromophenoxy) -7-chloro-N-methylthieno [2,3-c] pyridine- 2- carboxamide,

7- chloro-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide,

(2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine- 2- carboxamide,

7- (4-chlorophenoxy) -7-methoxy-ethyno [2,3-c] pyridine- 2- carboxamide,

7- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3-c] pyridine- 2- carboxamide,

7- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [2,3- c] pyridine- 2- carboxamide,

7- (4-methylphenoxy) [l, 3] thiazolo [5,4- c] pyridine- 2- carboxamide,

N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4- c] pyridine-

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide,

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide,

4 - [(E) -2-phenylethenyl] thieno [2,3-c] pyridine- 2- carboxamide,

4- (4-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide,

4- (3-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-bromophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (3-aminophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2- carboxamide,

4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide, and

4- (4-Bromophenoxy) -5-chlorothieno [2,3-c] pyridine-2-carboxamide.

Measurement of biological activity

The primary human intravenous cytokine (HUVEC) collection (Clonetics), which had been subcultured 3-7 times, was subcutaneously transfected with 5 × 10 ⁴ cells / ml of clonetics EBM / 2% FBS / EGF / bovine brain extract / gentamycin without hydrocortisone The cells were plated in a 96-well plate (Costar) at a concentration of 100 μl / well. On the next day, the compounds of the present invention were added in 10 쨉 l / well of medium, and the plate was incubated at 37 째 C. After 24 hours of compound addition, 10 [mu] l / well of TNF (Gibco / BRL) medium was added to a final concentration of 5 ng / ml and the cells were incubated at 37 [deg.] C for additional 6 hours. The medium was then removed and the plates were washed once with D-PBS (Gibco / BRL) and incubated with primary antibody (Becton Dickinson, City) in D-PBS / 2% BSA (Sigma) /0.01% azide Lt; / RTI > / well. Primary antibodies with an initial concentration of 1 mg / ml were used at the following dilution rates. Anti-ELAM-1, 1: 2000, anti-ICAM-1, 1: 2000 and anti-VCAM-1, 1: 3000. The plates were stored at 4 ° C overnight, washed three times with D-PBS, then diluted 1: 8000 in HRP-conjugated donkey anti-mouse IgG (H + L) in D-PBS / And treated with 100 μl / well of secondary antibody (Jackson Labs). The plate was incubated at room temperature for a minimum of 1 hour, washed three times with D-PBS and treated with 100 μl / well of ortho-phenylenediamine 2HCl reagent. The plate was developed for about 15 minutes and then neutralized with 100 μl / well of 1 N sulfuric acid. Absorbance was read at 490 nm. The inhibition rates of the representative compounds described in the present invention are shown in Table 1.

CAM ELISA% inhibition at 1 [mu] M% Example E-selectin ICAM-1 VCAM-1 2 28 35 4 3 37 32 19 16 35 32 19 17 29 30 14 19 79 67 41 20 55 46 26 21 63 55 23 22 64 64 33 32 75 63 41 33 69 60 28 53 70 67 48 54 74 59 33 60 74 71 42 61 82 74 50 79 66 63 38 89 62 64 50 90 47 51 27 95 85 71 61 102 78 68 53 104 78 72 53 110 44 48 39 119 59 61 36 120 72 72 49 135 29 22 34 123 39 31 12 124 18 29 26 125 72 69 44 142 151 69 73 44 158 61 65 26 159 30 45 13 161 51 58 51 170 66 67 53 171 67 72 50 183 63 69 48 184 52 56 30 187 78 72 54 190C 70 65 37 202 80 68 49 210 64 58 42 217 64 63 42 218 66 64 51 219 62 68 50

CAM ELISA% inhibition at 1 [mu] M% Example E-selectin ICAM-1 VCAM-1 220 60 51 32 222 40 42 44 223 34 36 36 224 61 55 41 225 75 78 60 226 77 74 56 227 61 62 44 228 70 68 54 228 67 64 52 229 54 55 46 230 56 53 45 233 74 79 62 236 59 59 33 237I 71 77 54 238 46 47 17 249 75 69 61 254 24 28 24 255 67 65 19 259 63 59 57 261 20 16 0 274 65 71 44 275 73 72 64 276 66 61 52 279 30 40 24 280 73 77 69 281 18 25 20 282A 8 15 5 283 39 57 52 284 56 68 45 285 56 65 50 286 54 64 46 287 49 49 27 289 64 62 52 290 42 53 48 294 46 45 24 295 59 56 44 301 44 48 34 303 65 66 33 311 72 77 36 312 64 76 42 313 57 68 39 316 76 68 42 320 64 67 55 325 76 68 42 329 72 62 64 340 18 33 20

That is, the compound of the present invention acts as an anti-inflammatory agent at an inhibition rate of 1 μM or less, and is useful for treating inflammatory diseases.

Pharmaceutical compositions and methods of treatment

The present invention provides a pharmaceutical composition comprising a compound of the invention formulated with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical composition can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of the present invention can be administered to humans and other animals as oral, rectal, parenteral, intramuscular, intrapulmonary, intraperitoneal, topical (as powders, ointments or drops), buccal or oral or as an untreated powder. As used herein, the term " parenteral " administration means a mode of administration including intravenous, intramuscular, intraperitoneal, intrasternal, transdermal and intraarticular injection and infusion.

The parenterally administrable pharmaceutical compositions of the present invention include sterile aqueous solutions or aqueous solutions, dispersions, suspensions or emulsions which are pharmaceutically acceptable, as well as sterile powders which can be reconstituted with a sterile injectable solution or dispersion immediately prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol and the like and suitable mixtures thereof, injections such as vegetable oils (e.g., olive oil) There are sex organic esters. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a predetermined particle size in the case of dispersions, and by the use of surfactants.

In addition, the compositions may further comprise adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The microbial action can be prevented by adding various antibacterial agents and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It is also preferable to add an isotonic agent such as sugar, sodium chloride and the like. Continuous absorption of the injectable pharmaceutical form can be achieved by adding an agent that delays absorption, such as aluminum monostearate and gelatin.

In some cases, it may be necessary to slow the rate of absorption of the drug from the transdermal or intramuscular injection to maintain the drug effect. This can be achieved using liquid suspensions of crystalline or amorphous material with low water solubility. The rate of absorption of the drug then depends on the rate of dissolution and, ultimately, on crystal size and crystal morphology. Alternatively, delayed absorption in the form of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle.

The injectable depot form is prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as a polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). In addition, depot injectable preparations are prepared by injecting drugs into liposomes or microemulsions compatible with body tissues.

The injectable preparation can be sterilized, for example, by adding a sterilizing agent to the form of sterile solid compositions that can be filtered or, for example, filtered through a bacteria-retaining filter, or dissolved or dispersed in sterile water or other sterile injectable solutions immediately prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may contain one or more inert, pharmaceutically acceptable excipients or carriers (e. G., Calcium citrate or sodium citrate) and / or a) fillers or extenders such as starches, lactose, sucrose, Gelatin, polyvinylpyrrolidone, sucrose and acacia; c) wetting agents such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, calcium carbonate, G) wetting agents such as cetyl alcohol and glycerol monostearate, h) sorbents such as sorbitan monolaurate, sorbitan monolaurate, sorbitan monolaurate, sorbitan monolaurate, sorbitan monolaurate, Such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols , Sodium lauryl la is a sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may further comprise a buffering agent.

Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared using encapsulants and coatings such as enteric coatings and other coatings known in the art of pharmaceutical formulation. This form may optionally comprise a whitening agent and may also be a composition which releases the active ingredient in a predominantly, and possibly delayed manner, only in or at a particular part of the intestinal tract. Examples of syringe compositions that may be used include polymeric materials and waxes.

In addition, the active compound may be in a microencapsulated form, optionally containing at least one of the excipients described above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms can also include inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene Fatty acid esters of glycols and sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions may further comprise adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

The suspension may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof can do.

Rectal administration or enamel compositions can be prepared by dissolving the compound of the present invention in a suitable non-polymorphic excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is liquid at room temperature or solid at room temperature and melts in the rectum or vaginal cavity to release the active compound And the like.

The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid materials. Liposomes are prepared by dispersing hydrated liquid crystals of the single-lamella or multi-lamella type in an aqueous medium. All non-toxic, physiologically tolerable metabolizable lipids capable of forming liposomes can be used. Forms of the present invention in the form of liposomes may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are the phospholipids of natural and synthetic phosphatides and phosphatidyl choline (lecithin).

Methods of making liposomes are known in the art (Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.].

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. &Quot; Pharmaceutically acceptable salt " refers to salts suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and salts of acceptable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S. Medgege et al., J. Pharmaceutical Sciences, 1977, 66: 1 et seq., Describe pharmaceutically acceptable salts in detail. The salts may be prepared in situ during the final isolation and purification of the compounds of the present invention or may be prepared separately by reacting the free base with a suitable acid. Representative examples of acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, , Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2 -Naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate , p-toluenesulfonate and undecanoate. Further, the basic nitrogen-containing group may be a lower alkyl halide such as methyl chloride, ethyl chloride, propyl chloride and butyl chloride; Dialkylsulfates such as dimethylsulfate, diethylsulfate, dibutylsulfate and diamylsulfate; Long chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; But are not limited to, arylalkyl halides such as benzyl and phenethyl bromide. Whereby a water-soluble or oil-soluble or dispersible product can be obtained. Examples of acids which can be used to prepare the pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.

The basic addition salts are prepared by reacting a carboxylic acid containing moiety with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine to finally isolate and purify the compound of the present invention Can be manufactured in situ. Examples of the pharmaceutically acceptable salt include a cation of an alkali metal or an alkaline earth metal such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like, and ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethyl Non-toxic quaternary ammonia and amine cations including, but not limited to, amine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for base addition salt formation include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Preferred salts of the compounds described in the present invention include phosphates, tris and acetic acid salts.

Dosage forms suitable for topical administration of the compounds of this invention include powders, sprays, ointments and inhalants. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and, if desired, preservatives, buffers or propellants. Also, ophthalmic preparations, ophthalmic ointments, powders and solutions are also within the scope of the present invention.

The actual dosage level of the active ingredient used in the pharmaceutical composition of the present invention may be varied to obtain the amount of active compound effective to achieve the desired therapeutic response depending on the particular patient, composition and mode of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the disease being treated, and the symptoms and prior pharmacological history of the patient being treated. However, those skilled in the art will appreciate that the dosage of the compound is determined by gradually increasing the dosage starting from a lower concentration than is required to achieve the desired therapeutic effect, until the desired effect is achieved.

In general, when administered orally to a mammalian patient, the dosage is preferably about 1 to about 50 mg, more preferably about 5 to about 20 mg, of active compound per kilogram of body weight per day. If desired, an effective daily dose can be administered in divided doses, for example divided into two to four separate doses per day.

Preparation of the compounds described in the present invention

Abbreviation

The abbreviations used in the description of the reaction formulas and the examples are as follows. BH ₃ , borane; BH ₃ DMS, borane dimethylsulfide complex; BINAP, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl; BF ₃ OEt ₂ , boron trifluoride diethyl ether complex; n-BuLi, n-butyllithium; CCl ₄ , carbon tetrachloride; Cs ₂ CO _3, cesium carbonate; DBU, 1,8-diazabicyclo [5.4.0] undec-7-ene; DMA, N, N-dimethylacetamide; DIBAL, diisobutylaluminum hydride; DME, dimethoxyethane; DMF, N, N-dimethylformamide; DMSO, dimethyl sulfoxide; DIPEA, diisopropylethylamine; DPPA, diphenylphosphoryl azide; EDCI or EDC, 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride; Et ₃ N, triethylamine; Et ₂ O, diethyl ether; EtOAc, ethyl acetate; EtOH, ethanol; K ₂ CO ₃ , potassium carbonate; LiAlH ₄ , lithium aluminum hydride; LDA, lithium diisopropylamide; MeOH, methanol; NaOMe, sodium methoxide; NaOH, sodium hydride; HCl, hydrochloric acid; NMP, 1-methyl-2-pyrrolidone; H ₂ / Pd, hydrogen and palladium catalysts; iPrOH, isopropyl alcohol; PPh ₃ , triphenylphosphine; THF, tetrahydrofuran; THP, tetrahydropyran; TFA, trifluoroacetic acid; And pyBOP, benzotriazol-1-yloxypyrrolidinophosphonium hexafluorophosphate.

Synthetic method

The compounds and methods of the present invention are described in detail in connection with the following synthetic reaction schemes illustrating how the compounds of the present invention may be prepared.

Scheme 1 illustrates a method for preparing thieno [2,3-d] pyrimidines by an open procedure from esters of formula (I). Specifically, 4-chlorothieno [2,3-d] pyrimidine of formula (3) is substituted with thiol to obtain 4-thioether of formula (4) or substituted by an amine to obtain 4-aminothieno [ , 3-d] pyrimidine.

Scheme 2 illustrates the preparation of 2-carboxy-substituted thieno [2,3-d] pyrimidines. Specifically, the pyrimidinone of the formula (1) is reacted with phosphoryl chloride to obtain 4-chloropyrimidine of the formula (6), which is then substituted with thiol to obtain the thioether of the formula (7).

Scheme 3 illustrates a method for preparing thieno [3,2-d] pyrimidines derived from chloropyrimidines of formula (8). Substituting thiol for chloride to give the thioether of formula 9, replacing the chloride with an amine gave the aminopyrimidine of formula 10.

Thiophene [3,2-d] pyrimidine was prepared as shown in Scheme 4. < EMI ID = The thiophene-2-position was deprotonated with a strong base such as lithium diisopropylamide and the corresponding carbo anion was treated with carbon dioxide to give the acid of formula (11). This acid was converted to the corresponding amide of formula (12) via the intermediate acid chloride.

Scheme 5 depicts the preparation of a 6-alkyl substituted thieno [2,3-d] pyrimidine having an alkyl thio group at the 4-position. Using a known procedure, 2-aminothiophene (13) was acylated to give amide (14) and then cyclized to give thienopyrimidine (15). This pyrimidinone was converted to the chloride (16) and further to the thioether (17) according to standard procedures.

The general process for preparing 2,4-disubstituted thieno [2,3-c] pyridine is shown in FIG. The commercially available 3,5-dichloropyridine is treated with a strong base such as lithium diisopropylamide in a cold anhydrous solvent and then reacted with methyl formate (or dimethylformamide) to obtain the known pyridine-4-carboxaldehyde 18 ≪ / RTI > The aldehyde 18 is then substituted with one equivalent of thiol (R ¹ = substituted or unsubstituted aryl, alkyl or heterocyclic) to give the chloroaldehyde of formula 19. Treatment of 19 with a base such as cesium carbonate or potassium carbonate and methyl thioglycolate provided the 4-thioether [2,3-c] thienopyridine ester of formula 20. This ester was converted to the corresponding acid of formula 21 by basic hydrolysis, for example using lithium hydroxide, sodium or potassium, in a mixture of water and an alcohol or tetrahydrofuran. The acid of formula 21 can also be treated first with oxalyl chloride or thionyl chloride and then treated with the best amine (R ² , R ³ can be substituted or unsubstituted alkyl, aryl, heterocyclic) to give the intermediate acid chloride Lt; RTI ID = 0.0 > 22 < / RTI > Alternatively, the acid 21 may be converted to the corresponding compound by a coupling method such as carbodiimide (e.g. N-ethyl-N '- (3-dimethylamino) propyl carbodiimide hydrochloride (EDC), mixed anhydride (pivaloyl chloride or isobutyl chloroform Can be converted to amide 22 or 23 by treatment with an activated ester (e.g., derived from mate treatment) and an active ester (e.g., derived from N-hydroxysuccinimide, p-nitrophenol).

Scheme 7 relates to a similar process for the 4-ether-substituted thienopyridine of formula 30. Substituting the aldehyde 18 with an alcohol (R ¹ = substituted or unsubstituted aryl, heterocyclic) under basic conditions (e.g., anhydrous tetrahydrofuran or tert-butoxide or cesium carbonate in dimethylformamide) -Ether, which is then reacted with methyl thioglycolate to give the thieno [2,3-c] pyridine ester of formula 25. This ester was converted to the corresponding primary amide of formula 26 by heating in a methanolic ammonia solution. Alternatively, the ester of formula 25 can be reacted with a mono- or disubstituted amine in a polar solvent such as dimethylformamide or methanol. The ester of formula 25 was hydrolyzed to the carboxylic acid of formula 28 by basic hydrolysis with sodium hydroxide or lithium hydroxide in aqueous methanol or tetrahydrofuran. This acid was then converted to the amide of formula 30 by reaction of the amine with the corresponding acid chloride of formula 29. Alternatively, the acid 30 was coupled to an amine under standard peptide-coupling conditions as described for amide 22 or 23 in Scheme 6. [

As shown in Scheme 8, a similar method to the preparation of 4-bromothieno [2,3-c] pyridine 32 can be used. 3,5-dibromopyridine was converted to the aldehyde 31 according to the procedure described for the preparation of compound 18 in Scheme 6. [ Reaction of methyl thioglycolate with 31 gave 4-bromothieno [2,3-c] pyridine ester 32, for example, in the presence of cesium carbonate in DMF. Bromide 32 was provided as a starting material for the preparation of the 4-aryl, heterocyclic, alkyl or alkenyl derivatives of formula 33 using the Suzuki coupling method as shown. Further, the bromide 32 is coupled with a terminal alkyne, and the Sonogashira method [Sonogashira, K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett. 1975, 4467-70] to obtain an alkynyl derivative (R ¹ = alkynyl). The ester of formula 33 was converted to the amide of formula 34 according to the procedure described in scheme 7, 26, 27 or 30.

Scheme 9 illustrates a method of converting an acid of formula 21 into an aldehyde or ketone-derived compound. For example, an aldehyde of formula (36) was prepared by reducing N-methyl-N-methoxylamide of formula (35). In addition, the amide of formula 35 was reacted with Grignard reagent to yield the asymmetric ketone of formula 39. The oxime of formula (37) or (40) was produced from the reaction of the aldehyde of formula (36) and the ketone of formula (39) with hydroxylamine derivatives. The aldehyde of formula (36) was reacted with phosphorane (or phosphonoacetate salt) to give a 2-alkenyl substituted derivative of formula (38). The ketone of formula 39 was treated with hydrazine and a strong base such as potassium hydroxide to give the corresponding alkane of formula 41. A similar 2-position derivative of thienopyridine ether of formula 28 in Scheme 7 follows a synthetic route similar to that described in Scheme 9. That is, acid 28 can be converted to an aldehyde, ketone, oxime, alkene, or alkane substituent at the 2-position.

The amides of Formula 34 (or 26, 27 or 30) can be converted to the corresponding thioamides of Formula 42 by treatment with Lawesson's reagent as shown in Scheme 10.

As shown in Scheme 11, the 4-sulfoxide of formula 43 is prepared by reacting the thioether of formula 20 with an oxidizing agent such as m-chloroperoxybenzoic acid under controlled conditions.

The other functional group is metallated at the 2-position of the thienopyridine of formula 44 and then introduced into the 2-position by reaction with a suitable electrophile as shown in Scheme 12. The acid of formula 21 (L _A X _A = thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) is decarboxylated at elevated temperature (optionally in the presence of copper powder) Lt; / RTI > The compound of formula 44 is deprotonated with a strong organic base such as n-butyllithium and then reacted with an electrophile such as a borate, cyanoformate, aldehyde, or trialkyltin chloride and a standard procedure [Masakatsu, N .; Kazuhiro, N .; Ichiro, M .; Iwao; W. Chem. 1983, 6, 905-908.

Scheme 13 relates to an alternative process for the preparation of 2-carboxaldehyde of formula 36 or 37. The ester of formula 20 or 25 (R ¹ = thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) was reduced to the corresponding alcohol of formula 46 using calcium borohydride. The alcohol was then oxidized to aldehyde using Swern conditions. This aldehyde was then reacted with a bithiog reagent (e.g., phosphorane) to produce an acrylate derivative of formula 48 (Jung, ME and Kiankarami, MJ Ogg. Chem. 1998, 63, 2968-2974).

As shown in Scheme 14, the thienopyridine of formula (27) or (30) is made into the pyridinium salt of formula (49) by the introduction of an alkyl group onto pyridine nitrogen using alkyl iodide (or alkyl bromide or triflate). For example, R may be alkylcarbonyloxymethylene, aminocarbonyloxymethylene, alkoxycarbonyloxymethylene or alkyl. Such derivatives may be provided in the form of prodrugs of thienopyridine amide 27 or 30.

As shown in Scheme 15, various 2-aminothieno [2,3-c] pyridine derivatives can be obtained from the 2-carboxylic acid of Formula 21 or 28. Wherein R &^lt; ¹ > may be thioalkoxy, alkoxy, alkyl, alkenyl, aryl, or heterocyclic. The isocyanate of formula 50 is obtained via crotch rearrangement and is reacted with an alcohol (alkyl, aryl, heterocyclic or dialkylaminoalkyl) to give the carbamate of formula 51. Isocyanate 50 can be reacted with an amine (ammonia, primary alkyl or secondary alkyl) to provide urea of formula 52. The isocyanate 50 can also be reacted with an alkyl or arylmagnesium halide, an alkyl lithium salt to provide an amide of formula 53. Isocyanate 50 can be hydrolyzed under aqueous conditions to produce a 2-amino derivative of formula 54. [

The amine of formula 54 was reacted with a suitable electrophile to further derivatize the 2-position. That is, reacting 54 with aryl or alkylsulfonyl chloride (R ² = alkyl, aryl, heterocyclic) or sulfamoyl chloride (R ² = NH ₂ , monoalkylamino or dialkylamino) . In addition, the amide derivative 54 was reacted with acyl chloride (R ² = alkyl, heterocyclic or aryl) to give an amide of formula 53 as shown in Scheme 16.

The functional group present on the aryl ring bound to the 4-position of the thieno [2,3-c] pyridine can be advantageously further reacted as shown in Scheme 17. For example, the styryl derivative 56 was converted to 1,2-diol 57 by treatment with osmium tetroxide under standard conditions. The 4- (4-bromophenoxy) derivative 58 was easily substituted with an arylboronic acid under palladium catalysis under Suzuki conditions to give a biaryl derivative of the formula 59. Alternatively, alkoxycarbonylation under palladium catalysis effectively provides an ester of formula (61).

Scheme 19 relates to the use of boronic acid derivatives for functional attachment of the 4-position of thieno [2,3-c] pyridine. The chemistry shown is also applicable to a wide range of aryl olefins similar to bromostyrene 62. In the depicted embodiment, bromostyrene 62 is converted to boronic acid 63 under standard conditions, and boronic acid is coupled to 4-bromothienopyridine 32 under Suzuki conditions to provide styryl analog 64. This ester 64 was converted to amide 65 according to the previously disclosed method (Miyara, N and Suzuki, A. Chem. Rev. 1995, 95, 2457-2463). The olefin group can then be converted to epoxide 66, which can react with the nucleophilic reagent at low interference sites to produce an analog of formula 67. Alternatively, the styryl derivative 65 may be converted to diol 68 by standard methods.

Scheme 20 illustrates another method of introducing a substituent at the 4-position of thieno [2,3-c] pyridine. Bromide 32 can be converted to the corresponding cuprate via an intermediate zinc bromide reagent and then reacted with the appropriate electrophile (acid chloride, alkyl halide, aldehyde, ketone) to provide the substituted compound of formula 69 (Zhu , L. Wehmeyer, RM, Rieke, RDJ Org.Chem, 1991, 56, 1445-1453).

Scheme 21 relates to the preparation of 5-halothienopyridine derivatives as illustrated in the preparation of 5-chloro analog 75. The lithiated 2,3,5-trichloropyridine was formylated with methyl formate to give aldehyde 72. 3 and 5 chlorine were replaced with excess 4-bromophenol and reacted with methyl thioglycolate to yield a small amount of 5-chlorothienopyridine 74 with the main product 73. The 5-chloro isomer was treated with ammonia in methanol in a pressure tube to give amide 75. It is obvious that such a chemical procedure can be carried out using a range of phenol or hydroxyheterocyclic compounds instead of 4-bromophenol.

The 2-position of thienopyridine was substituted with an aryl, vinyl, acetylene or alkyl group according to the procedure shown in Scheme 22. The boronic acid of Formula 79, prepared according to Scheme 12, was coupled to an aryl halide under a palladium catalyst to produce a 2-aryl derivative of Formula 80.

Scheme 23 relates to the preparation of 4-acyl derivatives of thieno [2,3-c] pyridine. The carboxylic acid 85 was converted to the amide 86 via acid chloride and then the hydroxyamide 86 was cyclized with thionyl chloride to give oxazoline 87 (Meyers, AI ,; Stoianova, DJ Org. Chem. 1997, 62 , 5219-5221). Palladium mediated alkoxycarbonylation of the oxazoline 87 proceeded to produce ester 88 (Heck, R. F. et al. J. Org. Chem. 1974, 39, 3318). The ester 88 can be converted to the Weinreb amide 89 according to standard methods. Amide 89 was reacted with a suitable Grignard reagent to give the desired 4-acyl product of formula 90. [ The oxazoline was hydrolyzed and the resulting carboxylic acid was converted to the amide to yield the desired product of formula 91.

Scheme 24 relates to a preferred method by which 4-hydroxy substituted thieno [2,3-c] pyridine can be formed. Phenol 92 was reacted with dihydropyrane under acidic conditions to give tetrahydropyranyl ether 93 (Grant, H. N., et al., Helv. Chim. Acta. 1963, 46, 41). The above 93 was lithiated and then quenched with methyl formate to give aldehyde 94. Substituting the halide with methyl thioglycolate followed by cyclization with cesium carbonate yielded ester 95. Removal of the tetrahydropyranine ether with aqueous HCl gives the hydroxypyridine 96, which can be converted to the amide as described above.

Scheme 25 suggests the use of a 4-hydroxy group to introduce a functional group at the 4-position of thieno [2,3-c] pyridine. First, the 2-carboxylic acid group is protected as oxazoline 99 (via intermediate amide 98), and then the hydroxy group is converted to the aryl triflate 100 under standard conditions. The triflate 100 can then be converted to N-methyl-N-methoxyamide 89 under conditions analogous to the conversion conditions for bromide 87. It is clear that 4-triflate 100 can act as a coupling partner in various transition metal-mediated coupling with a suitable nucleophilic partner (e.g., boronic acid, borane, alkyl or aryl-zinc reagent).

Following the procedure outlined in Scheme 26, compounds with amino substituents at the 3-position of thieno [2,3-c] pyridine were prepared. Aldehyde 18 was converted to cyanopyridine 107 by treatment with hydroxylamine under dehydrating conditions. Cyanopyridine 107 was successively substituted with phenol and methyl thioglycolate in a similar manner to the reaction involving the aldehyde 18 to give 3-aminothieno [2,3-c] pyridine represented by the general formula (108). The ester of formula 108 was then converted to the amide of formula 109 according to standard procedures.

Scheme 27 relates to an amino ester of formula 108 or an additional derivative which may be derived from an aminoamide of formula 109. [ For example, treating the aminoamide of formula (109) with 1,1'-carbonyldiimidazole can produce a cyclic imide of formula (110). The 3-amino group is acylated (e. G., By coupling with an acid using a weak base or an acid chloride) to give the diamide of formula 111. The 3-amide group can be alkylated with an aldehyde and a reducing agent (e.g., triacetoxyborohydride) under reducing conditions to yield the alkylated amine of formula 11.

Scheme 28 shows the preparation of a compound having an alkyl substituent at the 3-position of thieno [2,3-c] pyridine. 3,5-dichloropyridine is deprotonated with a strong base (e.g., lithium diisopropylamide) and then reacted with an acylating reagent (ester, N-methyl-N- Methoxy-amide, acylpyrazole, etc.) to obtain ketone 113. [ Alternatively, the ketone 113 can be obtained by reacting the anion with an aldehyde (e.g., acetaldehyde) and then oxidizing the product (e.g., using tetrapropylammonium perruthenate). Following the protocol outlined in Example 30, the dichloro ketone is reacted with phenol, followed by methyl thioglycolate, to obtain the cyclic product of formula 114. The esters of formula 114 can be converted into various derivatives as described above.

Scheme 29 relates to a method analogous to that used to obtain derivatives having an alkoxy group at the 3-position of thieno [2,3-c] pyridine. The ester 116 was substituted and cyclized to give the 3-hydroxy analog of formula 117. This hydroxy group can be maintained in an unsubstituted state to form an amide of formula (118) (or other derivative). Alternatively, the hydroxy ester of formula 117 was alkylated according to standard procedures to give the 3-alkoxy derivative of formula 119, which was then amide-formed to give the compound of formula 120.

Scheme 30 depicts the procedure used to transform commercially available furo [2,3-b] pyridine 121 into amide 122.

Scheme 31 proposes the preparation of a thienopyridine derivative containing an amide group at the 3-position. Thienopyridine of formula 44 is halogenated using an electrophilic halide source (e.g., N-bromosuccinimide, I ₂ ) to give 3-halothienopyridine of formula 123. Following metal halide exchange, trapping with carbon dioxide gave the acid of formula 124. The acid may be converted to the amide of formula 125 by standard procedures or by an ester of formula 126 (for example, by the Arndt-Eisert procedure). The esters of formula 126 can then be converted to amides or other functional groups by the methods described above.

Scheme 32 relates to the method used for the preparation of various thieno [2,3-b] pyridines using the known 4-chloro-5-ester 127 as the starting material. Was treated with thiol in the presence of potassium carbonate to displace the chlorine of 127 to provide the 4-thioether of formula 128. In addition, ester 127 was hydrolyzed with acid 129 and converted to the amide of formula 130 according to standard coupling conditions.

Scheme 33 illustrates a method for converting Formula 128 to a 2,4-disubstituted analog. The corresponding acid of formula 131 was decarboxylated by heating to give the 5-unsubstituted analog of formula 132. The compound of formula 132 was treated with a strong base (e.g., n-butyl lithium) and reacted with carbon dioxide to provide the 2-carboxylic acid of formula 133. This acid was transformed to the amide of formula 134 according to the procedure described above.

Scheme 34 depicts the preparation of thieno [3,2-b] pyridine. Chloride 135 was modified under similar conditions to that described in Scheme 33 to give the acid of Formula 139 and the amide of Formula 140.

Scheme 35 depicts the preparation of thieno [3,2-c] pyridine. 1970, 79, 301; Troxler, F .; Wiskott, E., US Pat. Oxo-4,5-dihydrothiethano [3,2-c] pyridine-2-nitrile 144 was prepared according to the method described in Example 1, Thienopyridone 144 was treated with phosphoryl chloride at 130 < 0 > C to produce chloride 145, which was exposed to thiol under basic conditions to provide the thioether of formula 146. [ The nitrile group was hydrolyzed with polyphosphoric acid to provide the corresponding amide of formula 147.

Scheme 36 depicts the preparation of the ether of formula 149, which is prepared in a manner similar to that described above in scheme 35.

Scheme 37 depicts the preparation of the intermediate of formula 151 useful in the preparation of an alternative 2-derivative. Bromo-4-chlorothieno [3,2-c] pyridine 150 was treated with one equivalent of thiol to obtain 2-bromothieno [3,2-c] pyridine represented by the formula 151.

Scheme 38 shows a preparation example of a related inhibitor based on an oxazolopyridine structure. Specifically, the commercially available 3-chloropyridine was oxidized with N-oxide 152 with peracetic acid and then nitrified in a mixture of nitric acid, concentrated sulfuric acid and fuming sulfuric acid to produce the 4-nitro derivative 153. Subsequently, the chlorine in 153 was replaced with the sodium salt of p-cresol and the resulting biaryl ether 154 was hydrogenated (Raney nickel catalyst) to reduce both the nitro functionality and the N-oxide to provide 155. The amino group of 155 is protected with an N-trimethylacetyl group to form a double anion of 156, the reaction is terminated with trimethylborate, the intermediate boronate ester is oxidized and then hydrolyzed with basic hydrogen peroxide to produce hydroxypyridine 157, [Chu-Moyer and Berger, J. Org. Chem. 1995, 60, < RTI ID = 0.0 > 5721). ≪ / RTI > This amide was hydrolyzed with hydrochloric acid to give 158 which was condensed with methyl oxalyl chloride to provide the oxazolopyridine 158. [ The methyl ester 159 was then converted to the primary amide by treatment with ammonia in methanol to give the target compound 160. [

Scheme 39 shows a preparation example of a similar thiazolopyridine-based inhibitor. In this scheme, paracresol substituted pyridine is used as the starting material, but this synthesis method is also generally applicable to other aryl, heterocyclic or alkyl ethers. The double anion of 4- (N-trimethylacetyl) -amino-3- (4-methylphenoxy) -pyridine was quenched with tetramethylthiuram disulfide to give 5-mercaptopropyridine in the substituted pyridine ring as dithiocarbamate 161 We introduced pottery. Subsequently, the amine was deprotected under acidic conditions and the free aniline 162 was acylated with methyl oxalyl chloride to provide oxalamide 163. And then treated with a weak acid (e. G., Formic acid under reflux) to produce thiazolopyridine bicyclic nucleus 164. The ester functional group was converted to the corresponding amide 165 by treatment with an amine solution in methanol under heating.

Compounds of related imidazo pyridines can be prepared from the intermediates shown in Scheme 40. The 5-hydroxypyridine 157 can be converted to the corresponding aniline 166 by heating in ammonium hydroxide saturated with sulfur dioxide in a pressure vessel [Newman and Galt, J. Org. Chem., 1960, 25, 214]. Removal of the pivaloyl group of 166 with hydrochloric acid followed by condensation of the resulting diaminopyridine 167 with methyl oxalyl chloride provides the imidazopyridine 168. The ester functionality can then be converted to amide 169 by treatment with ammonia in methanol as described above.

Scheme 41 illustrates the preparation of a thienopyridazine-containing inhibitor. The protected thiophene 170 was deprotonated with a strong base (e.g., n-butyl lithium) and then reacted with the formylating reagent. The resulting oxazoline aldehyde 171 was hydrolyzed and cyclized with hydrazine to give hydroxy thienopyridazine 172. The hydroxy group was converted to the chloride 173 by the action of phosphorus oxychloride, followed by substitution with an alkoxide to give the ether 174. The amide group was introduced in a manner similar to that described above for thienopyridine to give amide 176. [

Scheme 42 illustrates the synthesis of the water-soluble glycosylamide derivative represented by the general formula (178). Coupling of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl azide and thienopyridine carboxylic acid represented by formula (21) or (28) under tributylphosphine mediation under the aid of PyBOP yields Lt; RTI ID = 0.0 > (3-glycosylamide < / RTI > No other isomers were detected in the reaction solution. The acetyl group was cleaved with methylamine to provide the compound of formula 178.

Scheme 43 outlines the preparation of 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxamide using the modification of the route described in Scheme 7. 182 < / RTI > The two-step procedure was employed to combine the thienopyridine nuclei. Dichloropyridine aldehyde was treated with 1 equivalent of N-BOC protected 4-hydroxy aniline to provide compound 179 which was cyclized to yield ester 180. The amide 181 was transformed according to the procedure described above and treated with trifluoroacetic acid to remove the Boc group. It is to be understood that aniline 182 also acts as a starting material for the Sandmeyer reaction via the diazonium salt, wherein the amino group can be converted into a variety of functional groups including halo, hydroxy, cyano, among other standard Sandmeyer products.

Scheme 44 is described by Wolfe, John; Buchwald, Stephen L. J. Org. Chem. 1997, 62, 6066, which is incorporated herein by reference in its entirety. The iodide 183 prepared by the above method was coupled with disubstituted amines (e.g., morpholine in the above example) in the presence of bis (dibenzylideneacetone) dipalladium and BINAP to provide substituted aniline 184.

Scheme 45 illustrates the preparation of 4- (4-hydroxymethylphenyl) thieno [2,3-c] pyridine 188 using the modification of the route exemplified in Scheme 7. Using monotritylated 4-hydroxybenzyl alcohol as the starting material, it was condensed with dichloroaldehyde 18 and then cyclized with methyl thioglycolate to give the protected benzyl alcohol 188. The standard variant provided alcohol 188.

Scheme 46 relates to the preparation of protected benzyl alcohol 190 using mono-tetrahydropyran-protected hydroxybenzyl alcohol 189 as the starting material. Standard acid catalyzed hydrolysis of the THP group can also produce the benzyl alcohol analog 188.

As shown in Scheme 47, benzyl alcohol 188 can be further derivatized as an ester, for example, under carbodiimide conditions described above or using standard coupling procedures using an acid chloride. In addition, the alcohol can be converted to a carbamate (R = NH ₂ , monosubstituted or disubstituted amino) by treatment with isocyanate or carbamoyl chloride.

The procedure outlined in Scheme 48 can be used to prepare the glycosides of benzyl alcohol 187. This alcohol 187 and tri-O-acetyl-D-glucal were treated with stoichiometric trivalent scandium triflate to obtain sterically specifically protected glycoside 192, which was deprotected with methylamine to give free glycoside 193.

Stille coupling of tributylethoxyvinyltin and iodophenyl derivative 194 (or its corresponding bromophenyl analogue) can introduce an acetyl group at the 4-position of the phenyl ether as illustrated in scheme 49 . The intermediate vinyl ether is hydrolyzed during the treatment conditions to provide the acetophenone derivative 195. Addition of methyl magnesium bromide to ketone 195 at -50 占 폚 resulted in no expected adduct but the aldol adduct 196 was isolated at a yield of 40%. Bromophenoxymethyl ester 197 in an aqueous medium was palladium catalyzed carbonylation to give the acid 198 in intermediate yield. After coupling with an amine via PyBOP- or EDC (as with morpholine), the 2-methyl ester was aminated to give the diamide 199.

Scheme 50 illustrates the preparation of cinnamide ether. Butyl acrylate and bromophenoxymethyl ester 197 were subjected to a heck reaction using tritolylphosphine as a ligand to obtain cinnamate 200 in good yield. The t-butyl ester was hydrolyzed with trifluoroacetic acid followed by coupling with an amine via PyBOP or EDC followed by amidation of the methyl ester to give the diamide 201.

Scheme 51 illustrates the preparation of 4-heterocycle phenoxy enopyridines. The para-cinnophenyl derivative 202 was readily treated with hydroxyamine in DMF and ethanol mixture to afford hydroxyimide amide 203 which was heated with trifluoroacetic anhydride in pyridine to give oxadiazole 204. The cyano derivative 202 was transformed into imidazoline 205 under the conditions described above. Other known heterocycles were fed using known Stille, Suzuki or Hek conditions, for example, styrene coupling of iodo compound 194 and tributylstannylthiophene to give compound 205A. The above-mentioned aryl coupling reaction can be applied to compounds having various substituents at C-2 of thienopyridine in addition to the methyl amide exemplified in the reaction scheme 51. [

Cyclopropylcarbinyl alcohol derivatives of 4-phenyl ethers may be prepared according to the procedures illustrated in schemes 52 and 53. The commercially available phenylcyclopropanecarboxylic acid was converted to the corresponding alcohol 206 by LAH reduction followed by demethylation and selective protection of the hydroxymethyl group to give phenol 207. Using the procedure of Scheme 7, phenol 207 was condensed with dichloroaldehyde 18 and then methyl thioglycolate to yield thienopyridine 208. Standard transformation gave the desired compounds 209 and 210.

Alcohol 206 was alkylated as illustrated in Scheme 53 to produce polyetherphenol 211 which was converted to cyclopropylcarbinylpolyether 212 according to a similar procedure as illustrated in Scheme 52. Such alkylation chemistry can be widely applied by replacing the diether sulphate shown with other alkyl halides or sulfonate esters.

In Scheme 54, a difluoroacetic acid derivative 213 was synthesized by coupling copper iodide 194 with ethyl iododifluoroacetate in the presence of phenol to confirm that the side reaction was significantly inhibited. The ester 213 was reduced to obtain difluoroethyl alcohol 214. Alcohol 214 was alkylated with ethoxyethyl tosylate in the presence of sodium hydride and 15-crown-5 to produce polyether 215.

Scheme 55 outlines alternative synthesis of 4-alkoxythieno [2,3-c] pyridine via a phenolic alkylation procedure. 5-Chloro-3-hydroxypyridine was mitsunobuylated to provide benzyl ether 216 which was deprotonated with an alkyl lithium base and the resulting anion was treated with methyl formate to yield pyridine carboxaldehyde 217. The preparation of the thienopyridine nucleus was carried out by condensation with methyl thioglycolate under the above-mentioned conditions, and as a result, ester 218 was obtained. This method was also applied to other alkyl ethers similar to 216 to yield a variety of 4-alkoxy derivatives related to 218. The ester 218 was then converted to another active derivative such as an amide using the procedure described above. The benzyl ether 218 was hydrogenolyzed with phenol 219 and then converted to the corresponding amide 220 according to standard procedures. Phenol 219 also acts as a partner in the Mitsunobu reaction using various primary or secondary alcohols to provide the alkyl ether of formula 221 (Huang, F., et al., J. Med. 1998, 41, 4216 -4223). The ester of formula 221 was converted to the amide of formula 222 by treatment with a methanolic amine solution under standard refluxing conditions.

A thienopyridine analog having a 4-carbonyl group can be prepared according to the procedure described in Scheme 56. [ Dichloropyridine aldehyde 18 was treated with methyl thioglycolate under the conditions described above to give 4-chlorothienopyridine ester 223. The acid 224 was subjected to base catalysed hydrolysis transesterification and tert-butyl esterification was performed on 225 using O-t-butyl trichloroacetimidate under Lewis acid catalysis. Palladium catalyzed carbethoxylation proceeded under the conditions described above to give the diester 226. The aldehyde 227 was obtained by reduction / oxidation reaction and then condensed with an aryl magnesium halide reagent (as in the above example using 4-chlorophenylmagnesium chloride) to give alcohol 228. Ester 228 can be converted directly into various di-substituted thienopyridine analogs or oxidized to the corresponding 4-keto derivatives 230. Standard synthesis of ester 230 with amide 231 is complete. Obviously, the ester 226 is firstly subjected to an alkali hydrolysis of the ethyl ester, followed by coupling to an amine, followed by acidic hydrolysis of the tert-butyl ester, followed by coupling to another amine to selectively convert it to an amide derivative 308 can be generated.

A variety of 2-substituted thieno [2,3-c] pyridines can be readily obtained from the 2-esters of formulas 20 and 25. Scheme 57 illustrates the product obtainable from the hydroxymethyl derivative of formula 232. The ester of formula 20 or 25 was reduced to calcium borohydride to give the alcohol of formula 232. 233 < RTI ID = 0.0 > aldehyde < / RTI > This volatile intermediate can be converted to an olefin under standard bithigic conditions as illustrated by the preparation of 2-vinylthienopyridine of formula 234 (Hibino, S.J.Org. Chem. 1984, 49, 5006-5008). Further modification with dihydroxyethyl compound 235 was carried out using catalytic osmium tetroxide with 4-methylmorpholine N-oxide as the stoichiometric oxidizing agent.

Scheme 58 illustrates a method of converting aldehyde 233 to acrylate 236, achieved by Horner-Emmons condensation with trimethylphosphonoacetate (Jung, ME and Kiankarami, MJ Ogg. Chem. 1998, 63, 2968-2974). This method can also be applied to analogues having various C4 substituents, including aryloxy, alkoxy, arylamino, aryl, alkyl. The derived ester 236 was then hydrolyzed to give the acid 237. Carboxylic acid 237 was treated under standard coupling conditions to give amide 238. [ The resulting acrylate of formula 239 can be oxidized to the corresponding diol of formula 240 by catalytic osmium tetroxide in the presence of 4-methylmorpholine-N-oxide.

Scheme 59 illustrates the use of L _{A A} = aryloxy aldehyde 233 as the starting material for preparing the oxime derivative of formula 241. This method is generally applicable to analogues with various L _A X _A substituents. In addition, the aldehyde of formula (233) reacted with an organomagnesium (or organolithium) reagent to produce a secondary alcohol, which upon oxidation oxidized to the corresponding ketone of formula (242). Oxidation is preferably carried out under standard Suwon conditions (treatment with oxalyl chloride and DMSO in CH ₂ Cl ₂ solution at low temperature followed by treatment with a tertiary amine such as ethyldiisopropylamine), but under different conditions (tetra- propyl perruthenate, manganese dioxide) may also be used. The ketone can then be converted to the oxime of formula 243 by the methods described above.

Scheme 60 illustrates the preparation of 2-heterocyclic thienopyridine of formula (249). The primary amide of Formula 26 was treated with trifluoroacetic anhydride in excess of pyridine to readily produce the nitrile of Formula 244, which served as a convenient intermediate in the preparation of amidine and azole derivatives. Thus, the nitrile of formula 244 was converted to the amide oxime of formula 245 by treatment with hydroxylamine hydrochloride and triethylamine. The amide oxime of formula 245 is reacted with acetyl chloride, trifluoroacetic anhydride, triethyl orthoformate or trichloroacetyl chloride in pyridine to give oxadiazole of formula 246, where X is varied depending on the choice of acylating agent / Respectively. Trichloromethyloxadiazole (X = CCl ₃ ) of formula 246 was converted with heating to ammonia in a sealed tube to the 5-amino-1,2,4-oxadiazole of formula 247. Also, the nitrile of formula 244 was converted to cyanoamidine of formula 248 when treated with cyanamide in excess THF using DBU as the base. The cyanoamidine of formula 248 was then treated with triethylamine and hydroxylamine hydrochloride in methanol to give 3-amino-1,2,4-oxadiazole of formula 249.

Scheme 61 illustrates the preparation of 2-arylcarbonylthienopyridine. The thienopyridine of formula 44 was deprotonated with an alkyl lithium base and condensed with nitrobenzaldehyde to give benzyl alcohol of formula 250. Nitrophenyl was reduced to the aniline of formula 251 by tin (II) derivatization followed by selective alcohol oxidation with pyridinium chlorochromate. The nitrobenzyl alcohol of formula 250 was converted to the corresponding ketone of formula 253 under supernatant conditions (e.g., treatment with oxalyl chloride / DMSO / CH ₂ Cl ₂ at low temperature followed by treatment with an amine base).

Scheme 62 illustrates the preparation of 2-carbamate thienopyridine and 2-ureaethienopyridine. The alcohol of formula (232) was converted to the amine of formula (254) by Mitsunobu reaction with phthalimide followed by deprotonation with hydrazine. The amine of formula 254 was converted to the corresponding urea of formula 255 by reaction with potassium isocyanate under acidic conditions. Similarly, the alcohol of formula 232 was converted to the corresponding carbamate of formula 256. This chemistry is generally applicable to the production of mono- or disubstituted carbamates or ureas using substituted isocyanates or carbamoyl chlorides.

Scheme 63 illustrates the preparation of 2-thiourethienopyridine using 2-aminothiopyridine of formula 54 as a starting material. Reaction of 54 with a substituted isothiocyanate in pyridine at reflux gave the thiourea of formula 257.

Scheme 64 illustrates the synthesis of the sulfonamides at the 2-position of thienopyridine. As an improved method of decarboxylating thienopyridine-2-carboxylic acid, the acid of formula 21 was heated in 210 [deg.] C in the presence of thienopyridine of formula 44 in high yield. Compound 44 was deprotonated with a strong base and then treated with sulfur dioxide to give the intermediate sulfinic acid. N-chlorosuccinimide was added to obtain the sulfonyl chloride of formula 258, from which it was reacted with ammonia, a primary or secondary amine in the presence of diisopropylethylamine in a proton solvent such as methanol to give the various sulfone of formula 259 (Prugh, JD, et al., J. Med. Chem. 1991, 34, 1805-1818; Davidsen, SK, et al. J. Med. Chem. 1998, 41, 74-95).

Scheme 65 outlines the synthesis of another 2-arylthienopyridine having an amino or hydroxy group on the aryl ring. Using the method of Scheme 24, the boronic acid of formula 79 was Suzuki coupling reaction with the nitro substituted aryl iodide to yield the biaryl of formula 260. The biaryl of formula 260 was reduced to the aminophenyl derivative of formula 261 using tin (II) chloride. Coupling of boronic acid 79 with methoxy iodobenzene gave the methyl ether of formula 262, which was then demethylated with boron tribromide to give the hydroxy derivative of formula 263.

Scheme 66-71 illustrates the synthesis of another 5-membered heterocycle at the 2 position of thienopyridine. Scheme 66 outlines a method for producing 1,3,4-oxadiazole. The hydrazine of formula 264 was prepared by treating the ester of formula 20 or 25 with hydrazine in methylene chloride. This hydrazide was converted to the 5-amino-1,3,4-oxadiazole of formula 265 by reaction with cyanogen bromide. The hydrazide of formula (264) can be converted to a 5-unsubstituted or 5-alkyl substituted -1,3,4-oxadiazole of formula (266) by condensation with orthoether under reflux conditions.

Scheme 67 illustrates a method for preparing 1,3,4-triazole from the methyl esters of formulas 20 or 25. Amino-1,3,4-triazole of formula 267 was condensed with aminoguanidine under basic conditions (e.g., using sodium methoxide in methanol). The 1,3,4-triazole of formula 267 was subjected to non-specific methylation using sodium hydride and methyl iodide to give the monomethyl triazole of formula 268, dimethyltriazole of formula 269 and trimethyl triazole of formula 270, These were chromatographically separable.

Scheme 68 illustrates a method for preparing 1,3,4-thiadiazole of formula 272. Acid chloride derived from an acid of formula 21 or 28 is reacted with a thiosemicarbazide or a substituted thiomethylcarbazide to provide the intermediate acylated thiosemicarbazide of formula 271 which is reacted with an acid catalyst such as , Methane sulfonic acid in refluxing toluene) to give the thiadiazole of formula (272).

Scheme 69 refers to the preparation of the alkyl thio substituted oxadiazole of Formula 274 and 1,3,4-oxadiazole-2-thione. Hydrazide of Formula 264 was treated with carbon disulfide in potassium hydroxide in aqueous ethanol to provide the cyclic thiocarbamate of Formula 273. The thiocarbonyl group was alkylated in low yield using an alkyl halide to give the alkylthio 1,3,4-oxadiazole of formula 274.

Scheme 70 illustrates the preparation of a tetrazole at the 2-position of thienopyridine. The 2-cyano derivative of formula 244 was converted to the tetrazole of formula 275 using trimethylsilyl azide in the presence of dibutyl tin oxide. This tetrazole was converted to the N-methyl derivative of formula 276 using a diazomethane solution in methanol.

Scheme 71 illustrates the synthesis of 2-oxazole and 2-imidazoline thienopyridine. The chloroethyl amide of formula 277 was prepared by chlorinating the corresponding hydroxyethyl amide followed by cyclization to the oxazoline of formula 278 under a basic catalyst (e. G., Diazabicyclo dodecane in dichloromethane). The oxazoline of formula 278 can be dehydrogenated according to the procedure of Meyers, A. I., et al. J. Amer. Chem. The aminoethylamide of formula 280 was cyclized to the imidazoline of formula 281 by treatment with calcium oxide at elevated temperature in diphenyl ether. Imidazoline of formula 281 can be converted to imidazole of formula 282 by the method of Hughey, J. L. et al., Synthesis (SYNTBF) 1980, (6), 489.

Scheme 72 illustrates an improved process for preparing 3-alkyl substituted thienopyridines of formula 115. Aldehyde 18 was condensed with the pre-prepared potassium phenoxide to give a mono-substituted and disubstituted aryloxy aldehyde mixture. This mixture was then reacted with the requisite Grignard reagent, and then the resulting mixture of secondary alcohols was subjected to Suwn Oxidation to obtain the desired aryloxy ketone compound. The aryloxy ketone mixture was further reacted with methyl thioglycolate in the presence of cesium carbonate to obtain 2,3,4-trisubstituted thieno [2,3-c] pyridine ester of formula 114. This ester was hydrolyzed to the corresponding acid by lithium hydroxide and then the acid was coupled with various amines such as carbodiimide to give the desired amide of formula 115.

Scheme 73 illustrates the synthesis of 3-carboxytithienopyridine. 3,5-Dichloropyridine was treated with a strong base such as lithium diisopropylamide in an anhydrous ether solvent at low temperature using a method analogous to that outlined for compound 20 or 25, followed by the addition of t-butyl chlorooxoacetate Tert-butyl-2-keto ester 283 of 3,5-dichloropyridine. This ester 283 was reacted with 1.25 equivalents of potassium phenoxide preliminarily prepared at room temperature to obtain a monoaryloxy derivative as the main product. Without purification, the monoaryloxyester was treated with a base such as potassium t-butoxide or cesium carbonate and methyl thioglycolate to give the target thienopyridine diester of formula 284. [ The diester of formula 284 was then treated with a methanolic amine to give the corresponding 3- tert -butyl ester amide of formula 285. The tert-butyl ester amide of formula (285) was solvolyzed with trifluoroacetic acid to give the corresponding acid amide of formula (287). In addition, the diester of formula (284) can be converted to an acid of formula (286) by a similar solvolysis reaction.

Scheme 74 illustrates a method for preparing a 4-amino substituted thienopyridine derivative using 4-bromothienopyridine 32. The ester 32 was converted to the amide of formula 288 by standard procedures and then purified by the method of Buchwald, J. Org. Chem. 1997, 62, 6066-6068, using palladium (0) catalyst to give the 4-amino derivatives of formula (289).

Scheme 75 outlines the preparation and reaction of 7-chloro and 7-bromothienopyridine derivatives. This analog is not only useful as a synthetic intermediate for various 7-substituted thienopyridines, but also useful for preparing active derivatives. The ester of formula 25 was oxidized with pyridine-N-oxide of formula 290 using metachloroperbenzoic acid. The N-oxide was warmed in phosphorus pentachloride or phosphorus pentachloride and rearranged into the 7-halo derivative of formula 291. The resulting 7-halide can be converted to the amide derivative of formula 292 by standard methods without reacting 7-chloro or 7-bromo. However, under more stringent conditions, the chloro or bromo group may be substituted with an amine or an alcohol to give the 7-amino derivative of formula 293 and the 7-alkoxy derivative of formula 294, respectively. The ester of formula 294 was converted to the amide of formula 295 using standard methods. The 7-hydroxy analog of formula 296 was prepared by hydrolysis of 291 derivative with acetic anhydride followed by water. In addition, the 7-halo derivative 291, particularly the 7-bromo derivative, acted as an effective extract in the Suzuki reaction with aryl boronic acids, similar to that described in Schemes 19 and 65.

Scheme 76 illustrates the preparation of furopyridine analogs such as 299 (Example 327). 20 or 25, dichloropyridine carboxaldehyde 18 was then reacted with potassium phenoxide, then ethyl glycolate, and then cyclized under basic conditions to give the furopyridine ester 298 in an amount of yield. Standard hydrolysis and coupling conditions provided amide 299. This amide was converted to the thioamide 300 by treatment with a Loewess reagent in hot toluene.

Scheme 77 illustrates the preparation of N-alkyl 5-amino-1,3,4-oxadiazole. After treatment of 265 in refluxing trimethylorthoformate, the enamine intermediate was reduced with sodium borohydride in refluxing ethanol to yield the N-alkylated 5-amino-1,3,4-oxadiazole of Formula 301.

Scheme 78 illustrates the synthesis of a substituted vinyl moiety at the 4-position of thienopyridine. Aldehyde 227 was treated with the appropriate diethylphosphonate in the presence of potassium bis (trimethylsilyl) amide to give 302. Compound 302 was then treated with sulfuric acid in methanol to give methyl ester 303, followed by standard amide formation with ammonia and methanol to give 4-vinyl substituted thienopyridine of formula 304. The substitution of the substituted vinyl can be completed by bithiogaphosphorane chemistry.

Scheme 79 illustrates the preparation of 4-substituted alkylthienopyridines. Alcohol 228 was treated with palladium on carbon in acetic acid to produce methylene hexafluoride 305. 305 was treated with sulfuric acid in methanol to give 306. Amide formation was carried out by treatment with ammonia in methanol to give 307.

Scheme 80 illustrates the preparation of a thiazole derivative at the 2-position of thienopyridine. The thioamide of formula 309 was alkylated and cyclized with ethyl bromopyruvate to give the thiazole ester of formula 310. Standard amide formation gave the amide of formula 311. Other amines were used to generate various substituted amides. Alternatively, the ester of formula 310 can be converted to the carbamate of formula 312 via a crotch rearrangement of the intermediate acid. The tert-butyl carbamate of formula 312 can be converted to the primary amine of formula 313 by the action of trifluoro acetic acid.

Scheme 81 outlines an alternative method for preparing 3-substituted thienopyridines, wherein Ar = unsubstituted or substituted aryl, or heterocycle, R = alkyl, alkoxy, substituted alkyl, aryl, arylalkyl will be. Aldehyde 18 was reacted with the appropriate organomagnesium halide to give the intermediate secondary alcohol and was oxidized to the corresponding ketone 314. As the oxidation method, the Suwon procedure is used and other standard oxidation methods of this type (eg PCC, TPAP) can be used. The procedure follows the procedure described above for the 3-unsubstituted analog to give the ester 315. Ester 315 was provided as starting material for the preparation of other heterocyclic derivatives or amides at the 2-position of thienopyridine.

Scheme 82 illustrates a method for preparing cyclic derivatives of 2-position and 3-position of thienopyridine. 3-methyl derivative 115 was treated with N-bromosuccinimide (or alternatively N-chlorosuccinimide) in carbon tetrachloride to give bromomethyl (or chloromethyl) compound 316 (X = Br, Cl). Compound 316 was then reacted with the primary amine to alkylate and acylate to give the tricyl lactam 317. Compound 316 was then treated with sodium alkoxide or aryl oxide (R ² = alkyl, aryl or heterocycle) to yield a 3-position extended alkoxymethyl derivative 318. This ester can also be reacted with a substituted amine to produce the corresponding amide 319.

The compounds and methods of the present invention are described in detail in the following examples, which are illustrative and do not limit the scope of the present invention.

Example 1

Methyl 2 - [(6-ethylthieno [2,3-d] pyridin-4-yl) thio] acetate

Example 1A

Methyl 6-ethyl-3,4-dihydro-4-oxothieno [2,3-d] pyrimidine-

The desired compound was prepared according to J. Heterocyclic Chem. 1987, 24, 581-587.

Example 1B

6-ethylthieno [2,3-d] pyrimidin-4 (3H) -one

Example 1A (35 g, 140 mmol) and LiCl (6.5 g, 153 mmol) in DMSO (80 mL) and water (8 mL) was heated at 150 < 0 > C for 18 h, cooled to room temperature, diluted with water and extracted with ethyl acetate Respectively. The extract was dried (MgSO ₄ ), filtered, and concentrated to obtain the desired compound.

Example 1C

4-Chloro-6-ethylthieno [2,3-d] pyrimidine

Example IB (3.97 g, 22.0 mmol) in POCl ₃ (22 mL) was heated at reflux for 2 hours, cooled, added to ice, diluted with water and then basified with concentrated ammonium hydroxide, Acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 10% ethyl acetate-hexane to give the title compound.

Example 1D

Methyl 2 - [(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate

Example 1C (0.25 g, 1.26 mmol) in DMF (1.2 mL) was successively treated with methyl thioglycolate (0.134 g, 1.26 mmol) and potassium carbonate (0.174 g, 1.26 mmol) and stirred at room temperature for 18 h Then it was cooled, added to water, diluted with brine and extracted with dichloromethane. The extract was washed with water and brine, dried (MgSO ₄₎ then filtered and concentrated. The residue was triturated and then washed with 10% ethyl acetate / hexanes to give the title compound.

mp 36-58 [deg.] C;

_{MS (DCI / NH 3) m} / z 269 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.33 (t, 3H), 2.99 (q, 2H), 3.75 (s, 2H), 4.26 (s, 3H), 7.23 (s, 1H), 8.76 (s , 1H).

Example 2

6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine

Example 1C was performed as in Example 1D but using thiocresol instead of methyl thioglycolate to give the title compound.

mp 56-58 C;

_{MS (DCI / NH 3) m} / z 286 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.32 (t, 3H), 2.38 (s, 3H), 2.99 (q, 2H), 7.20 (s, 1H), 7.33 (m, 2H), 7.52 (m , ≪ / RTI > 2H), 8.63 (s, 1H);

Elemental analysis for C ₁₅ H ₁₄ N ₂ S ₂ :

Calculated: C, 62.90; H, 4.93; N, 9.78

Found: C, 63.11; H, 4.82; N, 9.63.

Example 3

6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine

Example 1C was performed as in Example 1D but using 2-mercaptopyridine instead of methyl thioglycolate to give the title compound.

mp 76.5-79 < 0 >C;

_{MS (DCI / NH 3) m} / z 274 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.31 (t, 3H), 2.99 (q, 2H), 7.18 (s, 1H), 7.46 (dt, 1H), 7.81 (d, 1H), 7.90 (dt , ≪ / RTI > 1H), 8.60 (m, 1H), 8.74 (s, 1H).

Example 4

6-ethyl-4 - [(2-methylethyl) thio] thieno [2,3-d] pyrimidine

Example 1C was performed as in Example 1D but using isobutyl mercaptan instead of methyl thioglycolate to give the title compound.

_{MS (DCI / NH 3) m} / z 253 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.08 (d, 6H), 1.39 (t, 3H), 2.03 (hep, 1H), 2.95 (q, 2H), 3.28 (d, 2H), 7.01 (s , ≪ / RTI > 1H), 8.71 (s, 1H);

Elemental analysis for C ₁₂ H ₁₆ N ₂ S ₂ :

Calculated: C, 57.12; H, 6.38; N, 11.09

Found: C, 57.22; H, 6.29; N, 11.08

Example 5

6-ethyl-4 - [(phenylmethyl) thio] thieno [2,3-d] pyrimidine

Example 1C was performed as in Example 1D but replacing methylthioglycolate with benzylmercaptan to give the title compound.

mp 54-60 C;

_{MS (DCI / NH 3) m} / z 287 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.30 (t, 3H), 2.96 (q, 2H), 4.65 (s, 2H), 7.16 (s, 1H), 7.21-7.36 (m, 3H), 7.46 (m, 2 H), 8.83 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₄ N ₂ S ₂ :

Calculated: C, 62.90; H, 4.93; N, 9.78

Found: C, 62.11; H, 4.94; N, 9.71

Example 6

6-ethyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3-d] pyrimidine

Example 1C was performed as in Example 1D but using 5-methyl-1,3,4-thiadiazole-2-thiol instead of methyl thioglycolate to give the title compound.

mp 132-135 占 폚;

_{MS (DCI / NH 3) m} / z 295 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.35 (t, 3H), 2.82 (s, 3H), 3.05 (q, 2H), 7.42 (s, 1H), 8.88

Elemental analysis for C ₁₁ H ₁₀ N ₄ S ₃ :

Calculated: C, 44.88; H, 3.42; N, 19.03

Found: C, 44.61; H, 3.47; N, 18.92

Example 7

Ethyl 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine-

Example 1A was performed as in Examples 1C and 2 to give the title compound.

mp 87.5-90 < 0 >C;

_{MS (DCI / NH 3) m} / z 359 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.26 (t, 3H), 1.31 (t, 3H), 2.39 (s, 3H), 3.02 (q, 2H), 4.27 (q, 2H), 7.17 (s , 7.35 (m, 2H);

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₂ S ₂ :

Calculated: C, 60.31; H, 5.06; N, 7.81

Found: C, 60.44; H, 4.88; N, 7.65

Example 8

Ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidin-4-amine

A solution of Example 1C (0.27 g, 1.37 mmol) in isopropanol (1.5 mL) was treated with benzylamine (0.19 mL, 1.71 mmol) and sodium carbonate (0.24 g, 2.3 mmol) and stirred at room temperature overnight, . The residue was purified by flash chromatography on silica gel using 25% ethyl acetate / hexanes to give the title compound.

mp 128-113 C;

_{MS (DCI / NH 3) m} / z 270 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.30 (t, 3H), 2.88 (q, 2H), 4.72 (d, 2H), 7.20-7.40 (m, 6H), 8.26 (s, 1H), 8.34 (t, 2H);

Elemental analysis for C ₁₅ H ₁₅ N ₃ S ₂ :

Calculated: C, 66.89; H, 5.61; N, 15.60

Found: C, 66.66; H, 5.43; N, 15.43

Example 9

Thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine (5-methyl-

A solution of Example 1C (0.27 g, 1.37 mmol) in isopropanol (1.5 mL) was treated with 2-amino-5-methyl-1,3,4-thiadiazole (0.15 g, 1.27 mmol) , Treated with cesium carbonate (0.55 g, 1.7 mmol), refluxed for 24 hours, concentrated and then treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄₎ and filtered and concentrated. The residue was recrystallized from ethanol / water to give the title compound.

mp 277-280 占 폚;

_{MS (DCI / NH 3) m} / z 278 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.33 (t, 3H), 2.63 (s, 3H), 2.96 (q, 1H), 7.81 (brs, 1H), 8.65

Elemental analysis for C ₁₁ H ₁₁ N ₅ S ₂ :

Calculated: C, 47.63; H, 4.00; N, 25.25

Found: C, 47.48; H, 3.68; N, 24.89

Example 10

4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-ethyl- 2- (phenylmethyl) thieno [2,3- d] pyrimidine

Example 10A

2-Amino-5-ethylthiophene-3-carboxamide

Label compounds are described in J. Heterocyclic Chem. 1987, 24, pp. 581-587.

Example 10B

5-ethyl-2 - [(phenylacetyl) amino] -3-thiophenecarboxamide

Example 10A was prepared as described in Bull. Soc. Chim. France 1975, p.815] to give the title compound.

Example 10C

6-ethyl-2-phenylmethylthieno [2,3-d] pyrimidin-4 (3H)

Stirred for Example 10B in dioxane / water in the presence of 10% Na ₂ CO _3, to obtain the title compound.

Example 10D

4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine

Example 10C was treated as in Example 1C to give the title compound.

Example 10E

4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-ethyl- 2- (phenylmethyl) thieno [2,3- d] pyrimidine

Example 10D and 5-amino-l, 3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound.

_{MS (DCI / NH 3) m} / z 386 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.31 (t, 3H), 2.97 (q, 2H), 4.17 (s, 2H), 7.17-7.30 (m, 6H), 7.70 (br s, 2H);

Elemental analysis for C ₁₇ H ₁₅ N ₅ S ₃ :

Calculated: C, 52.96; H, 3.92; N, 18.17

Found: C, 53.10; H, 3.74; N, 18.03

Example 11

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine

Methyl-7-chlorothieno [3,2-d] pyrimidine was used as in Example 1D, except that p-thiocresol was used instead of methyl glycolate to give the title compound.

mp 103-107 C;

_{MS (DCI / NH 3) m} / z 273 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.40 (s, 6H), 7.36 (m, 2H), 7.57 (m, 2H), 8.04 (s, 1H), 8.88 (s, 1H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 61.73; H, 4.44; N, 10.28

Found: C, 61.73; H, 4.50; N, 10.21

Example 12

Methyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [3,2-d] pyrimidine

3-methyl-7-chlorothieno [3,2-d] pyrimidine and 5-methyl-1,3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound.

mp 144-147 占 폚;

_{MS (DCI / NH 3) m} / z 281 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.44 (s, 3H), 2.83 (s, 3H), 8.20 (s, 1H), 9.08

Elemental analysis for C ₁₀ H ₈ N ₄ S ₃ :

Calculated: C, 42.84; H, 2.88; N, 19.98

Found: C, 47.72; H, 2.83; N, 19.64

Example 13

7-methyl-4 - [[5- (methylthio) -1,3,4-thiadiazol-2-yl] thio] thieno [3,2- d] pyrimidine

3-methyl-7-chlorothieno [3,2-d] pyrimidine and 5- (methylthio) -1,3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound ≪ / RTI >

mp 163-166 < 0 >C;

_{MS (DCI / NH 3) m} / z 313 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.45 (s, 3H), 2.83 (s, 3H), 8.22 (s, 1H), 9.11 (s, 1H);

Elemental analysis for C ₁₀ H ₈ N ₄ S ₄ :

Calculated: C, 38.44; H, 2.58; N, 17.93

Found: C, 38.46; H, 2.63; N, 17.82

Example 14

4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -7-methylthieno [3,2-d] pyrimidine

3-methyl-7-chlorothieno [3,2-d] pyrimidine and 5-amino-1,3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound.

mp 221-223 [deg.] C;

_{MS (DCI / NH 3) m} / z 282 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 2.43 (s, 3H), 7.80 (br s, 2H), 8.15 (s, 1H), 9.02

Elemental analysis for C ₉ H ₇ N ₅ S ₃ :

Calculated: C, 38.42; H, 2.51; N, 24.89

Found: C, 38.41; H, 2.42; N, 24.97

Example 15

7-methyl-N - [(4- (methylthio) phenyl] thieno [3,2- d] pyrimidin-

A solution of 3-methyl-7-chlorothieno [3,2-d] pyrimidine dissolved in ethanol was treated with 4- (methylmercapto) aniline, refluxed for 45 minutes, cooled at room temperature, . The precipitate was recrystallized from ethanol / water to give the title compound.

mp 212-215 C;

_{MS (DCI / NH 3) m} / z 288 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.37 (s, 3H), 2.48 (s, 3H), 7.29 (m, 2H), 7.76 (m, 2H), 7.87 (br s, 1H), 8.60 ( s, 1 H), 9.63 (br s, 1 H);

Elemental analysis for C ₁₄ H ₁₃ N ₃ S ₂ :

Calculated: C, 58.51; H, 4.56; N, 14.62

Found: C, 58.31; H, 4.49; N, 14.47

Example 16

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2- d] pyrimidine-6- carboxamide

Example 16A

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2- d] pyrimidine-

A solution of LDA (0.1 M in THF, 9.6 ml) was treated with Example 11 (0.26 g, 0.96 mmol) at -78 <0> C and warmed to 0 <0> C over 1 h, then added to dry ice under constant stirring, After quenching with saturated NH ₄ Cl, the mixture was extracted with 3: 1 chloroform / isopropanol. The extract was concentrated and the residue was purified by flash chromatography on silica gel using 7% methanol / dichloromethane to give the title compound.

Example 16B

7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine-

The suspension of Example 16A suspended in dichloromethane (3.3 mL) was treated successively with oxalyl chloride (0.03 mL, 0.33 mmol) and DMF (1 drop) and concentrated after formation of the acid chloride. The residue was suspended in THF (10 mL) and added to a vigorously stirred 1: 1 ammonium hydroxide / water (10 mL) solution and extracted with dichloromethane. The extract was dried (MgSO ₄₎ and filtered and concentrated. The residue was recrystallized from ethyl acetate / hexane to give the title compound.

mp 243-246 占 폚;

_{MS (DCI / NH 3) m} / z 316 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.40 (s, 3H), 2.58 (s, 3H), 7.35 (m, 2H), 7.57 (m, 2H), 8.01 (br s, 2H), 8.93 ( s, 1H);

Elemental analysis for C ₁₅ H ₁₃ N ₃ OS ₂ :

Calculated: C, 57.12; H, 4.15; N, 13.32

Found: C, 56.81; H, 4.06; N, 13.25

Example 17

Methyl 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

Example 17A

3,5-Dichloropyridine-4-carboxaldehyde

Diisopropylamine (15.6 mL, 0.111 mol) in anhydrous THF (15 mL, 0.111 mol) was treated with n-BuLi (44.6 mL, 2.5 M in hexane, 0.111 mol) at 0 ° C for 35 min and stirred for 30 min The mixture was cooled to -78 ° C and diluted with THF (100 ml). Then, a solution of 3,5-dichloropyridine (15.0 g, 0.101 mol) dissolved in THF (175 ml) The temperature was maintained at &lt; -74 deg. The solution was stirred at -78 <0> C for 30 min and methylformate (12.5 mL, 0.203 mmol) in THF (50 mL) was added dropwise over 35 min maintaining the internal temperature <-74 <0> Chemistry ℃ stirred at for 1.4 hours, rapidly into ice-cooling being strongly stirred saturated NaHCO ₃ solution and the injection cannula, and fractions with ethyl acetate (500㎖), saturated NaHCO ₃ in a row (2x100㎖), brine (3x150㎖) extracted and dried (MgSO ₄₎ a rear, and concentrated. The residue was purified by flash chromatography on silica gel using 10% acetone / hexanes.

_{MS (DCI / NH 3) m} / z 176, 178, 180 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 8.80 (s, 2H), 10.31 (s, 1H).

Example 17B

3- (4-methylphenylthio) -5-chloro-4-pyridinecarboxaldehyde

Example 17A (5.05 g, 28.7 mmol) in DMF (70 mL) was treated with p-thiocresol (3.56 g, 28.7 mmol) and potassium carbonate (4.36 g, 3.16 mmol) For 1 hour, then water was added, diluted with brine, and extracted with dichloromethane. The extract was washed successively with water and brine, dried (MgSO ₄ ), filtered and concentrated to give the title compound.

Example 17C

Methyl 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

The solution of Example 17B was treated as in Example 1D to give the title compound.

mp 116-119 占 폚;

_{MS (DCI / NH 3) m} / z 316 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 3.91 (s, 3H), 7.20 (m, 2H), 7.29 (m, 2H), 8.00 (s, 1H), 8.44 (s , &Lt; / RTI &gt; 1H), 9.36 (s, 1H);

Elemental analysis for C ₁₆ H ₁₃ NO ₂ S ₂ · 0.25H ₂ O:

Calculated: C, 60.07; H, 4.25; N, 4.37

Found: C, 60.04; H, 4.08; N, 4.27

Example 18

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

A suspension of Example 17C (2.0 g, 6.35 mmol) and LiOH.H ₂ O (1.4 g, 32 mmol) suspended in isopropanol (25 mL) and water (15 mL) was heated at 75 ° C for 1 hour, , Treated with water and washed with diethyl ether. The aqueous layer was cooled in an ice bath and adjusted to pH 2 using 10% HCl. The resulting solid was collected, washed with water, dried and recrystallized from ethanol / water to give the title compound.

mp 272-274 占 폚;

_{MS (DCI / NH 3) m} / z 302 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 7.20 (m, 2H), 7.28 (m, 2H), 7.92 (s, 1H), 8.44 (s, 1H), 9.34 (s , 1H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.78; H, 3.67; N, 4.64

Found: C, 59.48; H, 3.58; N, 4.54

Example 19

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

A suspension of Example 18 (0.535 g, 1.78 mmol) suspended in dichloromethane (25 mL) was successively treated with oxalyl chloride (0.34 g, 2.67 mmol) and DMF (1 drop) at 0 C and treated at room temperature for 0.5 h Stirred, and concentrated. The residue was suspended in THF and treated with THF (60 mL), water (30 mL) and concentrated NH ₄ OH (30 mL) and stirred for 0.5 h. Separating the THF layer, and then washed with brine, partially dried (MgSO _4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5% methanol / dichloromethane and recrystallized from 95% ethanol to give the title compound.

mp 198-199 [deg.] C;

_{MS (DCI / NH 3) m} / z 301 (M + NH 4) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.29 (s, 3H), 7.20 (m, 2H), 7.30 s, 1 H), 8.54 (br s, 1 H), 9.16 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.97; H, 4.02; N, 9.32

Found: C, 59.84; H, 4.12; N, 9.31

Example 20

4- (2-pyridinylthio) thieno [2,3-c] pyridine-2-carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C, 18 and 19 using 2-mercaptopyridine instead of p-thiocresol used in Example 17B.

mp 239-242 [deg.] C;

_{MS (DCI / NH 3) m} / z 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.99 (d, 1H), 7.17 (dd, 1H), 7.65 (dt, 1H), 7.85 (br s, 1H), 8.18 (s, 1H), 8.36 ( m, 1 H), 8.49 (br s, 1 H), 8.69 (s, 1 H), 9.23 (s, 1 H);

Elemental analysis for C ₁₃ H ₉ N ₃ OS ₂ :

Calculated: C, 54.34; H, 3.16; N, 14.47

Found: C, 54.10; H, 3.14; N, 14.62

Example 21

4 - [(4-chlorophenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

Example 17A was processed as in Example 17B, 17C, 18 and 19 using 4-chlorothiophenol instead of p-thiocresol used in Example 17B to give the title compound.

mp 239-241 [deg.] C;

_{MS (DCI / NH 3) m} / z 321 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.31 (m, 2H), 7.43 (m, 2H), 7.89 (br s, 1H), 8.24 (s, 1H), 8.54 (br s, 1H), 8.56 (s, 1 H), 9.38 (s, 1 H);

Elemental analysis for C ₁₄ H ₉ ClN ₂ OS ₂ :

Calculated: C, 52.42; H, 2.83; N, 8.73

Found: C, 52.33; H, 2.80; N, 8.63

Example 22

Methoxy-N-methyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide

A solution of Example 18 (0.66 g, 2.2 mmol) in dichloromethane was successively treated with oxalyl chloride (0.29 mL, 3.3 mmol) and DMF (1 drop), stirred for 30 min and then concentrated. The residue was suspended in THF and added to a solution of N, O-dimethylhydroxylamine hydrochloride (0.32 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) dissolved in 1: 1 THF / water, Stir for 5 minutes. Separating the THF layer, and the mixture was concentrated and dried (MgSO _4), filtered. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

mp 103-107 C;

_{MS (DCI / NH 3) m} / z 345 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.27 (s, 3H), 3.34 (s, 3H), 3.74 (s, 3H), 7.19 (m, 2H), 7.27 (m, 2H), 8.02 (s , &Lt; / RTI &gt; 1H), 8.46 (s, 1H);

Elemental analysis for C ₁₇ H ₁₆ N ₂ O ₂ S ₂ :

Calculated: C, 59.28; H, 4.68; N, 8.13

Found: C, 58.76; H, 4.58; N, 8.06

Example 23

Methoxy-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide

The title compound was obtained by treating Example 18 as in Example 22, but using O-methylhydroxylamine hydrochloride instead of N, O-dimethylhydroxylamine hydrochloride.

mp 200-203 C;

_{MS (DCI / NH 3) m} / z 331 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 3.76 (s, 3H), 7.20 (m, 2H), 7.30 (m, 2H), 7.89 (br s, 1H), 8.15 ( s, 1 H), 8.4 (s, 1 H), 9.3 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ O ₂ S ₂ .0.25H ₂ OC:

Calculated: C, 58.16; H, 4.27; N, 8.48

Found: C, 57.46; H, 4.1; N, 8.01

Example 24

N- (4-chlorophenyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide

A solution of Example 18 (0.1 g, 0.33 mmol) in dichloromethane was treated with oxalyl chloride (0.03 mL, 0.33 mmol) and DMF (1 drop), refluxed for 20 minutes and then concentrated. The residue was suspended in benzene / dichloromethane (3: 1) (4 mL), treated with triethylamine (0.5 mL) and 4-chloroaniline (46 mg, 0.36 mmol), stirred under reflux overnight, Lt; / RTI &gt; The residue was treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄ ) and filtered. The residue was purified by flash chromatography on silica gel with ethyl acetate / hexane to give the title compound.

mp 208-211 C;

_{MS (DCI / NH 3) m} / z 411 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 7.23 (m, 2H), 7.33 (m, 2H), 7.47 (m, 2H), 7.81 (m, 2H), 8.34 (s , 1H), 8.57 (s, IH), 9.31 (s, IH), 10.90 (br s, IH);

Elemental analysis for C ₁₂ H ₁₅ ClN ₂ OS ₂ :

Calculated: C, 61.38; H, 3.68; N, 6.82

Found: C, 61.22; H, 3.67; N, 6.79

Example 25

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde

A solution of Example 22 (3.33 g, 9.6 mmol) in THF was treated dropwise with 1M DIBA1-H in THF (14.5 mL, 14.5 mmol) at -5 ° C and stirred for 45 minutes, / HCl, and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated to give the title compound.

_{MS (DCI / NH 3) m} / z 303 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 7.22 (m, 2H), 7.34 (m, 2H), 8.40 (s, 1H), 8.48 (s, 1H), 9.38 (s , &Lt; / RTI &gt; 1H), 10.23 (s, 1H);

Elemental analysis for C ₁₅ H ₁₁ NOS ₂ :

Calculated: C, 63.13; H, 3.33; N, 4.91

Found: C, 62.81; H, 3.97; N, 5.01

Example 26

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O-

A solution of Example 25 (0.22 g, 0.76 mmol) in 1: 1 pyridine: ethanol (8 mL) was treated with methoxylamine hydrochloride (0.51 mL, 1.52 mmol) and stirred at room temperature for 3 hours, Concentrated, treated with water and then extracted with dichloromethane. The extract was washed with 1N HCl, dried (MgSO ₄₎ a rear, filtered and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

mp 95-98 C;

_{MS (DCI / NH 3) m} / z 315 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 3.95 (s, 1.8H), 4.08 (s, 1.2H), 7.18 (m, 2H), 7.25 (m, 2H), 7.79 (s, 0.6H), 7.95 (s, 0.4H), 8.27 (s, 0.4H), 8.36 , &Lt; / RTI &gt; 0.6H), 9.30 (s, 0.4H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ OS ₂ :

Calculated: C, 61.12; H, 4.49; N, 8.91

Found: C, 60.93; H, 4.55; N, 8.98

Example 27

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- (phenylmethyl) oxime

Example 25 and O-benzylhydroxylamine hydrochloride were treated as in Example 26 for 18 hours instead of 3h to give the title compound.

mp 127-133 [deg.] C;

_{MS (DCI / NH 3) m} / z 391 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.27 (s, 3H), 5.22 (s, 1.2H), 5.38 (s, 0.8H), 7.15-7.26 (m, 4H), 7.31-7.47 0.6H), 8.74 (s, 0.6H), 7.96 (s, 0.4H), 8.31 (s, , 9.20 (s, 0.6H), 9.30 (s, 0.4H);

Elemental analysis for C ₂₂ H ₁₈ N ₂ OS ₂ :

Calculated: C, 67.66; H, 4.65; N, 7.17

Found: C, 67.45; H, 4.80; N, 7.13

Example 28

2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid &lt; EMI ID =

Example 25 was treated as in Example 26 using carboxymethoxylamine hemi hydrochloride instead of methoxylamine hydrochloride to give the title compound.

mp 227-230 占 폚;

_{MS (DCI / NH 3) m} / z 359 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 4.71 (s, 2H), 7.19 (m, 2H), 7.25 (m, 2H), 7.84 (s, 1H), 8.36 (s , &Lt; / RTI &gt; 1H), 8.79 (s, 1H), 9.20 (s, 1H);

Elemental analysis for C ₁₇ H ₁₄ N ₂ O ₃ S ₂ :

Calculated: C, 56.97; H, 3.94; N, 7.82

Found: C, 56.90; H, 4.10; N, 7.97

Example 29

4- [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxaldehyde, O-

Example 25 was treated as in Example 26 using O-phenylhydroxylamine hydrochloride instead of methoxylamine hydrochloride to give the title compound.

mp 94-97 C;

_{MS (DCI / NH 3) m} / z 377 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 2.38 (s, 3H), 7.09-7.50 (m, 9H), 7.98 ), 8.42 (s, 0.5H), 8.71 (s, 0.5H), 9.16 (s, 0.5H), 9.27 (s, 0.5H), 9.37 (s, 0.5H);

Elemental analysis for C ₂₁ H ₁₆ N ₂ OS ₂ :

Calculated: C, 67.00; H, 4.28; N, 7.44

Found: C, 67.14; H, 4.50; N, 7.57

Example 30

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, oxime

Example 25 was treated as in Example 26 using hydroxylamine hydrochloride instead of methoxylamine hydrochloride to give the title compound.

mp 209-210 C;

_{MS (DCI / NH 3) m} / z 301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 7.18 (m, 2H), 7.70 (s, 0.3H), 7.87 (s, 0.7H), 8.19 (s, 0.7H), 8.35 (s, 0.3H), 8.38 (s, 0.7H), 8.56 (s, 0.3H), 9.17 (s, 0.3H), 9.27 (s, 0.7H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.98; H, 4.03; N, 9.33

Found: C, 59.80; H, 4.08; N, 9.30

Example 31

2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide

Example 28 was treated as in Example 19 to give the title compound.

mp 152-156 C;

_{MS (DCI / NH 3) m} / z 358 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.27 (s, 3H), 4.52 (s, 0.6H), 4.66 (s, 0.4H), 7.19 (m, 2H), 7.25 (m, 2H), 7.32 (s, 0.6H), 8.40 (s, 1H), 7.40 (s, 1H), 7.40 , 0.4H), 8.75 (s, 0.6H), 9.21 (s, 0.6H), 9.32 (s, 0.4H);

Elemental analysis for C ₁₇ H ₁₅ N ₃ O ₂ S _2. (1.25H ₂ O):

Calculated: C, 57.12; H, 4.23; N, 11.76

Found: C, 56.19; H, 4.48; N, 10.94

Example 32

(E) -3 - [(4-methylphenyl) thio] thieno [2,3-c] pyridin-

Example 25 (0.23 g, 1.27 mmol) in chloroform (10 mL) was treated with carbamoylmethylene triphenylphosphorane (0.41 g, 1.27 mmol) and heated at reflux for 30 min, cooled and concentrated. The residue was purified by flash chromatography on silica gel using 2% methanol / dichloromethane to give the title compound.

mp 171-174 &lt; 0 &gt;C;

_{MS (DCI / NH 3) m} / z 327 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 6.64 (d, 1H), 7.19 (m, 2H), 7.25-7.37 (m, 3H), 7.68-7.82 (m, 3H) , 8.35 (s, 1 H), 9.19 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₄ N ₂ OS ₂ .H ₂ O:

Calculated: C, 62.55; H, 4.32; N, 8.58

Found: C, 59.78; H, 4.50; N, 8.20

Example 33

Thieno [2,3-c] pyridin-2-yl] ethanone

A solution of Example 22 dissolved in THF (25 mL) was treated with magnesium bromide (1.4 M in toluene / THF, 1.85 mL, 2.6 mmol) at 0 ° C, warmed to room temperature and stirred overnight, Was treated with bromide (1.4 M in toluene / THF, 0.7 mL, 1.3 mmol), stirred for 1 hour, added to ice / NH ₄ Cl under constant stirring, and extracted with ethyl acetate. The extracts were dried (MgSO ₄₎ and concentrated by filtration and back. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexanes to give the title compound.

mp 134-138 占 폚;

_{MS (DCI / NH 3) m} / z 317 (M + NH 4) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.33 (s, 3H), 2.71 (s, 3H), 7.24 (m, 2H), 7.38 (m, 2H), 8.28 (s, 1H), 8.31 (s , &Lt; / RTI &gt; 1H), 9.29 (s, 1H);

Elemental analysis for C ₁₆ H ₁₃ NOS ₂ :

Calculated: C, 64.19; H, 4.38; N, 4.68

Found: C, 64.11; H, 4.41; N, 4.61

Example 34

Benzoyl-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine

Example 22 and phenyllithium were treated as in Example 33 to give the title compound.

mp 103-107 C;

_{MS (DCI / NH 3) m} / z 362 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.33 (2, 3H), 7.26 (m, 4H), 7.57 (m, 2H), 7.71 (m, 4H), 8.49 (s, 1H), 9.40 (s , 1H);

Elemental analysis for C ₂₁ H ₁₅ NOS ₂ · 1.25 H ₂ O:

Calculated: C, 65.68; H, 4.59; N, 3.64

Found: C, 65.67; H, 4.09; N, 3.46

Example 35

2-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine

A solution of Example 33 dissolved in ethylene glycol (10 mL) was treated with hydrazine hydrate (0.18 mL, 5.8 mmol), stirred at 160 &lt; 0 &gt; C for 30 minutes, cooled to room temperature, treated with potassium hydroxide, Stir for 45 minutes at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; and cool to room temperature, then treat with water and extract with ethyl acetate. The extract was washed with water, dried (MgSO _4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate / hexane to give the title compound.

_{MS (DCI / NH 3) m} / z 286 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.28 (t, 3H), 2.26 (s, 3H), 2.99 (q, 2H), 7.14-7.27 (m, 5H), 8.34 (s, 1H), 9.11 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₅ CNS ₂ .0.25 H ₂ O:

Calculated: C, 67.33; H, 5.30; N, 4.91

Found: C, 66.63; H, 5.38; N, 4.72

Example 36

Thieno [2,3-c] pyridin-2-yl] ethanone, oxime

Example 33 and hydroxylamine hydrochloride were treated as in Example 26 to give the title compound.

mp 209 to 213 占 폚;

_{MS (DCI / NH 3) m} / z 315 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.22 (s, 1.5H), 2.28 (s, 3H), 2.32 (2, 1.5H), 7.20 (m, 2H), 7.30 (m, 2H), 7.62 (s, 0.5H), 7.70 (s, 0.5H), 8.30 (s, 0.5H), 8.34 (s, 0.5H), 9.12 (s, 0.5H), 9.24 (s, 0.5H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ OS ₂ :

Calculated: C, 61.16; H, 4.49; N, 8.91

Found: C, 60.83; H, 4.61; N, 9.03

Example 37

N- (2,3-dihydroxypropyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine-

A solution of Example 18 (2.5 g, 8.3 mmol) and N-hydroxysuccinimide (0.95 g, 8.3 mmol) in dichloromethane (35 mL) was treated with DCC (1.882 g, 9.13 mmol) in methylene chloride mmol), stirred at room temperature for 18 hours and concentrated. The residue was dissolved in ethyl acetate, and the back, washed with water, dried (MgSO _4), filtered and concentrated. The residue was added to a solution of 3-amino-1,2-propanediol (0.144 g, 1.6 mmol) in 3: 1 dioxane / methanol (20 mL), stirred at room temperature for 18 hours, dissolved in acetate, it was washed with water after dried (MgSO _4), then filtered and concentrated. The residue was purified by flash chromatography on silica gel using 6% methanol / dichloromethane to give the title compound.

mp 120-122 占 폚;

_{MS (DCI / NH 3) m} / z 375 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 3.19 (m, 1H), 3.4 (m, 1H), 3.65 (m, 1H), 4.62 (t, 1H), 4.88 (d , 7.20 (m, 2H), 7.30 (m, 2H), 8.38 (s, 1H), 9.1 (s, 1H), 9.28 (s, 1H);

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₃ S ₂ .0.75 H ₂ O:

Calculated: C, 57.73; H, 4.84; N, 7.48

Found: C, 55.54; H, 5.23; N, 6.7

Example 38

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxylic acid, hydrazide

Example 18 was treated as in Example 37 using hydrazine instead of 3-amino-1,2-propanediol to give the title compound.

mp 176-178 [deg.] C;

_{MS (DCI / NH 3) m} / z 316 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 4.68 (br s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 8.2 (s, 1H), 8.4 ( s, 1 H), 9.28 (s, 1 H), 10.4 (br s, 1 H);

Elemental analysis for C ₁₅ H ₁₃ N ₃ OS ₂ .0.25 H ₂ O:

Calculated: C, 57.12; H, 4.15; N, 13.32

Found: C, 56.49; H, 4.19; N, 12.29

Example 39

N ² -4 - [(4- methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] carbonyl] -N ⁶ - [(nitro) methyl-imino] -L- lysine, methyl ester

N-ω-nitroarginine methyl ester hydrochloride and NaHCO ₃ were treated as in Example 37. The residue was purified by flash chromatography on silica gel using 5% methanol / dichloromethane to give the title compound.

mp 84-87 [deg.] C;

_{MS (DCI / NH 3) m} / z 517 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.60 (m, 2H), 1.85 (m, 2H), 2.29 (s, 3H), 3.20 (m, 2H), 3.68 (s, 3H), 4.35 (t 2H), 7.30 (m, 2H), 8.32 (s, 1H), 8.48 (s, 1H), 8.52 (br s, 1H), 9.30 , &Lt; / RTI &gt; 1H), 9.42 (d, 1H);

Elemental analysis for C ₂₂ H ₂₄ N ₆ O ₅ S ₂ .0.25 H ₂ O:

Calculated: C, 51.15; H, 4.68; N, 16.27

Found: C, 50.95; H, 4.89; N, 15.73

Example 40

N- (aminoiminomethyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine-2- carboxamide

A solution of guanidine hydrochloride (0.095 g, 1 mmol) in methanol was treated with potassium t-butoxide (0.112 g, 1 mmol), stirred at room temperature for 30 min and then treated with Example 17 (0.1 g, 0.3 mmol) , Warmed to room temperature for 16 h and concentrated. After washing the concentrate taken up in ethyl acetate (100㎖), and with water, dried (MgSO ₄₎ and filtered and concentrated. The residue was purified by flash chromatography on silica gel using 6% methanol / dichloromethane to give the title compound.

mp 202-205 DEG C;

_{MS (DCI / NH 3) m} / z 343 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 6.90 (br s, 2H), 7.20 (m, 4H), 7.80 (s, 1H), 8.00 (br s, 2H), 8.20 (s, 1 H), 8.40 (s, 1 H), 9.24 (s, 1 H).

Example 41

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carbothioamide

A solution of Example 19 (190 mg, 0.63 mmol) and Rochesen reagent (383 mg, 9.48 mmol) in toluene (15 mL) was heated to room temperature for 5 hours and concentrated. The residue was purified by flash chromatography on silica gel using 4% methanol / dichloromethane to give the title compound.

mp 181-183 C;

_{MS (DCI / NH 3) m} / z 317 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 7.20 (m, 2H), 7.30 (m, 2H), 8.18 (br s, 1H), 8.32 (s, 1H), 9.2 ( s, 1 H), 10.1 (br s, 1 H), 10.2 (br s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ S ₃ .0.25 H ₂ O:

Calculated: C, 59.93; H, 3.82; N, 8.85

Found: C, 55.89; H, 3.83; N, 8.48

Example 42

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine

(0.6 g, 1.99 mmol) and copper powder (0.3 g) and stirred for 5 minutes, then cooled, diluted with hexane , And purified by silica gel flash chromatography using 15% ethyl acetate / hexane. The product was recrystallized from hexane to give the title compound.

mp 94-95 C;

_{MS (DCI / NH 3) m} / z 258 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.27 (s, 3H), 7.16 (m, 2H), 7.23 (m, 2H), 7.44 (d, 1H), 8.20 (d, 1H), 8.40 (s , &Lt; / RTI &gt; 1H), 9.27 (s, 1H);

Elemental analysis for C ₁₄ H ₁₁ NS ₂ :

Calculated: C, 65.33; H, 4.30; N, 5.44

Found: C, 65.44; H, 4.20; N, 5.26

Example 43

Methyl 4 - [(2-methoxy-2-oxoethyl) thio] thieno [2,3- c] pyridine-

Example 93A was performed as in Examples 17B and 17C except that methylthioglycolate was used instead of p-thiocresol used in Example 17B to give the title compound.

_{MS (DCI / NH 3) m} / z 4298 (M + H) +;

¹ H NMR (500 MHz, DMSO-d ₆ )? 3.59 (s, 3H), 3.94 (s, 3H), 4.04 (s, 2H), 8.14 , 1H).

Example 44

4 - [(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine-

Example 43 was dissolved in 2M methanolic ammonia and then heated to 45 &lt; 0 &gt; C in a sealed tube for 18 hours. The precipitate was filtered, washed with methanol-diethyl ether (1: 1) and dried under vacuum to give the title compound.

MS (APCI) m / z 268 (M + H) &lt; ⁺ &gt;;

¹ H NMR (400 MHz, DMSO- d ₆ )? 3.81 (s, 2H), 7.17 (br s, 1 H), 7.59 , 8.46 (s, 1 H), 8.52 (br s, 1 H), 9.14 (s, 1 H).

Example 45

4 - [(4-bromophenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

Example 17A was performed as in Examples 17B, 17C and 44 except that 4-bromothiophenol was used instead of p-thiocresol used in Example 17B to give the title compound.

_{MS (DCI / NH 3) m} / z 365 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.20 (dt, 2H), 7.53 (dt, 2H), 7.87 (br s, 1H), 8.21 (s, 1H), 8.51 (br s, 1H), 8.54 (s, 1 H), 9.36 (s, 1 H);

Elemental analysis for C ₁₄ H ₉ BrN ₂ OS ₂ :

Calculated: C, 46.04; H, 2.48; N, 7.67

Found: C, 45.86; H, 2.30; N, 7.51

Example 46

4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide

Example 17A was performed as in Examples 17B, 17C and 44 except that 4-thiophenol was used instead of p-thiocresol used in Example 17B to give the title compound.

_{MS (DCI / NH 3) m} / z 287 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.29-7.40 (m, 5H), 7.86 (br s, 1 H), 8.25 , 9.31 (s, 1 H);

Elemental analysis for C ₁₄ H ₁₀ N ₂ OS ₂ :

Calculated: C, 58.72; H, 3.52; N, 9.28

Found: C, 58.62; H, 3.42; N, 9.48

Example 47

4 - [[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pyridine- 2- carboxamide

Example 17A was performed as in Examples 17B, 17C and 44 except that?,?,? -Trifluorothiocresol was used instead of p-thiocresol used in Example 17B to give the title compound .

_{MS (DCI / NH 3) m} / z 355 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.31 (d, 2H), 7.65 (d, 2H), 7.85 (br s, 1H), 8.19 (s, 1H), 8.50 (br s, 1H), 8.68 (s, 1 H), 9.44 (s, 1 H);

Elemental analysis for C ₁₅ H ₉ F ₃ N ₂ OS ₂ :

Calculated: C, 50.84; H, 2.56; N, 7.91

Found: C, 50.63; H, 2.44; N, 7.82

Example 48

4 - [(2-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except 2-methylthiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by column chromatography using 5% methanol in chloromethane as eluent to give the title compound.

mp 170-172 占 폚;

_{MS (DCI / NH 3) m} / z 301 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.41 (s, 3H), 7.04 (dd, 1H0, 7.15 (dt, IH), 7.27 (s, IH), 8.20 (s, IH), 8.23 (s, IH), 8.53 (br s, IH), 9.28

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.97; H, 4.03; N, 9.33

Found: C, 59.86; H, 4.16; N, 9.11

Example 49

4 - [(3-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 3-methylthiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 171-173 C;

_{MS (DCI / NH 3) m} / z 301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.27 (s, 3H), 7.06-7.13 (m, 2H), 7.21-7.27 (m, 2H), 7.89 (br s, 1H), 8.26 (s, 1H ), 8.42 (s, 1 H), 8.55 (br s, 1 H), 9.30 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ .0.25 H ₂ O:

Calculated: C, 59.08; H, 4.13; N, 9.19

Found: C, 59.10; H, 4.16; N, 9.11

Example 50

4 - [(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 3,4-dimethylthiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 192-194 DEG C;

MS (APCI) m / z 315 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.09 (s, 3H), 2.11 (s, 3H), 7.05 (m, 2H), 7.19 (s, 1H), 7.81 (br s, 1H), 8.12 ( d, 2 H), 8.49 (br s, 1 H), 9.15 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ OS ₂ .0.25 H ₂ O:

Calculated: C, 60.25; H, 4.58; N, 8.78

Found: C, 60.34; H, 4.52; N, 8.75

Example 51

4 - [(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 3,5-dimethylthiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 177-179 C;

_{MS (DCI / NH 3) m} / z 315 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.13 (s, 6H), 6.83 (s, IH), 6.92 s, 1 H), 8.50 (br s, 1 H), 9.19 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ OS ₂ :

Calculated: C, 61.12; H, 4.49; N, 8.91

Found: C, 60.82; H, 4.48; N, 8.75

Example 52

4 - [(2,4-dimethylphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 2,4-dimethylthiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 193-195 占 폚;

MS (APCI) m / z 315 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.28 (s, 3H), 2.38 (s, 3H), 7.02 (d, 1H), 7.13 (d, 1H), 7.20 (s, 1H), 7.91 (br s, 1 H), 8.05 (s, 1 H), 8.58 (br s, 1 H), 9.22 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₆ N ₂ OS ₂ .0.25 H ₂ O:

Calculated: C, 60.25; H, 4.58; N, 8.78

Found: C, 60.40; H, 4.52; N, 8.72

Example 53

4 - [(2-methyl-3-furanyl) thio] thieno [2,3- c] pyridine- 2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 2-methyl-3-furanthiol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 236-239 [deg.] C;

MS (ESI) m / z 291 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.41 (s, 3H), 6.68 (d, 1H), 7.74 (d, 1H), 7.93 (br s, 1H), 8.19 (s, 1H), 8.38 ( s, 1 H), 8.60 (br s, 1 H), 9.15 (s, 1 H);

Elemental analysis for C ₁₃ H ₁₀ N ₂ O ₂ S ₂ .0.25 H ₂ O:

Calculated: C, 52.95; H, 3.59; N, 9.50

Found: C, 52.57; H, 3.41; N, 9.30

Example 54

4 - [[(4-chlorophenyl) methyl] thio] thieno [2,3-c] pyridine- 2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except 4-chlorobenzylmercaptan was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 198-199 [deg.] C;

MS (APCI) m / z 335 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.40 (s, 2H), 7.31 (s, 4H), 7.86 (br s, 1H), 8.26 (s, 1H), 8.41 (s, 1H), 8.52 ( br s, 1 H), 9.15 (s, 1 H);

C ₁₅ H ₁₁ CIN ₂ Elemental analysis for OS ₂ :

Calculated: C, 53.80; H, 3.31; N, 8.37

Found: C, 53.52; H, 3.18; N, 8.31

Example 55

4 - [(3,4-dichlorophenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

Example 17A was performed as in Examples 17B, 17C and 44 except that 3,4-dichlorothiophenol was used instead of p-thiocresol used in Example 17B to give the title compound. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

MS (ESI) m / z 355 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.10 (dd, 1H), 7.55 (d, 1H), 7.59 (d, 1H), 7.91 (br s, 1H), 8.21 (s, 1H), 8.53 ( br s, 1 H), 8.62 (s, 1 H), 9.41 (s, 1 H);

Elemental analysis for C ₁₄ H ₈ CI ₂ N ₂ OS ₂ :

Calculated: C, 47.33; H, 2.27; N, 7.89

Found: C, 47.34; H, 2.52; N, 8.05

Example 56

4 - [(4-methoxyphenyl) thio] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that 4-methoxythiophenol was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 219-221 C;

MS (ESI) m / z 317 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.76 (s, 3H), 6.99 (d, 2H), 7.46 (d, 2H), 7.89 (br s, 1H), 8.17 (s, 1H), 8.30 ( s, 1 H), 8.54 (br s, 1 H), 9.18 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ O ₂ S ₂ :

Calculated: C, 56.94; H, 3.82; N, 8.85

Found: C, 56.80; H, 3.78; N, 8.79

Example 57

4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide

The title compound was obtained by treating Example 17A as in Examples 17B, 17C and 44 except that cyclohexylmercaptan was used instead of p-thiocresol used in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane as eluent to give the title compound.

mp 205-207 占 폚;

MS (ESI) m / z 293 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO- d ₆ )? 1.14-1.43 (br m, 6H), 1.51-1.61 (br m, 1H), 1.66-1.78 (br m, 2H), 1.83-1.98 ), 7.90 (br s, IH), 8.33 (s, IH), 8.52 (s, IH), 8.57 (br s, IH), 9.22

Elemental analysis for C ₁₄ H ₁₅ N ₂ OS ₂ :

Calculated: C, 57.50; H, 5.51; N, 9.58

Found: C, 57.53; H, 5.39; N, 9.51

Example 58

(4-methylphenyl) thio] -N- [3- (4-morpholinyl) propyl] thieno [2,3- c] pyridine- 2- carboxamide, trifluoromethyl acetate (salt)

Example 17C (200 mg, 0.635 mmol) in 9: 1 4- (3-aminopropyl) morpholine / acetic acid (2 mL) was heated at 70 <0> C for 4 hours and diluted with acetonitrile Followed by purification by C-18 reverse phase HPLC eluting with 100% CH ₃ CN containing 20% acetonitrile / water to 0.1% trifluoroacetic acid to give the title compound.

MS (APCI) m / z 428 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.95 (m, 2H), 3.08 (m, 2H), 3.18 (m, 2H), 3.36 (m, 2H), 3.43 (m, 2H), 3.68 (m 2H), 7.28 (d, 2H), 8.0 (br s, 1H), 8.27 (s, 1H), 8.34 (m, 1H), 9.27 (m, 1H).

Example 59

4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 2- carboxamide

Example 59A

Methyl 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine-

A solution of Example 17C (144 mg, 0.46 mmol) in dichloromethane (10 mL) was treated with 3-chloroperoxybenzoic acid (57-86%, 82 mg) at 0 C and warmed to room temperature for 4 hours after which dichloromethane (50 ㎖) by treatment, 1N NaOH, then washed successively with water and brine, dried (MgSO ₄₎ and filtered and concentrated. The residue was purified by silica gel flash chromatography using 50% ethyl acetate / hexane to give the title compound.

_{MS (DCI / NH 3) m} / z 332 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.25 (s, 3H), 3.84 (s, 3H), 7.38 (d, 2H), 7.65 (d, 2H), 8.41 (s, 1H), 9.0 (s , &Lt; / RTI &gt; 1H), 9.58 (s, 1H).

Example 59B

4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 2- carboxamide

Example 59A was treated as in Example 44 to give the title compound.

_{MS (DCI / NH 3) m} / z 317 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.31 (s, 3H), 7.38 (d, 2H), 7.79 (d 2H), 7.94 (br s, 1H), 8.43 (s, 1H), 8.62 (br s, 1 H), 8.85 (s, 1 H), 9.43 (s, 1 H).

Example 60

4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 60A

Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxylate

Example 17A was performed as in Examples 17B and 17C except that p-cresol was used instead of p-thiocresol used in Example 17B to give the title compound.

mp 96-98 C;

_{MS (DCI / NH 3) m} / z 317 (M + NH 4) +, 300 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.32 (s, 3H), 3.91 (s, 3H), 7.05 (m, 2H), 7.24 (m, 2H), 7.95 (s, 1H), 8.12 (s , &Lt; / RTI &gt; 1H), 9.17 (s, 1H);

Elemental analysis for C ₁₆ H ₁₃ NO ₃ S:

Calculated: C, 64.19; H, 4.37; N, 4.67

Found: C, 64.05; H, 4.34; N, 4.52

Example 60B

4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 60A was treated as in examples 18 and 19 to give the title compound.

mp 196-197 占 폚;

_{MS (DCI / NH 3) m} / z 285 (M + H) +, 302 (M + NH 4) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.31 (s, 3H), 7.04 (m, 2H), 7.25 (m, 2H), 7.82 (br s, 1H), 8.00 (s, 1H), 8.21 ( s, 1 H), 8.42 (br s, 1 H), 9.07 (s, 1 H);

C ₁₅ H ₁₂ N ₂ O ₂ S ₂ Elemental analysis:

Calculated: C, 63.36; H, 4.25; N, 9.85

Found: C, 63.29; H, 4.28; N, 9.68

Example 61

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 61A

Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate

A solution of 4-chlorophenol (2.63 g, 20.5 mmol) dissolved in THF (20 mL) was added dropwise at 0 ° C to a solution of potassium tert-butoxide (1.0 M solution in THF, 20.4 mL, 20.5 mmol) After stirring for 1 h at 0 C, the mixture was cooled to 0 C and treated with a solution of Example 17A (3.54 g, 20.23 mmol) in THF (40 mL), warmed at 60 C for 0.5 h, cooled to 0 C later, methyl thioglycolate treated, and allowed to warm at 60 ℃ for 0.25 hours (1.989㎖, 22.25mmol) and _{Cs 2 CO 3 (6.59g, 20.23mmol} ) and then cooled to room temperature and filtered. Dilute the filtrate with ethyl acetate, washed successively with water and brine, dried (MgSO ₄₎ was then filtered and concentrated. The residue was purified by silica gel flash chromatography using 4% acetone / hexane to obtain the title compound.

mp 99-100 C;

MS (APCI) m / z 320 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.91 (s, 3H, OCH 3), 7.14 (d, 2H), 7.48 (d, 2H), 7.95 (s, 1H), 8.23 (s, 1H), 9.23 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 56.45 (OCH 3), 120.19 (CH), 123.06 (Ar-CH), 128.04 (Ar-CH), 131.34 (C), 132.37 (Ar-CH), 133.38 (Ar-CH), 136.40 (Ar-CH), 139.38 (C), 141.75 (C), 142.09 (C), 144.89 (Ar-CH), 150.91 (C), 158.64 (C), 164.95 (CO);

Elemental analysis for C ₁₅ H ₁₀ ClNO ₃ S:

Calculated: C, 56.34; H, 3.15; N, 4.38

Found: C, 56.23; H, 3.16; N, 4.38

Example 61B

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 61A was processed as in Example 44 to give the title compound.

mp 176-177 C;

_{MS (DCI / NH 3) m} / z 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.15 (m, 2H), 7.50 (m, 2H), 7.95 (b, 1H), 8.25 (d, 2H), 8.45 (b, 1H), 9.15 (s , 1H);

Elemental analysis for C ₁₄ H ₁₉ ClN ₂ O ₂ S 0.25 H ₂ O:

Calculated: C, 54.37; H, 3.10; N, 9.06

Found: C, 54.44; H, 2.74; N, 9.06

Example 62

4 - [(4-Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 17A was performed as in Example 61, but using 4- (trifluoromethyl) phenol instead of 4-chlorophenol to give the title compound.

_{MS (DCI / NH 3) m} / z 339 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.24 (d, 2H), 7.77 (d, 2H), 7.88 br s, 1 H), 9.24 (s, 1 H);

Elemental analysis for C ₁₅ H ₉ F ₃ N ₂ O ₂ S:

Calculated: C, 53.26; H, 2.68; N, 8.28

Found: C, 53.06; H, 2.55; N, 8.19

Example 63

4- (4-octylphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 4-octylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 383 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 0.88 (t, 3H), 1.22-1.38 (m, 10H), 1.62 (m, 2H), 2.61 (t, 2H), 6.05 (br s, 2H), 6.99 ( d, 2H), 7.20 (d, 2H), 7.87 (s, IH), 8.07 (br s, IH), 8.92 (br s, IH);

Elemental analysis for C ₂₂ H ₂₆ N ₂ O ₂ S:

Calculated: C, 69.08; H, 6.85; N, 7.32

Found: C, 69.04; H, 6.82; N, 7.22

Example 64

4- [4- (1-methylethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 4- (1-methylethyl) phenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 313 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.21 (d, 6H), 2.92 (septet, 1H), 7.05 (d, 2H), 7.30 (d, 2H), 7.82 (br s, 1H), 8.03 ( s, 1 H), 8.21 (s, 1 H), 8.44 (br s, 1 H), 9.09 (s,

Example 65

4- (2-bromo-4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide

Example 17A and 2-bromo-4-chlorophenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 383 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.18 (d, 1H), 7.49 (dd, 1H), 7.90 (br s, 1H), 7.98 (s, 2H), 8.23 (s, 1H), 8.49 ( br s, 1 H), 9.14 (s, 1 H);

Elemental analysis for C ₁₄ H ₈ BrClN ₂ O ₂ S:

Calculated: C, 43.83; H, 2.10; N, 7.30

Found: C, 43.53; H, 1.97; N, 6.99

Example 66

4- (4-ethylphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 4-ethylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 299 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.19 (t, 3H), 2.62 (q, 2H), 7.05 (dt, 2H), 7.26 (dt, 2H), 7.81 (br s, 1H), 8.07 ( s, 1 H), 8.21 (s, 1 H), 8.43 (br s, 1 H), 9.08 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ O ₂ S CH ₃ OH:

Calculated: C, 63.71; H, 4.69; N, 9.14

Found: C, 63.34; H, 4.51; N, 9.51

Example 67

4- (4-ethynylphenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 67A

4-vinylphenol

A solution of 4-vinylphenol in propylene glycol was treated with water and extracted with diethyl ether to remove propylene glycol and give the title compound in diethyl ether.

Example 67B

4- (4-ethynylphenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 17A and Example 67A were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 297 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.24 (d, 1H), 5.79 (d, 1H), 6.75 (dd, 1H), 7.10 (d, 2H), 7.54 (d, 2H), 7.87 (br s, 1H), 8.12 (s, 1H), 8.18 (s, 1H), 8.45 (brs, 1H), 9.13

Elemental analysis for C ₁₆ H ₁₂ N ₂ O ₂ S 0.25 CH ₃ OH:

Calculated: C, 64.13; H, 4.06; N, 9.20

Found: C, 64.40; H, 4.12; N, 9.27

Example 68

4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

A solution of Example 67B (35 mg, 0.118 mmol) in pyridine (5 mL) was treated with OsO ₄ (90 mg, 0.354 mmol), stirred for 5 h, treated with 10% aqueous NaHSO ₃ , After stirring for 5 h, it was treated with brine and extracted with ethyl acetate. The extracts were dried (MgSO ₄₎ and filtered and concentrated. The residue was purified by silica gel flash chromatography using 1: 10 methanol / dichloromethane to give the title compound.

_{MS (DCI / NH 3) m} / z 331 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.44 (t, 2H), 4.55 (q, 1H), 4.73 (t, 1H), 5.27 (d, 1H), 7.08 (d, 2H), 7.39 (d 2H), 7.85 (br s, IH), 8.03 (s, IH), 8.21 (s, IH), 8.47 (br s, IH), 9.10 (s, IH);

Elemental analysis for C ₁₆ H ₁₄ N ₂ O ₄ S · 0.25 CH ₃ OH:

Calculated: C, 57.68; H, 4.24; N, 8.28

Found: C, 57.92; H, 4.35; N, 8.24

Example 69

4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 2-allylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 311 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.43 (d, 2H), 5.01 (m, 1H), 5.05 (m, 1H), 5.98 (m, 1H), 7.00 (dd, 1H), 7.27 (m 2H), 7.39 (dd, IH), 7.82 (s, IH), 7.88 (brs, IH), 8.27 (s, IH), 8.49 (brs, IH), 9.05

Elemental analysis for C ₁₇ H ₁₄ N ₂ O ₂ S:

Calculated: C, 65.79; H, 4.55; N, 9.03

Found: C, 65.53; H, 4.37; N, 8.95

Example 70

4- [2- (2,3-dihydroxypropyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 69 was treated as in Example 68 to give the title compound.

_{MS (DCI / NH 3) m} / z 345 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.60 (dd, 1H), 2.88 (dd, 1H), 3.29 (t, 2H), 3.76 (m, 1H), 4.55 (t, 1H), 4.63 (d (D, 1H), 6.94 (dd, 1H), 7.22 (m, 2H), 7.45 s, 1 H), 9.04 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₆ N ₂ O ₄ S:

Calculated: C, 59.29; H, 4.68; N, 8.13

Found: C, 59.16; H, 4.51; N, 8.06

Example 71

4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, 1-

A solution of Example 62 (26 mg, 0.077 mmol) in (1 mL) and dichloromethane (5 mL) was treated with m-CPBA (80-85%, 30 mg, 0.14 mmol) Lt; 0 &gt; C for 1 hour and at room temperature for 10 hours. The formed precipitate was collected by filtration and washed with dichloromethane. The product was analyzed by HPLC (C-18, reversed phase), and it was confirmed that the desired sulfoxide was mixed with the starting material, thiepene, at a ratio of 8: 1. The mixture was recrystallized from DMF / methanol / dichloromethane to give the title compound (97.5% pure, HPLC analysis).

_{MS (HPCI / NH 3) m} / z 355 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 7.39 (d, 2H), 7.79 (br s, IH), 7.81 (d, 2H), 8.02 br s, 1 H), 9.02 (s, 1 H);

Elemental analysis for C ₁₅ H ₉ F ₃ NO ₃ S · 0.25 CH ₃ OH:

Calculated: C, 50.55; H, 2.57; N, 7.73

Found: C, 50.55; H, 2.59; N, 7.69

Example 72

4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 3-pentadecylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 481 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 0.84 (t, 3H), 1.20-1.28 (m, 24H), 1.54 (m, 2H), 2.57 (t, 2H), 6.92 (m, 1H), 6.97 1H), 7.03 (d, IH), 7.33 (t, IH), 7.85 (br s, IH), 8.03 9.09 (s, 1 H);

Elemental analysis for C ₂₉ H ₄₀ N ₂ O ₂ S:

Calculated: C, 72.46; H, 8.39; N, 5.83

Found: C, 72.69; H, 8.18; N, 5.47

Example 73

Methyl 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxylate

To a solution of 4-bromophenol (4.94 g, 28.55 mmol) in anhydrous tetrahydrofuran (10 ml) under a nitrogen atmosphere was added dropwise a solution of potassium t-butoxide (1 M solution in THF, 28.6 ml, 28.6 mmol) Respectively. The reaction mixture was stirred at room temperature for 30 minutes, then a solution of Example 17A (2 g, 11.4 mmol) dissolved in anhydrous tetrahydrofuran (20 mL) was added and refluxed for 8 hours. The reaction mixture was cooled to 25 DEG C and methylthioglycolate (1.23 mL, 13.7 mmol) was added and refluxed for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate (300 mL) and partitioned into 1 N NaOH (3 x 75 mL) ice-cold solution. The organic layer was washed with brine (3 x 100 mL), dried (MgSO ₄ ) and the solvent removed under reduced pressure to give the crude product (4.2 g). This was purified by silica gel flash chromatography using 10% acetone-hexane as an eluent to give the title compound (1.81 g) in 44% yield.

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.91 (s, 3H), 7.10 (d, J = 9Hz, 2H), 7.59 (d, J = 9Hz, 2H), 7.94 (s, 1H), 8.25 ( s, 1 H), 9.24 (s, 1 H);

MS (APCI) m / e 364; 366 (M + H) &lt; ⁺ & gt ^; .

Example 74

4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 3-chlorophenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.10 (m, 1H), 7.30 (m, 2H), 7.45 (b, 1H), 7.95 (b, 1H0, 8.20 (d, 1H), 8.30 (s, 1H), 8.6 (b, 1 H), 9.30 (s, 1 H).

Example 75

4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 4-chloro-3-methylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 327 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.3 (s, 9H), 7.10 (d, 2H), 7.45 (d, 2H), 7.85 (br s, 1H), 8.05 (s, 1H), 8.20 ( s, 1 H), 8.45 (br s, 1 H), 9.1 (s, 1 H).

Example 76

4- (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide

Example 17A and 4-chloro-3-methylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 319 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.30 (s, 3H), 6.95 (dd, 1H), 7.20 (d, 1H), 7.45 (d, 1H), 7.85 (br s, 1H), 8.15 ( s, 1 H), 8.19 (s, 1 H), 8.45 (br s, 1 H), 9.15 (s, 1 H).

Example 77

4- (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide

Example 17A and 4-chloro-2-methylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 319 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.30 (s, 3H), 6.95 (dd, 1H), 7.30 (d, 1H), 7.50 (d, 1H), 7.85 (br s, 1H), 7.95 ( s, 1 H), 8.25 (s, 1 H), 8.45 (br s, 1 H), 9.15 (s, 1 H).

Example 78

4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 4-methoxyphenol were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.78 (s, 3H), 7.00 (dd, 2H), 7.15 (d, 2H), 7.85 (b, 1H), 7.90 (s, 1H), 8.30 (s , &Lt; / RTI &gt; 1H), 8.45 (b, 1H), 9.05 (s, 1H).

Example 79

Ethyl 3 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate

Example 17A and ethyl 3-hydroxybenzoate were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 343 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.30 (t, 3H), 4.30 (s, 3H), 7.40 (dd, , 8.15 (s, IH), 8.20 (s, IH), 8.42 (b, IH), 9.17 (s, IH).

Example 80

4-phenoxy-ethano [2,3-c] pyridine-2-carboxamide

Example 17A and phenol were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 271 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.15 (dd, 2H), 7.20 (t, 1H), 7.45 (t, 2H), 7.85 (b, 1H), 8.10 (s, 1H), 8.20 (s , &Lt; / RTI &gt; 1H), 8.45 (b, 1H), 9.15 (s, 1H).

Example 81

4- (3-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 3-bromophenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 349, 351 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.07 (dt, 2 Hz, 1 H), 7.36-7.39 (m, 3H), 7.87 ), 8.45 (br s, 1 H), 9.17 (s, 1 H);

Elemental analysis for C ₁₄ H ₉ N ₂ O ₂ S CH ₃ OH:

Calculated: C, 47.26; H, 2.64; N, 7.35

Found: C, 47.26; H, 3.21; N, 7.29

Example 82

4- (4-Fluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 4-fluorophenol were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 289 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.25 (m, 4H), 7.85 (b, 1H), 8.05 (s, 1H), 8.20 (s, 1H), 8.42 (b, 1H), 9.10 (s , 1H).

Example 83

4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 3,5-dimethylphenol were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 299 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.30 (s, 6H), 6.75 (s, 2H), 6.85 (s, 1H), 7.80 (b, 1H), 8.05 (s, 1H), 8.18 (s , &Lt; / RTI &gt; 1H), 8.45 (b, 1H), 9.10 (s, 1H).

Example 84

4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide

Example 17A and 3-chloro-4-methylphenol were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / z 319 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.35 (s, 3H), 7.00 (dd, 1H), 7.25 (d, 1H), 7.45 (H, 1H), 7.85 (b, 1H), 8.15 (s , 8.20 (s, 1H), 8.45 (b, 1H), 9.15 (s, 1H).

Example 85

4- (4-Iodophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 4-iodophenol were treated as in Example 61 to provide the title compound.

_{MS (DCI / NH 3) m} / z 397 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 6.94 (d, 2H), 7.74 (d, 2H), 7.86 br s, 1 H), 9.16 (s, 1 H);

Elemental analysis for C ₁₄ H ₁₉ IN ₂ O ₂ S:

Calculated: C, 42.44; H, 2.29; N, 7.07

Found: C, 42.58; H, 2.27; N, 7.08

Example 86

4- (4-methoxymethyl) phenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 4- (methoxymethyl) phenol were treated as in Example 61 to give the title compound.

mp 168 to 168.5 캜;

_{MS (DCI / NH 3) m} / z 315 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.30 (s, 3H), 4.41 (s, 2H), 7.10 (d, 2H), 7.37 (d, 2H), 7.86 (s, 1H), 8.08 (s , 8.19 (s, 1 H), 8.45 (br s, 1 H), 9.12 (s, 1 H).

Example 87

2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridinium, iodide

Example 61 (0.11 g, 0.0033 mmol) was refluxed with methyl iodide (0.2 mL, 0.0033 mmol) for 2 h and filtered. The precipitate was washed with ether, dried and then recrystallized from acetonitrile to give the title compound.

_{MS (DCI / NH 3) m} / z 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.40 (s, 3H), 7.40 (dd, 2H), 7.65 (dd, 2H), 8.25 (br s, 1H), 8.55 (s, 1H), 8.65 ( s, 1 H), 8.70 (br s, 1 H), 9.70 (s, 1 H).

Example 88

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid

(3 mL) was added to 3: 1 methanol / water (4 mL), followed by stirring at room temperature for 20 hours, followed by the addition of 90% formic acid (100 mg, 0.13 ml) and filtered to give the title compound.

_{MS (DCI / NH 3) m} / z 306, 308 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.26 (m, 2H), 7.47 (m, 2H), 7.83 (s, 1H), 8.23 (s, 1H), 9.21

Elemental analysis for C ₁₄ H ₈ ClNO ₃ S:

Calculated: C, 55.00; H, 2.64; N, 4.58

Found: C, 54.77; H, 2.60; N, 4.44

Example 89

2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate

A suspension of Example 88 (100 mg, 0.327 mmol) in toluene (2 mL) was treated with ethyldiisopropylamine (63 mg, 0.49 mmol) and diphenylphosphoryl azide (109 mg, 0.394 mmol) , Treated with (±) -3-hydroxytetrahydrofuran (130 mg, 1.47 mmol) at 110 ° C. and stirred for 18 hours and then concentrated. The residue was purified by silica gel flash chromatography using 30% ethyl acetate / hexane and recrystallized from ethyl acetate to give the title compound.

mp 194-201 C;

MS (APCI) m / z 391 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.93-2.04 (m, IH), 2.13-2.28 (m, IH), 3.29-3.34 2H), 7.43 (dt, 2H), 8.14 (s, 1H), 8.91 (s, 1H);

Elemental analysis for C ₁₈ H ₁₅ ClN ₂ O ₄ S:

Calculated: C, 55.32; H, 3.87; N, 7.17

Found: C, 55.08; H, 3.69; N, 7.05

Example 90

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-methanol

A solution of Example 61A (254 mg, 0.793 mmol) in anhydrous alcohol (4 mL) was treated with anhydrous CaCl ₂ (177 mg, 1.59 mmol) and stirred for 1 hour, then cooled to 0 & ₄ (123 mg, 3.25 mmol) and then stirred at 0 &lt; 0 &gt; C for 4 hours and at room temperature for 18 hours, treated with water and then extracted with dichloromethane. The extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel using 30% ethyl acetate / hexane to give the title compound.

mp 90-91 C;

MS (APCI) m / z 292, 294 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 2.2-2.65 (vbr s, 1H), 4.97 (d, 2H), 6.95 (dt, 2H), 7.43 (m, 1H), 7.31 (dt, 2H), 8.13 ( s, 1 H), 8.89 (s, 1 H);

Elemental analysis for C ₁₄ H ₁₀ CINO ₂ S:

Calculated: C, 57.64; H, 3.45; N, 4.80

Found: C, 57.50; H, 3.58; N, 4.66

Example 91

(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

Example 91 (A)

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde

To a solution of DMSO (77 mg, 0.99 mmol) in 1.7 mL of dichloromethane was added oxalyl chloride (109 mg, 0.86 mmol) dropwise at 78 째 C, stirred for 5 min and then treated in 2 mL of dichloromethane Example 12 (123 mg, 0.420 mmol) was added dropwise, stirred at -78 &lt; 0 &gt; C for 1 hour, treated with ethyl diisopropylamine (326 mg, 2.53 mmol), warmed to -20 & For a period of time, and then fractionated between 10 ml of dichloromethane and 5 ml of water and extracted. The extract was washed with water (5 mL) and brine (5 mL), dried (Na ₂ SO ₄ ) and filtered. The residue was rotary evaporated and dried under high vacuum to give the title compound.

MS (APCI) m / z 290, 292 (M + H) &lt; ⁺ & gt ^; .

Example 91B

(E) -methyl 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -2-propenoate

Example 91A (138 mg, 0.42 mmol) and methyltriphenylphosphoranylidene acetate (210 mg, 0.628 mmol) were stirred in dichloroethane (2 mL) at 65 &lt; 0 &gt; C for 3 hours and concentrated. The residue was purified by silica gel flash chromatography using 25% ethyl acetate / hexane to give the title compound.

MS (APCI) m / z 346,348 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.83 (s, 3H), 6.43 (d, 1H), 7.00 (dt, 2H), 7.35 (dt, 2H), 7.48 (s, 1H), 7.84 (d, 1H ), 8.11 (s, 1 H), 8.88 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₇ ClNO ₃ S:

Calculated: C, 59.05; H, 3.50; N, 4.05

Found: C, 58.82; H, 3.46; N, 3.86

Example 91C

(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

Example 91B was processed as in Example 88 to provide the title compound.

MS (ESI-) m / z 330, 332 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.46 (d, 1H), 7.14 (dt, 2H), 7.46 (dt, 2H), 7.83 (s, 1H), 7.92 (d, 1H), 8.15 (s , &Lt; / RTI &gt; 1H), 9.10 (s, 1H);

Elemental analysis for C ₁₇ H ₁₇ ClNO ₃ S:

Calculated: C, 59.05; H, 3.50; N, 4.05

Found: C, 58.82; H, 3.46; N, 3.86

Example 92

(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 2-yl] -2-propenamide

(51.5 mg, 0.155 mmol), N-hydroxybenzotriazole monohydrate (34.5 mg, 0.225 mmol), 4-methylmorpholine (47 mg, 0.464 mmol) and NH ₄ Cl (31.6 mg, 0.591 mmol ) In DMF (1 ml) was treated with EDC (45.0 mg, 0.235 mmol) at 0 ° C and stirred at 0 ° C for 4 hours and at room temperature for 10 hours, then treated with chloroform (5 ml) , Washed successively with 1 M NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash chromatography with 5% methanol / dichloromethane to give the title compound.

mp 176-178 [deg.] C;

MS (ESI) m / z 331, 333 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 5.60 (br s, 2H), 6.46 (d, 1H), 7.01 (m, 2H), 7.35 (m, 2H), 7.46 (s, 1H), 7.84 (d, 1H), 8.11 (s, 1 H), 8.88 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₁ ClN ₂ O ₂ S:

Calculated: C, 58.10; H, 3.35; N, 8.47

Found: C, 57.98; H, 3.24; N, 8.45

Example 93

4-bromothieno [2,3-c] pyridine-2-carboxamide

Example 93A

3,5-dibromopyridine-4-carboxaldehyde

A solution of diisopropylamine (6.6 mL, 46.43 mmol) in THF (40 mL) was treated with n-butyllithium (2.50 M solution, 18.6 mL, 46.43 mmol) in hexane over 15 minutes at 0 & After stirring at 0 C for 30 min, it was diluted with THF (200 mL), cooled to -78 C and then treated with 3,5-dibromopyridine (10 g, 42.21 mmol) in THF (110 mL) a treatment over a number and then, stirred for 2 hours at -78 ℃ and added into ice-cold saturated NaHCO ₃ solution, stirred for 15 minutes and then extracted with diethyl ether. The extract was washed with brine, dried (MgSO _4), filtered and concentrated. The residue was purified by silica gel flash chromatography using 10% acetone / hexane to give the title compound.

_{MS (DCI / NH 3) m} / z 266 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 8.91 (s, 2H), 10.09 (s, 1H).

Example 93B

Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylate

The title compound was obtained by treating Example 93A as in Example 17C, but from 0 to 25 &lt; 0 &gt; C.

_{MS (DCI / NH 3) m} / z 274 (M + H) +;

^{1 H NMR (500MHz, DMSO-} d 6) δ 3.95 (s, 3H), 7.99 (s, 1H), 8.67 (s, 1H), 9.31 (s, 1H).

Example 93C

4-bromothieno [2,3-c] pyridine-2-carboxamide

Example 93B was treated as in Example 44 to give the title compound.

_{MS (DCI / NH 3) m} / z 257 (M + H) +;

¹ H NMR (400 MHz, DMSO-d ₆ )? 7.97 (br s, 1H), 8.11 (s, 1H), 8.33 (br s, 1H), 8.43 (s, 1H), 9.24

Example 94

4-Chlorothieno [2,3-c] pyridine-2-carboxamide

3,5-Dichloropyridine was treated as in Example 93 to give the title compound.

_{MS (DCI / NH 3) m} / z 213 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.93 (br s, 1H, NH), 8.28 (s, 1H), 8.55 (br s, 1H, NH), 8.58 (s, 1H), 9.28 (s, 1H).

Example 95

4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide

Example 95A

Methyl 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxylate

A solution of Example 93B (272 mg, 1 mmol), 4- (trifluoromethyl) phenylboronic acid (209 mg, 1.1 mmol) and cesium fluoride (347 mg, 2.1 mmol) in DME (5 mL) degassed for 15 minutes and tetrakis (triphenylphosphine) palladium (O) (35 ㎎, 0.03mmol ) was warmed for a later, 6 hours at 80 ℃ treatment, the stirring for 12 hours at room temperature, Celite ^R &Lt; / RTI &gt; filtered and concentrated. The residue was purified by silica gel flash chromatography using 5% acetone / hexane to purify the title compound.

_{MS (DCI / NH 3) m} / z 338 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 3.92 (s, 3H), 7.94 (m, 4H), 8.06 (s, IH), 8.66 (s, IH), 9.47

Example 95B

4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide

Example 95A was processed as in Example 44 to give the title compound.

MS (APCI) m / z 323 (M + H) ⁺ , 321 (MH) ^- , and 357 (M + Cl) ^- ;

¹ H NMR (400 MHz, DMSO-d ₆ )? 7.81 (br s, 1 H), 7.93 (m, 4H), 8.24 (s, 3H), 8.45 9.37 (br s, 1 H).

Example 96

Methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide

The title compound was obtained by treating Example 95A as in Example 44 but using methylamine (2.0M in methanol) instead of methanolic ammonia.

MS (APCI) m / z 337 (M + H) +, 335 (MH) _, and 371 (M + Cl) ^-;

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.82 (d, 3H), 7.90 (d, 2H), 7.94 (d, 2H), 8.17 (s, 1H), 8.58 (s, 1H), 8.93 (br d, 1 H), 9.36 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ: 26.1 (CH 3), 121.6 (Ar-CH), 123.1, 125.3 (C), 125.7 (CH), 125.8 (CH), 128.3, 128.6, 128.8, 129.1 _{(CF 3), 129.9 (2xAr} -CH), 136.6 (C), 140.6 (C), 142.4 (C), 142.5 (CH), 145.0 (2xCH), 146.6 (C), 161.1 (C).

Example 97

4-phenylthieno [2,3-c] pyridine-2-carboxamide

Example 97A

Methyl 4-phenylthieno [2,3-c] pyridine-2-carboxylate

Example 93B and phenylboronic acid were treated as in Example 95 to give the title compound.

_{MS (DCI / NH 3) m} / z 338 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 3.92 (s, 3H), 7.94 (m, 4H), 8.06 (s, IH), 8.66 (s, IH), 9.47

Example 97B

4-phenylthieno [2,3-c] pyridine-2-carboxamide

Example 97A was treated as in Example 44 to give the title compound.

_{MS (DCI / NH 3) m} / z 255 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.52-7.69 (m, 5H), 7.78 (br s, 1H), 8.23 (s, 1H), 8.44 (br s, 1H), 8.52 (s, 1H) , 9.30 (s, 1 H);

Elemental analysis for C ₁₄ H ₁₀ N ₂ OS:

Calculated: C, 66.12; H, 3.96; N, 11.02

Found: C, 66.02; H, 3.94; N, 11.00

Example 98

4 - ([1,1'-biphenyl] -4-ylthio) thieno [2,3-c] pyridine- 2- carboxamide

Example 73 and phenylboronic acid were processed and purified as in Example 95 and then purified by HPLC (C18 reversed phase, 0-90% acetonitrile gradient in water containing 0.1% TFA) to give the title compound.

_{MS (DCI / NH 3) m} / z 363 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.36-7.48 (m, 5H), 7.63-7.68 (m, 4H), 7.91 (br s, 1H), 8.30 (s, 1H), 8.54 (s, 1H ), 8.57 (br s, 1 H), 9.36 (s, 1 H).

Example 99

Methyl 4- [3- (2,3,4,5-tetrahydrofuranyl) oxy] thieno [2,3-c] pyridine-2- carboxamide

Example 99A

Methyl 4- [3- (2,3,4,5-tetrahydrofuranyl) oxy] thieno [2,3-c] pyridine-

To a solution of Example 236E (110 mg, 0.53 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature under a nitrogen atmosphere was added 3-hydroxytetrahydrofuran (0.043 ml, 0.53 mmol), triphenylphosphine Mg, 0.53 mmol) and diethyl azodicarboxylate (0.083 ml, 0.53 mmol) were added. After 22 h, the reaction mixture was diluted with ethyl acetate (100 mL), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel (Biotage Flash 40S) flash chromatography using 10% acetone-hexane as eluent to give the title compound in 22% yield.

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.05-2.18 (m, 1H), 2.26-2.49 (m, 1H), 3.61-3.77 (m, 2H), 3.93 (s, 2H), 4.25-4.31 ( m, 2H), 5.32-5.39 (m, IH), 8.10 (s, IH), 8.26 (s, IH), 8.99 (s, IH);

MS (APCI) m / e 280 (M + H) &lt; ⁺ &gt;;

Example 99B

Methyl 4- [3- (2,3,4,5-tetrahydrofuranyl) oxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound (5.3 mg, 19%) was prepared as described in example 171 from Example 99A (30 mg, 0.108 mmol). The product was separated by a C-18 reverse phase HPLC using _{20% CH 3 CN-H 2} O gradient containing 0.1% trifluoroacetic acid as eluent.

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.05-22.13 (m, 1H), 2.30-2.40 (m, 1H), 2.81 (d, J = 5Hz, 3H), 3.78-3.84 (m, 1H), 1H), 8.21 (s, 1H), 8.90 (s, 1H), 8.85 (d, J = 5 Hz, 1H);

^{13 C NMR (75MHz, DMSO-} d 6) δ 26.2 (CH 3), 32.5 (CH 2), 66.4 (CH 2), 72.3 (CH 2), 78.5 (CH), 119.6 (CH), 126.7 (CH) , 135.6 (C), 137.3 (C), 137.8 (CH), 144.3 (C), 148.6 (C), 161.1 (CO);

MS (APCI) m / e 279 (M + H) ⁺ , 313 (M + Cl) ^- ;

Example 100

Ethyl 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate

(120 mg, 0.33 mmol), palladium (II) acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (20.6 mg, 0.05 mmol) and triethylamine , 0.99 mmol) in DMF (6 ml) and ethanol (3 ml) was charged with carbon monoxide, heated at 105 ° C for 12 hours under a carbon monoxide atmosphere (apparatus), treated with ether, Washed successively, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography (20% ethyl acetate / hexanes) to give the title compound.

_{MS (DCI / NH 3) m} / z 358 (M + H) +.

Example 101

4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoic acid

A solution of Example 100 (50 mg) in DMF (5 mL) and methanol (10 mL) was treated with an aqueous NaOH solution (0.5 mL) and stirred for 13 h before acetic acid (500 mg) And water, and then filtered. The residue was recrystallized from DMF / water to give the title compound.

_{MS (DCI / NH 3) m} / z 315 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.13 (dt, 1.8Hz, 2H), 7.86 (br s, 1H), 7.98 (dt, 2H), 8.09 (s, 1H), 8.31 (s, 1H) , 8.44 (br s, 1 H), 9.22 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₀ N ₂ O ₄ S:

Calculated: C, 57.32; H, 3.21; N, 8.91

Found: C, 57.32; H, 3.30; N, 8.92

Example 102

4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 102A

Styrene? -Boranic acid

A solution of a-bromostyrene (5.5 g, 30 mmol) in diethyl ether (30 mL) was treated with a solution of tert-BuLi (1.7 M solution, 21.2 mL, 36 mmol) at -78 < (8.31 ml, 36 mmol) for 48 minutes, stirred for 1 hour, then warmed to room temperature for 18 hours and then diluted with diethyl ether (100 ml) , Treated with 1M HCl (100 mL) and stirred at room temperature for 5 hours. It was then concentrated to remove THF, adjusted to pH 14 with 1 N NaOH, washed with hexane, adjusted to pH 1 with 1M HCl, and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound.

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.75 (d, 1H), 5.83 (d, 1H), 7.2-7.39 (m, 5H, Ar-CH).

Example 102B

Methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxylate

Example 93B and styrene-a-boronic acid were treated as in Example 95 to give the title compound.

MS (APCI) m / z 296 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 3.84 (s, 3H), 5.56 (s, 1H), 5.95 (s, 1H), 7.31 (m, 2H), 7.36 (m, 3H), 7.47 (s , &Lt; / RTI &gt; 1H), 8.5 (s, 1H), 9.40 (s, 1H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 53.03 (OCH 3), 118.37 ( vinyl _{CH 2), 126.79 (Ar-} CH), 127.60 (Ar-CH), 128.38 (Ar-CH), 128.75 (Ar -CH), 132.55 (Ar-CH), 137.20 (C), 138.10 (C), 139.59 (C), 141.88 (C), 142.97 CO).

Example 102C

4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 102B was processed as in Example 44 to give the title compound.

MS (DCI) m / z 281 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 5.53 (s, 1H), 6.04 (s, 1H), 7.31 (m, 2H), 7.35 (m, 3H), 7.72 (br s, 1H), 7.82 ( s, 1 H), 8.33 (s, 1 H), 8.37 (br s, 1 H), 9.29 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 118.0 (CH 2), 123.10 (CH), 126.73 (Ar-CH), 128.22 (CH), 128.60 (Ar-CH), 132.41 (C), 136.59 (C ), 139.42 (C), 142.73 (3-CH), 143.41 (C), 144.01 (C), 144.66 (5-CH), 146.0 (C), 162.5 (CO).

Example 103

4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-

NaBH ₄ (28 ㎎, 0.743mmol) 2: treated with 3 THF / ethanol (2㎖) The suspension was stirred for 10 min at 0 ℃, and CaCl ₂ (41.2㎎, 0.37mmol) is suspended in, and for 15 minutes After stirring, the solution was treated with a solution of Example 17C (117 mg, 0.37 mmol) dissolved in 2: 3 THF / ethanol (3 mL) and stirred at 0 ° C for 4 hours, then a 20% aqueous acetic acid solution ) And concentrated to remove the low boiling point solvent. The resulting mixture was adjusted to pH 7 with saturated NaHCO ₃ and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel column chromatography using 15% acetone / hexane as an eluent to give the title compound.

_{MS (DCI / NH 3) m} / z 288 (M + H) +;

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.25 (s, 3H), 4.80 (s, 2H), 5.90 (br s, 1H), 7.14 (d, 2H), 7.18 (d, 2H), 7.32 ( s, 1 H), 8.36 (s, 1 H), 9.15 (s, 1 H).

Example 103A

4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

A solution of Example 61A (100 mg, 0.3135 mmol) and methylamine (2 M solution in THF, 0.467 mL, 0.941 mmol) in THF (2 mL) was treated with NaH (12 mg, 0.47 mmol) at 0 & , Stirred at room temperature for 1 hour, then treated with water (0.1 ml) and concentrated. The residue was purified by silica gel flash chromatography with 20% acetone / hexane to give the title compound.

MS (APCI) m / z 319 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H), 7.13 (d, 2H), 7.45 (d, 2H), 8.06 (s, 1H), 8.19 (s, 1H), 8.94 (d , &Lt; / RTI &gt; 1H), 9.16 (s, 1H).

Example 104

4- (4-chlorophenoxy) -N, N-dimethylthieno [2,3-c] pyridine- 2- carboxamide

Example 61A and dimethylamine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 333 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.03 (br s, 3H), 3.12 (br s, 3H), 7.17 (d, 2H), 7.46 (d, 2H), 7.62 (s, 1H), 8.18 (s, 1 H), 9.15 (s, 1 H).

Example 105

N- (4-chlorophenoxy) -N, N-diethylthieno [2,3-c] pyridine- 2- carboxamide

Example 61A and diethylamine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 361 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.09 (m, 6H), 3.42 (m, 4H), 7.15 (d, 2H), 7.45 (d, 2H), 7.49 (s, 1H), 8.74 (s , &Lt; / RTI &gt; 1H), 9.17 (s, 1H).

Example 106

4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyridine-2- carboxamide

Example 61A and cyclopropylamine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 345 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (500MHz, DMSO-} d 6) δ 2.85 (m, 1H), 7.12 (d, 2H), 7.46 (d, 2H), 8.11 (s, 1H), 8.13 (s, 1H), 8.93 (d , &Lt; / RTI &gt; 1H), 9.12 (s, 1H).

Example 107

1 - [[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2- yl] carbonyl] pyrrolidine

Example 61A and pyrrolidine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 359 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.83-1.93 (m, 4H), 3.53 (t, 2H), 3.71 (t, 2H), 7.17 (d, 2H), 7.47 (d, 2H), 7.70 (s, 1 H), 8.16 (s, 1 H), 9.12 (s, 1 H).

Example 108

1 - [[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2- yl] carbonyl] piperidine

Example 61A and piperidine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 373 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.52 (m, 3H), 1.62 (m, 2H), 3.53 (m, 5H), 7.14 (d, 2H), 7.46 (d, 2H), 7.47 (s , &Lt; / RTI &gt; 1H), 8.20 (s, 1H), 9.14 (s, 1H).

Example 109

4 - [[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2- yl] carbonyl]

Example 61A and porphorin were treated as in Example 103A to give the title compound.

MS (APCI) m / z 375 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (500MHz, DMSO-} d 6) δ 3.6 (m, 8H), 7.14 (d, 2H), 7.45 (d, 2H), 7.55 (s, 1h), 8.17 (s, 1H), 9.14 (s , 1H).

Example 110

Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine

Example 61A and methylpiperazine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 388 (M + H) &lt; ⁺ &gt;;

¹ H NMR (400 MHz, DMSO-d ₆ )? 2.2 (s, 3H), 2.32 (br s, 4H), 8.58 (br s, 4H), 7.15 (s, 1 H), 8.2 (d, 1 H), 9.15 (s, 1 H).

Example 111

Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine

Example 61A and phenylpiperazine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 450 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (500MHz, DMSO-} d 6) δ 3.18 (br s, 4H), 3.73 (br s, 4H), 6.81 (t, 1H0, 6.95 (d, 2H), 7.15 (d, 2H), 7.24 ( d, 2H), 7.46 (d, 2H), 7.57 (s, IH), 8.20 (s, IH), 9.17 (s, IH).

Example 112

2,3-c] pyridin-2-yl] carbonyl] -4- (phenylmethyl) -piperazine

Example 61A and benzylpiperazine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 464 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (500MHz, DMSO-} d 6) δ 2.38 (br s, 4H), 3.51 (s, 2H), 3.58 (br s, 4H), 7.13 (d, 2H), 7.32 (m, 5H), 7.45 (d, 2H), 7.47 (s, IH), 8.91 (s, IH), 9.13 (s, IH).

Example 113 Synthesis of

2,3-c] pyridin-2-yl] carbonyl] -4- (2-pyridinyl) -piperazine

Example 61A and 2-pyridylpiperazine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 451 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (500MHz, DMSO-} d 6) δ 3.65 (br s, 4H), 3.85 (br s, 4H), 6.70 (m, 2H), 7.07 (d, 2H), 7.34 (d, 2H), 7.50 (s, IH), 7.54 (m, IH), 8.15 (s, IH), 8.29 (m, IH), 8.96 (s.

Example 114

4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide

Example 61A and ethanolamine were treated as in Example 103A to give the title compound.

_{MS (DCI / NH 3) m} / z 349 (M + H) +;

^{1 H NMR (400MHz, DMSO-} d 6) δ 3.33 (m, 2H), 3.51 (m, 2H), 5.76 (t, 1H), 7.12 (d, 2H), 7.26 (d, 2H), 8.17 (s , 2H), 8.98 (br t, 1 H), 9.14 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 42.3 (N-CH 2), 59.4 (O-CH 2), 119.2 (CH), 119.3 (Ar-CH), 127.6 (C), 130.0 (Ar-CH ), 133.2 (CH), 137.5 (C), 137.9 (C), 141.4 (CH), 146.4 (C), 147.1 (C), 155.6 (C), 160.6 (CO).

Example 115

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -N- Acetate (salt)

Example 61A and N-isopropylpiperazine acetamide were treated as in Example 103A to give the title compound. The residue was purified by C-18 reverse phase HPLC using a gradient of 100% CH ₃ CN and 20% CH ₃ CN / water containing 0.1% trifluoroacetic acid.

MS (APCI) m / z 473 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.09 (m, 6H), 3.05 (br s, 4H), 3.43 (s, 2H), 3.87 (br s, 4H), 7.16 (d, 2H), 7.67 (d, 2H), 7.68 (s, IH), 8.20 (s, IH), 9.18 (s, IH).

Example 116

N- (l- (hydroxymethyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide

Example 61A and DL-2-amino-l-propanol were treated as in Example 103A to give the title compound.

MS (APCI) m / z 363 (M + H) +, 361 (MH) _, 397 (M + Cl) -;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.14 (d, 3H), 3.36-3.40 (m, 1H), 3.43-3.5 (m, 1H), 3.97-4.04 (m, 1H), 4.77 (t, 1H), 7.15 (d, 2H), 7.48 (d, 2H), 8.14 (s, IH), 8.26 (s, IH), 8.67 (d, IH), 9.14

^{13 C NMR (100MHz, DMSO-} d 6) δ16.87 (CH 3), 47.74 (CH), 64.06 (CH 2 OH), 119.16 (3-CH), 119.46 (2xAr-CH), 127.72 (C), CH), 147.61 (C), 147.28 (C), 155.53 (C), 160.01 (CO) .

Example 117

Thiophene [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

Example 61A and 2-amino-2-methyl-l, 3-propanol were treated as in Example 103A to give the title compound.

MS (APCI) m / z 393 (M + H) ⁺ , 391 (MH) ^- , 393 (M + Cl);

^{1 H NMR (400MHz, DMSO-} d 6) δ1.28 (s, 3H), 3.56-3.66 (m, 4H), 4.71 (t, 2H), 7.16 (d, 2H), 7.48 (d, 2H), 7.92 (s, 1 H), 8.11 (s, 1 H), 8.31 (s, 1 H), 9.12 (s, 1 H);

¹³ C (100 MHz, DMSO-d ₆ )? 18.45 (CH ₃ ), 59.80 (C), 63.08 (CH ₂ ), 119.46 (CH), 119.74 (2xAr-CH), 127.83 -CH), 132.53 (CH), 137.43 (C), 137.84 (C), 140.99 (CH), 147.38 (C), 147.50 (C), 155.40 (C), 160.59 (CO);

Example 118

(D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl) thieno [2,3- c] pyridine-

Example 61A and DL-1-amino-2-propanol were treated as in Example 103A to give the title compound.

MS (APCI) m / z 363 (M + H) &lt; ⁺ & gt ^; and 397 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ1.08 (d, 3H), 3.21 (m, 2H), 3.75-3.84 (m, 1H), 4.8 (br s, 1H), 7.14 (d, 2H) , 7.48 (d, 2H), 8.17 (s, IH), 8.22 (s, IH), 8.98 (brs, IH), 9.15

¹³ C NMR (100 MHz, DMSO-d ₆ )? 21.13 (CH ₃ ), 47.24 (CH ₂ ), 64.84 (CH), 119.30 (3-CH), 119.42 (2xAr-CH) 133.05 (CH), 137.48 (C), 137.92 (C), 141.30 (CH), 146.37 (C), 147.16 (C), 155.58 (C), 160.59 (CO).

Example 119

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

Example 61A and 4- (2-aminoethyl) morpholine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 418 (M + H) ⁺ , 452 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ2.41 (t, 4H), 2.48 (m, 2H), 3.40 (m, 2H), 3.56 (t, 4H), 7.15 (d, 2H), 7.47 ( d, 2H), 8.13 (s, IH), 8.17 (s, IH), 8.94 (t, IH), 9.04 (s, IH);

^{13 C NMR (100MHz, DMSO-} d 6) δ36.73 (N-CH 2), 53.21 ( morpholine ring _{2xN-CH 2), 57.07 (} N-CH 2), 66.12 ( morpholine ring 2x-OCH ₂₎ , 119.14 (3-CH), 119.50 (2xAr-CH), 127.73 (C), 130.06 (2xAr-CH), 132.96 (pyridyl ring CH), 137.35 (C), 137.91 CH), 146.20 (C), 147.20 (C), 155.40 (C), 160.45 (CO).

Example 120

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide

To a solution of Example 124A (261 mg, 1 mmol) in anhydrous THF (5 mL) was added tert-Butyl (1.7 M solution in hexanes, 0.647 mL, 1.1 mmol) in a nitrogen atmosphere at -78 deg. The reaction mixture was stirred at -78 ℃ for 15 minutes, which was then injected for 15 minutes, SO ₂ gas in the solution. Then, it was stirred at -72 占 폚 for 2.5 hours and at 0 占 폚 for 4 hours. The reaction mixture was diluted with hexane (10 mL) and evaporated, the residue was suspended in CH ₂ Cl ₂ (5 mL) and treated with N-chlorosuccinimide (214 mg, 1.6 mmol) at 0 ° C . After 2 h at ambient temperature, the reaction mixture was diluted with CH ₂ Cl ₂ and washed with 10% aqueous NaHSO ₃ ( ₃ x 25 mL) and brine (3 x 25 mL). The dried (MgSO ₄ ) organic layer was evaporated to dryness under reduced pressure to give crude sulfonyl chloride as an oil. This was dissolved in acetone (5 mL) and treated with an ice cold solution of NH ₄ OH (5 mL) at 0 ° C. After 2 hours, the reaction mixture was evaporated from toluene at 0 C to give the crude product as an oil. 20% acetone-hexane was used as an eluent, and the resulting product was subjected to silica gel flash chromatography using 40% acetone-hexane to obtain the title compound (57 g, 16%).

^{1 H NMR (400MHz, DMSO-} d 6) δ7.21 (d, J = 9Hz, 2H), 7.51 (d, J = 9Hz, 2H) (s, 1H), 8.14 (br.s, 2H), 8.30 (s, 1 H), 9.27 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ119.65 (CH), 120.88 (CH), 127.94 (C), 130.12 (CH), 133.67 (CH), 135.61 (C), 141.65 (CH) 152.11 (C ), 155.41 (C);

MS (APCI) m / z 341 (M + H) ⁺ , 339 (MH), 375 (M + Cl).

Example 121

4 - [(4-methylphenyl) methyl] thieno [2,3-c] pyridine-

Example 121A

Methyl 4 - [(4-methylphenyl) methyl] thieno [2,3-c] pyridine-

Example 121A was treated as described in J. Org. Chem. 1988, 53, pp. 392-2394. For example, a suspension of Zn dust (92 mg, 1.4 mmol) suspended in THF (2 mL) containing 1,2-dibromoethane (0.05 mL, 0.054 mmol) was heated at 65 &lt; , Cooled to 25 C and then treated with trimethylsilyl chloride (0.009 mL, 0.043 mM), stirred at room temperature for 25 minutes, cooled to 0 C and treated with 4-methylbenzylbromide ( 0.27 mL, 1.0 mmol), warmed to 40 &lt; 0 &gt; C for 3 h and then cooled to -10 [deg.] C and CuCN (106 mg, 1.18 mM) and LiCl (100 mg, 2.35 mM) followed by stirring at 0 ° C for 30 minutes and then slowly treated with a solution of Example 93B (272 mg, 1 mmol) dissolved in THF (5 ml), stirred at 0 ° C for 3 hours, after the temperature was raised to 25 ℃ over time, a washing treatment with ethyl acetate, successively with a saturated NH ₄ Cl and brine, dried (MgSO ₄₎ and filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound.

Example 121B

4 - [(4-methylphenyl) methyl] thieno [2,3-c] pyridine-2- carboxamide

Example 121A was treated as in Example 44 to give the title compound.

Example 122

Methyl 4- (morpholinyl) thieno [2,3-c] pyridine-2-carboxamide

Example 122 (241 mg, 72%) was prepared as described in example 308 using 4-dioxo-8-azaspiro [4,5] decane (0.256 ml, 2 mmol) .

^{1 H NMR (400MHz, DMSO-} d 6) δ1.91 (m, 4H), 2.85 (d, J = 4Hz, 3H), 3.25 (m, 4H), 3.96 (s, 4H), 8.10 (s, 1H ), 8.12 (s, 1 H), 8.87 (s, 1 H), 8.96 (d, J = 4 Hz, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ26.1 (CH 3), 35.0 (CH 2), 49.7 (CH 2), 63.8 (CH 2), 69.8 (CH 2), 106.1 (C), 121.3 ( CH), 132.0 (CH), 136.9 (C), 138.3 (C), 138.7 (CH), 143.6 (C), 143.8 (C), 161.3 (C);

MS (APCI) m / e 334 (M + H) ⁺ , 368 (M + Cl) ^- .

Example 123

Thieno [2,3-c] pyridine-2-carboxylic acid, N-oxide

Example 123A

Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid,

A solution of methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate (319 mg, 1 mmol) in dichloromethane (15 mL) (302 mg, 1.75 mmol), stirred at 0 ° C for 0.5 hour and at room temperature for 4 hours, washed successively with water, saturated sodium bicarbonate, water and brine, dried (Na ₂ SO ₄ ) Filtration and concentration afforded the title compound.

_{MS (DCI / NH 3) m} / z336 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.89 (s, 3H), 7.30 (m, 2H), 7.52 (m, 2H), 7.84 (s, 1H), 7.88 (s, 1H), 9.02 ( s, 1H).

Example 123B

(4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, N-oxide

Example 123A was treated as in Example 44 to give the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ )? 7.30 (m, 2H), 7.52 (m, 2H), 7.74 8.34 (br s, 1 H), 8.93 (s, 1 H).

Example 124

2- (2-methoxyphenyl) thieno [2,3-c] pyridine

Example 124A

4- (4-chlorophenoxy) thieno [2,3-c] pyridine

Example 88 (4.5 g, 14.75 mmol) was added to a solution of diphenyl ether (55 mL) at 210 占 폚 and maintained at this temperature for 10 hours. The reaction mixture was cooled and purified directly by silica gel flash chromatography using hexane as eluent, then 10% acetone-hexane to give the title compound (3.83 g, 99.5%).

_{MS (DCI / NH 3) m} / e 262 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.09 (d, J = 9Hz, 2H), 7.35 (d, J = 6Hz, 1H), 7.45 (d, J = 9Hz, 2H), 8.13 (d, J = 6 Hz, 1 H), 8.18 (s, 1 H), 9.15 (s, 1 H);

Elemental analysis for C ₁₃ H ₈ Cl ₁ N ₁ O ₁ S ₁ :

Calculated: C, 59.66; H, 3.08; N, 5.35.

Found: C, 59.52; H, 3.08; N, 5.15.

Example 124B

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-boronic acid

A solution of sec-butyllithium (0.92 mmol) in THF (2 mL) was added dropwise to Example 124A in THF (1 mL) at -78 <0> C and stirred at -78 <0> C for 30 min, tributylborate , Then stirred at -78 ° C for 5 minutes and at room temperature for 45 minutes, treated with 2M NaOH (3 mL), stirred for 5 minutes, washed with hexane and acidified to pH 2 with 6M HCl Respectively. The resulting precipitate was collected and dried in vacuo to give the title compound.

MS (APCI) m / z 262, 264 (M + HB (OH) ₂ ) ⁺ , 340, and 342 (M + Cl-) ^- ;

¹ H NMR (300 MHz, CD ₃ OD)? 7.29 (d, 2H), 7.53 (d, 2H), 8.08 (s, 1H), 8.11

Example 124C

2- (2-methoxyphenyl) thieno [2,3-c] pyridine

The title compound was obtained by treating 2-iodoanisole instead of Example 93B and Example 124B as in Example 95 but using 4- (trifluoromethyl) phenylboronic acid in place of Example 124B .

Example 125

4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide

Example 125A

Methyl 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylate

4-Chlorophenol was dissolved in THF (20 mL), treated with 1M potassium t-butoxide (13 mL, 13 mmol) and stirred at room temperature for 1 hour. To this solution was added Example 17A (1.76 g, 10 mmol) in THF (5 mL). The reaction was heated at 70 &lt; 0 &gt; C for 4 h and cooled to room temperature. Added to water, diluted with brine, and extracted with ethyl acetate. The ethyl acetate was washed (3 x 20 mL), dried and evaporated. The residue was dissolved in THF (20 mL), then cooled in an ice bath and 3M methylmagnesium bromide in ethyl ether (4 mL, 12 mmol) was added. The reaction was stirred at room temperature overnight. The excess Grignard reagent was broken down with saturated aqueous ammonium chloride (25 ml) and then extracted with ethyl acetate (3 x 25 ml). The ethyl acetate was washed with brine (3 x 25 mL), dried and evaporated to obtain the objective phenoxy compound. The alcohol was then oxidized by succinic acid using the following conditions. Dimethyl sulfoxide (1.85 ml, 24 mmol) was added to the solution cooled to -78 캜 and oxalyl chloride (1.1 ml, 12 mmol) dissolved in anhydrous methylene chloride (20 ml) for 30 minutes. A solution of the phenoxy alcohol dissolved in methylene chloride (20 ml) was then added over 15 minutes. Triethylamine (7.5 ml) was added and the reaction was allowed to warm to room temperature over 2 hours. Ice water was then added and the mixture was extracted with ethyl acetate. The ethyl acetate was washed with brine (3 x 20 mL), dried and evaporated. Methyl thioglycolate (0.88 ml, 10 mmol) and cesium carbonate (3.2 g, 10 mmol) were added to a 0 ° C solution of the residue dissolved in THF (20 ml). The reaction was then heated at 70 &lt; 0 &gt; C for 1 hour, cooled, then added to water, diluted with brine, and extracted with ethyl acetate. The ethyl acetate was then washed with 1 N NaOH (2 x 20 mL), brine (3 x 20 mL), dried and evaporated to give an oil. The oil was triturated with methanol to give the title compound.

mp 140-141 [deg.] C;

MS (DCI / NH) m / e 334 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.80 (s, 3H), 3.90 (s, 3H), 7.22 (d, 2H), 7.45 (d, 2H), 8.12 (s, 1H), 9.15 ( s, 1H);

Elemental analysis for C ₁₆ H ₁₂ ClNO ₃ S 0.5 H ₂ O:

Calculated: C, 56.06; H, 3.82; N, 4.09.

Found: C, 56.03; H, 3.43; N, 3.71.

Example 125B

3-methylthieno [2,3-c] pyridine-2-carboxylic acid (4-chlorophenoxy)

A solution of Example 125A (1.1 g, 3.3 mmol) and LiOH.H ₂ O (0.30 g, 6.9 mmol) in THF (20 mL) and H ₂ O (10 mL) was heated at 50 & , Cooled, acidified with formic acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3 x 15 mL), then dried and evaporated to give the title compound as a white solid.

mp 315-317 [deg.] C;

_{MS (DCI / NH 3) m} / e 320 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.76 (s, 3H), 3.30 (m, 1H), 7.10 (d, 2H), 7.45 (d, 2H), 8.12 (s, 1H), 9.15 ( s, 1H);

Example 125C

4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide

Example 125B was treated as in Example 92 to give the title compound.

mp 174-175 [deg.] C;

_{MS (DCI / NH 3) m} / e 319 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.55 (s, 3H), 7.05 (d, 2H), 7.45 (d, 2H), 7.90 (m, 1H), 7.95 (m, 1H), 8.15 ( s, 1 H), 9.12 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₁ ClN ₂ O ₂ S:

Calculated: C, 56.52; H, 3.48; N, 8.79.

Found: C, 56.36; H, 3.50; N, 8.69

Example 126

4- (4-chlorophenoxy) -3-hydroxcityeno [2,3-c] pyridine-2- carboxamide

Example 126A

Ethyl 3,5-dichloropyridine-4-carboxylate

A stirred solution of lithium diisopropylamide (45 mL, 1.5 M in THF, 67.6 mmol) in 150 mL of THF at -78 <0> C was treated with 3,5-dichloropyridine (10 g, 67.6 mmol) , Treated at -78 ° C for 1 hour, treated with ethyl chloroformate (9.5ml, 100mmol), stirred for 2 hours, then added to a saturated solution of sodium bicarbonate (200ml) at 0 ° C, Treat with diethyl ether (200 mL) and extract with ethyl ether (2 x 100 mL). The extract was washed successively with saturated sodium bicarbonate solution (2x100㎖), brine (2x100㎖), dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography with hexane / ethyl acetate to give the title compound.

Example 126B

Methyl 4- (4-chlorophenoxy) -3-hydroxcityeno [2,3-c] pyridine-2-carboxylate

Example 126A was treated as in Example 61A to give the title compound.

Example 126C

4- (4-chlorophenoxy) -3-hydroxcityeno [2,3-c] pyridine-2- carboxamide

Example 126B was treated as in Example 61B to give the title compound.

Example 127

(4-chlorophenoxy) -3- (1-methylethoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 127 was prepared as described in J. Medicinal. 1992,35, p. 958. &lt; / RTI &gt; Example 126C (0.10 g, 0.3 mmol) in cesium carbonate (1.0 g, 0.1 mmol) and 50 mL of THF was treated with 2-bromopropane (0.37 g, 0.3 mmol), heated for 2 hours, , Extracted with ethyl ether, washed successively with 1N aqueous sodium hydroxide and brine, and concentrated. The residue was purified by silica gel flash chromatography with hexane-acetone (7: 3) to give the title compound.

Example 128

3-Bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine

The method described in Arkiv For Kemi (1970-74), 32, p.249 can be used. Example 124A in thionyl chloride was treated with bromine at 90 &lt; 0 &gt; C for 4 hours to give the title compound.

Example 129

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3-carboxylic acid

The method described in Arkiv For Kemi (1970-74), 32, p.249 can be used. Example 128, cooled to -78 占 폚, was treated with ethyllithium and then reacted with carbon dioxide to give the title compound.

Example 130

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3-carboxamide

Example 129 was treated as in Example 19 to give the title compound.

Example 131

Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 131A

3,5-Dichloropyridine-4-carbonitrile

Example 17A (2.0 g, 11.4 mmol) in formic acid (10 mL) was treated with hydroxylamine hydrochloride (1.04 g, 11.4 mmol) and concentrated sulfuric acid (0.05 mL), refluxed for 18 h and then concentrated. The residue was a 1: 1 ethyl acetate-water fraction Chemistry, saturated sodium bicarbonate solution, water, and subsequently washed with brine, dried (Na ₂ SO ₄₎ and concentrated. The residue was recrystallized from hexane to give the title compound.

mp 117-118 [deg.] C;

¹ H NMR (300 MHz, CDCl ₃ )? 8.70 (S);

IR (KBr, v cm ^-1 ) 1710, 1525, 1400, 1250, 1190, 1100, 920, 820, 800, 750.

Example 131B

Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-

A solution of 4-chlorophenyl (1.12 g, 8.72 mmol) in THF (20 mL) at 0 ° C was treated with potassium t-butoxide solution (8.72 mL, 8.72 mmol, IM in THF) And treated with Example 131A (1.5 g, 8.72 mmol) in THF (10 mL) at 0 C, then warmed to room temperature, stirred overnight, concentrated and chromatographed with 1: 1 ethyl acetate- And then extracted. The extract was washed with brine, dried (Na ₂ SO ₄₎ and concentrated. A solution of the concentrate in DMF (50 mL) was treated with potassium carbonate (2.42 g, 17.51 mmol) and methyl thioglycolate (778 L, 8.72 mmol) at 0 ° C and warmed to room temperature and stirred overnight And added to the ether (400 mL). The organic layer was washed with brine, dried (Na ₂ SO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography with 0-5% acetone-hexane to give the title compound.

mp 194-196 [deg.] C;

MS (APCI) m / z 335 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.81 (s, 3H), 6.86 (br s, 2H), 7.22-7.32 (m, 2H), 7.45-7.56 (m, 2H), 7.88 (s, 1H), &lt; / RTI &gt; 8.89 (s, 1H);

Elemental analysis for C ₁₅ H ₁₁ ClN ₂ O ₃ S:

Calculated: C, 53.81; H, 3.31; N, 8.36.

Found: C, 53.80; H, 3.27; N, 8.27.

Example 131C

Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid

The title compound was prepared from the compound of Example 131B using the procedure of Example 18.

mp 173-176 [deg.] C (decomposition);

^{1 H NMR (300MHz, DMSO-} d 6) δ7.29 (m, 2H), 7.52 (m, 2H), 7.88 (s, 1H), 8.89 (s, 1H);

MS (ESI) m / e 321 (M + H) &lt; ⁺ &gt;;

Elemental analysis for C ₁₄ H ₉ ClN ₂ O ₃ S0.25H ₂ O:

Calculated: C, 51.70; H, 2.94; N, 8.61.

Example 131D

Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

A solution of Example 131C (96 mg, 0.3 mmol) in DMF (2 mL) was treated with 1-hydroxybenzotriazole hydrate (67 mg, 0.44 mmol), NH ₄ Cl (61 mg, 1.14 mmol) Was treated with methyl morpholine (100 쨉 l, 0.9 mmol), cooled to 0 째 C and then treated with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) , Warmed to room temperature, stirred overnight, added to saturated NaHCO ₃ , collected, washed with water and dried. The residue was recrystallized from methanol / toluene / hexane to give the title compound.

mp 202-204 [deg.] C;

MS (APCI) m / z 320 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ6.84 (br s, 2H), 7.21-7.30 (m, 2H), 7.39 (br s, 2H), 7.47-7.56 (m, 2H), 7.88 (s , &Lt; / RTI &gt; 1H), 8.90 (s, 1H);

Elemental analysis for C ₁₄ H ₁₀ ClN ₃ O ₂ S:

Calculated: C, 52.58; H, 3.15; N, 13.14.

Found: C, 52.63; H, 3.18; N, 13.12.

Example 132A

Ethyl 4-chlorothieno [2,3-b] pyridine-5-carboxylate

Example 132A was prepared as described in J. Heterocyclic Chem. 1977, 14, pp. 807-812) to give the title compound.

mp 71-72 [deg.] C;

_{MS (DCI / NH 3) m} / z 259 (MH) +; ^{_{242 (M + NH 4) +}} ;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.37 (t, 3H), 4.41 (q, 2H), 7.64 (d, IH), 8.17 (d, IH), 8.95

Elemental analysis for C ₁₀ H ₈ ClNO ₂ S:

Calculated: C, 49.69; H, 3.33; N, 5.79; S, 13.26.

Found: C, 49.46; H, 3.13; N, 5.62; S, 13.42.

Example 132B

Ethyl 4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-5-

Example 132A and thiocresol were treated as in Example 2 to give the title compound.

mp 60-63 [deg.] C;

_{MS (DCI / NH 3) m} / z 347 (M + NH 4) + and 330 (M ⁺ H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 1.30 (t, 3H), 2.28 (s, 3H), 4.26 (q, 2H), 7.00 (d, 1H), 7.17 (m, 2H), 7.24 (m, 2H), 7.91 (d, 1 H), 8.81 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₅ NO ₂ S ₂ :

Calculated: C, 61.98; H, 4.59; N, 4.25.

Found: C, 61.92, H, 4.53, N, 4.21.

Example 132C

4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine

Example 132B was treated as in examples 18 and 42 to give the title compound.

mp 90-92 [deg.] C;

_{MS (DCI / NH 3) m} / z 275 (M + NH 4) + and 258 (M ⁺ H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.39 (s, 3H), 6.66 (d, 1H), 7.38 (m, 2H), 7.46 (d, 1H), 7.53 (m, 2H), 7.46 ( d, 1 H), 7.53 (m, 2 H), 7.95 (d, 1 H), 8.12 (d, 1 H);

Elemental analysis for C ₁₄ H ₁₁ NS ₂ :

Calculated: C, 65.33; H, 4.30; N, 5.44.

Found: C, 65.40; H, 4.26, N, 5.26.

Example 132D

4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- 2- carboxamide

A solution of diisopropylamine (0.056 g, 0.56 mmol) in THF (10 mL) at -78 ° C was treated with n-butyllithium (0.22 mL, 0.56 mmol, 2.5 M in hexanes) and stirred for 15 min , Treated with Example 132C (0.13 g, 0.51 mmol) in THF (5 mL), stirred for 0.5 h, then warmed to 0 &lt; 0 &gt; C for 1 min, ₂ , and the mixture was stirred for 0.5 hour. It was then diluted with saturated NH ₄ Cl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound.

mp 280-282 [deg.] C;

_{MS (DCk / NH 3) m} / z 318 (M + NH 4) + and 301 (M ⁺ H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.41 (s, 3H), 6.62 (d, 1H), 7.40 (m, 2H), 7.57 (m, 2H), 7.77 (br s, 1H), 8.26 (s, 1 H), 8.36 (d, 1 H), 8.43 (br s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.97; H, 4.02; N, 9.32.

Found: C, 59.83; H, 4.03; N, 9.11.

Example 133

Chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5- carboxamide

The title compound was obtained by treating Example 132A as in Examples 18 and 19 using 4-chloroaniline instead of concentrated NH ₄ OH in Example 19.

mp 199-202 [deg.] C;

_{MS (DCI / NH 3) m} / z 340 (M + NH 4) +, 342 (M + NH 4) +, 323 (M + H) +, 325 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.6 (m, 2H), 7.62 (d, 1H), 7.77 (m, 2H), 8.19 (d, 1H), 8.79

Elemental analysis for C ₁₄ H ₈ Cl ₂ N ₂ OS ₂ :

Calculated: C, 52.03; H, 2.49; N, 8.67.

Found: C, 52.02; H, 2.15; N, 8.50.

Example 134

Ethyl 4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3- b] pyridine-5-

Example 132A and 5-methyl-l, 3,4-thiadiazole-2-thiol were treated as in Example 17B to give the title compound.

mp 93-94 [deg.] C;

_{MS (DCI / NH 3) m} / z 355 (M + NH 4) + and 238 (M ⁺ H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.32 (t, 3H), 2.66 (s, 3H), 4.36 (q, 2H), 7.34 (d, 1H), 8.13 (d, 1H), 9.00 (s , 1H);

Elemental analysis for C ₁₃ H ₁₁ N ₃ O ₂ S ₃ :

Calculated: C, 46.27; H, 3.28; N, 12.45; S, 28.50.

Found: C, 46.04; H, 3.20; N, 12.32; S, 28.39.

Example 135

7 - [(4-methylphenyl) thio] thieno [3,2-b] pyridine- 2- carboxamide

Ethyl 7-chlorothieno [3,2-b] pyridine-6-carboxylate was processed as in Example 17B, 18 and 19 to give the title compound.

_{MS (DCI / NH 3) m} / z 301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.38 (s, 3H), 6.83 (d, 1H), 7.37 (m, 2H), 7.56 (m, 2H), 7.83 (br s, 1H), 8.25 (s, 1 H), 8.41 (br s, 1 H), 8.53 (d, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.98; H, 4.03; N, 9.33.

Found: C, 59.79; H, 4.01; N, 9.16.

Example 136

Methyl 6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-

Example 136A

2,5-Dichloro-3-pyridinecarbonitrile

Example 136B

Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate

Example 136A and methyl thioglycolate were treated as in Example 1D to give the title compound.

Example 136C

Methyl 6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-

To a solution of Example 136B (32 g, 1.34 mmol) in 75% H ₂ SO ₄ (7.4 mL) at 0 ° C was added dropwise aqueous NaNO ₂ (0.24 g / 1.5 mL, 3.5 mmol) Was added to the cold 50% H ₂ PO ₃ (11.8 mL), stirred for 30 minutes, then stored at 0 ° C for 60 hours, then warmed to room temperature, treated with NaHCO ₃ and extracted with ether . The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was dissolved in methanol (7 ㎖) and, after heating to 50 ℃, NaOCH successively with ₃ (0.08g, 1.45mmol) and p- thio-cresol (0.18g, 1.45mmol) and treated, at room temperature for 18 hours Stirred, and concentrated. The residue was treated with 10% citric acid and extracted with dichloromethane. The extracts were dried (MgSO ₄₎ and concentrated by filtration and back. The residue was purified by silica gel flash chromatography using 25% ethyl acetate / hexane to give the title compound.

mp 127-130 [deg.] C;

_{MS (DCI / NH 3) m} / z 316 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 2.39 (s, 3H), 3.89 (s, 3H), 7.02 (d, 7.36 (m, 2H)), 7.57 (m, 2H), 8.13 (s, 1H) , 8.23 (d, 1 H);

Elemental analysis for C ₁₆ H ₁₃ NO ₂ S ₂ :

Calculated: C, 60.93; H, 4.15; N, 4.44.

Found: C, 60.79; H, 4.18; N, 4.35.

Example 137

6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-2- carboxamide

The title compound can be prepared from the compound of Example 136C using the procedure of Example 44. LCMS:

Example 138

2-Bromo-4 - [(4-methylphenyl) thio] thieno [3,2- c] pyridine

(500 mg, 4 mmol) in DMF (10 mL) was treated with potassium t-butoxide (451 mg, 4 mmol) at room temperature and cooled to 0 &lt; 0 &gt; C after 15 min. 2-Bromo- Thieno [3,2-c] pyridine (prepared in 6 steps according to the method of F. Eloy and A. Deryckere (Bull. Soc. Chim.Belg. 1970, 79, 301)] (1.0 g, 4.0 mmol ), And the mixture was stirred at 0 ° C for 2 hours and at room temperature for 12 hours, added to water and extracted with diethyl ether. The extract was washed with water, dried (Na ₂ SO ₄ ) . The residue was purified by silica gel flash chromatography using 1: 20 ethyl acetate-hexane to give the title compound.

_{MS (DCI / NH 3) m} / z 336, 338 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ2.36 (s, 3H), 7.18 (d, 2H), 7.40 (d, 2H), 7.48 (br s, 1H), 7.52 (br d, 1H), 8.16 ( d, 1H).

Example 139

4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine-2- carboxamide

Example 139A

4-Chlorothieno [3,2-c] pyridine-2-carbonitrile

4-oxo-4,5-dihydrothieno [3,2-c] pyridine-2-nitrile (500 mg, 2.84 mmol, F. Eloy and A. Derickere (Bull. 79, 301) and phosphoryl chloride (5 ml) was heated to reflux for 1 hour The resulting red solution was added to ice and extracted with methylene chloride (2 x 150 ml). A dichloromethane solution Dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography with 1:10 EtOAc / hexane to give the title compound.

_{MS (DCI / NH 3) m} / z195 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.74 (d, 1H), 8.10 (s, 1H), 8.41 (d, 1H).

Example 139B

4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-carbonitrile

A solution of para-thiocresol (192 mg, 1.54 mmol) dissolved in DMF (5 mL) at room temperature was treated with potassium tert-butoxide (173 mg, 1.54 mmol), stirred for 15 min, Then at room temperature for 48 h, then treated with water and extracted with dichloromethane. The extracts were dried (MgSO _4), filtered and concentrated. The residue was purified by silica gel flash chromatography with 1: 7 ethyl acetate-hexane to give the title compound.

IR (KBr, cm- ¹ ) 2200 (w, CN), 1550 (s), 1520 (s) cm- ¹ ;

_{MS (DCI / NH 3) m} / z283 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 2.40 (s, 3H), 7.25 (d, 2H), 7.47 (d, 2H), 7.49 (d, 1H), 8.07 (s, 1H), 8.33 (d, 1H );

Elemental analysis for C ₁₅ H ₁₀ N ₂ S ₂ :

Calculated: C, 63.80; H, 3.57; N, 9.92%.

Found: C, 63.80; H, 3.52; N, 9.98.

Example 139C

4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine-2- carboxamide

A solution of Example 139B (198 mg, 0.7 mmol) in polyphosphoric acid (5 mL) was heated at 110 &lt; 0 &gt; C for 3 h, cooled, treated with water and extracted with dichloromethane. The extracts were dried (MgSO _4), filtered and concentrated. The residue was purified by silica gel flash chromatography with 4: 5 ethyl acetate-hexane to give the title compound.

IR (KBr) 3300 (m), 3130 (s), 1660 (s), 1600 (s);

_{MS (DCI / NH 3) m} / z301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.36 (s, 3H), 7.28 (d, 2H), 7.47 (d, 2H), 7.78 (br s, 1H), 7.84 (d, 1H), 8.19 (d, 1 H), 8.34 (s, 1 H), 8.46 (br s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ OS ₂ :

Calculated: C, 59.98; H, 4.03; N, 9.33.

Found: C, 59.77; H, 3.88; N, 9.15.

Example 140

4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboxamide

Example 140A

4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonitrile

Example 139A and 4-methylphenol were treated as in Example 139B to give the title compound.

IR (KBr) 2200 (w), 1580 (s), 1540 (s), 1500 (s), 1440 (s) cm- ¹ ;

_{MS (DCI / NH 3) m} / z267 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ2.39 (s, 3H), 7.09 (dt, 2H), 7.25 (br d, 2H), 7.43 (dd, 1H), 8.10 (d, 1H), 8.21 (s , 1H);

Elemental analysis for C ₁₅ H ₁₀ N ₂ OS:

Calculated: C, 67.65; H, 3.78; N, 1052.

Found: C, 67.60; H, 3.66; N, 10.48.

Example 140B

4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboxamide

Example 140A was treated as in Example 139C to give the title compound.

IR (KBr) 3400 (m), 1680 (m), 1650 (s), 1600 (s), 1500 (s) cm ^-1 .

_{MS (DCI / NH 3) m} / z285 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.34 (s, 3H), 7.13 (d, 2H), 7.25 (d, 2H), 7.75 (d, 1H), 7.76 (br s, 1H), 7.95 (d, 1 H), 8.38 (br s, 1 H), 8.41 (s, 1 H);

Elemental analysis for C ₁₅ H ₁₂ N ₂ O ₂ S:

Calculated: C, 63.36; H, 4.25; N, 9.85.

Found: C, 63.16; H, 4.18; N, 9.77.

Example 141

7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2-carboxamide

Example 141A

3-Chloropyridine-N-oxide

Example 141A was treated as described in Caldwell and Martin, J. Heterocyclic Chem., 1980, 17, 989. A solution of 3-chloropyridine (15.0 g, 132 mmol) dissolved in acetic anhydride (75 mL) was treated with hydrogen peroxide (75 mL of 30% aqueous solution) so that the internal temperature remained below 30 DEG C and stirred at room temperature for 3 hours Then, it was heated at 60 占 폚 for 18 hours, diluted with water (200 ml), concentrated, and solid sodium bisulfite was added in portions until the peroxide was no longer detected (by enzymatic peroxide test). The remaining solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The washings were filtered and concentrated to give the title compound.

Example 141B

4-Nitro-3-chloropyridine-N-oxide

Example 141B was treated as described in Caldwell and Martin, J. Heterocyclic Chem., 1980, 17, 989. Sulfuric acid (25㎖, 98%), fuming sulfuric acid (30% SO _3, 10㎖) and nitric acid carried out (60㎖, 90%) Example 141A (16.8g, 130mmol) is heated in a 120 ℃ for 2 hours, and room temperature , Added to ice water (200 ml) and then added with solid ammonium carbonate to pH = 9 of the solution and extracted with methylene chloride (4 x 100 ml). The extracts were dried (Na ₂ SO ₄₎ and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the purified title compound as a primary product. Recrystallization of the secondary product provided a mixture of the title compound and the by-product.

_{MS (DCI / NH 3) m} / z 194 (37 Cl) / 192 (35 Cl), (M + NH 4) +; 177 ( ³⁷ CI) / 175 ( ³⁵ CI), (M + H) ⁺ ;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ8.01 (d, 1H), 8.14 (dd, 1H), 8.32 (d, 1H).

Example 141C

4-nitro-3- (4-methylphenoxy) pyridine-N-oxide

NaH (834 mg, 34.8 mmol) in DMF (20 ml) was successively treated with p-cresol (3.57 g, 33.0 mmol), Example 141B (5.75 g, 32.9 mmol) at room temperature and stirred at room temperature for 10 min , Then partitioned between ethyl acetate and 1N aqueous HCl. The aqueous phase was separated and washed with ethyl acetate. The organic phase was washed with 1N aqueous HCl, dried (Na ₃ SO ₄ ) and concentrated.

Recrystallization from diethyl ether gave the title compound.

_{MS (DCI / NH 3) m} / z 264 (MhNH) +, 247 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.39 (s, 3H), 7.02 (d, 2H), 7.26 (d, 2H), 7.78 (d, 1H), 7.89 (dd, 1H), 7.98 (d, 2H).

Example 141D

3- (4-Methylphenoxy) -4-pyridinamine

Example 141C (3.65 g, 14.8 mmol) was dissolved in methanol (100 mL), treated with Raney nickel (1.00 g), washed with hydrogen, pressurized at 4 atm for 2.5 h at 37 [ . The filtrate was concentrated to give the title compound.

_{MS (DCI / NH 3) m} / z 201 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.32 (s, 23H), 4.40 (br s, 2H), 6.68 (br s, 1H), 6.88 (d, 2H), 7.12 (d, 2H), 8.01 ( m, 2H).

Example 141E

2,2-dimethyl-N- [3- (4-methylphenoxy) -4-pyridinyl] propanamide

Example 141D (2.80 g, 14.0 mmol) was dissolved in methylene chloride (50 mL), cooled to 0 C and treated with triethylamine (1.78 g, 17.6 mmol) and trimethylacetyl chloride (1.86 g, 15.4 mmol) Treated for 15 hours at room temperature, and then added to water (100 ml) containing a slight amount of sodium chloride. The organic layer was separated, then treated with activated charcoal, filtered through Celite (registered trade mark), washed with saturated sodium bicarbonate solution, dried (Na ₂ SO ₄₎ and concentrated to give the title compound.

_{MS (DCI / NH 3) m} / z 285 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 1.24 (s, 9H), 2.35 (s, 3H), 6.93 (d, 2H), 7.18 (d, 2H), 8.14 (br s, 1H), 8.15 (s, 1H), 8.32 (d, 1 H), 8.42 (d, 1 H).

Example 141F

5-hydroxy-4- (N-trimethylacetyl) amino-3- (4-methylphenoxy)

The procedure of Chu-Moyer and Berger (J. Org. Chem. 1995, 60, 5721) was used. Example 141E (5.50 g, 19.3 mmol) was dissolved in diethyl ether and cooled to -78 &lt; 0 &gt; C. Tert-butyllithium (1.7 M solution in pentane, 24.0 mL, 40.8 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. Trimethylborate (5.01 g, 48.3 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 18 hours. Glacial acetic acid (3.9 ml) was added followed by a 30% aqueous hydrogen peroxide solution (5.8 ml). The reaction was stirred at room temperature for 2 hours and added to water. The resulting mixture was washed twice with CH ₂ Cl ₂ , the organic layer was treated with activated charcoal, and filtered through celite. The filtrate was washed once with water, once with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a mixture of two compounds (higher R _f is preferred). The mixture was purified by flash silica gel using a 40M Biotage cartridge, 1.5% methanol in eluent CH ₂ Cl ₂ to give 0.15 mmol (15% yield) of the desired product and 0.73 mmol (73%) of the title compound.

_{MS (DCI / NH 3) m} / e 301 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 1.20 (s, 9H), 2.27 (s, 3H), 6.84 (d, 2H), 7.09 (d, 2H), 7.65 (br s, 1H), 8.08 (s, 1H), 8.14 (br s, 1 H), 10.26 (br s, 1 H).

Example 141G

5-hydroxy-4-amino-3- (4-methylphenoxy) pyridine

Example 141F (850 mg, 2.83 mmol) was suspended in 3N aqueous HCl and stirred at 90 &lt; 0 &gt; C for 18 h. The reaction was cooled to 0 ℃, and was neutralized with 6N aqueous NaOH, and extracted with CH ₂ Cl _2. The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the desired product (612 mg, 100% yield).

_{MS (DCI / NH 3) m} / e 217 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.25 (s, 3H), 5.16 (s, 2H), 6.81 (d, 2H), 7.12 (d, 2H), 7.50 (s, 1H), 7.71 ( s, 1 H), 8.14 (s, 1 H), 9.55 (br s, 1 H).

Example 141H

Methyloxazolo [5,4-c] -4- (4-methylphenoxy) pyridine-2-carboxylate

Pyridine (1.10 mmol) and methyloxalyl chloride (1.10 mmol) were added to Example 141G (1.00 mmol) in DMF and the resulting solution was stirred at room temperature overnight. The reaction was partitioned between methylene chloride and 1N aqueous HCl, and the organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound.

Example 141I

Oxazolo [5,4-c] -4- (4-methylphenoxy) pyridine-2- carboxamide

Example 141H was treated according to the procedure of Example 44 to give the title compound.

Example 142 [

7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-2- carboxamide

Example 142A

5- (N, N-dimethylthiuram) sulfide-4- (N-trimethylacetyl) amino-3- (4-methylphenoxy)

Example 141E (284 mg, 1.00 mmol) in diethyl ether (12 mL) was treated dropwise with tert-butyllithium (1.3 mL of a 1.7 M solution in pentane, 2.21 mmol, Aldrich) 78 C &lt; / RTI &gt; for 3 hours. Tetramethylthiuram disulfide (529 mg, 2.20 mmol) was added to the resulting zine ion, and stirring and heating were continued for 18 hours. The reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The title compound (50 mg, 12% yield) was isolated by rapid silica gel column chromatography.

_{MS (DCI / NH 3) m} / e 404 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.32 (s, 3H), 3.55 (s, 3H), 3.58 (s, 3H), 6.92 (d, 2H), 7.12 (d, 2H), 7.93 (s, 1H), 8.43 (s, 1 H), 8.45 (s, 1 H).

Example 142B

5- (N, N-dimethylthiuram) sulfide-4-amino-3- (4-methylphenoxy)

Example 142A (270 mg, 0.67 mmol) was combined with formic acid (96%, 20 mL, Aldrich) and stirred at 90 占 폚 for 72 hours. The reaction was cooled to room temperature and formic acid was removed under reduced pressure. The resulting residue was purified by rapid silica gel chromatography (70% EtOAc in hexanes) to give the title compound (96 mg, 45% yield).

_{MS (DCI / NH 3) m} / e 320 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.33 (s, 3H), 3.56 (s, 3H), 3.58 (s, 3H), 4.93 (br s, 2H), 6.94 (d, 2H), 7.15 (d , 2H), 8.04 (s, 1 H), 8.12 (s, 1 H).

Example 142C

5- (N, N-dimethylthiuram) sulfide-4-methyloxamate-3- (4-methylphenoxy)

Example 142B (90 mg, 0.28 mmol) was combined with CH ₂ Cl ₂ (7.0 mL). Triethylamine (0.39 mL, 2.2 mmol) was added followed by methyl oxalyl chloride (120 mL, 1.30 mmol, Aldrich). After 6 h, the mixture was combined with a saturated aqueous sodium bicarbonate solution and extracted three times with CH ₂ Cl ₂ . The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure.

_{MS (DCI / NH 3) m} / e 406 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.33 (s, 3H), 3.54 (s, 3H), 3.58 (s, 3H), 3.90 (s, 3H), 7.00 (d, 2H), 7.15 (d, 2H), 8.37 (s, 1 H), 8.41 (s, 1 H), 9.20 (br s, 1 H).

Example 142D

Methyl 4- (4-methylphenoxy) thiazolo [5,4-c] -pyridine-2-carboxylate

Example 142C (50 mg, 0.12 mmol) was dissolved in formic acid (14 mL, 96%, Aldrich) and heated to reflux. After 4 hours, the reaction was cooled and volatiles were removed. Rapid silica gel column chromatography (60% EtOAc in hexanes) gave the title compound (15 mg, 39% yield) as a white solid.

_{MS (DCI / NH 3) m} / e 301 (M + H) +, 318 (M + NH 3) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) 2.39 (s, 3H), 4.10 (s, 3H), 7.08 (d, J = 8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 8.14 (s , &Lt; / RTI &gt; 1H), 9.00 (s, 1H).

Example 142E

4- (4-methylphenoxy) thiazole [5,4-c] -pyridine-2-carboxamide

Example 142D (2.0 mg, 6.7 mmol) was treated according to the procedure of Example 44 to give the title compound (1.5 mg, 75%) as a white solid.

_{MS (DCI / NH 3) m} / e 286 (M + H) +, 303 (M + NH 3) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ2.39 (s, 3H), 5.66 (br s, 1H), 7.06 (d, J = 8.2Hz, 2H), 7.22 (d, J = 7.8Hz, 2H), 7.32 (br s, 1 H), 8.20 (s, 1 H), 9.04 (s, 1 H).

Example 143

7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2- carboxamide

Example 143A

N- [3-amino-5- (4-methylphenoxy) -4-pyridinyl] -2,2-dimethylpropanamide

Example 141F (1.00 mmol) was suspended in ammonium hydroxide (28%), saturated with sulfur dioxide and heated to 150 &lt; 0 &gt; C in a pressure vessel for 27 h, then cooled and extracted with ethyl acetate. The extract was concentrated to give the title compound.

Example 143B

5- (4-methylphenoxy) -3,4-pyridine diamine

Example 143A (1.00 mmol) was suspended in HCl (3 N aqueous), stirred at 90 &lt; 0 &gt; C for 18 h, cooled to 0 &lt; 0 &gt; C, neutralized with 6N aqueous NaOH, then water was removed. The resulting residue was triturated with methanol. The washed material was concentrated to give the title compound.

Example 143C

Methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-carboxylate

Example 143B (1.00 mmol) in DMF was treated with pyridine (1.10 mmol) and methyl oxalyl chloride (1.10 mmol), stirred at room temperature overnight, then partitioned between methylene chloride and 1N aqueous HCl. The organic phase was separated, dried (Na ₂ SO ₄ ) and concentrated to give the title compound.

Example 143D

7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2- carboxamide

Example 143C was treated as in Example 44 to give the title compound.

Example 144

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carboxamide

Example 144A

3-Bromothiophene-2-carboxaldehyde

Example 144A was prepared as described in Prugh, et al., J. Med. Chem. 1991, 34, 1805). A solution of dibromothiophene (14 g, 58 mmol) in THF (100 mL) at -78 ° C was treated with n-butyllithium (24 mL, 59 mmol) and stirred for 15 min before anhydrous DMF , 87 mmol), stirred at -78 &lt; 0 &gt; C for 10 min, slowly warmed to 0 &lt; 0 &gt; C over 15 min, added to cold 1N aqueous HCl and extracted with diethyl ether. The extracts were washed with 1N aqueous HCl, water and saturated sodium bicarbonate. The washed material was extracted with diethyl ether. The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using 5% ethyl acetate / hexane to give the title compound.

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ7.16 (d, 1H), 7.74 (d, 1H), 10.0 (s, 1H).

Example 144B

3-Bromo- (2-dioxolanyl) thiophene

Example 144B is prepared as described in Prugh, et al., J. Med. Chem. 1991, 34, 1805). To a three necked flask equipped with a Dean-Stark trap was added Example 144A (5.24 g, 27.4 mmol), ethylene glycol (6.2 mL, 110 mmol), pyridinium tosylate (276 mg, 1.10 mmol) and toluene , Heated at reflux for 14 hours, cooled to room temperature, added to water and extracted with diethyl ether. The organic layer was washed with water and saturated sodium bicarbonate solution, and the mixture was concentrated and dried (MgSO _4), filtered back. The residue was purified by silica gel flash chromatography using 5% ethyl acetate / hexane to give the title compound.

_{MS (DCI / NH 3) m} / z 252 (79 Br) / 254 (81 Br), (M + NH 4) +; 235 ( ⁷⁹ Br) / 237 ( ⁸¹ Br), (M + H) ⁺ ;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ4.11-4.02 (m, 4H), 6.14 (s, 1H), 6.97 (d, 1H), 7.30 (d, 2H).

Example 144C

Ethyl-2- (2-dioxilanyl) thiophene-3-carboxylate

Example 144C is described in Prugh, et al., J. Med. Chem. 1991, 34, 1805). Example 144B (1.00 g, 4.25 mmol) in THF (12 mL) was treated with n-butyllithium (1.7 mL, 4.25 mmol) maintaining the temperature between -105 and -95 C and 0.57 mL , 4.68 mmol) and the temperature was raised to room temperature. The solution was added to water and extracted with diethyl ether. The extract was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 5% ethyl acetate / hexane to give the title compound.

Example 144D

2-formylthiophene-3-carboxylic acid

Example 144C (1.0 mmol) and ethanol (1.0 ml) were treated with a 1 N aqueous sodium hydroxide solution (100 mmol) and stirred for 1 hour, followed by addition of glacial acetic acid to pH = 5, stirred for 1 hour, Diluted and extracted with ethyl acetate. The combined extracts were washed with brine, washed with saturated sodium bicarbonate, dried (MgSO _4), filtered and concentrated. The title compound can be used without further purification.

Example 144E

Oxothieno [2,3-d] pyridazine

Example 144D was prepared as described in Bull. Soc. Chim. 1967, 2495).

Example 144F

4-chlorothieno [2,3-d] pyridazine

Example 144E was prepared as described in Bull. Soc. Chim. 1967, 2495).

Example 144G

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine

The method described in Robba and others, Bull. Soc. Chim. Fr., 1967, 4220 was used. Example 144F (100 mg, 0.59 mmol) was combined with 4-chlorophenol (1.0 mL, 10.0 mmol) and sodium metal (21 mg, 0.90 mmol). The mixture was stirred for 14 hours at 100 占 폚. And heated. After cooling to room temperature, the residue was diluted with chloroform, washed once with 2N aqueous sodium hydroxide and once with brine. Dry the organic layer (MgSO ₄₎ and filtered and concentrated under reduced pressure. Recrystallization from diethyl ether gave the title compound as a white solid (124 mg, 85%).

_{MS (DCI / NH 3) m} / e 363 (M + H) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) d 7.27 (d, J = 8.9Hz, 2H), 7.42 (d, J = 8.9Hz, 2H), 7.72 (d, J = 5.5Hz, 1H), 7.88 (d, J = 5.2 Hz, 1 H), 9.41 (s, 1 H).

Example 144H

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carboxylic acid

(1.0 mmol) in THF (1.0 mL) was treated with n-butyllithium (1.0 mmol) in THF (1.0 mL) and stirred for 15 min, then saturated with CO ₂ and slowly warmed to room temperature, Glacial acetic acid was added to the aqueous layer until pH = 5 after fractionation between 1N aqueous sodium hydroxide solution and diethyl ether. The acidic solution was extracted three times with methylene chloride. The combined extracts were washed with dilute sodium bicarbonate, dried (MgSO ₄ ), filtered and concentrated to give the title compound.

Example 144I

4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carbamide

Example 144I can be treated as in Desai and Stramiello, Tetrahedron Lett., 1993, 34, 7685. (1.0 mmol), 1-hydroxybenzotriazole (1.4 mmol), N-methylmorpholine (12 mmol) and DMF (1.0 ml) were combined and cooled to 0 C and then 1- (1.4 mmol), stirred at 0 &lt; 0 &gt; C for 1 hour, partitioned between methylene chloride and saturated sodium bicarbonate solution, and then separated. The extracts were dried (MgSO ₄₎ and filtered and concentrated. Recrystallization from hot methanol gave the title compound.

Example 145

7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carbamide

Example 145A

2,5-dibromo-3-thiopentaboxaldehyde

3-thiophenecarboxaldehyde solution was treated as in Bull.Sco.Chim.Fr., 1974, 3040 to give the title compound.

Example 145B

Dimethyl acetyl- (2,5-dibromo-3-thienyl) carboximinoethane

Example 145A was treated as in Bull.Sco.Chim.Fr., 1974, 3040 to give the title compound.

Example 145C

6,7-dihydro-7-oxothieno [3,2-c] pyridine

Example 145B was treated as in Bull.Sco.Chim.Fr., 1974, 3040 to give the title compound.

Example 145D

7- (4-chlorophenoxy) thieno [3,2-c] pyridine

Example 145D can be treated as in Lindley, Tetrahedron, 1983, 1433. A solution of Example 145C (1.0 mmol) and DMF (2.0 mL) was treated with sodium hydride (1.0 mmol) at 0 &lt; 0 &gt; C and slowly warmed to room temperature. It was then treated with 1-chloro-4-iodobenzene (1.0 mmol) and copper iodide (0.1 mmol), heated at 80 &lt; 0 &gt; C overnight and then cooled. The solution was added to water and extracted with diethyl ether. The extracts were combined, and concentrated after drying (MgSO _4). Recrystallization from ethyl acetate / hexane gave the title compound.

Example 145E

7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid

The title compound was treated in the manner described in Example 144H.

Example 145 F

7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carboxamide

The title compound was treated in the manner described in Example 144I.

Example 146

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboethioamide

A solution obtained by dissolving Röwensen reagent (73 mg, 0.18 mmol) and Example 61 (50 mg, 0.16 mmol) in toluene (2 ml) was heated under reflux for 4 hours. The solvent was removed under reduced pressure to give the crude product (150 mg) as a yellow residue. Purification by silica gel flash chromatography using 10% methanol in dichloromethane as eluent gave the purified title compound (24 mg, 47%).

_{MS (DCI / NH 3) m} / e 321 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.14 (m, 2H), 7.47 (m, 2H), 8.18 (s, 1H), 8.21 (s, 1H), 9.14 (s, 1H), 9.86 ( s, 1H), 10,15 (s, 1H).

Example 147

4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2- carboxamide

The title compound (209 mg, 100%) was prepared as in Example 171 using ethylamine (1 mL, 17.65 mmol) instead of methylamine as Example 61A (200 mg, 0.627 mmol).

_{MS (DCI / NH 3) m} / e 333 (M + H) +, 303;

^{1 H NMR (400MHz, DMSO-} d 6) δ1.14 (t, J = 8Hz, 3H), 3.30 (m, 2H), 7.14 (D, J = 9HZ, 2H), 7.47 (d, J = 9Hz, 2H), 8.13 (s, 1H), 8.17 (s, 1H), 8.91 (t, J = 6 Hz, 1H), 9.15

Example 148

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

Example 148 was prepared in analogy to example 103A, but replacing the 3-amino-1,2-propanediol (60 mL, 0.782 mmol) with Example 61A (250 mg, 0.782 mmol) % Yield) as a white solid.

_{MS (DCI / NH 3) m} / e 379 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.16 (m, 2H), 3.38 (m, 2H), 3.63 (m, 1H), 4.56 (t, J = 5.7Hz, 1H), 4.81 (d, (D, J = 9.2 Hz, 2H), 8.18 (s, 1H), 8.21 (s, 1H), 8.95 = 5.7 Hz, 1 H), 9.16 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₅ ClN ₂ O ₄ S0.25H ₂ O:

Calculated: C, 53.27; H, 4.08; N, 7.31.

Found: C, 53.19; H, 4.22; N, 6.22.

Example 149

N- (2,3-dihydroxypropyl) thieno [2,3-c] pyridine-2-carboxamide

The compound of Example 149 was prepared according to the procedure of Example 114 using methyl 4- (4-bromophenoxy) -thieno [2,3-c] pyridine-2-carboxylate instead of Example 61A .

mp 76-77 [deg.] C;

_{MS (DCI / NH 3) m} / e 423, 425 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.12 (m, 2H), 3.41 (m, 3H), 3.63 (m, 2H), 7.06 (d, 2H, J = 8.8Hz), 7.59 (d, 2H, J = 8.8Hz), 8.20 (s, 1H), 8.22 (s, 1H), 8.99 (t, 1H, J = 5.5Hz), 9.18 (s, 1H).

Example 150

N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide

Thionyl chloride (0.34 mL, 4.60 mmol) was slowly added to a solution of Example 114 (0.32 g, 0.92 mmol) in anhydrous THF (5 mL). After the reaction was heated for 18 hours at 50 ℃, it cooled to room temperature and neutralized with saturated NaHCO _3. The aqueous suspension was extracted with dichloromethane (100 mL) and the organic layer was washed with dilute NaHCO ₃ (2 x 100 mL), brine (50 mL), partially dried (Na ₂ SO ₄ ) and concentrated to a solid. The crude product was purified by silica gel flash chromatography using EtOAc / hexane as eluent to afford the title compound as a solid (0.27 g, 80%).

mp 60-62 [deg.] C (decomposition);

_{MS (DCI-NH 3) m} / e 362 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.60 (m, 2H), 3.75 (t, J = 6.1Hz, 2H), 7.15 (m, 2H), 7.48 (m, 2H), 8.18 (s, 1H), 8.18 (s, IH), 9.17 (s, IH), 9.26 (m, IH);

Elemental analysis for C ₁₆ H ₁₂ Cl ₂ N ₂ O ₂ S:

Calculated: C, 52.33; H, 3.29; N, 7.63.

Found: C, 52.22; H, 3.47; N, 7.35.

Example 151

4- (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide

The compound of Example 151 was prepared according to the procedure of Example 114 using methyl 4- (4-bromophenoxy) -thieno [2,3-c] pyridine-2-carboxylate instead of Example 61A .

mp 158-159 [deg.] C;

_{MS (DCI / NH 3) m} / e 393,395 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.32 (m, 2H), 3.51 (m, 3H), 4.79 (t, 1H, J = 5.9Hz), 7.06 (d, 2H, J = 8.8Hz) , 7.59 (d, 2H, J = 8.8Hz), 8.17 (s, 1H), 8.20 (s, 1H), 9.02 (t, 1H, J = 5.5Hz). 9.17 (s, 1 H).

Example 152

4- (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3- c] pyridine- 2- carboxamide

The compound of Example 152 was prepared according to the procedure of Example 114 using 2-bromo-4-chlorophenol instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e 428 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.86 (q, 1H, J = 5.4Hz), 3.34 (m, 2H), 3.55 (m, 2H); (D, 1H, J = 2.4, 8.8 Hz), 7.97 (d, 1H, J = 2.7 Hz), 8.02 ), 9.05 (t, 1H, J = 5.4 Hz), 9.16 (s, 1H).

Example 153

N- (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide

A solution of 322 mg (0.912 mmol) of Example 62A in 10 ml of dichloromethane was treated with 226 mg (3.65 mmol) of ethanolamine. This solution was heated to reflux for 4 hours. Crystals formed upon cooling. Recrystallization from ethyl acetate gave 170 mg (48.8%) of white crystals.

mp 181-182 [deg.] C;

_{MS (DCI / NH 3) m} / e 383 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.3-3.4 (m, 2H), 3.5-3.6 (m, 2H), 4.80 (t, 1H), 7.21 (d, 2H), 7.79 (d, 2H ), 8.15 (s, 1H), 8.38 (s, 1H), 9.01 (t, 1H), 9.25 (s, 1H);

Elemental analysis for C ₁₇ H ₁₃ F ₃ N ₂ O ₃ S:

Calculated: C, 53.40; H, 3.43; N, 7.33.

Found: C, 53.41; H, 3.62; N, 7.30.

Example 154

N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide

N, N-diisopropylethylamine (0.57 mL, 3.28 mmol) was added to a suspension of Example 88 (0.50 g, 1.64 mmol) suspended in anhydrous methylene chloride (15 mL). The reaction was cooled in an ice bath and pivaloyl chloride (0.24 mL, 1.97 mmol) was slowly added. After 10 minutes, the reaction mixture was taken out of the ice bath and the reaction was stirred at room temperature for 1.5 hours. The reaction contents were slowly added via cannula to anhydrous solution of ethylenediamine (0.33 ml, 4.92 mmol) in methylene chloride (5 ml) at 0 ° C over 5 minutes. The reaction was stirred for 15 min and separated in a cold bath. The reaction was stirred for 1 hour, and was screen fraction between CHCl ₃ / saturated NaHCO _3. The organic layer was washed with dilute aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated to give a pale yellow foam. The crude product was purified by preparative HPLC over 40 min using a gradient of 25% to 65% acetonitrile / water + 0.1% TFA as eluent. The product was neutralized with a saturated aqueous NaHCO ₃ solution and the precipitate was collected by filtration and dried in a dehumidifier to give the title compound as a white solid (0.45 g, 79%).

mp 111-114 [deg.] C;

MS (APCI) m / e 348 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.69 (t, J = 6.4Hz, 2H), 3.25 (t, J = 6.4Hz, 2H), 7.14 (m, 2H), 7.47 (m, 2H) , 8.16 (s, 1 H), 8.18 (s, 1 H), 9.15 (s, 1 H).

Example 155

4- (4-chlorophenoxy) -N-hydroxcityeno [2,3-c] pyridine-2- carboxamide

The title compound (40 mg, 24% yield) was prepared as a white solid from the compound of Example 155 as in Example 92 by combining hydroxylamine hydrochloride (37.0 mg, 0.527 mmol) and Example 88 (161 mg, 0527 mmol) .

mp 145 [deg.] C (decomposition);

_{MS (DCI / NH 3) m} / e 321 (M + H) +;

_{^{1 H NMR (300MHz, CD 3}} OD) δ7.11 (d, J = 9.2Hz, 2H), 7.42 (d, J = 9.2Hz, 2H), 7.90 (s, 1H), 8.05 (s, 1H), 9.01 (s, 1 H);

IR (KBr) 3200-2800 (m), 1660 (s), 1640 (s), 1560 (m), 1485 (s), 1420 (s) cm- ¹ ;

Elemental analysis for C ₁₄ H ₉ ClN ₂ O ₃ S + 0.25H ₂ O:

Calculated: C, 51.70; H, 2.94; N, 8.61.

Found: C, 51.64; H, 2.71; N, 8.80.

Example 156

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide

Example 61A (0.50 g, 1.56 mmol) was dissolved in dichloromethane (10 mL) and anhydrous hydrazine (1 mL) was added. After 24 h, the precipitate was collected by filtration and washed with dichloromethane (2 x 25 mL) and water (2 x 50 mL). The product was dried in a dehumidifier to give the title compound as a white solid (0.35 g, 70%).

mp 197-199 [deg.] C;

MS (APCI) m / e 320 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO-d ₆ )? 4.62 (br s, 2H), 7.12 (m, 2H), 7.46 (S, 1 H), 10.24 (br s, 1 H);

Elemental analysis for C ₁₄ H ₁₀ ClN ₃ O ₂ S:

Calculated: C, 52.59; H, 3.15; N, 13.14.

Found: C, 52.59; H, 3.12; N, 13.18.

Example 157

4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide

Example 73A (0.21 g, 0.58 mmol) was dissolved in dichloromethane (2 mL) and anhydrous hydrazine (1 mL) was added. After 18 h, the precipitate was collected by filtration and washed with dichloromethane (2 x 5 mL), water (2 x 5 mL), acetonitrile (2 x 5 mL) to give a white solid. The washings were combined, diluted with saturated NaHCO ₃ (100 mL) and extracted with dichloromethane (4 x 25 mL). The organic extracts were combined, partially dried (Na ₂ SO ₄ ) and cooled to give a white solid which was combined with the collected precipitate and dried in a dehumidifier (0.21 g, 99%).

mp 176-178 [deg.] C;

MS (APCI) m / e 364 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ4.62 (br s, 2H), 7.06 (m, 2H), 7.58 (m, 2H), 8.02 (s, 1H), 8.21 (s, 1H), 9.16 (s, 1 H), 10.24 (br s, 1 H);

Elemental analysis for C ₁₄ H ₁₀ BrN ₃ O ₂ S:

Calculated: C, 46.17; H, 2.77; N, 11.54.

Found: C, 46.08; H, 2.90; H, 11.41.

Example 158

4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide

Example 62A was treated according to the procedure of Example 157 to give the title compound.

mp 146-147 [deg.] C;

MS (ESI) m / e 353.9 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.18 (d, 2H), 4.11 (t, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.78 (s, 1H), 8.36 ( s, 1 H), 9.21 (s, 1 H).

Example 159

2,3-c] pyridin-2-yl] carbonyl} amino) acetic acid &lt; EMI ID =

Example 159A

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid

Example 61A (354㎎, 1.11mmol) was suspended to the suspension and the mixture treated with lithium hydroxide monohydrate (98㎎, 2.33mmol), and generating at room temperature (under N ₂₎ in methanol and water 3㎖ 1㎖ 20 Lt; / RTI &gt; The reaction was acidified with 0.13 ml of 90% formic acid and the white suspension was stirred for 5 minutes and then filtered off with suction to separate the solid. The solid was washed successively with 15 ml of water and 5 ml of diethyl ether and dried under vacuum to give 302 mg (89%) of the title compound.

_{MS (DCI-NH 3) m} / e: 306, 308 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.15 (m, 2H), 7.47 (m, 2H), 7.82 15 (br s, 1H);

Elemental analysis for C ₁₇ H ₈ ClNO ₃ S:

Calculated: C, 55.00; H, 2.64; N, 4.58.

Found: C, 54.77; H, 2.60; N, 4.44.

Example 159B

Thieno [2,3-c] pyridin-2-yl] carbonyl} amino) acetate

The title compound was prepared from Example 159A in an analogous manner to Example 92, using glycine methyl ester hydrochloride instead of ammonium chloride. HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 eluent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 19.04 min.

MS (APCI) m / e: 377 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.68 (s, 3H), 4.05 (d, J = 6Hz, 2H), 7.13 (m, 2H), 7.49 (m, 2H), 8.19 (s, 1H ), 8.21 (s, 1 H), 9.19 (s, 1 H), 9.50 (br t, J = 6 Hz, 1 H);

Elemental analysis for C ₁₇ H ₁₃ ClN ₂ O ₄ S:

Calculated: C, 54.19; H, 3.48; N, 7.43.

Found: C, 53.92; H, 3.61; N, 7.52.

Example 159C

2,3-c] pyridin-2-yl] carbonyl} amino) acetic acid &lt; EMI ID =

The title compound was prepared from the compound of Example 159B following the procedure of Example 18.

MS (APCI) m / e: 363 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.95 (d, J = 6Hz, 2H), 7.13 (m, 2H), 7.48 (m, 2H), 8.19 (s, 1H), 8.21 (s, 1H ), 9.19 (s, 1 H), 9.41 (br t, J = 6 Hz, 1 H), 12.77 (br s, 1 H);

Elemental analysis for C ₁₆ H ₁₁ ClN ₂ O ₄ S 1 H ₂ O:

Calculated: C, 50.46; H, 3.44; N, 7.36.

Found: C, 50.33; H, 3.38; N, 7.29.

Example 160

N- (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno [2,3- c] pyridine-

The title compound was prepared from the compound of Example 159C in analogy to example 92.

mp 222-225 [deg.] C.

MS (APCI) m / e: 362 (M + H).

^{1 H NMR (300MHz, DMSO-} d 6) δ3.82 (br s, 2H), 7.12 (m, 2H), 7.49 (m, 2H), 8.19 (s, 1H), 8.21 (s, 1H), 9.02 (s, 1 H), 9.29 (br s, 1 H);

Elemental analysis for C ₁₆ H ₁₂ ClN ₃ S 揃 1.35H ₂ O:

Calculated: C, 49.77; H, 3.84; N, 10.88.

Found: C, 49.86; H, 3.79; N, 10.59.

Example 161

N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine-

Example 161A

Methyl-N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine-

Example 73A was hydrolyzed according to the procedure of Example 18. The derivatized carboxylic acid was coupled to glycine methyl ester hydrochloride in a manner similar to Example 92. &lt; RTI ID = 0.0 &gt;

_{MS (DCI / NH 3) m} / e: 421 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.70 (s, 3H), 4.11 (br d, 2H), 7.11 (br d, 2H), 7.61 (br d, 2H), 8.22 (br d, 2H) , 9.19 (s, 1 H), 9.51 (br t, 1 H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 41.15, 51.84, 104.95, 115.57, 119.74, 119.97. 132.93, 133.32, 137.36, 138.04, 141.45, 145.06, 147.03, 156.10, 161.098, 169.80;

Elemental analysis for C ₁₇ H ₁₃ BrN ₂ O ₄ S:

Calculated: C, 48.47; H, 3.11; N, 6.65.

Found: C, 48.16; H, 3.27; N, 6.65.

Example 161B

2,3- c] pyridin-2-yl] carbonyl} amino) acetic acid &lt; EMI ID =

The title compound was prepared from the compound of Example 161A using the procedure of Example 18.

_{MS (DCI / NH 3) m} / el 407 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ4.11 (br d, 2H), 7.10 (br d, 2H), 7.60 (br d, 2H), 8.21 (br d, 2H), 9.19 (s, 1H ), 9.40 (br t, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ41.50, 115.85, 120.00, 120.09, 133.25, 133.67, 137.76, 138.34, 141.79, 145.74, 147.29, 156.46, 161.28, 171.05;

Elemental analysis for C ₁₆ H ₁₁ BrN ₂ O ₄ S · H ₂ O:

Calculated: C, 45.19; H, 3.08; N, 6.59.

Found: C, 45.20; H, 3.15; N, 6.45.

Example 161C

N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine-

The title compound was obtained from the compound of Example 161B in analogy to example 92. [

MS (APCI) m / e: 406 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.81 (br d, J = 6Hz, 2H), 7.08 (m, 2H), 7.10 (br s, 1H), 7.60 (m, 2H), 8.19 (s 1H), 8.22 (s, IH), 9.20 (s, IH), 9.28 (brt, J = 6 Hz, IH);

Elemental analysis for C ₁₆ H ₁₂ BrN ₃ O ₃ S · 0.3H ₂ O:

Calculated: C, 46.68; H, 3.09; N, 10.21.

Found: C, 46.68; H, 3.30; N, 10.16.

Example 162

Thieno [2,3-c] pyridine-2-carboxamide (100 mg) was obtained in the same manner as in Example 1,

Example 162A

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid

The compound of Example 162A was prepared in a similar manner to Example 92, but using L-serine ethyl ester hydrochloride instead of ammonium chloride. The intermediate ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 15.93 min.

MS (APCI) m / e: 392 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.70 (m, 2H), 4.43 (br t, 2H), 5.04 (br s, 1H), 7.13 (m, 3H), 7.49 (m, 3H), 8.18 (s, 1 H), 8.37 (s, 1 H), 8.98 (br s, 1 H), 9.18 (s, 1 H).

Example 162B

Thieno [2,3-c] pyridine-2-carboxamide (100 mg) was obtained in the same manner as in Example 1,

The compound of Example 162B was prepared from Example 162A in analogy to Example 92. &lt; 1 &gt;

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 15.93 min.

MS (APCI) m / e: 392 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.70 (m, 2H), 4.43 (br t, 2H), 5.04 (br s, 1H), 7.13 (m, 3H), 7.49 (m, 3H), 8.18 (s, 1 H), 8.37 (s, 1 H), 8.98 (br s, 1 H), 9.18 (s, 1 H).

Example 163

(4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid

The compound of Example 163 was prepared in analogy to Example 92 using D-serine methyl ester hydrochloride instead of ammonium chloride. The derived ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 16.47 min.

MS (ESI) m / e: 393 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.78 (br d, 2H), 4.49 (m, 1H), 5.02 (br s, 1H), 7.13 (m, 2H), 7.48 (m, 2H), 8.18 (s, 1H), 8.39 (s, 1H), 9.14 (d, 1H), 9.18 (s, 1H), 12.81 (br s, 1H).

Example 164

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

Example 164A

Thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid

The compound of Example 164A was prepared in analogy to Example 92 using D-alanine methyl ester hydrochloride instead of ammonium chloride. The derived ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 18.36 min.

_{MS (DCI / NH 3) m} / e: 377 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ1.40 (d, J = 7Hz, 3H), 4.41 (q, J = 7Hz, 1H), 7.15 (m, 2H), 7.49 (m, 2H), 8.19 (s, 1H), 8.32 (s, 1H), 9.17 (s, 1H), 9.23 (d, J = 7 Hz, 1H), 12.71 (br s, 1H).

Example 164B

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

The compound of Example 164 was prepared in analogy to example 92 using D-alanine methyl ester hydrochloride instead of ammonium chloride. The resulting ester was treated according to the procedure of Example 171 to give the title compound.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 eluent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 17.46 min.

_{MS (DCI / NH 3) m} / e: 390 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ1.32 (d, 3H), 2.60 (d, 3H), 4.41 (m, 1H), 7.13 (m, 2H), 7.49 (m, 2H), 7.96 ( (d, IH), 8.19 (s, IH), 8.38 (s, IH), 9.13 (br d, IH), 9.19

Example 165

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

Example 165A

Thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid

The compound of Example 165A was prepared in analogy to Example 92 using L-alanine methyl ester hydrochloride instead of ammonium chloride. The derived ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 18.40 min.

_{MS (DCI / NH 3) m} / e: 377 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ1.40 (d, J = 7Hz, 3H), 4.41 (q, J = 7Hz), 7.15 (m, 2H), 7.48 (m, 2H), 8.18 (s 1H), 8.31 (s, 1H), 9.16 (s, 1H), 9.21 (d, J = 7 Hz, 1H), 12.71 (br s, 1H);

^{13 C NMR (100MHz, DMSO-} d 6) δ16.78, 48.46, 119.52, 119.80, 119.97, 127.84, 130.13, 132.97, 137.54, 137.60, 138.09, 141.30, 145.59, 147.38, 155.59, 160.54, 173.68.

Example 165B

Thieno [2,3-c] pyridine-2-carboxamide &lt; / RTI &gt;

The compound of Example 165B was prepared from Example 165A in analogy to Example 92 using L-alanine methyl ester instead of ammonium chloride. The intermediate ester was converted to the title compound by following the procedure in Example 171 using methanolic methylamine.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 17.48 min.

_{MS (DCI / NH 3) m} / e: 390 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ1.32 (d, 3H), 2.59 (d, 3H), 4.41 (m, 1H), 7.13 (m, 2H), 7.49 (m, 2H), 7.94 ( (d, IH), 8.18 (s, IH), 8.36 (s, IH), 9.12 (br d, IH), 9.19

Example 166

Thieno [2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide

The title compound was prepared in analogy to example 164B using D-serine methyl ester.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 16.10 min.

MS (APCI) m / e: 404 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.59 (d, 2H), 3.69 (m, 2H), 4.45 (m, 1H), 4.96 (t, 1H), 7.14 (m, 2H), 7.49 ( (m, 2H), 7.97 (m, IH), 8.18 (s, IH), 8.49 (s, IH), 9.01 (br d, IH), 9.19

Example 167

2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide

The title compound was prepared in a manner similar to Example 164B using L-serine methyl ester.

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 Solvent gradient (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 16.18 min.

MS (APCI) m / e: 404 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.59 (d, 2H), 3.69 (m, 2H), 4.45 (m, 1H), 4.96 (t, 1H), 7.14 (m, 2H), 7.49 ( (m, 2H), 7.97 (br d, IH), 8.18 (s, IH), 8.49 (s, IH), 9.01 (br d, IH), 9.19

Example 170

4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2-carboxamide

Example 17A and 3-hydroxypyridine were treated as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / e: 272 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.50 (m, 2H), 7.85 (m, 1H), 8.20 (s, 2H), 8.45 (dd, 2H), 8.55 (d, 1H), 9.20 ( s, 1H);

Elemental analysis for C ₁₃ H ₉ N ₃ O ₂ S · 0.25H ₂ O:

Calculated: C, 56.61; H, 3.47; N, 15.24.

Found: C, 57.01; H, 3.50; N, 15.16.

Example 171

Methyl 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide

(2g, 5.5mmol) was suspended in a solution of methylamine dissolved in methanol (2M solution, 15ml) and recirculated for 1 hour under a nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel flash chromatography using 30% acetone in hexane as the eluent to give the title compound (1.96 g, 98%).

mp 78-80 [deg.] C;

_{MS (DCI / NH 3) m} / e: 363,365 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d) δ2.79 (d, 3H, J = 4.8Hz), 7.06 (d, 2H, J = 8.8Hz), 7.59 (d, 2H, J = 8.8Hz), 8.06 ( s, 1H), 8.20 (s, 1H), 8.96 (q, 1H, J = 4.8Hz), 9.17 (s, 1H).

Example 172

N- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyridine-2- carboxamide

The compound of Example 172 was prepared according to the procedure of Example 104 using methyl 4- (4-bromophenoxy) -thieno [2,3-c] pyridine-2-carboxylate instead of Example 61A .

mp 93-95 [deg.] C;

_{MS (DCI / NH 3) m} / e: 377,379 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.02 (br s, 3H), 3.13 (br s, 3H), 7.09 (d, 2H, J = 8.8Hz), 7.5d, 2H, J = 8.8Hz ), 7.60 (s, 1H), 8.19 (s, 1H), 9.15 (s, 1H) ppm.

Example 173

N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-

The compound of Example 173 was synthesized according to the procedure of Example 104 using methyl 4- (4-trifluoromethylphenoxy) -thieno [2,3-c] pyridine-2-carboxylate instead of Example 61A. .

mp 74-76 [deg.] C;

_{MS (DCI / NH 3) m} / e: 367 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ3.17 (br s, 6H), 7.11 (d, 2H, J = 8.0Hz), 7.45 (s, 1H), 7.63 (d, 2H, J = 8.0Hz), 8.24 (br s, 1 H), 9.01 (br s, 1 H).

Example 174

4- (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide

The title compound of Example 174 was prepared as in Example 103 but using 4-chloro-3-fluorophenol instead of 4-chlorophenol.

mp 62-64 [deg.] C;

_{MS (DCI / NH 3) m} / e: 337 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.05 (d, 3H, J = 4.7Hz), 6.24 (br s, 1H), 6.77 (d, 1H, J = 9.8Hz), 6.84 (dd, 1H 1H, J = 2.4, 9.5 Hz), 7.26 (s, 2H), 7.37 (t, 1H, J = 8.5 Hz), 7.69 (s, 1H), 8.21 (s, 1H), 9.00

Elemental analysis for C ₁₅ H ₁₀ N ₂ ClFO ₂ S:

Calculated: C, 53.50; H, 2.99; N, 8.32.

Found: C, 53.78; H, 3.26; N, 8.02.

Example 175

4- (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 175 was prepared as in Example 61 but using 4-chloro-3-fluorophenol instead of 4-chlorophenol.

mp 227-228 [deg.] C;

_{MS (DCI / NH 3) m} / e: 323 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ6.94 (m, 1H), 7.34 (dD, 1H, J = 3.0, 10.5Hz), 7.60 (t, 1H, J = 8.7Hz), 7.87 (s, 1H), 8.11 (s, 1H), 8.26 (s, 1H), 8.44 (s, 1H), 9.19 (s, 1H);

Elemental analysis for C ₁₄ H ₈ N ₂ ClFO ₂ S:

Calculated: C, 52.10; H, 2.50; N, 8.68.

Found: C, 52.06; H, 2.49; N, 8.52.

Example 176

4- (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide

Treatment of Example 17A and 4-chloro-3-ethylphenol as in Example 61 provided the title compound.

mp 185-187 [deg.] C;

_{MS (DCI / NH 3) m} / e: 333 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ1.15 (t, 3H), 2.70 (q, 2H), 6.95 (dd, 1H), 7.20 (d, 1H), 7.45 (d, 1H), 7.85 ( br s, 1 H), 8.15 (s, 1 H), 8.45 (m, 1 H), 9.15 (s, 1 H).

Example 177

4- (3-Fluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

The compound of Example 177 was prepared according to the procedure of Example 61, except that 3-fluorophenol was used instead of 4-chlorophenol.

mp 215-216 [deg.] C;

_{MS (DCI / NH 3) m} / e: 289 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ6.90 (m, 1H), 7.05 (m, 2H), 7.43 (q, 1H, J = 8.6Hz), 7.86 (br s, 1H), 8.14 (s , 8.20 (s, 1 H), 8.45 (br s, 1 H), 9.17 (s, 1 H).

Example 178

4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

The compound of Example 178 was prepared according to the procedure of Example 61 except 2,3-difluorophenol was used instead of 4-chlorophenol.

mp 207-209 [deg.] C;

_{MS (DCI / NH 3) m} / e: 307 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ6.97 (t, 1H, J = 8.5Hz), 7.22 (q, 1H, J = 8.5Hz), 7.32 (q, 1H, J = 8.5Hz), 7.87 (br s, IH), 8.18 (s, IH), 8.21 (s, IH), 8.43 (br s, IH), 9.17 (s, IH).

Example 179

4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

The compound of Example 179 was prepared according to the procedure of Example 103 except 2,3-difluorophenol was used instead of 4-chlorophenol.

mp 169-171 [deg.] C;

_{MS (DCI / NH 3) m} / e: 321 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.88 (d, 3H, J = 4.4Hz), 6.94 (t, 1H, J = 8.5Hz), 7.21 (q, 1H, J = 8.5Hz), 7.31 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.95 (q, 1H), J = 4.5 Hz), 9.17 (s, 1H).

Example 180

4- (3-Fluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

The compound of example 180 was prepared according to the procedure of example 103, except that 3-fluorophenol was used instead of 4-chlorophenol.

mp 194-195 [deg.] C;

_{MS (DCI / NH 3) m} / e: 303 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.79 (d, 3H, J = 4.4Hz), 6.87 (d, 1H, J = 8.5Hz), 7.05 (m, 2H), 7.42 (q, 1H, J = 8.5 Hz), 8.05 (s, IH), 8.23 (s, IH), 8.95 (q, IH, J = 4.4 Hz), 9.17 (s,

Example 181

Methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

The compound of Example 181 was prepared according to the procedure of Example 103 except 2,3,4-trifluorophenol was used instead of 4-chlorophenol.

mp 170-171 [deg.] C;

_{MS (DCI / NH 3) m} / e: 339 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.82 (d, 3H, J = 4.4 Hz), 7.13 , 8.17 (s, IH), 8.97 (q, IH, J = 4.5 Hz), 9.16 (s, IH).

Example 182

4- (2,3,4-Trifluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

The compound of Example 182 was prepared according to the procedure of Example 61, except that 2,3,4-trifluorophenol was used instead of 4-chlorophenol.

mp 218-219 [deg.] C;

_{MS (DCI / NH 3) m} / e: 325 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.15 (m, 1H), 7.38 (q, 1H, J = 8.5Hz), 7.89 (br s, 1H), 8.15 (s, 1H), 8.23 (s , 8.45 (br s, 1 H), 9.15 (s, 1 H).

Example 183

Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The compound of Example 183 was prepared according to the procedure of Example 103 except 4-trifluoromethylphenol was used instead of 4-chlorophenol.

mp 157-158 [deg.] C;

_{MS (DCI / NH 3) m} / e: 353 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.78 (d, 3H, J = 4.4Hz), 7.22 (d, 2H, J = 8.5Hz), 7.76 (d, 2H, J = 8.5Hz), 8.01 (s, IH), 8.34 (s, IH), 8.92 (q, IH, J = 4.4 Hz), 9.24 (s, IH).

Example 184

4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 17A and 3-trifluoromethylphenol were treated as in Example 183 to give the title compound.

mp 175-176 [deg.] C;

_{MS (DCI / NH 3) m} / e: 353 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.80 (d, 3H), 7.35 (d, 1H), 7.20 (d, 1H), 7.60 (m, 3H), 8.10 (s, 1H), 8.30 ( s, 1 H), 9.00 (b, 2 H), 9.25 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₁ F ₃ N ₂ O ₂ S · 0.25H ₂ O:

Calculated: C, 53.86; H, 3.25; N, 7.85.

Found: C, 53.60; H, 3.06; N, 7.78.

Example 185

N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide

The compound of Example 185 was prepared according to the procedure of Example 104 except 4-vinylphenol was used instead of 4-chlorophenol.

mp 80-81 [deg.] C;

_{MS (DCI / NH 3) m} / e: 325 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ3.02 (br s, 3H), 3.13 (br s, 3H), 5.24 (d, 1H, J = 11.1Hz), 5.78 (d, 1H, J = 17.3 J = 8.5 Hz), 7.61 (s, 1H), 8.16 (d, 2H), 6.74 (dd, 1H, J = 11.4,17.3 Hz), 7.09 s, 1 H), 9.13 (s, 1 H).

Example 186

4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 186 was prepared according to the procedure of Example 103, except that 4-cyanophenol was used instead of 4-chlorophenol.

_{MS (ESI / NH 3) m} / e: 310 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.78 (d, 3H, J = 4.4Hz), 7.20 (d, 2H, J = 8.8Hz), 7.89 (d, 2H, J = 8.8Hz), 7.97 (s, 1H), 8.37 (s, 1H), 8.94 (q, 1H, J = 4.4 Hz), 9.26 (s, 1H);

Elemental analysis for C ₁₆ H ₁₁ N ₃ O ₂ S · 0.05CH ₂ Cl ₂ :

Calculated: C, 61.46; H, 3.56; N, 13.30.

Found: C, 61.29; H, 3.53; N, 13.23.

Example 187

4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2-carboxamide

The title compound of Example 187 was prepared according to the procedure of Example 61 but using 4-cyanophenol instead of 4-chlorophenol.

mp 255-257 [deg.] C;

_{MS (ESI / NH 3) m} / e: 296 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.20 (d, 2H, J = 8.8Hz), 7.84 (s, 1H), 7.89 (d, 2H, J = 8.8Hz), 8.05 (s, 1H) , 8.36 (s, 1H), 8.41 (q, 1H, J = 4.4 Hz), 9.26 (s, 1H);

Elemental analysis for C ₁₅ H ₉ N ₃ O ₂ S 1.5CH ₃ OH:

Calculated: C, 57.71; H, 3.08; N, 12.24.

Found: C, 57.45; H, 3.28; N, 12.43.

Example 188

4- (4-aminophenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 188A

3-chloro-5- (4-tert-butyloxycarbonyl) amino) phenoxy-4-pyridinecarboxaldehyde

Butyl N- (4-hydroxyphenyl) carbamate (2.38 g, prepared according to the method of A. Vigroux, M.Bergon, C. Zedde; J. Med. , 11.4 mmol) and Example 17A (2.0 g, 11.4 mmol) in DMF (30 mL) was treated with CsCO ₃ (3.70 g, 11.4 mmol) at room temperature for 1 hour and at 70 ° C for 30 minutes. Brine (150 ml) was added and the mixture was extracted with ether / ethyl acetate (2 x 200 ml). The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel flash chromatography using 1: 6 ethyl acetate / hexane to obtain the title compound (2.65 g, 67%).

_{MS (ESI / NH 3) m} / e: 349 (M + H) +.

Example 188B

Methyl 4 - ((4- tert -butyloxycarbonylamino) phenoxy) thieno [2,3-c] pyridine-2-carboxylate

A solution of Example 188A (2.64 g, 7.58 mmol) in THF (30 mL) was treated with methyl thioglycolate (804 mg, 7.58 mmol) at 0 C for 0.5 h, at room temperature for 1 h, Cs ₂ CO ₃ (2.47 g, 7.58 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and at 70 &lt; 0 &gt; C for 0.5 hour. Brine (150 mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic phases were dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography with 20% ethyl acetate in hexane to give the desired compound (1.29 g, 43%).

_{MS (ESI / NH 3) m} / e: 401 (M + H) +;

Example 188C

4 - [(4- tert -butyloxycarbonylamino) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 188C was prepared as in Example 44 but using Example 188B instead of Example 43.

_{MS (ESI / NH 3) m} / e: 386 (M + H) +.

Example 188D

4- (4-aminophenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 188C was dissolved in trifluoroacetic acid (20 mL) and the solution was kept at room temperature for 1 hour before TFA was removed. The residual oil was treated with a mixture of ethyl acetate and NaHCO ₃ solution. The solid formed was collected by filtration and washed successively with ethyl acetate, aqueous NaHCO ₃ , water, methanol and ethyl acetate, and dried to give the title compound (492 mg, 86% yield from Example 188B) as a yellow solid.

mp &gt; 250 DEG C;

_{MS (DCI / NH 3) m} / e: 286 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ5.62 (br s, 2H), 6.65 (d, 2H, J = 8.8Hz), 6.93 (d, 2H, J = 8.8Hz), 7.86 (s, 1H ), 8.30 (s, 1 H), 8.44 (s, 1 H), 9.00 (br s, 1 H);

Elemental analysis for C ₁₄ H ₁₁ N ₃ O ₂ S 0.5CH ₃ OH:

Calculated: C, 57.79; H, 3.85; N, 13.94.

Found: C, 57.69; H, 3.95; N, 13.57.

Example 189

4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 189 was obtained in the same manner as in Example 188C except that 4- (acetylamino) phenol was used instead of tert-butyl N- (4-hydroxyphenyl) carbamate.

_{MS (DCI / NH 3) m} / e: 328 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.04 (s, 3H), 7.10 (d, 2H, J = 8.8Hz), 7.65 (d, 2H, 8.8Hz), 7.82 (br s, 1H), 7.99 (s, 1H), 8.20 (s, 1H), 8.43 (brs, 1H), 9.06 (s, 1H), 9.99 (s, 1H);

Elemental analysis for C ₁₆ H ₁₃ N ₃ O ₃ S 1 .0 CH ₃ OH:

Calculated: C, 56.81; H, 3.93; N, 11.69.

Found: C, 56.51; H, 3.93; N, 11.57.

Example 190

Methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c] pyridine-

Example 190A

Methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-

The title compound of Example 190A was prepared in analogy to Example 61A but using 4-iodophenol instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e: 412 (M + H) +.

Example 190B

Methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-2- carboxamide

A solution of Example 190A (2.0 M solution, 70 mL) in methylamine / methanol was stirred at 45 &lt; 0 &gt; C for 15 hours and concentrated in vacuo. The residue was purified by silica gel flash chromatography using EtOAc / hexane (1.5 / 1) as eluent to give the title compound (1.3 g, 93%).

_{MS (DCI / NH 3) m} / e: 411 (M + H) +.

Example 190C

Methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c] pyridine-

In a two-necked flask were placed Example 190B (150 mg, 0.37 mmol), NaOBu-t (71 mg, 0.74 mmol), Pd ₂ (dba) ₃ (14 mg, 0.014 mmol), BINAP -Crown-6 (196 mg, 0.74 mmol) was added and rinsed with nitrogen. Anhydrous deaerated THF (10 mL) and morpholine (64 mg, 0.74 mmol) were successively added. The clear dark red solution was heated at 60 &lt; 0 &gt; C for 70 h and quenched with brine. The mixture was extracted with methylene chloride. The organic layer was dried (MgSO ₄₎ and concentrated. The crude product was purified by silica gel flash chromatography (EtOAc / hexane) and further purified by HPLC (C-18, CH ₃ CN / H ₂ O) to give the title compound (26 mg).

_{MS (DCI / NH 3) m} / e: 370 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ2.81 (d, 3H, J = 4.5Hz), 3.1 (m, 2H), 3.74 (m, 2H), 6.99 (d, 2H, J = 8.8Hz) , 7.05 (d, 2H, J = 8.8Hz), 7.92 (s, 1H), 8.20 (s, 1H), 8.98 (q, 1H, J = 4.8Hz), 9.04

Example 191

4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 191A

Methyl 4- {4 - [(trityloxy) methyl] phenoxy} thieno [2,3-c] pyridine-

4-chlorophenol instead of 4-chlorophenol [Frank, R .; The title compound of Example 191A was prepared as in Example 61A but using 4-trityloxymethylphenol, prepared according to Doring, R.Tetrahedron 1988, 44, 6031.

_{MS (DCI / NH 3) m} / e: 558 (M + H) +.

Example 191B

4- {4 - [(trityloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 91A was prepared as in Example 61 but using 4-trityloxymethylphenol instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e: 543 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ4.10 (s, 2H), 7.11 (d, 2H, J = 8.5Hz), 7.26-7.46 (m, 17H), 7.87 (br s, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8.46 (brs, 1H), 9.12 (s, 1H) ppm.

Elemental analysis for C ₃₄ H ₂₆ N ₂ O ₃ S:

Calculated: C, 75.25; H, 4.83; N, 5.16.

Found: C, 75.17; H, 4.76; N, 5.15.

Example 191C

Methyl 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate

A solution of Example 191A (5.50 g, 9 mmol) dissolved in a mixture of chloroform (20 mL) and methanol (8 mL) was treated with trifluoroacetic acid (10 mL) at 0 C for 6 h, NaHCO ₃ was added to the mixture. The mixture was extracted with methylene chloride (2 x 200 mL). The combined organic layers were dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography using 66% EtOAc / hexane to give the title compound (2.11 g, 74%).

_{MS (DCI / NH 3) m} / e: 316 (M + H) +.

Example 191D

4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 191D was prepared as in Example 61 but using Example 191C instead of Example 61A.

_{MS (DCI / NH 3) m} / e: 301 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.50 (d, 2H, J = 5.8Hz), 5.19 (t, 1H, J = 5.8Hz), 7.10 (d, 2H, J = 8.5Hz), 7.37 ( d, 2H, J = 8.5 Hz), 7.82 (br s, 1H), 8.03 (s, 1H), 8.43 (br s, 1H), 9.09

Elemental analysis for C ₁₅ H ₁₂ N ₂ O ₃ S

Calculated: C, 59.99; H, 4.03; N, 9.33.

Found: C, 59.82; H, 3.93; N, 8.82.

Example 192

4- [4- (hydroxymethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 192 was obtained in the same manner as in Example 103 except that Example 191C was used instead of Example 61A.

mp 195-196 [deg.] C;

_{MS (DCI / NH 3) m} / e: 315 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H, J = 4.5Hz), 4.49 (d, 2H, J = 4.5Hz), 5.19 (t, 1H, J = 4.5Hz), 7.08 ( 1H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 8.07 (s, s, 1H);

Elemental analysis for C ₁₆ H ₁₄ N ₂ O ₃ S 0.75 CH ₃ OH

Calculated: C, 59.45; H, 4.39; N, 8.28.

Found: C, 59.31; H, 4.35; N, 8.49.

Example 193

4- [4- (methoxymethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 193 was obtained in analogy to Example 188C, except that 4-methoxymethylphenol was used in the place of 4-tert-butyloxycarbonylaminophenol and methylamine was used instead of ammonia.

mp 163-164 [deg.] C;

_{MS (DCI / NH 3) m} / e: 329 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.4Hz), 3.29 (s, 3H), 4.40 (s, 2H), 7.08 (d, 2H, J = 8.5Hz), 1H), 7.37 (d, 2H, J = 8.5 Hz), 8.09 (s, 1H), 8.12 (s, 1H), 8.94 (q, 1H, J = 4.4 Hz), 9.12

Elemental analysis for C ₁₇ H ₁₆ N ₂ O ₃ S

Calculated: C, 62.18; H, 4.91; N, 8.53.

Found: C, 61.86; H, 4.79; N, 8.40.

Example 194

4- {4 - [(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-c] pyridine- 2- carboxamide

The title compound of Example 194 was prepared as in Example 188C but using 4- (2-methoxyethoxymethyl) phenol instead of 4-tert-butyloxycarbonylaminophenol.

_{MS (DCI / NH 3) m} / e: 359 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.40 (s, 3H), 3.60 (m, 2H), 3.65 (m, 2H), 4.56 (s, 2H), 7.02 (d, 2H, J = 8.5Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.80 (s, 1H), 8.13 (s, 1H), 8.94 (s, 1H);

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₄ S

Calculated: C, 60.32; H, 5.06; N, 7.82.

Found: C, 60.33; H, 5.03; N, 7.63.

Example 195

4- {4 - [(2-methoxyethoxy) methyl] phenoxy} -N-methylthieno [2,3- c] pyridine-2- carboxamide

The title compound was prepared in analogy to Example 195C, except that 4- (2-methoxyethoxymethyl) phenol was used instead of 4-tert-butyloxycarbonylaminophenol and methylamine was used instead of ammonia. Of the title compound.

mp 133-134 [deg.] C;

_{MS (DCI / NH 3) m} / e: 373 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.01 (d, 3H, J = 5.1Hz), 3.40 (s, 3H), 3.60 (m, 2H), 3.65 (m, 2H), 4.54 (s, 2H), 1H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.73 (s, 8.94 (s, 1 H);

Elemental analysis for C ₁₉ H ₂₀ N ₂ O ₄ S

Calculated: C, 61.27; H, 5.41; N, 7.52.

Found: C, 61.28; H, 5.35; N, 7.46.

Example 196

Methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxamide

The title compound of Example 196 was prepared as in Example 188C but using 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol instead of 4-tert-butyloxycarbonylaminophenol. .

_{MS (DCI / NH 3) m} / e: 403 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.38 (s, 3H), 3.57 (m, 2H), 3.63-3.70 (m, 6H), 4.55 (s, 2H), 7.02 (d, 2H, J = 8.5Hz ), 7.36 (d, 2H, J = 8.5 Hz), 7.71 (s, 1H), 8.15 (s, 1H), 8.95

Example 197

Methyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide &lt; EMI ID =

The title compound of Example 197 was prepared as in Example 188C but using 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol instead of 4- (tert-butyloxycarbonylaminophenol) .

_{MS (DCI / NH 3) m} / e: 417 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.02 (d, 2H, J = 4.8Hz), 3.38 (s, 3H), 3.57 (m, 2H), 3.63-3.70 (m, 6H), 4.54 (s, 2H ), 6.45 (s, 1H), 7.00 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz) , 1H).

Example 198

2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide

Example 198A

Methyl} phenoxy} thieno [2,3-c] pyridine-2-carboxylate &lt; EMI ID =

4 - [(2,3,4,5-tetrahydro-2H-pyran-2-yl) oxy] methylphenol (PAGrieco, et al., J. Med. The title compound of Example 198A was prepared in analogy to Example 188B, except that the title compound was prepared according to the procedure described in Example &lt; RTI ID = 0.0 &gt; 188B. &Lt; / RTI &gt;

_{MS (DCI / NH 3) m} / e: 400 (M + H) +.

Example 198B

2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide

The title compound of Example 198B was prepared as in Example 61 but using Example 198A instead of Example 61A.

mp 95-96 [deg.] C;

_{MS (DCI / NH 3) m} / e: 385 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.49 (m, 4H), 1.69 (m, 2H), 3.49 2H, J = 8.8 Hz), 7.87 (d, 1H, J = 12.1 Hz), 4.70 ), 8.08 (s, IH), 8.20 (s, IH), 8.46 (s, IH), 9.12 (s, IH);

Elemental analysis for C ₂₀ H ₂₀ N ₂ O ₄ S · CH ₃ OH

Calculated: C, 60.56; H, 5.08; N, 6.73.

Found: C, 60.51; H, 5.07; N, 6.59.

Example 199

Methyl-4- {4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3- c] pyridine-

The title compound of Example 199 was prepared as in Example 103 but replacing Example 61A with Example 198A.

mp 195-196 [deg.] C;

_{MS (DCI / NH 3) m} / e: 399 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.49 (m, 4H), 1.69 (m, 2H), 2.79 (d, 3H, J = 4.8Hz), 3.50 (m, 1H), 3.80 (m, 1H ), 4.44 (d, 1H, J = 12.1 Hz), 4.67 (d, 1H, J = 12.1 Hz), 4.70 (m, 1H, J = 8.8Hz), 8.11 (s, 1H), 8.12 (s, 1H), 8.97 (q, 1H, J = 4.8Hz), 9.13

Elemental analysis for C ₂₁ H ₂₂ N ₂ O ₄ S

Calculated: C, 63.30; H, 5.56; N, 7.03.

Found: C, 63.22; H, 5.58; N, 6.93.

Example 200

4 - {[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy} benzyl 2-furoate

(45 mg, 0.4 mmol), HOBt (54 mg, 0.4 mmol), EDC (77 mg, 0.4 mmol) dissolved in DMF (5 mL) And 2 drops of triethylamine at room temperature for 48 hours. Brine was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 65% EtOAc / hexane to give the title compound.

mp 180-182 [deg.] C;

_{MS (DCI / NH 3) m} / e: 395 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.31 (s, 2H), 6.70 (dd, 1H, J = 1.7, 3.4Hz), 7.14 (d, 2H, J = 8.5Hz), 7.36 (d, 1H 1H, J = 3.4 Hz), 7.50 (d, 2H, J = 8.5 Hz), 7.84 , &Lt; / RTI &gt; 1H), 8.44 (s, 1H), 9.14 (s, 1H).

Example 201

2-yl] oxy} methyl) phenoxy) -2,3-dihydroxy-6- (hydroxymethyl) ] -N-methylthieno [2,3-c] pyridine-2-carboxamide

Example 201A

Dihydro-2H-pyran-2-yl] oxy} methyl) phenoxy) - &lt; / RTI &gt; Yl] thieno [2,3-c] pyridine-2-carboxylate

A solution of 200 mg, 0.63 mmol) and tri-O-acetyl-D-glycal (520 mg, 1.92 mmol) in anhydrous CH ₂ Cl ₂ (10 mL) was treated with Sc (OTf) ₃ Mg, 0.75 mmol) at room temperature for 12 hours and purified directly by silica gel flash chromatography using 40% EtOAc / hexane to give the title compound.

_{MS (DCI / NH 3) m} / e: 528 (M-OAc) +.

Example 201B

2-yl] oxy} methyl) phenoxy) -2-methyl-4- (4-fluoropyrimidin- ] -N-methylthieno [2,3-c] pyridine-2-carboxamide

A solution of Example 201A (167 mg) in a 2 M solution of methylamine in methanol (10 mL) was heated at 45 &lt; 0 &gt; C for 12 h and concentrated. The residual oil was purified by silica gel chromatography using 8% MeOH / CH ₂ Cl ₂ to give the title compound (120 mg, 91%).

_{MS (ESI / NH 3) m} / e: 443 (M-OH) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.8Hz), 3.53 (m, 3H), 3.67 (m, 1H), 3.87 (m, 1H), 4.50 (d, 1H J = 11.5 Hz), 4.64 (t, IH, J = 5.4 Hz), 4.76 (d, IH, J = 11.5 Hz), 5.06 (m, 2H), 5.70 2H, J = 8.5 Hz), 8.10 (s, 1H), 8.11 (s, 1H, J = ), 8.95 (q, IH, J = 4.8 Hz), 9.12 (s, IH).

Example 202

4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

Pd (OAc) ₂ (27 mg, 0.12 mmol), (Tol) ₃ P (110 mg, 0.36 mmol), anhydrous degassed DMF (20 mL ), Tributylethoxyvinyltin (810 ml, 2.4 mmol) and triethylamine (835 ml, 6 mmol) were added. The suspension was stirred at 80 &lt; 0 &gt; C for 14 hours. After dilution with ethyl acetate, the reaction mixture was washed with 1% aqueous HCl solution, water, dried (MgSO ₄ ) and concentrated. The residue was separated by HPLC (C-18, CH ₃ CN / H ₂ O containing 0.1% TFA) to give the title compound (476 mg, 89%).

_{MS (DCI / NH 3) m} / e: 327 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.56 (s, 3H), 2.78 (d, 3H, J = 4.8Hz), 7.15 (d, 2H, J = 8.8Hz), 8.00 (d, 2H, J = 8.8 Hz), 8.03 (s, IH), 8.36 (s, IH), 8.98 (q, IH, J = 4.8 Hz), 9.28 (s, IH);

Elemental analysis for C ₁₇ H ₁₄ N ₂ O ₄ S · 1.35 CF ₃ CO ₂ H

Calculated: C, 49.25; H, 3.45; N, 5.83.

Found: C, 49.31; H, 3.60; N, 5.93.

Example 203

4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

Example 203A

Methyl 4- [4- (4-carboxy) phenoxy] thieno [2,3-c] pyridine-2-carboxylate

THF (15㎖) and HO ₂ (15㎖) mixture of methyl 4-bromo-no to all the city phenoxy [2,3-c] pyridine-2-carboxylate _{(1.0g, 2.74mmol), PdCl 2} DPPFCH 2 Cl 2 (0.284 g) and triethylamine (0.55 g) was heated at 130 &lt; 0 &gt; C for 19 hours under a CO atmosphere (400 psi). EtOAc (200 mL) was added and the mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 5% CH ₃ OH / CH ₂ Cl ₂ to give the title compound (311 mg, 34%).

_{MS (DCI / NH 3) m} / e: 330 (M + H) +;

Example 203B

Methyl 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate

A solution of Example 203A (200 mg, 0.61 mmol) in DMF (5 mL) and CH ₂ Cl ₂ (15 mL) was treated with morpholine (80 mg, 0.91 mmol), PyBOP (474 mg, Was treated with DIPEA (296 mg, 2.28 mmol) at room temperature for 2 hours. After dilution with CH ₂ Cl ₂ , the solution was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 90% EtOAc / hexane to give the title compound (277 mg, 100%).

_{MS (DCI / NH 3) m} / e: 399 (M + H) +;

Example 203C

4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 203C was prepared as in Example 61 but using Example 203B instead of Example 61A.

mp &gt; 260 DEG C;

_{MS (DCI / NH 3) m} / e: 401 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.50 (m, 4H), 3.60 (m, 4H), 7.14 (d, 2H, J = 8.5Hz), 7.48 (d, 2H, J = 8.5hz), 7.86 (s, 1H), 8.15 (s, 1H), 8.22 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H);

Elemental analysis for C ₁₉ H ₁₇ N ₃ O ₄ S

Calculated: C, 59.52; H, 4.47; N, 10.96.

Found: C, 59.64; H, 4.52; N, 10.90.

Example 204

Methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 204 was prepared as in Example 103 but replacing Example 61A with Example 203B.

mp 173-175 [deg.] C;

_{MS (DCI / NH 3) m} / e: 415 (M + NH 4) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.4Hz), 3.50 (m, 4H), 3.60 (m, 4H), 7.12 (d, 2H, J = 8.5Hz), 7.48 (d, 2H, J = 8.5 Hz), 8.07 (s, 1H), 8.24 (s, 1H), 8.96 (q, 1H, J = 4.4 Hz), 9.18

Elemental analysis for C ₂₀ H ₁₉ N ₃ O ₄ S 1.5 CH ₃ OH

Calculated: C, 57.96; H, 4.64; N, 9.43.

Found: C, 57.99; H, 4.86; N, 9.63.

Example 206

Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide

Example 206A

Methyl] phenoxy] thieno [2,3-c] pyridine-2-carboxylate &lt; EMI ID =

A solution of Example 203A (200 mg, 0.61 mmol) in DMF (1 mL) was treated with 4- (2-aminoethyl) morpholine (158 mg, 1.21 mmol), EDC (232 mg, 1.21 mmol), HOBt 164 mg, 1.21 mmol) and triethylamine (122 mg, 1.21 mmol) were treated at room temperature for 18 hours. After dilution with EtOAc, washing the reaction mixture with brine, dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography using 10% MeOH / EtOAc to give the title compound (239 mg, 89%).

_{MS (DCI / NH 3) m} / e: 442 (M + H) +.

Example 206B

Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide

The title compound of Example 206A was prepared in analogy to Example 61, but using Example 206A instead of Example 61A.

mp 214-216 [deg.] C;

_{MS (DCI / NH 3) m} / e: 427 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.41 (t, 4H, J = 4.8Hz), 3.37 (q, 2H, J = 6.1Hz), 3.56 (t, 4H, J = 4.8Hz), 7.14 ( 1H, J = 8.8Hz), 7.84 (s, 1H), 7.87 (d, 2H, J = 8.8Hz) = 6.0 Hz), 8.43 (s, 1 H), 9.17 (s, 1 H).

Example 207

Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide

The title compound of Example 207 was prepared as in Example 103 but replacing Example 61A with Example 206A.

mp 226-228 [deg.] C;

_{MS (DCI / NH 3) m} / e: 441 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.42 (m, 4H), 2.78 (d, 3H, J = 4.4Hz), 3.36 (q, 2H, J = 6.1Hz), 3.56 (t, 4H, J (D, 2H, J = 8.5 Hz), 8.02 (s, 1H), 8.12 = 6.0 Hz), 8.95 (q, 1H, J = 4.4 Hz), 9.20 (s, 1H).

Example 208

Phenoxy} thieno [2,3-c] pyridine-2-carboxamide (Compound B)

Example 208A

2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

O-tolylphosphine (64 mg, 0.21 mmol), anhydrous degassed DMF (50 mg, 1.37 mmol), Pd ₂ (dba) ₃ (20 mL), t-butyl acrylate (602 mL, 4.11 mmol) and triethylamine (575 mL, 4.11 mmol). The suspension was stirred under nitrogen at 100 &lt; 0 &gt; C for 12 hours. Washing was diluted with ethyl acetate, the reaction mixture in brine, water, dried (MgSO ₄₎ and concentrated. The residue was separated by silica gel flash chromatography using 20% EtOAc / hexane to give the title compound (323 mg, 57%).

_{MS (DCI / NH 3) m} / e: 412 (N + H) +.

Example 208B

2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

A solution of Example 208A (1.76 g, 4.2 mmol) in chloroform (50 mL) was treated with trifluoroacetic acid (10 mL) at room temperature for 4 h and then added to ice-cold aqueous NaHCO ₃ . The white solid formed was collected by filtration, washed with water, MeOH, CH ₂ Cl ₂ and dried to give the title compound (1.38 g, 100%).

_{MS (DCI / NH 3) m} / e: 356 (M + H) +;

Example 208C

2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

A solution of Example 208B (260 mg, 0.73 mmol) in a mixture of DMF (5 mL) and CHCl 3 (10 mL) was treated with morpholine (127 mg, 1.46 mmol), PyBOP (760 mg, 1.46 mmol) 380 mg, 2.92 mmol) at room temperature for 12 hours. After dilution with CH ₂ Cl ₂ , the solution was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 90% EtOAc / hexane to give the title compound.

_{MS (DCI / NH 3) m} / e: 425 (M + H) +;

Example 208D

Phenoxy} thieno [2,3-c] pyridine-2-carboxamide (Compound B)

Example 208D was prepared as in Example 61 using Example 208C instead of Example 61A to give the title compound.

_{MS (DCI / NH 3) m} / e: 410 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.59 (m, 6H), 3.70 (m, 2H), 7.13 (d, 2H, J = 8.5Hz), 7.20 (d, 1H, J = 15.5Hz), 1H, J = 8.5 Hz), 7.79 (d, 2H, J = 8.5 Hz), 7.86 (s, ), 9.17 (s, 1 H).

Example 209

3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine -2-carboxamide

Example 209A

Methyl] phenoxy} thieno [2,3-c] pyridin-2-ylmethyl] amino} Pyridine-2-carboxylate

The title compound of Example 209A was prepared in analogy to Example 208C but using 4- (2-aminoethyl) morpholine instead of morpholine.

_{MS (DCI / NH 3) m} / e: 468 (M + H) +;

Example 209B

3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine -2-carboxamide

Example 209B was prepared as in Example 61 but using Example 209A instead of Example 61A to give the title compound.

_{MS (DCI / NH 3) m} / e: 453 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.44 (m, 4H), 3.30 (m, 4H), 3.59 (t, 4H, J = 4.8Hz), 6.60 (d, 1H, J = 15.8Hz), (D, 2H, J = 8.8 Hz), 7.87 (s, 1H), 8.06 (t, 1H, J = 4.8 Hz), 8.16 (s, IH), 8.21 (s, IH), 8.45 (s, IH), 9.17 (s, IH).

Example 210

Methyl-4- [4 - ((E) -3 - {[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3 -c] pyridine-2-carboxamide

The title compound of Example 210 was prepared as in Example 103 but using Example 209A instead of Example 61A.

_{MS (DCI / NH 3) m} / e: 467 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.38 (m, 4H), 2.79 (d, 3H, J = 4.4Hz), 3.59 (m, 8H), 6.58 (d, 1H, J = 15.8Hz), 1H, J = 8.8 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.61 8.95 (q, 1H, J = 4.4 Hz), 9.17 (s, 1H).

Example 211

Thieno [2,3-c] pyridin-2 (1 H) -quinolin-2- - carboxamide

Example 211A

2,3-c] pyridine-2-carboxylic acid methyl ester was prepared by reacting methyl 4- (4 - {(E) -3 - [(2,3- dihydroxypropyl) amino] 2-carboxylate

A solution of Example 208A (250 mg, 0.71 mmol) in DMF (10 mL) was treated with 3-amino-1,2-propanediol (128 mg, 1.41 mmol), EDC (270 mg, 1.41 mmol), HOBt 191 mg, 1.41 mmol) and triethylamine (142 mg, 1.41 mmol) at room temperature for 18 hours. After dilution with EtOAc, washing the reaction mixture with brine, dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography to give the title compound (189 mg, 63%).

_{MS (DCI / NH 3) m} / e: 429 (M + H) +;

Example 211B

Thieno [2,3-c] pyridin-2 (1 H) -quinolin-2- - carboxamide

The title compound of Example 211B was prepared as in Example 61 but using Example 211A instead of Example 61A.

mp 185-187 [deg.] C;

_{MS (DCI / NH 3) m} / e: 414 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.10 (m, 1H), 3.30 (m, 2H), 3.54 (m, 1H), 4.60 (t, 1H, J = 5.9Hz), 4.84 (d, 1H 2H, J = 8.8 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.61 (d, 2H, J = 1H), 8.15 (s, 1H), 8.15 (s, 1H), 7.86 (s, );

Elemental analysis for C ₂₀ H ₁₉ N ₃ O ₅ S

Calculated: C, 58.10; H, 4.63; N, 10.16.

Found: C, 57.99; H, 4.54; N, 10.08.

Example 212

Amino] -3-oxo-1-propenyl} phenoxy) -N-methylthieno [2,3-c] quinolin-2- ] Pyridine-2-carboxamide

The title compound of Example 212 was prepared as in Example 103 but using Example 211A instead of Example 61A.

mp 225-226 [deg.] C;

_{MS (DCI / NH 3) m} / e: 428 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.8Hz), 3.10 (m, 1H), 3.30 (m, 2H), 3.54 (m, 1H), 4.60 (t, 1H J = 5.5 Hz), 4.84 (d, IH, J = 4.8 Hz), 6.66 (d, IH, J = 15.8 Hz), 7.11 1H, J = 5.5 Hz), 8.23 (s, 1H), 8.97 (q, 1H, J = = 4.8 Hz), 9.18 (s, 1 H);

Elemental analysis for C ₂₁ H ₂₁ N ₃ O ₅ S

Calculated: C, 59.00; H, 4.95; N, 9.83.

Found: C, 58.85; H, 4.90; N, 9.58.

Example 213

Amino] -3-oxo-1-propenyl) phenoxy] -N-methyl thieno [3, 2,3-c] pyridine-2-carboxamide

The title compound of Example 213 was prepared as in Example 212 but using 2- (1H-imidazol-5-yl) ethylamine instead of 3-amino-1,2-propanediol.

_{MS (DCI / NH 3) m} / e: 448 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.5Hz), 2.85 (t, 2H, J = 6.6Hz), 3.49 (q, 2H, J = 6.0Hz), 6.53 ( 1H, J = 15.8 Hz), 7.11 (d, 2H, J = 8.5 Hz), 7.42 1H), 8.27 (s, 1H), 8.27 (t, 1H, J = 5.5Hz), 8.97 (q, 1H, J = 4.8Hz), 9.01 s, 1H).

Example 214

Amino] ethyl} -3-oxo-1-propenyl] phenoxy} -N-methylthieno [ [2,3-c] pyridine-2-carboxamide

The title compound of Example 214 was prepared as in Example 212 but using 2- [bis (2-hydroxyethyl) amino] ethylamine instead of 3-amino-1,2-propanediol.

_{MS (DCI / NH 3) m} / e: 485 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.79 (d, 3H, J = 4.8Hz), 3.34 (m, 6H), 3.58 (q, 2H, J = 6.1Hz), 3.77 (t, 4H, J J = 8.5 Hz), 7.48 (d, 1H, J = 15.6 Hz), 7.64 (d, 2H, J = 8.5 Hz) 1H), 8.07 (s, 1H), 8.24 (s, 1H), 8.43 (t, 1H, J = 4.8Hz), 8.97 (q, 1H, J = 4.8Hz)

Example 215

Amino} -3-oxo-1-propenyl] phenoxy} thieno [2,3-b] -c] pyridine-2-carboxamide

The title compound of Example 215 was prepared as in Example 211 but using bis (2-hydroxyethyl) aminoethylamine instead of 3-amino-1,2-propanediol.

_{MS (DCI / NH 3) m} / e: 471 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.56 (m, 4H), 3.21 (m, 2H), 3.41 (m, 4H), 4.37 (t, 2H, J = 5.6Hz), 6.56 (d, 1H 1H, J = 15.4 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.42 8.00 (t, 1H, J = 5.5 Hz), 8.15 (s, 1H), 8.21 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H);

Elemental analysis for C ₂₃ H ₂₆ N ₄ O ₅ S CH ₃ OH

Calculated: C, 56.36; H, 5.41; N, 11.15.

Found: C, 56.40; H, 5.76; N, 11.40.

Example 216

Thieno [2,3-c] pyridin-4-yl} oxy) phenyl] butanoyl} Phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide

A solution of Example 202 (200 mg, 0.45 mmol) in THF (5 mL) was treated with methylmagnesium bromide (3M solution in ether, 0.18 mL, 0.55 mmol) at -50 <0> C for 30 min, It was gradually warmed at room temperature. An aqueous solution of NH ₄ Cl was added and the mixture was extracted with ether. The combined organic phases were washed in brine, water, dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel flash chromatography using 5% MeOH / EtOAc to give the title compound (60 mg, 40%).

_{MS (ESI / NH 3) m} / e: 653 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.58 (s, 3H), 2.77 (d, 3H, J = 4.8Hz), 2.80 (d, 3H, J = 4.8Hz), 3.35 (d, 1H, J 2H, J = 8.8 Hz), 7.08 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8Hz), 7.96 (d, 2H, J = 8.8Hz), 7.99 (s, 2H), 8.13 9.08 (s, 1 H), 9.21 (s, 1 H);

Elemental analysis for C ₃₄ H ₂₈ N ₄ O ₆ S ₂ CH ₃ OH

Calculated: C, 61.39; H, 4.27; N, 8.18.

Found: C, 61.26; H, 4.29; N, 7.95.

Example 217

4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide

Example 217A

Methyl 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3- c] pyridine-

Example 17A (0.88 g, 5 mmol) in THF (15 mL) and DMF (5 mL) was treated with 4- (1-imidazoyl) phenol and potassium t-butoxide (IN in THF, 5.0 mL, 5 mmol) C for 4 hours, then cooled to 0 C and methylthioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 mmol) were added and refluxed for 1 hour. The reaction was added to water, diluted with brine, and extracted with ethyl acetate. Washing the ethyl acetate with 1N NaOH (2x20㎖) and brine (3x20㎖), dried (MgSO ₄₎ to give the title compound.

_{MS (DCI / NH 3) m} / e: 352 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.90 (s, 3H), 7.10 (s, 1H), 7.30 (d, 2H), 7.70 (s, 1H), 7.25 (d, 2H), 8.00 (s , &Lt; / RTI &gt; 1H), 8.25 (d, 2H), 9.25 (s, 1H).

Example 217B

4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide

Example 217A was dissolved in 2M methanolic ammonia and warmed to 50 &lt; 0 &gt; C for 24 hours in a sealed tube. The reaction was evaporated and crystallized from methanol to give the title compound.

mp 310-312 [deg.] C;

_{MS (DCI / NH 3) m} / e: 337 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.10 (s, 1H), 7.28 (m, 2H), 7.68 (t, 1H), 7.25 (dd, 2H), 7.85 (br s, 1H), 8.15 ( s, 1 H), 8.20 (d, 2H), 8.45 (br s, 1 H), 9.15 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₂ N ₄ O ₂ S · 0.50H ₂ O

Calculated: C, 59.12; H, 3.79; N, 16.22.

Found: C, 59.40; H, 3.63; N, 16.30.

Example 218

Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine-

Example 218A

Methyl-4- (4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine-

Example 17A (0.8 g, 5 mmol) in THF (15 mL) was treated with 4- (1H-pyrazol-1-yl) phenol and cesium carbonate (1.6 g, 5 mmol) C, methylthioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 mmol) were added and the mixture was then recycled for 1 h. The mixture was added to water, diluted with brine, and extracted with ethyl acetate. The ethyl acetate was then washed with 1 N NaOH (2 x 20 mL) and brine (3 x 20 mL) and dried (MgSO ₄ ) to give the title compound.

_{MS (DCI / NH 3) m} / e: 352 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.80 (s, 3H), 6.55 (m, 1H), 7.30 (d, 2H), 7.42 (d, 1H), 7.75 (d, 1H), 7.90 (d , 2H), 8.25 (s, IH), 8.50 (d, IH), 9.22 (s, IH).

Example 218B

Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine-

Example 218A was dissolved in 2M methanolic methylamine and warmed in a round bottom flask at 50 &lt; 0 &gt; C for 4 hours. The reaction was evaporated and crystallized from methanol to give the title compound.

mp 192-194 [deg.] C;

_{MS (DCI / NH 3) m} / e: 351 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.70 (d, 3H), 6.55 (m, 1H), 7.25 (d, 2H), 7.75 (br s, 1H), 7.90 (d, 2H), 8.12 ( (s, 1H), 8.20 (s, 1H), 8.50 (d, 1H), 9.00 (m, 1H), 9.18

Elemental analysis for C ₁₈ H ₁₄ N ₄ O ₂ S · 0.25H ₂ O

Calculated: C, 60.15; H, 4.21; N, 15.59.

Found: C, 60.30; H, 3.93; N, 15.73

Example 219

Methyl-4- [4- (1H-1,2,4-triazol-1-yl) phenoxy] thieno [2,3- c] pyridine-

Example 17A and 4- (lH-1,2,4-triazol-l-) phenol were processed as in Example 218 to give the title compound.

mp 214-215 [deg.] C;

_{MS (DCI / NH 3) m} / e: 352 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.70 (d, 3H), 7.30 (d, 2H), 7.55 (b, 1H), 7.90 (d, 2H), 8.12 (s, 1H), 8.25 (d , &Lt; / RTI &gt; 1H), 9.00 (q, 1H), 9.30 (s, 1H).

Example 220

2-yl] phenoxy} thieno [2,3-c] pyridine-2-carbaldehyde Vox amide

Example 220A

N-methyl-4- [4- (N-hydroxyaminedino) phenoxy} thieno [2,3-c] pyridine-

A solution of Example 186 (500 mg, 1.62 mmol) in DMF (10 mL) and EtOH (10 mL) was treated with triethylamine (279 mg, 2.75 mmol) and hydroxylamine hydrochloride (169 mg, 2.43 mmol) At room temperature for 18 hours. The white solid formed was collected by filtration, washed with EtOH and then dried to give the title compound (376 mg, 68%).

_{MS (ESI / NH 3) m} / e: 343 (M + H) +;

Example 220B

3-yl] phenoxy} thieno [2,3-c] pyridine-2-carbaldehyde Vox amide

A suspension of Example 220A (200 mg, 0.58 mmol) in pyridine (8 mL) was treated with trifluoroacetic anhydride (178 mg, 0.85 mmol) at room temperature for 1 h. The resulting yellow solution was heated at 120 &lt; 0 &gt; C for 18 hours and then concentrated. The residue was separated by HPLC (C-18, CH ₃ CN / H ₂ O containing 0.1% TFA) to give the title compound (169 mg, 69%).

mp 174-176 [deg.] C;

_{MS (ESI / NH 3) m} / e: 421 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.78 (d, 3H, J = 4.4Hz), 7.26 (d, 2H, J = 8.8Hz), 8.03 (s, 1H), 8.10 (d, 2H, J = 8.8 Hz), 8.38 (s, 2H), 8.96 (q, 1H, J = 4.4 Hz), 9.25 (s, 1H);

Elemental analysis for C ₁₈ H ₁₁ N ₄ O ₃ SF ₃

Calculated: C, 51.43; H, 2.64; N, 13.33.

Found: C, 51.56; H, 2.76; N, 13.32.

Example 221

2-yl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide

A solution of Example 186 (800 mg, 2.6 mmol) in a mixture of MeOH (30 mL), Et ₂ O (20 mL) and CH ₂ Cl ₂ (30 mL) was purged with hydrogen chloride gas at 0 ° C. for 1.5 h , Stirred at room temperature for 24 hours and then concentrated. The residue was dissolved in MeOH (30 mL) and ethylenediamine (3 mL) and heated at 70 &lt; 0 &gt; C for 2 hours. After cooling the reaction product, the resulting white solid was collected by filtration, washed with methanol and then dried to obtain the title compound (804 mg, 88%).

mp &gt; 280 DEG C;

_{MS (ESI / NH 3) m} / e: 353 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.78 (d, 3H, J = 4.4Hz), 3.32 (br s, 4H), 6.88 (br s, 1H), 7.11 (d, 2H, J = 8.8Hz ), 7.85 (d, 2H, J = 8.8 Hz), 8.04 (s, 1H), 8.22 (s, 2H), 8.93 (q, 1H, J = 4.4 Hz), 9.17

Elemental analysis for C ₁₈ H ₁₆ N ₄ O ₂ S

Calculated: C, 59.36; H, 4.46; N, 14.57.

Found: C, 59.60; H, 4.55; N, 14.40.

Example 222

Methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide

To a nitrogen-purged flask was added Example 190B (200 mg, 0.48 mmol), Pd (OAc) ₂ (11 mg, 0.048 mmol), tri-o-tolylphosphine (44 mg, 0.14 mmol), anhydrous degassed DMF ML), 2-tributylstannylthiophene (305 mL, 0.96 mmol) and triethylamine (334 mL, 2.4 mmol) were added. The suspension was stirred at 80 &lt; 0 &gt; C for 15 hours. After dilution with ethyl acetate, the reaction mixture was washed with brine, H ₂ O, dried (MgSO ₄ ) and concentrated. The residue was separated by HPLC (C-18, CH ₃ CN / H ₂ O containing 0.1% TFA) to give the title compound (212 mg, 90%).

_{MS (ESI / NH 3) m} / e: 367 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H, J = 4.4Hz), 7.13 (m, 1H), 7.17 (d, 2H, J = 8.8Hz), 7.48 (d, 1H, J 1H), 7.54 (d, 1H, J = 5.1 Hz), 7.71 (d, 2H, J = 8.8 Hz), 8.15 = 4.4 Hz), 9.22 (s, 1 H).

Example 223

4 - ([1,1'-biphenyl] -4-yloxy) -N-methylthieno [2,3- c] pyridine-2- carboxamide

The title compound of Example 223 was prepared as in Example 222 but using tributylphenyltin instead of thiophene (tributylstannyl) thiophene.

_{MS (ESI / NH 3) m} / e: 361 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H, J = 4.5Hz), 7.19 (d, 2H, J = 8.8Hz), 7.36 (t, 1H, J = 7.4Hz), 7.47 ( 1H, J = 7.3 Hz), 7.66 (d, 2H, J = 7.3 Hz), 7.72 (d, 2H, J = 8.8 Hz), 8.15 q, 1 H, J = 4.4 Hz), 9.19 (s, 1 H).

Example 224

Methyl-4- [4- (1-methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3- c] pyridine-

Methyl-5-tributylstannyl) imidazole (prepared according to the literature method (K. Gaare, et al., Acta Chem.Scand. 1993, 47, 57) The title compound of Example 224 was prepared in analogy to example 222, but using &lt; RTI ID = 0.0 &gt;

mp 256-258 [deg.] C;

_{MS (ESI / NH 3) m} / e: 365 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H, J = 2.1Hz), 3.67 (s, 3H), 7.03 (s, 1H), 7.17 (d, 2H, J = 8.8Hz), 1H, J = 2.1 Hz), 9.16 (s, 1H), 7.53 (d, 2H, J = 8.8 Hz), 7.69 );

Elemental analysis for C ₁₉ H ₁₆ N ₄ O ₂ S

Calculated: C, 62.62; H, 4.43; N, 15.37.

Found: C, 62.38; H, 4.23; N, 15.13.

Example 225

4- {4- [1- (hydroxymethyl) cyclopropyl] phenoxy} -N-methylthieno [2,3-c] pyridine- 2- carboxamide

Example 225A

4- (1-hydroxymethylcyclopropyl) anisole

A solution of l- (4-methoxyphenyl) -1-cyclopropanecarboxylic acid (5.0 g, 26 mmol) in THF (100 mL) was slowly treated with LiAlH ₄ (0.95 g, 25 mmol) at -20 <0> C for 0.5 h , And then the temperature was raised to room temperature for 2 hours. EtOH was slowly added to consume excess LiAlH ₄ . After diluting with ether, washing the reaction mixture was 2% HCl, in saline water, dried (MgSO ₄₎ and concentrated to give the title compound (5.0g, 100%).

_{MS (DCI / NH 3) m} / e: 196 (M + NH 4) +;

Example 225B

4- (1-hydroxymethylcyclopropyl) phenol

Pure ethane thiol (610 mg, 9.8 mmol) was slowly added to a suspension of NaH (60% in mineral oil, 392 mg, 9.8 mmol) suspended in DMF (10 mL) at room temperature. The reaction mixture was stirred for 10 minutes to obtain a clear liquid. Then, Example 225A (500 mg, 2.8 mmol) was added and the mixture was heated at 145 占 폚 for 4 hours. After dilution with ether, the reaction mixture was washed with 2% HCl in brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 50% EtOAc / hexane to give the title compound (373 mg, 81%).

_{MS (DCI / NH 3) m} / e: 182 (M + NH 4) +.

Example 225C

4- (1-triphenylmethoxymethylcyclopropyl) phenol

A solution of Example 225B (1.0 g, 6 mmol) in pyridine (7 mL) was treated with triphenylmethyl chloride (1.87 g, 6.7 mmol) at room temperature for 18 hours. After diluting with ether, the reaction mixture was washed with 1% aqueous HCl and water, dried (MgSO _4). The residue was purified by silica gel flash chromatography with 12% EtOAc / hexane to give the title compound.

_{MS (DCI / NH 3) m} / e: 407 (M + H) +.

Example 225D

Methyl [4- (1-triphenylmethoxymethyl) cyclopropyl] phenoxy- [2,3-c] pyridine-

The title compound of Example 225D was prepared in analogy to Example 61A but using Example 225C instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e: 598 (M + H) +.

Example 225E

Methyl 4- [4- (1-hydroxymethyl) cyclopropyl] phenoxy- [2,3-c] pyridine-2-

A solution of Example 225D (230 mg, 0.38 mmol) in a mixture of CH ₂ Cl ₂ (10 mL) and MeOH (5 mL) was treated with trifluoroacetic acid (1 mL) at 0 ° C. for 1 hour, after stirring for 1 hour and allowed to warm to adding the next, NaHCO ₃ aqueous solution. The mixture was extracted with methylene chloride. The combined organic phases were washed with water, dried (MgSO _4). The residue was purified by silica gel flash chromatography using 65% EtOAc / hexane to give the title compound (78 mg, 58%).

_{MS (DCI / NH 3) m} / e: 356 (M + H) +.

Example 225F

4- [4- (1-hydroxymethyl) cyclopropyl] phenoxy-N-methylthieno [2,3-c] pyridine- 2- carboxamide

The title compound of Example 225F was prepared as in Example 103 but using Example 225E instead of Example 61A.

_{MS (ESI / NH 3) m} / e: 355 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 0.72 (m, 2H), 0.82 (m, 2H), 2.80 (d, 3H, J = 4.7Hz), 3.51 (d, 2H, J = 5.8Hz), 2H, J = 8.8 Hz), 8.06 (s, IH), 8.13 (s, IH), 7.31 (d, 2H, J = 8.96 (q, 1 H, J = 4.7 Hz), 9.10 (s, 1 H).

Example 226

Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxaldehyde amides

Example 226A

4- (2- (2-ethoxyethoxy) ethoxy) methylcyclopropyl) anisole

A solution of Example 225A (1.0 g, 5.6 mmol) in THF (15 mL) was treated with NaH (60% in mineral oil, 312 mg, 7.8 mmol) and 15-crown-5 (1.33 mL, 6.7 mmol) After treatment for 15 minutes, 2- (2-ethoxyethoxy) ethyl tosylate (1.93 g, 6.7 mmol), prepared according to literature method (C. Almansa, et al., Tetrahedron 1991, 47, 5867) . The brown slurry was stirred at room temperature for 5 hours and added to brine. The mixture was extracted with CH ₂ Cl ₂ , the organic phases were combined, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 25% EtOAc / hexane to give the title compound (1.58 g, 95%).

_{MS (ESI / NH 3) m} / e: 312 (M + NH 4) +.

Example 226B

4- (2- (2-ethoxyethoxy) ethoxy) methylcyclopropyl) phenol

A solution of Example 226A (1.5 g, 5.1 mmol) in DMF (15 mL) was treated with sodium thiomethoxide (1.25 g, 17.8 mmol) at 145 &lt; 0 &gt; C for 5 h. After cooling to room temperature, methylene chloride (100 ml) was added and the mixture was washed with 2% HCl in brine. The organic layer was dried (MgSO ₄ ), concentrated, and the residue was purified by silica gel flash chromatography using 35% EtOAc / hexane to give the title compound (1.33 g, 93%).

_{MS (ESI / NH 3) m} / e: 298 (M + NH 4) +;

Example 226C

Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxylate Rate

The title compound of Example 226C was prepared in analogy to Example 61A but using Example 226B instead of 4-chlorophenol.

_{MS (ESI / NH 3) m} / e: 472 (M + H) +.

Example 226D

Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxaldehyde amides

The title compound of Example 226D was prepared as in Example 103 but using Example 226C instead of Example 61A.

_{MS (ESI / NH 3) m} / e: 471 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 0.84 (m, 2H), 0.87 (m, 2H), 1.06 (t, 3H, J = 6.7Hz), 2.82 (d, 3H, J = 4.4Hz), 2H), 7.37 (d, 2H, J = 8.8Hz), 8.13 (s, 1H, J = ), 8.26 (s, 1H), 9.10 (q, 1H, J = 4.4 Hz), 9.28 (s, 1H);

Elemental analysis for C ₂₅ H ₃₀ N ₄ O ₅ S

Calculated: C, 59.22; H, 6.16; N, 5.52.

Found: C, 59.50; H, 6.16; N, 5.26.

Example 227

Methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-c] pyridine-2- carboxamide

The title compound of Example 227 was prepared as in Example 103 but using 4-trifluoromethoxyphenol instead of 4-chlorophenol.

mp 132-133 [deg.] C;

_{MS (ESI / NH 3) m} / e: 368 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H, J = 4.4Hz), 7.20 (d, 2H, J = 9.2Hz), 7.41 (d, 2H, J = 9.2Hz), 8.08 ( s, 1H), 8.21 (s, 1H), 8.95 (q, 1H, J = 4.4 Hz), 9.18 (s, 1H);

Elemental analysis for C ₁₆ H ₁₁ N ₂ O ₃ SF ₃

Calculated: C, 52.17; H, 3.01; N, 7.61.

Found: C, 52.21; H, 3.26; N, 7.29.

Example 228

2,3-c] pyridin-2-yl} - (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] thieno [ 1,3,4-oxadiazole-2-amine

The title compound of Example 228 was prepared as in Example 275 and Example 156 but using Example 226C instead of Example 61A.

mp 113-114 [deg.] C;

_{MS (ESI / NH 3) m} / e: 497 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 0.82 (m, 2H), 0.85 (m, 2H), 1.05 (t, 3H, J = 7.1Hz), 3.40 (t, 2H, J = 7.1Hz), 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz), 7.55 (s, 1H), 7.58 s, 1 H), 9.15 (br s, 1 H).

Example 229

Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide

Example 229A

Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide

A suspension of active copper (512 mg, 8 mmol) suspended in anhydrous DMSO (5 mL) was treated with ethyl iododifluoroacetate (1.0 g, 4 mmol) at room temperature for 10 min. Phenol (188 mg, 2 mmol) and Example 190B were then added. The reaction mixture was stirred at room temperature for 20 hours. After diluting with 1: 1 ether / EtOAc, the mixture was washed with 1% HCl in brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography using 65% EtOAc / hexane and further purified by HPLC (C-18, CH ₃ CN / H ₂ O containing 0.1% TFA) to give the title compound (85 mg , 15%).

_{MS (ESI / NH 3) m} / e: 407 (M + H) +.

Example 229B

Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide

A solution of Example 229A (40 mg, 0.1 mmol) in MeOH (5 mL) was treated with NaBH ₄ (50 mg) at room temperature for 2 hours. Brine was added and the mixture was extracted with EtOAc. The organic phases were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by HPLC (C-18, CH ₃ CN / H ₂ O containing 0.1% TFA) to give the title compound (44.4 mg, 94%).

_{MS (ESI / NH 3) m} / e: 365 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.94 (s, 3H), 3.93 (t, 2H, J = 13.5Hz), 7.27 (d, 2H, J = 9.2Hz), 7.65 (d, 2H, J = 9.2 Hz), 8.15 (s, 2H), 9.24 (s, 1 H);

Elemental analysis for C ₁₇ H ₁₄ N ₂ O ₃ SF ₂ · TFA

Calculated: C, 47.70; H, 3.16; N, 5.86.

Found: C, 47.67; H, 3.10; N, 5.76.

Example 230

2,3-c] pyridine-1-carboxylic acid ethyl ester was used in place of 4- (4- {2- [2- (2- ethoxyethoxy) ethoxy] -1,1- difluoroethyl} phenoxy) 2-carboxamide

A solution of Example 229B (40 mg, 0.11 mmol) in THF (3 mL) was treated with NaH (60% in mineral oil, 7 mg, 0.16 mmol) and 15-crown-5 (35 mg, 0.16 mmol) And treated for 15 minutes. 2- (2-ethoxyethoxy) ethyl tosylate (46 mg, 0.16 mmol), prepared according to the literature method (C. Almansa, et al., Tetrahedron 1991, 47, 5867) was added. The reaction mixture was stirred at room temperature for 15 hours and directly separated on HPLC (C-18, CH ₃ CN / H ₂ O with 0.1% TFA) to give the title compound (46 mg, 81%).

_{MS (ESI / NH 3) m} / e: 481 (M + H) +;

_{^{1 H NMR (300MHz, CD 3}} OD) δ 1.16 (t, 3H, J = 7.1Hz), 2.97 (s, 3H), 3.49 (q, 2H, J = 7.1Hz), 3.57 (m, 6H), 3.70 (m, 2H), 4.01 (t, 2H, J = 12.7 Hz), 7.37 (d, 2H, J = 8.8 Hz), 7.72 (d, 2H, J = 8.8 Hz) (s, 1 H), 9.46 (s, 1 H).

Example 231

2,3-c] pyridine-1-carboxylic acid ethyl ester, which was prepared in accordance with the general method of example 1 from 2- 6-ium trifluoroacetate

Example 103 (47.4 mg, 0.149 mmol) was dissolved in 1.5 mL anhydrous acetonitrile (warm) (under N ₂ atmosphere) and chloromethyl pivalate (25 mg, 0.167 mmol) was added at room temperature. The reaction was stirred for 16 h, then tetrabutylammonium iodide (1 mg) was added and the solution was then warmed to reflux for 48 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C-18 column, eluent gradient 20-70% acetonitrile-0.1% aqueous TFA, eluted for 60 minutes) to afford the title compound as a foam (34%).

HPLC: Supelco C-18 column, 0.1% aqueous TFA: acetonitrile 0:90 to 90: 0 gradient elution (30 min elution), detection at 254 nm, flow rate 0.8 ml / min, RT 20.0 min.

MS (APCI +) m / e: 433 (M) ^&lt; ⁺ &^gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.18 (s, 9H), 3.01 (s, 3H), 6.4-6.6 (br s, 2H), 7.1-7.3 (br s, about 2H), 7.49 (br s, 2H), 7.74 (br s, 1H), 8.41 (br s, 1H), 8.64 (br s, 1H), 9.3-9.9 (br s, 1H);

Elemental analysis for C ₂₃ H ₂₂ F ₃ Cl ₂ O ₆ S

Calculated: C, 45.43; H, 3.51; N, 4.24.

Found: C, 45.93; H, 3.70; N, 4.34.

Example 232

Methyl] carbonyl] thieno [2,3-c] pyridine prepared in Step 1 was added to a solution of 4- (4-bromophenoxy) -6 - {[(2,2- dimethylpropanoyl) oxy] -6-ium

Example 171 (69.4 mg, 0.191 mmol) was dissolved in 2 mL acetonitrile followed by addition of tetrabutylammonium iodide (1 mg) followed by chloromethyl pivalate (22 mg, 0.146 mmol). The reaction solution was warmed to reflux for 24 hours. Additional chloromethyl pivalate (11 mg, 0.073 mmol) was added and the reaction was refluxed for a further 72 h. The reaction was concentrated under reduced pressure and the solid partitioned between 15 ml of water and 15 ml of EtOAc. The aqueous phase was extracted with 2 x 15 mL EtOAc, then the aqueous phase was concentrated under reduced pressure to a yellow solid (93.5 mg). HPLC purification (C-18 column, 20-75% acetonitrile-0.1% aqueous TFA) gave the pure title compound (55.9 mg, 49%).

HPLC: Supelco C-18 column, 0.1 aqueous TFA: acetonitrile gradient eluent 0:90 to 90: 0 (30 min), detection at 254 nm, flow rate 0.8 ml / min, RT 20.3 min.

MS (APCI-) m / e: 475, 477 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.17 (s, 9H), 3.02 (br m, 3H), 6.0-6.7 (vbr s, 2H), 7.14 (br d, 2H), 7.64 (br d, 2H), 7.78 (s, 1H), 8.07-8.17 (brs, 1H), 8.34 (s, 1H), 9.44-9.65 (brbr, 1H);

Elemental analysis for C ₂₃ H ₂₂ F ₃ BrN ₂ O ₆ S · 1.5H ₂ O

Calculated: C, 40.99; H, 3.58; N, 3.82.

Found: C, 40.94; H, 3.25; N, 3.76.

Example 233

2,3-c] pyridin-6-ynyl) -2 - [(4-chlorophenoxy) -6 - {[(isopropoxycarbonyl) oxy] methyl} thieno [

To a solution of Example 61 (300 mg, 0.94 mmol) in acetonitrile (15 mL) under a nitrogen atmosphere was added sodium tetraphenylboron (387 mg, 1.13 mmol), sodium iodide (169 mg, 1.13 mmol) Propyloxycarbonyl) oxy] methyl chloride (172 mg, 1.13 mmol). The reaction mixture was heated under reflux for 4 hours, cooled to room temperature, then diluted with acetonitrile (100 mL) and filtered through Celite ^R ). The filtrate was concentrated to obtain a foamed product, which was pulverized in methanol to obtain pyridinium tetraphenylborate (550 mg) as a yellow solid. A tetraphenyl borate 1: 1 CH ₃ CN: dissolved in i-PrOH and, using Dowex 1X2 chloride (50 to 100 mesh) and passed through an ion exchange column. The eluate was concentrated and the resulting residue was triturated with Et ₂ O to give Example 233 as a white solid (210 mg, 49%).

MS (FAB) m / e: 421 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.26 (d, J = 7Hz, 6H), 4.81 (q, J = 7Hz, 1H), 6.44 (s, 2H), 7.41 (m, 2H), 7.62 ( (m, 2H), 8.31 (br s, IH), 8.59 (s, IH), 8.68 (s, IH), 8.80 (br s, IH), 9.98

Elemental analysis for C ₁₉ H ₁₈ Cl ₂ N ₂ O ₅ S ^-

Calculated: C, 49.90; H, 3.96; N, 6.13.

Found: C, 49.74; H, 3.95; N, 6.14.

Example 234

4- (Cyclopentyloxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide

Example 234A

5-Chloro-3-cyclopentyloxypyridine

The title compound (5.91 g, 77%) was prepared as described in example 236A but using cyclopentanol (4.2 mL, 46.31 mmol) instead of benzyl alcohol.

MS (APCI) m / e: 198 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.53-1.76 (m, 6H), 1.86-2.02 (m, 2H), 4.92-4.99 (m, 1H), 7.55 (t, J = 2.25Hz, 1H) , 8.18 (d, J = 2.25 Hz, 1 H), 8.22 (d, J = 3 Hz, 1 H).

Example 234B

5-Chloro-3-cyclopentyloxypyridine-4-carboxaldehyde

The title compound (5.22 g, 77%) was prepared as described in example 236B but using Example 234A (5.9 g, 30 mmol) instead of Example 236A.

MS (APCI) m / e: 226 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.55-1.85 (m, 6H), 1.93-2.04 (m, 2H), 5.14-5.22 (m, 1H), 8.36 (s, 1H), 8.63 (s, 1H), 10.31 (s, 1 H).

Example 234C

Methyl 4- [cyclopentyloxy] thieno [2,3-c] pyridine-2-carboxylate

The title compound (4.31 g, 67%) was prepared as described in example 236C but using 234B (5.2 g, 23.11 mmol) instead of Example 236B.

MS (APCI) m / e: 278 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.59-1.69 (m, 2H), 1.74-1.81 (m, 2H), 1.83-1.90 (m, 2H), 1.97-2.07 (m, 2H), 3.93 ( s, 3H), 5.12-5.17 (m, IH), 8.05 (s, IH), 8.24 (s, IH), 8.94 (s, IH);

^{13 C NMR (100MHz, DMSO-} d 6) δ 23.63 (CH 2), 32.30 (CH 2), 52.98 (OCH 3), 80.33 (CH), 125.52 (CH), 127.09 (CH), 134.72 (C), 136.45 (C), 137.44 (CH), 138.05 (C), 149.27 (C), 161.90 (C = O).

Example 234D

4- [cyclopentyloxy] thieno [2,3-c] pyridin-2-ylmethylamide

The compound of Example 234C (1.6 g, 61%) was prepared as described in example 171 but using Example 234C (2.6 g, 9.4 mmol) instead of Example 73A.

mp 216-217 [deg.] C;

MS (APCI) m / e: 277 (M + H) ⁺ , 244 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.60-1.69 (m, 2H), 1.73-1.90 (m, 4H), 1.97-2.08 (m, 2H), 2.83 (d, J = 4Hz, 3H), 8.10 (s, 1H), 8.19 (s, 1H), 8.85 (s, 1H), 8.93 (d, J = 4 Hz, 1H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 23.60 (CH 2), 26.14 (NCH 3), 32.34 (CH 2), 80.14 (CH), 119.68 (CH), 126.91 (CH), 135.73 (C), 137.17 (CH), 144.2 (C), 149.02 (C), 161.18 (C).

Example 235

N- (2-cyclohexen-1-yloxy) -N-methylthieno [2,3-c] pyridine-

Example 235A

Methyl 4- [2-cyclohexene-3-oxy] thieno [2,3-c] pyridine-

The title compound (158 mg, 57%) was prepared as described in example 99A but using 2-cyclohexeneol (0.113 mL, 0.115 mmol) instead of 3-hydroxy tetrahydrofuran. Purification by silica gel flash chromatography eluting with 10% acetone-hexane gave pure product.

MS (APCI) m / e: 290 (M + H) ⁺ , 288 (MH) ^- ; 324 (M + Cl) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.95-1.62 (m, 1H), 1.66-2.14 (m, 5H), 3.92 (s, 3H, OCH 3), 5.22-5.26 (m, 1H), 5.91 2H), 8.03 (s, 1H, CH), 8.36 (s, 1H, CH), 8.95 (s, 1H, CH).

Example 235B

N- (2-cyclohexen-1-yloxy) -N-methylthieno [2,3-c] pyridine-

Example 235 (59 mg, 40%), which is the title compound, was prepared from Example 235A (150 mg, 0.519 mmol) as described in Example 171.

MS (APCI) m / e: 289 (M + H) &lt; ⁺ & gt ^; , 287 (MH) ^- ; 323 (M + Cl) ^- ;

¹ H NMR (500 MHz, DMSO-d ₆ )? 1.62-1.70 (m, 1 H), 1.78-1.91 (m, 2H), 1.96-2.17 (S, 1H), 8.87 (s, 1H), 8.75 (m, 1H) , J = 5 Hz, 1H);

^{13 C NMR (75MHz, DMSO-} d 6) δ 18.2 (CH 2), 24.6 (CH 2), 26.2 (CH 3), 27.7 (CH 2), 71.3 (CH), 119.7 (CH), 125.6 (CH) , 127.4 (CH), 132.6 (CH), 136.0 (C), 137.3 (C), 137.4 (CH), 144.1 (C), 149.0 (C), 161.2 (C).

Example 236

4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide

Example 236A

5-chloro-3-benzyloxypyridine

To a solution of 5-chloro-3-pyridinol (10 g, 77.19 mmol) in anhydrous tetrahydrofuran (155 ml) at 0 ° C in a nitrogen atmosphere with stirring was added benzyl alcohol (9.6 ml, 92.63 mmol), triphenylphosphine 26.32 g, 100.35 mmol) and diethyl azodicarboxylate (15.8 mL, 100.35 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was removed under reduced pressure. The resulting residue (70 g) was treated with diethyl ether (2 x 300 ml) and the solid was filtered off. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with 5% acetone and hexane to give the title compound in 36% (5.8 g).

MS (APCI) m / e: 220 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.22 (s, 2H), 7.33-7.49 (m, 5H), 7.77 (t, J = 5Hz, 1H), 8.23 (d, J = 5H, 1H), 8.34 (d, J = 5 Hz, 1 H).

Example 236B

5-Chloro 3-benzyloxypyridine-4-carboxaldehyde

To a solution of diisopropylamine (4.5 mL, 31.78 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere at -5 ° C was added n-BuLi (2.5 M solution, 12.8 mL, 31.78 mmol) in hexane , While the internal use of the reaction mixture was maintained at &lt; RTI ID = 0.0 &gt; 0 C &lt; / RTI &gt; The reaction mixture was stirred at -10 [deg.] C for 10 min, then at 0 [deg.] C for 30 min. This was cooled to -78 ° C and a solution of Example 236A (5.8 g, 26.5 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) was slowly added. And the mixture was stirred at -78 ° C for 1 hour. Then, methyl formate (5 ml, 79.5 mmol) in anhydrous THF (15 ml) was added dropwise to stop the reaction, and the mixture was stirred at -78 캜 for 3.5 hours. The internal temperature of the reaction mixture was kept at -74 캜 or below throughout the reaction. After 3.5 h, the reaction mixture was added to a saturated aqueous solution of NaHCO ₃ (200 mL) and stirred for 15 min. The mixture was partitioned between ethyl acetate (250ml) and the organic layer was separated and washed with brine (2x60ml). The dried (MgSO ₄₎ and concentrated the organic layer under a reduced pressure to obtain the crude product (8.5g). Purification by flash chromatography on silica gel eluting with 6% acetone-hexane gave the title compound in 75% yield (4.2 g).

MS (APCI) m / e: 248 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.42 (s, 2H), 7.33-7.45 (m, 3H), 7.48-7.52 (m, 2H), 8.41 (s, 1H), 8.72 (s, 1H) , 10.39 (s, 1 H).

Example 236C

Methyl 4-benzyloxythieno [2,3-c] pyridine-2-carboxylate

To an ice-cooled solution of Example 236B (4.2 g, 17 mmol) in anhydrous tetrahydrofuran (42 mL) under a nitrogen atmosphere was added methylthioglycolate (1.83 mL, 20.4 mmol) and then powdered cesium carbonate (6.65 g, 20.4 mmol). The reaction mixture was then allowed to warm to room temperature while stirring under nitrogen. After 30 minutes, the reaction was refluxed for 15 minutes and cooled to room temperature. The reaction mixture was quenched with ice (50 mL) and partitioned with ethyl acetate (250 mL). The organic layer was separated, washed with saturated NaCl (3 x 60 mL) ice-cold solution, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the crude product which was recrystallized from methanol. The mother liquor was purified by silica gel flash chromatography, eluting with 7% acetone-hexane. The fractions were combined to give the title compound in 55% yield, 3.07 g.

MS (APCI) m / e: 300 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.92 (s, 3H), 5.42 (s, 2H), 7.35-7.47 (m, 3H), 7.52-7.57 (m, 2H, Ar-CH), 8.12 ( s, 1 H), 8.36 (s, 1 H), 8.98 (s, 1 H).

Example 236D

Methyl 4-hydroxyt eno [2,3-c] pyridine-2-carboxylate

(380 mg, 1.3 mmol) dissolved in ethanol (82 ml) was added to a suspension of 10 wt% of Pd (38 mg, 10% w / w) on activated carbon suspended in anhydrous ethanol (3 ml) Was added under a nitrogen atmosphere. The reaction mixture was then degassed and stirred under hydrogen atmosphere at room temperature. After overnight, the reaction mixture was further treated with 10wt% Pd (190mg, 50% w / w) on activated carbon and stirred under a hydrogen atmosphere. After 48 hours, a further catalyst (100 mg, 26% w / w) was added to the reaction mixture. The reaction mixture was further stirred under hydrogen atmosphere for 24 hours and filtered through Celite ^R ). The filtrate was evaporated to dryness under reduced pressure to give the crude product (320 mg). Purification by silica gel flash chromatography eluting with 5% acetone-hexane then 40% acetone-hexane gave the title compound Example 236E as a 75% yield (200 mg).

MS (APCI) m / e: 210 (M + H) ⁺ , 208 (MH) ^- , 244 (M + Cl) ^- ;

¹ H NMR (300 MHz, DMSO-d ₆ )? 3.93 (s, 3H), 8.08 (s, .

Example 236E

4-benzyloxythieno [2,3-c] pyridine-2-carboxamide

The title compound (50 mg, 67%) was prepared as described in Example 44 using the product of Example 236C (75 mg, 0.25 mmol).

MS (APCI) m / e: 285 (M + H) &lt; ⁺ & gt ^; , 319 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 5.43 (s, 2H), 7.49-7.50 (m, 3H), 7.58-7.63 (m, 2H), 7.79 (br s, 1H), 8.30 (s, 1H ), 8.36 (s, 1 H), 8.48 (br s, 1 H), 8.93 (s, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 70.13 (CH 2), 120.56 (CH), 126.21 (CH), 127.5 (CH), 128.14 (CH), 128.51 (CH), 135.30 (C), 136.35 ( c), 137.48 (c), 137.86 (CH), 144.75 (C), 149.82 (C), 162.61 (C).

Example 237

4- (4-Chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2- carboxamide

Example 237A

Methyl 4-chlorothieno [2,3-c] pyridine-2-carboxylate

Example 17A The product (15.00 g, 85.22 mmol) was dissolved in THF (80 mL) and cesium carbonate (27.77 g, 85.22 mmol) was added. Methyl thioglycolate (7.62 mL, 85.22 mmol) diluted in THF (20 mL) was added dropwise over 20 minutes. The reaction was stirred for 1.5 h and then heated to 40 &lt; 0 &gt; C for 1 h. The reaction mixture was poured into 850 mL of stirred water. After 10 minutes, the precipitate was collected by filtration and washed twice with water. The product was dried in a drier to give the title compound as a solid (15.2 g, 78%).

_{MS (DCI / NH 3) m} / e: 228 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 3.96 (s, 3H), 8.15 (s, IH), 8.65 (s, IH), 9.38

Example 237B

4-Chlorothieno [2,3-c] pyridine-2-carboxylic acid

Example 237A (15.17 g, 66.63 mmol) was added at 1: 4 MeOH / water (500 mL) and a solution of LiOH hydrate (4.34 g, 103.50 mmol). The reaction was stirred for 1.5 h and then concentrated (100 mL). The aqueous phase was washed with Et ₂ O and acidified to pH 5 with 1 N HCl (aq). The precipitate was separated by filtration and washed once with water and twice with acetonitrile. The product was dried in a drier to give 4-chlorothieno [2,3-c] pyridine-2-carboxylic acid as a solid (12.10 g, 85%).

_{MS (DCI / NH 3) m} / e: 214 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 8.05 (s, 1H), 8.62 (s, 1H), 9.34 (s, 1H).

Example 237C

To a solution of dimethylethyl 4-chlorothieno [2,3-c] pyridine-2-carboxylate

A suspension of the product of Example 237B (12.07 g, 56.50 mmol) in THF (200 mL) was added t-butyl 2,2,2-trichloroacetamidate (25.00 g, 114.41 mmol) at 0 & Fluoride-diethyl etherate (2.14 mL, 16.95 mmol) was added dropwise. Additional t-butyl 2,2,2-trichloroacetamidate (12.50 g, 57.21 mmol) was added and the reaction was stirred for 3 hours. The stirred reaction was treated with NaHCO ₃ (14 g) and then diluted with water (300 mL). The reaction solution was partitioned between water (300 mL) and 50% EtOAc / Et ₂ O. The organic layer was washed with saturated NaHCO ₃ and brine, partially dried over sodium sulphate, then filtered and concentrated. As eluent and the residue was purified by flash chromatography on silica gel neutralized with Et ₃ N by using EtOAc / hexane. The title compound was isolated as a solid (10.04, 66%).

_{MS (DCI / NH 3) m} / e: 270 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.59 (s, 9H), 8.04 (s, 1H), 8.64 (s, 1H), 9.35

Example 237D

Dimethylethyl 4- (ethoxycarbonyl) thieno [2,3-c] pyridine-2-carboxylate

A solution of Example 237C (1.00 g, 3.71 mmol), 1,3-bis (diphenylphosphino) propane (0.46 g, 1.11 mmol) and triethylamine (1.55 mL, 11.13 mmol) in 2: 3 EtOH / DMF mmol) in THF (5 mL) was added palladium (II) acetate (0.25 g, 1.11 mmol). A CO stream (g) was injected into the reaction solution for 15 minutes. CO (g) was applied and the reaction was heated to 105 DEG C for 16 hours and then cooled to room temperature. The reaction was poured into water (400 mL). The aqueous phase was diluted with brine (25 mL) and saturated NaHCO ₃ (25 mL) and extracted with EtOAc (4 x 50 mL). The organic extracts were combined and washed with 20% saturated NaHCO ₃ (2 x 200 mL) and brine (2 x 100 mL), then partially dried with sodium sulfate, filtered and concentrated. The residue was flash chromatographed on silica gel using EtOAc / hexane as eluent to give the title compound as a solid (0.60, 53%).

MS (APCI) m / e: 308 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CD 2}} Cl 2) δ 1.44 (t, J = 7.1Hz, 3H), 1.59 (s, 9H), 4.44 (q, J = 7.1Hz, 2H), 8.65 (s, 1H), 9.12 (s, 1 H), 9.25 (s, 1 H).

Example 237E

Dimethyl 4-formylthienol [2,3-c] pyridine-2-carboxylate

To a stirred solution of NaBH ₄ (0.18 g, 4.89 mmol) in anhydrous 50% MeOH / THF was added powdered CaCl ₂ (0.54 g, 4.89 mmol) at 0 ° C. The suspension was stirred for 20 minutes and a solution of Example 237D (0.50 g, 1.63 mmol) in anhydrous 50% MeOH / THF was slowly added over 10 minutes. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for 16 hours. The reaction was quenched with a slurry of dilute AcOH (aq) / ice. After all gas evolution ceased with stirring, the aqueous phase was basified with saturated NaHCO ₃ . The aqueous phase was extracted with dichloromethane (3 x 40 mL) and the extracts were combined. The organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a solid (0.14 g, 32%).

MS (APCI) m / e: 266 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CD ₂ Cl ₂ )? 1.54 (s, 9H), 4.94 (s, 2H), 8.08 (s,

To a stirred solution of oxalyl chloride (0.10 mL, 1.17 mmol) in anhydrous dichloromethane (1 mL) was added DMSO (0.19 mL, 2.65 mmol) at -78 < After 20 minutes, a solution of dimethyl 4-formylthienol [2,3-c] pyridine-2-carboxylate (0.28 g, 1.06 mmol) in anhydrous dichloromethane (4 mL) was added dropwise. The reaction was stirred at -78 &lt; 0 &gt; C for 1 h and then treated with triethylamine (0.74 mL, 5.30 mmol). After 5 minutes, the reaction was allowed to warm to room temperature over 30 minutes. The reaction was quenched with water (5 mL) and partitioned between dichloromethane (50 mL) and 50% saturated aqueous NaHCO ₃ (50 mL). The organic phase was washed with 50% saturated aqueous NaHCO ₃ (1 x 50 mL), dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated to dryness in a drier to afford the title compound as a solid (0.25 g, 90%).

MS (APCI) m / e: 264 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CD 2}} Cl 2) δ 1.59 (s, 9H), 8.74 (s, 1H), 8.91 (s, 1H), 9.31 (s, 1H), 10.24 (s, 1H).

Example 237F

Methyl] thieno [2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) was slowly added a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (2.85 mL, 2.85 mmol) at -5 ° C. The reaction solution was quenched by dropwise addition of water (1 mL) after 10 minutes, and partitioned between chloroform (25 mL) and 50% saturated NaHCO ₃ (50 mL). The aqueous phase was extracted with dichloromethane (25 mL) and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a foam. The bubbles were ground and dried in a drier to give powder (0.36 g, 100%).

MS (APCI) m / e: 376 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CD ₂ Cl ₂ )? 1.52 (s, 9H), 6.18 (d, 1H), 7.25-7.34 , 9.03 (s, 1 H).

Example 237G

Methyl 4 - [(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pyridine-

Example 237F product (0.12 g, 0.32 mmol) was dissolved in a solution of _{10% H 2 SO 4 / MeOH} (10 mL) was heated for 18 hours at 50 ℃. The reaction was quenched with saturated NaHCO ₃ (100 mL). The aqueous phase was extracted with dichloromethane (2 x 50 mL) and the organic extracts were combined. The organic layer was washed with saturated NaHCO ₃ (1 x 100 mL) and brine (1 x 100 mL), partially dried over sodium sulfate, filtered and concentrated. The product was dried in a drier to give the title compound as a solid (0.10 g, 94%).

MS (APCI) m / e: 334 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CD ₂ Cl ₂ )? 3.85 (s, 3H), 6.17 (d, 1H), 7.23-7.33 , 9.05 (s, 1 H).

Example 237H

Methyl 4 - [(4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-

To a stirred solution of oxalyl chloride (0.023 mL, 0.26 mmol) in anhydrous dichloromethane (1 mL) at -78 <0> C was added DMSO (0.045 mL, 0.63 mmol). After 15 min, a solution of the product of Example 237G (0.07 g, 0.21 mmol) in anhydrous 1: 4 DMSO / dichloromethane (5 mL) was added dropwise. The reaction was stirred at 78 &lt; 0 &gt; C for 1 hour and then treated with triethylamine (0.15 mL, 1.05 mmol). After 5 minutes, the reaction solution was warmed to room temperature over 1 hour. The reaction was quenched with water (2 mL) and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO ₃ (50 mL). The organic layer was washed with 50% saturated aq. NaHCO ₃ (2 x 50 mL) and brine (1 x 50 mL), dried over sodium sulfate, filtered and concentrated. The product was dried in a drier to give the title compound as a white solid (0.07 g, 100%).

MS (APCI) m / e: 332 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CD 2}} Cl 2) δ 3.95 (s, 3H), 7.68 (m, 2H), 7.87 (m, 2H), 8.31 (s, 1H), 8.74 (s, 1H), 9.66 (s , 1H);) ^&lt; ⁺ &^gt;;

IR (KBr) 3208, 2959, 1719, 1657, 1585, 1567, 1434, 1308, 1268 cm ^-1 .

Example 237I

4- (4-chlorobenzoyl) -N-methyl] thieno [2,3-c] pyridine- 2- carboxamide

Example 237H The product (70 mg, 0.21 mmol) was suspended in MeOH (5 mL) and chloroform was added until solids dissolved. Ammonia was applied and the reaction was heated to &lt; RTI ID = 0.0 &gt; 50 C &lt; / RTI &gt; The reaction solution was concentrated and the residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent. The resulting title compound was dried in a drier to give a white solid (35 mg, 53%).

mp 216-218 [deg.] C;

MS (APCI) m / e: 317 (M) ^&lt; ⁺ &^gt;;

_{^{1 H NMR (DMSO-d 6}} ) δ 7.68 (m, 2H), 7.86 (br s, 1H), 7.88 (m, 2H), 8.38 (s, 1H), 8.53 (br s, 1H), 8.67 (s , &Lt; / RTI &gt; 1H), 9.55 (s, 1H);

_{^{13 C NMR (DMSO-d 6}} ) δ 123.4, 128.0, 129.3, 132.0, 135.9, 137.9, 138.9, 143.2, 145.1, 148.8, 148.9, 162.7, 193.6;

IR (KBr) 3289, 3145, 1681, 1655, 1399, 1270 cm &lt; ^{-1 &} gt ;;

Elemental analysis for C ₁₅ H ₉ CIN ₂ O ₂ S · 0.1C ₆ H ₁₄

Calculated: C, 57.59; H, 3.22; N, 8.61.

Found: C, 57.58; H, 3.22; N, 8.41.

Example 238

N-4- (4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide

Example 238A

4- (ethoxycarbonyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 94 was treated according to the procedure of Example 237D to provide the title compound.

Example 238B

4- (Carboxy) thieno [2,3-c] pyridine-2-carboxamide

The title compound was prepared according to the procedure of Example 159A by treating the product of Example 238A.

Example 238C

N-4- (4- (chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide

The product of Example 238B was treated according to the procedure of Example 24 to yield the title compound.

mp &gt; 270 DEG C;

MS (ESI) m / e: 332 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.46 (m, 2H), 7.84 (br s, 1H), 7.85 (m, 2H), 8.52 (m, 1H), 8.56 (br s, 1H), 8.90 (m, 1 H), 9.47 (m, 1 H), 10.79 (br s, 1 H).

Example 239

[4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] methanol

The compound of Example 239 (900 mg, 97%) was prepared as described in Example 90 using Example 73 (1 g, 2.74 mmol) instead of Example 61A.

MS (APCI) m / e: 336; 338 (M + H) &lt; ⁺ & gt ^; , 370; 372 (M + Cl) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.78 (d, J = 6Hz, 2H), 5.88 (t, J = 6Hz, 1H), 6.98 (d, J = 9Hz, 2H), 7.14 (s, 1H ), 7.55 (d, J = 9 Hz, 2H), 8.19 (s, 1H), 9.06 (s, 1H).

Example 240

4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde

The compound of Example 240 (400 mg, 80%) was prepared as described in Example 91A using Example 239 (500 mg, 1.49 mmol) instead of Example 90.

MS (APCI) m / e: 334; 336 (M + H) &lt; ⁺ & gt ^; , 333; 335 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.62 (d, J = 9Hz, 2H), 7.62 (d, J = 9Hz, 2H), 8.26 (s, 1H), 8.40 (s, 1H), 9.27 ( s, 1 H), 10.21 (s, 1 H).

Example 241

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime

The title compound was prepared from &lt; RTI ID = 0.0 &gt; Example 91A &lt; / RTI &gt;

HPLC: Spelco C-18 column, water: acetonitrile 0: 90-90: 0, elution 30 min, flow rate 0.8 mL / min, rt 19.61 min and 20.28 min

_{MS (DCI / NH 3) m} / e: 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.40 (s, 3H, toluene), 7.15 (m, 4H) , 7.25 (m, 5H, toluene), 7.48 (m, 4H) , 7.58 (s, 1H) , 7.75 (s, IH), 8.16 (m, 3H), 8.51 (s, IH), 9.05 (s, IH), 9.14 (s, IH), 11.91 (s, IH), 12.66

^{13 C NMR (100MHz, DMSO-} d 6) δ 119.28, 119.33, 120.58, 122.21, 125.25, 127.51, 128.13, 128.82, 129.99, 133.03, 133.84, 135.37, 136.10, 136.60, 137.11, 139.40, 139.95, 140.83, 141.28, 143.24, 143.66, 146.31, 146.58, 155.69;

Elemental analysis for C ₁₄ H ₉ ClN ₂ O ₂ S 0.4 Toluene

Calculated: C, 59.07; H, 3.60; N, 8.20.

Found: C, 59.15; H, 3.65; N, 8.25.

Example 242

Thiophene [2,3-c] pyridine-2-carbaldehyde O-Methyl oxime

The title compound was prepared from &lt; RTI ID = 0.0 &gt; Example 91A &lt; / RTI &gt;

E Spectra data for isomers:

HPLC: Spupelco C-18 column, water: acetonitrile 0: 90-90: 0, elution 30 min, flow rate 0.8 mL / min, rt 22.72 min and 23.60 min

MS (ESI) m / e: 319 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.94 (s, 3H), 7.12 (m, 2H), 7.47 (m, 2H), 7.65 (s, 1H), 8.18 (s, 1H), 8.61 (s , &Lt; / RTI &gt; 1H), 9.08 (s, 1H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 62.29, 119.35, 122.26, 124.01, 127.60, 130.01, 133.77, 136.85, 140.91, 141.38, 144.34, 146.46, 155.58.

Example 243A

2,3-c] pyridin-2-yl] -1-ethanone O-Methyl oxime

The product of Example 159A was similarly treated according to the procedure of Example 22. The derived amide was treated according to the procedure of Example 33 to produce the corresponding methyl ketone. This ketone was treated according to the procedure of Example 26 to give the title compound as a mixture of E- and Z-isomers. The isomers were separated by column chromatography using a Type H (Sigma) silica gel eluting with 25% EtOAc: hexane.

Spectral data for Z isomers:

mp 126-128 [deg.] C;

MS (APCI) m / e: 333 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.29 (s, 3H), 3.97 (s, 3H), 7.15 (m, 2H), 7.48 (m, 2H), 7.72 (s, 1H), 8.09 (s , &Lt; / RTI &gt; 1H), 9.01 (s, 1H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 12.18, 62.32, 118.85, 119.88, 127.77, 130.01, 132.98, 136.94, 136.98, 140.32, 145.60, 146.94, 150.84, 155.40;

Elemental analysis for C ₁₆ H ₁₃ ClN ₂ O ₂ S toluene

Calculated: C, 57.74; H, 3.94; N, 8.42.

Found: C, 58.03; H, 3.92; N, 8.14.

Example 243B

2,3-c] pyridin-2-yl] -1-ethanone O-Methyl oxime

E-isomer was isolated from Example 243A:

MS (APCI) m / e: 333 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.38 (s, 3H), 4.04 (s, 3H), 7.18 (m, 2H), 7.48 (m, 2H), 7.82 (s, 1H), 8.11 (s , &Lt; / RTI &gt; 1H), 9.12 (s, 1H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 19.25, 62.16, 119.88, 120.17, 121.60, 127.95, 130.04, 131.98, 134.49, 136.52, 138.85, 140.68, 146.21, 147.39, 155.22;

Example 244A

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

Example 244A was similarly prepared according to Example 243A using hydroxylamine hydrochloride instead of methoxyamine hydrochloride.

MS (APCI) m / e: 319 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.23 (s, 3H), 7.15 (m, 2H), 7.48 (m, 2H), 7.62 (s, 1H), 8.10 (s, 1H), 9.02 (s , &Lt; / RTI &gt; 1H), 11.89 (s, 1H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 11.41, 117.45, 119.73, 124.45, 127.65, 129.97, 133.14, 136.78, 137.17, 140.28, 146.72, 147.39, 149.85, 155.51;

Elemental analysis for C ₁₅ H ₁₁ ClNO ₂ S

Calculated: C, 54.96; H, 3.69; N, 8.55.

Found: C, 55.37; H, 3.47; N, 8.37.

Example 244B

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

The Z-isomer was isolated from Example 244A:

MS (APCI) m / e: 319 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.38 (s, 3H), 7.15 (d, J = 9Hz, 2H), 7.48 (d, J = 9Hz, 2H), 7.73 (s, 1H), 8.10 ( s, 1 H), 9.12 (s, 1 H), 12.35 (S, 1 H);

¹³ C NMR (100 MHz, DMSO-d ₆ )? 19.32, 118.36, 119.96, 120.01, 127.81, 130.02, 132.08, 134.60, 136.99, 138.95, 140.73, 145.08, 147.18, 155.40.

Example 245

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

The title compound was prepared according to Example 33 using ethylmagnesium bromide instead of methylmagnesium bromide.

mp 101-102 [deg.] C;

MS (APCI) m / e: 318 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.11 (t, J = 8Hz, 3H), 3.18 (d, J = 8Hz, 2H); 7.21 (m, 2H), 7.51 (m, 2H), 8.13 (s, 1H), 8.32 (s, 1H), 9.19 (s, 1H).

Example 246

L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

Using the hydroxylamine hydrochloride and following the procedure of Example 26, the product of Example 245 was treated to produce the title compound as a mixture of E- and Z-oximes.

mp 195-196 [deg.] C (decomposition);

MS (APCI) m / e: 333 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.10 (m, 6H), 2.77 (m, 4H), 7.17 (m, 4H), 7.48 1H), 8.09 (s, 1H), 8.11 (s, 1H), 9.00 (s, 1H), 9.12 (s, 1H), 11.88

HPLC: Supelco C-18 column, 0.1% aqueous TFA: acetonitrile 0:90 to 90: 0 gradient elution (30 min elution), detection at 254 nm, flow rate 0.8 ml / min, RT 20.20 min and 21.10 min E- And Z-isomers).

Elemental analysis for C ₁₆ H ₁₃ ClN ₂ O ₂ S

Calculated: C, 57.74; H, 3.94; N, 8.42.

Found: C, 57.51; H, 4.12; N, 8.22.

Example 247

2,3- c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide

The product of Example 88 (0.38 mmol) as described in Example 42 was prepared and then mixed with THF (1.0 mL) and LDA (0.92 mL of a freshly prepared 0.5 M solution in THF, 0.46 mmol) at -78 & . The bright yellow solution was stirred at -78 &lt; 0 &gt; C for 1.25 h and then the solution was added via cannula to a solution of bis (N, O-dimethylhydroxyl) oxamide (88 mg, 0.50 mmol) in THF Lt; 0 &gt; C. The solution was slowly warmed to room temperature, diluted with 2 N HCl (20 mL) and extracted with CH ₂ Cl ₂ (3 x 20 mL). The organic extracts were combined and washed with brine (1 x 10 mL), then dried over magnesium sulfate and concentrated to give a yellow solid. Flash chromatography on silica gel (15% acetone in hexanes) gave the title compound (25 mg, 17% yield) as a yellow solid.

mp 135.0-137.8 [deg.] C;

_{MS (DCI / NH 3) m} / e: 377 (35 Cl) / 379 (37 Cl);

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.31 (s, 3H), 3.64 (s, 3H), 7.27 (d, J = 8.8Hz, 2H), 7.52 (d, J = 8.8Hz, 2H), 8.15 (s, 1 H), 8.22 (s, 1 H), 9.26 (s, 1 H).

Example 248

4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile

A solution of the product of Example 61B (500 mg, 1.64 mmol) in pyridine (7 mL) was treated with trifluoroacetic anhydride (1 mL, 6.6 mmol) at -78 <0> C under nitrogen and stirred at -78 < It was then slowly warmed to room temperature and stirred for an additional 2 hours. The mixture was washed with diluted with ethyl acetate and saturated NaHCO ₃ and brine and dried over magnesium sulfate and concentrated. The resulting pale purple solid was dissolved in a minimal amount of ethyl acetate, filtered through a plug of silica, washed with 50/50 hexanes / ethyl acetate and concentrated to give 395 mg of the title compound as a white solid (84%).

mp 140-142 [deg.] C;

_{MS (APCI-NH 3) m} / e: 287 (M + H) +;

¹ H NMR (300 MHz, CDCl ₃ )? 7.04 (d, 2H), 7.40 (d, 2H), 8.00 (s, IH), 8.14 (s, IH), 8.96

Elemental analysis for C ₁₄ H ₇ ClN ₂ OS

Calculated: C, 58.64; H, 2.46; N, 9.77.

Found: C, 58.45; H, 2.62; N, 9.52.

Example 249

4- (4-chlorophenoxy) -N'-hydroxyacenone [2,3-c] pyridine-2- carboximidamide

A solution of the product of example 248 (100 mg, 0.35 mmol) in ethanol (2 mL) was treated with triethylamine (90 mL, 0.6 mmol) and hydroxylamine hydrochloride (40 mg, 0.53 mmol) Stir for 18 hours. The resulting white heterogeneous mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ and brine, dried over magnesium sulfate and concentrated to give 120 mg of gray bubbles. The bubbles were dissolved in ethyl acetate and filtered through a plug of silica and then concentrated to give the title compound as a white solid (110 mg, 98%).

mp 194-196 [deg.] C;

_{MS (APCI-NH 3) m} / e: 320 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 10.23 (s, 1H), 9.02 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.46 (d, 2H), 7.11 (d , &Lt; / RTI &gt; 2H), 6.26 (br s, 2H);

Elemental analysis for C ₁₄ H ₁₀ ClN ₃ O ₂ S

Calculated: C, 52.59; H, 3.15; N, 13.14.

Found: C, 52.72; H, 3.05; N, 12.82.

Example 250

4- (4-chlorophenoxy) -N'-cyanothieno [2,3-c] pyridine-2- carboximidamide

A solution of the compound of Example 248 (100 mg, 0.35 mmol) in THF (2 mL) was treated at ambient temperature under nitrogen with cyanamide (74 mg, 1.75 mmol), 1.8-diazabicyclo [5.4.0] undec- (52 mL, 0.35 mmol) and stirred for 24 h. Diluted uniform solution of the resulting yellow with ethyl acetate and dried over magnesium sulfate and concentrated, washed with saturated NaHCO ₃ and brine to give a pale yellow solid. This solid was triturated with CH ₂ Cl ₂ to yield 123 mg of a white powder which was dissolved in ethyl acetate and THF, washed with distilled water and brine, dried over magnesium sulfate and concentrated to give 99 mg of white powder (MgSO ₄ ) Lt; / RTI &gt; The powder was triturated with CH ₂ Cl ₂ and then placed in a vacuum oven at 60 ° C overnight to give the title compound as a white powder (78 mg, 69%).

mp 265-268 [deg.] C;

_{MS (APCI-NH 3) m} / e: 329 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 9.58 (br s, IH), 9.17 (s, IH), 9.05 (d, 2 H), 7.15 (d, 2 H);

Elemental analysis for C ₁₅ H ₉ ClN ₄ OS

Calculated: C, 54.80; H, 2.76; N, 17.04.

Found: C, 54.50; H, 3.01; N, 17.16.

Example 251

(2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

Example 251A

2,3-c] pyridin-2-yl] (2-nitrophenyl) methanol

To a stirred solution of Example 124A (1.00 g, 3.82 mmol) in THF (40 mL) at -78 <0> C was added dropwise a 1.3 M suspension of sec-butyllithium in cyclohexane (3.52 mL, 4.58 mmol) over 10 minutes . After 40 minutes, the reaction was transferred via cannula to a stirred solution of 2-nitrobenzaldehyde (1.43 g, 9.55 mmol) in THF (10 mL) at -48 ° C. After 20 minutes, the reaction solution was quenched by the slow addition of MeOH (6 mL). The reaction solution was diluted with EtOAc (125 mL) and the organic layer was 1: 1 and washed with saturated NaHCO ₃ / water (1x75 mL) and brine (1x75 mL), then it was partially dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel using EtOAc / hexane as eluent to give the title compound as a solid (1.49 g, 95%).

mp 85-90 [deg.] C;

MS (APCI) m / e: 413 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.54 (s, 1H), 6.95 (s, 1H), 7.03 (m, 1H), 7.06 (m, 2H), 7.42 (m, 2H), 7.60 (m 1H), 7.78 (m, 1H), 7.85 (m, 1H), 7.98 (m, 1H), 8.12 (s, 1H), 9.02

Elemental analysis for C ₂₀ H ₁₃ ClN ₂ O ₄ S · 0.3H ₂ O

Calculated: C, 57.43; H, 3.28; N, 6.70.

Found: C, 57.42; H, 3.45; N, 6.42.

Example 251B

(2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

The product of Example 251A (0.10 g, 0.24 mmol) was dissolved in EtOH (1.7 mL) and a solution of the tin (II) chloride dihydrate (0.43 g, 1.92 mmol) in conc. HCl (0.70 mL) was slowly added. The reaction was stirred for 18 h and then partitioned between CHCl ₃ (50 mL) and saturated NaHCO ₃ (75 mL). The aqueous layer was extracted with EtOAc (1 x 50 mL) and all the organic extracts were combined and then partially dried with sodium sulfate and concentrated. The residue was purified by flash chromatography on silica using EtOAc / hexane as eluent to give the title compound as a light colored solid (0.08 g, 87%).

mp 92-96 [deg.] C;

MS (APCI) m / e: 383 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.08 (br s, 2H), 6.10 (d, J = 4.3Hz, 1H), 6.54 (d, J = 4.3Hz, 1H), 6.55 (m, 1H) 1H), 6.61 (m, 1H), 6.98 (m, 1H), 7.05 (m, 2H), 7.13 8.98 (s, 1 H);

Elemental analysis for C ₂₀ H ₁₅ ClN ₂ O ₂ S

Calculated: C, 62.74; H, 3.95; N, 7.32.

Found: C, 63.09; H, 4.05; N, 7.06.

Example 251C

(2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

Pyridinium chlorochromate (0.13 g, 0.59 mmol) was added to a dry suspension suspension of silica gel (0.13 g) and celite (0.13 g) in dichloromethane (6 mL). A solution of the product of Example 251B (0.15 g, 0.39 mmol) in anhydrous dichloromethane (9 mL) was slowly added dropwise. After 1 h, saturated NaHCO ₃ (5 mL) was added and the reaction was stirred for 1 h. The reaction was filtered and the black solid was triturated and washed with 5% MeOH / dichloromethane (3 x 20 mL). The organic filtrate and washings were combined, washed with saturated NaHCO ₃ (2 x 100 mL) and brine (1 x 75 mL), then partially dried with sodium sulfate and concentrated. The residue was purified by flash chromatography on silica using EtOAc / hexane as eluent to give the title compound as a light colored solid (45 mg, 39%).

mp 152-154 [deg.] C;

MS (APCI) m / e: 381 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.54 (m, 1H), 6.87 (m, 1H), 7.05 (broad s, 2H), 7.18 (m, 2H), 7.33 (m, 1H), 7.47 ( m, 2H), 7.57 (s, IH), 7.58 (m, IH), 8.24 (s, IH), 9.21 (s, IH);

^{13 C NMR (300MHz, DMSO-} d 6) δ 114.5, 115.9, 117.1, 120.1, 123.8, 128.0, 130.0, 132.5, 133.0, 134.9, 136.0, 138.2, 141.2, 147.8, 148.5, 151.8, 155.3, 188.5;

IR (KBr) 3440, 3411, 3293, 3190, 1616, 1587, 1483, 1409, 1267, 1245, 1219, 1155 cm ^-1 ;

Elemental analysis for C ₂₀ H ₁₃ ClN ₂ O ₂ S

Calculated: C, 63.08; H, 3.44; N, 7.36.

Found: C, 62.94; H, 3.51; N, 7.25.

Example 252

(3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

Example 252A

Thieno [2,3-c] pyridin-2-yl] (3-nitrophenyl) methanol

The procedure of Example 251 was followed using 3-nitrobenzaldehyde instead of 2-nitrobenzaldehyde.

mp 79-83 [deg.] C;

MS (APCI) m / e: 413 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.33 (d, J = 4.4Hz, 1H), 6.99 (d J = 4.4Hz, 1H), 7.07 (m, 2H), 7.27 (m, 1H), 7.43 (m, 2H), 7.66 (m, IH), 7.92 (m, IH), 8.13 (s, IH), 8.15 (m, IH), 8.34

Elemental analysis for C ₂₀ H ₁₃ ClN ₂ O ₄ S

Calculated: C, 58.19; H, 3.17; N, 6.79.

Found: C, 59.97; H, 3.23; N, 6.70.

Example 252B

(3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

The product of Example 252A was treated according to the procedure of Example 251B to give the title compound.

mp 73-78 [deg.] C;

MS (APCI) m / e: 383 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.03 (s, 2H), 5.88 (s, 1H), 6.45 ( series of m, 2H), 6.57 (m , 1H), 6.64 (m, 1H), 6.96 (m, IH), 7.06 (m, 2H), 7.11 (m, IH), 7.42 (m, 2H), 8.08 (s, IH), 8.97

Elemental analysis for C ₂₀ H ₁₅ ClN ₂ O ₂ S

Calculated: C, 62.74; H, 3.95; N, 7.32.

Found: C, 63.06; H, 4.22; N, 6.92.

Example 252C

(3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-

The product of Example 252B was treated according to the procedure of Example 251C to give the title compound.

mp 174-178 [deg.] C;

MS (APCI) m / e: 481 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.47 (br s, 2H), 6.86-6.96 ( series of m, 2H), 7.06 (m , 1H), 7.16-7.23 ( series of m, 3H), 7.48 (m, 2H), 7.77 (s, IH), 8.20 (s, IH), 9.22 (s, IH).

Example 253

4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine

To a stirred suspension of methyl triphenylphosphonium bromide (113 mg, 0.314 mmol) in anhydrous tetrahydrofuran (2 mL) at -78 ° C was added a solution of n-BuLi (2.5 M solution in hexanes, 0.125 mL, 0.314 mmol) was added dropwise. The reaction mixture was then stirred at 0 &lt; 0 &gt; C for 40 min and cooled to -78 &lt; 0 &gt; C. To this was added a solution of the product of Example 240 (100 mg, 0.3 mmol) in anhydrous tetrahydrofuran (2 mL) while maintaining the internal temperature at -72 占 폚. After the addition was complete, the reaction mixture was stirred at 0 &lt; 0 &gt; C for 15 minutes and then at ambient temperature for 1 hour. The reaction mixture was then partitioned between ethyl acetate (60 mL) and brine (20 mL). The organic layer was washed with brine (2 x 20 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give the crude product (145 mg). Flash chromatography on silica gel eluting with 25% acetone-hexanes gave the title compound in 26% yield (26 mg).

MS (APCI) m / e: 332; 334 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 5.53 (d, J = 10Hz, 1H), 5.86 (d, J = 16Hz, 1H), 7.02 (d, J = 9Hz, 2H), 7.06-7.14 (m 1H), 7.37 (s, 1H), 7.57 (d, J = 9 Hz, 1H), 8.17 (s,

Example 254

1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol

Example 254A

4- (4-chlorophenoxy) -2-ethenylthieno [2,3-c] pyridine

Example 240 By carrying out example 253 using the product of example 91A (700 mg, 2.42 mmol) instead of the product, the title compound (70 mg, 10%) was prepared.

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.53 (d, J = 10.5Hz, 1H), 5.86 (d, J = 18Hz, 1H), 7.04-7.14 (m, 1H), 7.10 (d, J = 1H), 9.04 (s, 1H), 7.38 (s, 1H), 7.45 (d, J = 9 Hz, 2H).

Example 254B

1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol

Example 254A The title compound (22 mg, 28%) was prepared following the method of Example 255 while using the product of Example 254A (70 mg, 0.26 mmol) instead of the product.

MS (APCI) m / e: 332 (M + H) &lt; ⁺ &gt;; 356 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 3.50-3.64 (m, 2H), 4.86-4.91 (m, 1H), 5.0 (t, J = 6Hz, 1H), 6.04 (d, J = 4Hz, 1H ), 7.07 (d, J = 9 Hz, 2H), 7.21 (s, 1H), 7.43 (d, J = 9 Hz, 2H), 8.14 (s, 1H), 9.04

^{13 C NMR (100MHz, DMSO-} d 6) d: 66.52 (CH 2), 70.24 (CH), 114.60 (CH), 119.06 (CH), 127.22 (C), 129.91 (CH), 133.36 (CH), 137.16 (C), 137.42 (C), 140.79 (CH), 145.79 (C), 155.91 (C), 156.69 (C).

Example 255

1- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol

To a solution of the product of example 253 (90 mg, 0.271 mmol) in tetrahydrofuran (2 mL) at room temperature was added 4-methylmorpholine N-oxide (63.5 mg, 0.542 mmol) and osmium tetrachloride (14 mL) mg, 0.054 mmol). The reaction mixture was stirred for 48 hours and the solvent was removed. The obtained residue was purified directly by flash chromatography on silica gel eluting with 20% acetone-hexane to give the title compound (52 mg, 53%).

MS (APCI) m / e: 366; 368 (M + H) &lt; ⁺ &gt;; 402 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 3.50-3.65 (m, 2H), 4.89 (m, 1H), 5.01 (t, J = 6Hz, 1H), 6.05 (d, J = 4Hz, 1H), 7.01 (d, J = 9 Hz, 2H), 7.21 (s, 1H), 7.55 (d, J = 9 Hz, 2H), 8.15 (s, 1H), 9.04

¹³ C NMR (100 MHz, DMSO-d ₆ )? 66.52 (CH ₂ ), 70.25 (CH), 114.60 (CH), 115.08 (C), 119.24 C), 137.48 (C), 140.87 (CH), 145.67 (C), 156.46 (C), 156.65 (C).

Example 256

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methanamine

Diethylazodicarboxylate (180 mL, 1.13 mmol) was added to a solution of the product of Example 90 (220 mg, 0.750 mmol), THF (7.5 mL), triphenylphosphine (297 mg, 1.13 mmol) and phthalimide , 1.13 mmol). After 16 h the organic solution was concentrated in vacuo to an orange solid. Flash silica gel column chromatography (20% acetone in hexane) afforded one compound (100% yield) as the parent product. This compound was mixed with hydrazine hydrate (230 mL, 7.50 mmol) and ethanol (75 mL) and heated to reflux. After 4 h the solution was cooled to room temperature, concentrated and then diluted with 5 N HCl (30 mL) and extracted through a fritted glass funnel. The filtrate was mixed with 3 N NaOH until pH> 12 and extracted with EtOAc (3 x 30 mL). The organic extracts were combined, washed once with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (190 mg, 87% yield) as a white solid.

mp 78.6-79.8 [deg.] C;

_{MS (DCI / NH 3) m} / e: 321 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.24 (br s, 2H), 4.02 (s, 2H), 7.03 (d, J = 9.1Hz, 2H), 7.15 (s, 1H), 7.42 (d, J = 9.1 Hz, 2H), 8.14 (s, 1H), 9.01 (s, 1H).

Elemental analysis for C ₁₄ H ₁₁ ClN ₂ OS · 0.25H ₂ O

Calculated: C, 56.95; H, 3.93; N, 9.49%.

Found: C, 56.86; H, 3.81; N, 9.62.

Example 257

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methylcarbamate

The product (50 mg, 0.17 mmol) was mixed with CH ₂ Cl ₂ (0.5 mL), sodium cyanate (22 mg, 0.34 mmol) and trifluoroacetic acid (40 mL, 0.34 mmol). Gas evolution was observed. After 24 hours, the mixture was partitioned between distilled water (15 mL) and CH ₂ Cl ₂ (50 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated. Silica gel column chromatography (30% acetone in hexanes) gave the title compound (21 mg, 37% yield) as a white solid.

mp 113-115 [deg.] C;

_{MS (DCI / NH 3) m} / e: 335 (35 Cl) / 337 (37 Cl);

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.30 (s, 2H), 6.80 (br s, 2H), 7.06 (d, J = 9.2Hz, 2H), 7.37 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 8.18 (s, IH), 9.10 (s, IH).

Example 258

N - {[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2- yl] methyl} urea

Potassium cyanate (41 mg, 0.50 mmol) was added to a mixture of Example 256 (130 mg, 0.45 mmol), distilled water (2.0 mL) and concentrated HCl (40 mL, 0.45 mmol) and the solution was heated to 50 < After 3 h, the solution was slowly cooled to 0 &lt; 0 &gt; C and the resulting precipitate was isolated by filtration. Flash chromatography on silica gel (20% acetone in hexanes followed by 10% MeOH in EtOAc) afforded the title compound (63 mg, 42% yield) as a white solid.

mp 202-204 C;

_{MS (DCI / NH 3) m} / e: 334 (35Cl) + / 336 (37Cl) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.47 (d, J = 6.1Hz, 2H), 5.68 (s, 2H), 6.68 (t, J = 6.1Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 8.14 (s, 1H), 9.02 (s, 1H);

Elemental analysis for C ₁₅ H ₁₂ ClN ₃ O ₂ S;

Calculated: C, 53.97; H, 3.62; N, 12.59.

Found: C, 53.80; H, 3.67; N, 12.37.

Example 259

(E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin- 2-yl} -2-propenamide

Example 259A

Methyl 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl) propanoate

Example 91A The title compound (590 mg, 57%) was prepared following the procedure described in Example 91B substituting the product of Example 240 (890 mg, 2.67 mmol) for the product.

MS (APCI) m / e: 390; 392 (M + H) ⁺ , 389; 392 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.75 (s, 3H), 6.58 (d, J = 16Hz, 1H), 7.07 (d, J = 9Hz, 2H), 7.59 (d, J = 9Hz, 2H ), 7.89 (s, 1H), 8.02 (d, J = 16 Hz, 1H), 8.17 (s, 1H), 9.12 (s, 1H).

Example 259B

Thieno [2,3-c] pyridin-2-yl} -2-propenoic acid

The product of Example 259A and the procedure of Example 88 were carried out to give the title compound (270 mg, 93%).

MS (APCI) m / e: 376; 378 (M + H) ⁺ ;

^{1 H NMR (300MHz, DMSO-} d 6) d: 6.45 (d, J = 16Hz, 1H), 7.07 (d, J = 9Hz, 2H), 7.58 (d, J = 9Hz, 2H), 7.81 (s, 1H), 7.90 (d, J = 16 Hz, 1H), 8.16 (s, 1H), 9.10 (s, 1H).

Example 259C

3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl) propenamide

Using the product of Example 259B instead of the product of Example 91C and carrying out the procedure of Example 259B (222 mg, 81%) and Example 92, the title compound was obtained.

mp 195-196 占 폚;

MS (APCI) m / e: 375; 377 (M + H) ⁺ , 409; 411 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 6.62 (d, 16Hz, 1H), 7.04 (d, J = 9Hz, 2H), 7.26 (s, 1H), 7.56 (d, J = 9Hz, 2H), 7.64 (s, 1H), 7.68 (s, 1H), 7.72 (d, J = 16 Hz, 1H), 8.13 (s, 1H), 9.05 (s, 1H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 115.55 (C), 119.98 (CH), 122.11 (CH), 126.68 (CH), 131.80 (CH), 132.91 (CH), 133.71 (CH), 136.69 (C ), 137.48 (C), 140.84 (CH), 145.79 (C), 146.43 (C), 156.07 (C), 165.37 (C).

Example 260

Methyl (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-

The title compound (25 mg, 50%) was prepared from the product of Example 259A (50 mg, 0.13 mmol) by following the procedure described in Example 171. [

MS (APCI) m / e: 389 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.71 (d, J = 4.5Hz, 3H), 6.62 (d, J = 16Hz, 1H), 7.06 (d, J = 9Hz, 2H), 7.58 (d, J = 9 Hz, 2H), 7.69 (s, 1H), 7.74 (d, J = 16 Hz, 1H), 8.15 ;

^{13 C NMR (100MHz, DMSO-} d 5) δ 25.7 (CH 3), 115.6 (C), 120.0 (CH), 122.1 (CH), 126.4 (CH), 131.1 (CH), 132.9 (CH), 133.7 ( CH), 136.7 (C), 137.5 (C), 140.9 (CH), 145.9 (C), 146.4 (C), 156.1 (C), 164.3 (C).

Example 261

Methyl 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl) -2,3-dihydroxypropenamide

The title compound (52 mg, 53%) was prepared as described in Example 255 using the product 260 (90 mg, 0.232 mmol).

MS (APCI) m / e: 423; 425 (M + H) ⁺ , 456 (M + Cl) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.61 (d, J = 4.5Hz, 3H), 4.09 (br d, J = 3Hz, 1H), 5.27 (br d, J = 3Hz, 1H), 5.68 ( J = 6 Hz, 1H), 7.00 (d, J = 9 Hz, 2H), 7.23 (s, (d, J = 4.5 Hz, 1 H), 8.14 (s, 1 H), 9.04 (s, 1 H);

^{13 C NMR (75MHz, DMSO-} d 6) δ 25.5 (CH 3), 70.3 (CH), 75.1 (CH), 115.0 (CH), 115.1 (C), 119.5 (CH), 132.9 (CH), 133.5 ( CH), 137.5 (C), 137.5 (C), 140.9 (CH), 145.8 (C), 156.3 (C), 156.5 (C), 171.7 (C).

Example 262

3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] -2,3-dihydroxypropanamide

The title compound can be prepared using the procedure of Example 261 and the product of Example 259C.

Example 263

4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine

To a solution of Example 159A (0.500 g, 1.64 mmol) and 1,8-bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine (0.350 g, 1.64 mmol) was warmed until all solids had turned into a solution. The solution was stirred for 15 minutes at which time diphenylphosphoryl azide (0.450 g, 1.64 mmol) was added. The solution was heated to reflux for 18 hours. The resulting deep red solution was evaporated to dryness under reduced pressure. The product was passed through 5 g of silica gel eluting with 20% ethyl acetate / hexanes to give 422 mg of intermediate isocyanate as a light orange solid. The product was dissolved in 100 mL of toluene and the solution was heated to reflux for 6 hours. The product was evaporated to dryness. The resulting dark orange solid was dissolved in 20 mL of 2.0 M hydrogen chloride in dioxane. The solution was evaporated to yield 313 mg (84.9%) of the title compound.

MS (APCI) m / e: 277 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.91 (s, 1H), 7.18 (d, 2H), 7.47 (d, 2H), 8.34 (s, 1H), 9.21 (s, 1H).

Example 264

4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylformamide

A mixture of 5 mL of acetic anhydride and 1.8 mL of 96% formic acid was heated to 70 &lt; 0 &gt; C for 3 h. The solution was cooled and at this time the amine obtained from Example 263 (32 mg, 0.12 mmol) was added. The mixture was stirred for 4 days and then poured into 50 mL of dilute HCl. The mixture was extracted with ethyl acetate and the combined extracts were washed sequentially with saturated sodium carbonate and water, then dried over magnesium sulfate and evaporated. The product was purified by preparative HPLC over 40 minutes with a gradient of 30% -70% acetonitrile / water + 0.1% TFA to give 18 mg (49%) of the title compound.

MS (APCI) m / e: 305 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CD ₃ OD)? 7.16 (s, IH), 7.24 (d, 2H), 7.46 (d, 2H), 8.08 1H).

Example 265

N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] urea

A mixture of isocyanates obtained from Example 263 (110 mg, 0.364 mmol) in 10 mL of ammonium hydroxide was vigorously stirred for 18 hours. The resulting red solid was collected and dried under vacuum to give 60.7 g (52.2%) of the title compound.

MS (APCI) m / e: 320 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.20 (d, 2H), 7.34 (s, 1H), 7.50 (d, 2H), 7.65-7.79 (m, 4H), 8.06-8.16 (m, 2H) , 9.18 (s, 1 H).

Example 266

N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N'-methylthiourea

A solution of the amine (150 mg, 0.542 mmol) from Example 263 in 5 mL of pyridine was treated with methyl isothiocyanate (198 mg, 2.71 mmol). The solution was heated to 100 &lt; 0 &gt; C under a nitrogen atmosphere for 5 days. All volatiles were removed under reduced pressure. The product was purified by flash column chromatography on a silica gel, eluting with chloroform / NHOH, to give 110 mg (58.1%) of the title compound.

MS (APCI) m / e: 350 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CD 3}} OD) δ 3.31 (s, 3H), 6.61 (bs, 1H), 6.96 (d, 2H), 7.34 (d, 2H), 7.88 (s, 1H), 7.96 (s, 1H), &lt; / RTI &gt; 8.67 (s, 1H).

Example 267

Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide

N-BuLi (2.5 M solution in hexane, 0.60 mL, 1.5 mmol) was added to a solution of the product of Example 124A (261 mg, 1 mmol) in anhydrous THF (2 mL) at -78 <0> C under a nitrogen atmosphere. This was stirred for 2 h at -78 ℃ was injected into SO ₂ in a rapid stream to the surface of the reaction mixture. After 15 minutes, it allowed to warm the reaction mixture to 0 ℃ while continuing injection of SO _2. From 0 ℃ After 10 minutes, stop the SO ₂ gas, and the reaction mixture was warmed to 10 ℃. The solvent and excess SO ₂ gas were then removed under reduced pressure to give the sulfinic acid lithium salt as a cream colored solid. This material was dissolved in a saturated aqueous NaHCO ₃ solution (1 mL) and treated with N-chloro succinimide (200 mg, 1.5 mmol) at 0 ° C. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and at room temperature for 2 hours. The formed product was extracted with CH ₂ Cl ₂ ( ₂ x 50 mL) and washed with water ( ₂ x 20 mL). The dried (sodium sulfate) organic layer was evaporated to dryness under reduced pressure to obtain a sulfonyl chloride derivative. A portion of this material (143 mg, 0.398 mmol) was dissolved in CH ₂ Cl ₂ (1 mL) at -5 ° C and diisopropylethylamine (0.083 mL, 0.478 mmol) and methylamine in methanol Lt; / RTI &gt; The reaction mixture was stirred at room temperature for 1 hour. This was purified directly by silica gel flash chromatography, eluting sequentially with 10% acetone-hexane and 25% acetone-hexane to give the title compound (19 mg, 13.5%).

MS (APCI) m / e: 355 (M + H) &lt; ⁺ & gt ^; , 353 (MH) ^- ;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.57 (s, 3H), 7.19 (d, J = 9 Hz, 2H), 7.49 br d, J = 3 Hz, 1 H), 8.24 (s, 1 H), 9.24 (s, 1 H).

Example 268

2,3-dihydroxypropyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide

The title compound (8.6 mg, 7.5%) was prepared as described in Example 267 using 3-amino-1,2-propanediol (0.086 mL, 1.12 mmol) instead of methylamine.

MS (APCI) m / e: 415 (M + H) &lt; ⁺ & gt ^; , 413 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.76 (d, J = 7.5Hz, 1H), 2.81 (d, J = 7.5Hz, 1H), 3.02 (d, J = 4.5Hz, 1H), 3.08 ( (d, J = 4.5 Hz, 1H), 3.44-3.55 (m, 1H), 4.47-4.64 7.48 (d, J = 9 Hz, 2H), 7.77 (s, 1H), 8.23 (s, 1H), 9.22 (s, 1H).

Example 269

2-hydroxyethyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide

The title compound (25 mg, 16%) was prepared as described in Example 267 using 2-hydroxyethylamine (0.072 mL, 1.2 mmol) instead of methylamine.

MS (APCI) m / e: 385 (M + H) &lt; ⁺ & gt ^; , 383 (MH) ^- ;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.97 (t, J = 6Hz, 2H), 3.38-3.45 (m, 2H), 4.69-4.78 (m, 1H), 7.18 (d, J = 9Hz, 2H ), 7.48 (d, J = 9 Hz, 2H), 7.78 (s, 1H), 8.23 (s, 1H), 9.21 (s, 1H);

^{13 C NMR (75MHz, DMSO-} d 6) δ 45.4 (CH 2), 59.7 (CH 2), 119.9 (CH), 122.2 (CH), 128.0 (C), 130.1 (CH), 133.3 (CH), 135.5 (C), 138.2 (C), 141.4 (CH), 147.5 (C), 148.4 (C), 155.2 (C).

Example 270

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] phenol

Example 270A

4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-boronic acid

A 1.3 M suspension of sec-butyllithium in cyclohexane (3.52 mL, 4.58 mmol) was added to THF (10 mL) at -78 <0> C. A solution of Example 124A (1.00 g, 3.82 mmol) in THF (5 mL) was added dropwise. The reaction was stirred for 30 min and tributylborate (1.55 mL, 5.73 mmol) was slowly added. The cold bath was removed and the reaction was stirred for 45 minutes while warming to room temperature. A solution of 2 N NaOH (15 mL) was added. After 10 min, the reaction was diluted with hexane (15 mL) and the aqueous layer was collected. The organic layer was extracted with 2 N NaOH (2 x 5 mL) and all the aqueous layers were combined, acidified to pH 2 with 6 N HCl and extracted with 10% MeOH / CH ₂ Cl ₂ (4 x 25 mL). The organic extracts were combined and concentrated. The resulting solid was washed with acetonitrile (1 x 25 mL) and dried in a drier to afford the title compound as a brown solid (0.83 g, 71%).

MS (APCI) m / e: 262 (M + HB (OH) 2) +, m / e: 340 (M + Cl -) -;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.15 (m, 2H), 7.48 (m, 2H), 8.03 (s, 1H), 8.24 (s, 1H), 9.29 (s, 1H).

Example 270B

4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

A solution of the product of Example 270A (0.25 g, 0.82 mmol), 4-iodoanisole (0.19 g, 0.82 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium II) To a mixture of the dichloromethane complex (1:) (0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.46 mmol) and triethylamine (0.11 mL, 0.82 mmol) was added anhydrous nitrogen for 10 min. The reaction was heated to 75 ℃ for 18 h then partitioned between EtOAc (100 mL) and saturated NaHCO ₃ (100 mL). The organic layer was washed with saturated NaHCO ₃ (100 mL) and brine (75 mL), partially dried over sodium sulfate, and then concentrated to a colored wet solid. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give a colored solid. The title product was determined from hot acetonitrile (0.11 g, 37%).

mp 121-123 [deg.] C;

MS (APCI) m / e: 368 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.82 (s, 3H), 7.05 (m, 2H), 7.13 (m, 2H), 7.45 (m, 2H), 7.67 (s, 1H), 7.81 (m , &Lt; / RTI &gt; 2H), 8.13 (s, 1H), 9.05 (s, 1H);

Elemental analysis for C ₂₀ H ₁₄ ClNO ₂ S

Calculated: C, 65.30; H, 3.84; N, 3.81.

Found: C, 65.06; H, 3.69; N, 4.05.

Example 270C

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] phenol

To a solution of the product of Example 270B (0.09 g, 0.24 mmol) in anhydrous CH ₂ Cl ₂ (4 mL) was added a 1 M solution of boron tribromide in CH ₂ Cl ₂ (0.96 mL, 0.96 mmol). After 2 h, the reaction was quenched by the slow addition of MeOH (2 mL) and then concentrated. The residue was diluted with CH ₂ Cl ₂ (50 mL) and the organic layer was washed with 1: 1 saturated NaHCO ₃ / brine (50 mL), then partially dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a solid (0.08 g, 96%).

mp 213-215 占 폚;

MS (ESI) m / e: 354 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.86 (m, 2H), 7.11 (m, 2H), 7.45 (m, 2H), 7.56 (s, 1H), 7.68 (m, 2H), 8.13 (s , &Lt; / RTI &gt; 1H), 9.03 (s, 1H), 9.99 (s, 1H);

Elemental analysis for C ₁₉ H ₁₂ ClNO ₂ S · 0.5H ₂ O

Calculated: C, 62.90; H, 3.61; N, 3.86.

Found: C, 62.96; H, 3.61; N, 3.52.

Example 271

3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] aniline

Example 272

4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] aniline

Example 272A

[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

(0.25 g, 0.82 mmol), 1-iodo-4-nitrobenzene (0.20 g, 0.82 mmol) and [l, l ' -bis (diphenylphosphino) ferrocene] in DME (8 mL) To a mixture of dichloropalladium (II) dichloromethane complex (1: 1) (0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.46 mmol) and triethylamine (0.11 mL, 0.82 mmol) Respectively. The reaction was heated for 18 hours at 70 ℃ and then was partitioned between EtOAc (100 mL) and saturated NaHCO ₃ (100 mL). The organic layer was washed with saturated NaHCO ₃ (100 mL) and brine (75 mL), partially dried over sodium sulfate, and then concentrated to a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give a colored solid (0.15 g, 48%).

mp 193-195 占 폚;

MS (ESI) m / e: 383 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.17 (m, 2H), 7.48 (m, 2H), 8.15 (m, 1H), 8.17 (s, 1H), 8.19 (m, 2H), 8.32 (m , &Lt; / RTI &gt; 2H), 9.17 (s, 1H);

Elemental analysis for C ₁₉ H ₁₁ ClN ₂ O ₃ S

Calculated: C, 59.61; H, 2.90; N, 7.32.

Found: C, 59.35; H, 2.94; N, 7.22.

Example 272B

4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] aniline

To a suspension of Example 272A (0.13 g, 0.34 mmol) in EtOH (3.5 mL) was slowly added a solution of the tin (II) chloride dihydrate (0.31 g, 1.36 mmol) in concentrated HCl (0.68 mL). The reaction was stirred for 22 hours and partitioned between dichloromethane (75 mL) and 1 N NaOH (75 mL). The organic layer was washed with 1 N NaOH (1 x 50 mL) and brine (1 x 50 mL), then partially washed with sodium sulfate and concentrated to give a colored solid (0.13 g). The desired product was crystallized from acetonitrile to give colored crystals (0.08 g, 68%).

mp 178-182 DEG C;

MS (APCI) m / e: 353 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.68 (br s, 2H), 6.62 (m, 2H), 7.09 (m, 2H), 7.39 (s, 1H), 7.44 (m, 2H), 7.51 ( m, 2 H), 8.11 (s, 1 H), 8.97 (s, 1 H);

Elemental analysis for C ₁₉ H ₁₃ ClN ₂ OS

Calculated: C, 64.68; H, 3.71; N, 7.94.

Found: C, 64.65; H, 3.73; N, 8.13.

Example 273

6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

Example 273A

6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -3-nitropyridine

The title compound (120 mg, 32%) was obtained as described in Example 272A using 2-bromo-5-nitropyridine instead of 1-iodo-4-nitrobenzene.

mp 221-223 [deg.] C;

MS (APCI) m / e: 384 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.20 (m, 2H), 7.49 (m, 2H), 8.16 (s, 1H), 8.50 (s, 1H), 8.61 (d, J = 8.8Hz, 1H ), 8.70 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 9.17 (s, 1H), 9.44 (d, J = 2.4 Hz, 1H).

Example 273B

6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]

Carbaldehyde was carried out as in Example 272B to give the title compound (0.07 g, 59%).

mp 225-222 &lt; 0 &gt;C;

MS (APCI) m / e: 354 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.82 (broad s, 2H), 6.92 (dd, J = 8.5, 2.6Hz, 1H), 7.05 (m, 2H), 7.39 (m, 2H), 7.60 ( 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 8.04 (s, 1H), 8.93

Elemental analysis for C ₁₈ H ₁₂ ClN ₃ OS

Calculated: C, 61.10; H, 3.42; N, 11.88.

Found: C, 60.97; H, 3.39; N, 12.08.

Example 274

5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -2-pyridinamine

A solution of the product of Example 270A (0.20 g, 0.65 mmol), 2-amino-5-bromopyridine (0.11 g, 0.65 mmol), [1,1'- bis (diphenylphosphino) ferrocene] To a mixture of dichloropalladium (II) dichloromethane complex (1: 1) (0.11 g, 0.13 mmol), cesium fluoride (0.30 g, 1.95 mmol) and triethylamine (0.09 mL, 0.65 mmol) Respectively. The reaction was heated at reflux for 4 h and then concentrated. The residue was dissolved in 10% PrOH / CHCl ₃ (100 mL) and filtered, and the organic layer was washed with saturated NaHCO ₃ (2 x 100 mL), partially dried with sodium sulfate and then concentrated to give a colored crude solid. The residue was purified by preparative HPLC using 40% gradient of 25% -65% acetonitrile / water + 0.1% TFA. The product was neutralized with saturated NaHCO ₃ and the precipitate was collected by filtration and then dried in a drier to give the title compound as a brightly colored solid (54 mg, 23%).

mp 208-210 C;

MS (APCI) m / e: 254 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.50 (br s, 2H), 6.53 (dd, J = 8.9,0.9Hz, 1H), 7.11 (m, 2H), 7.44 (m, 2H), 7.55 ( s, 1H), 7.85 (dd, J = 8.9, 2.6 Hz, 1H), 8.11 (s, 1H), 8.41 (dd, J = 2.6, 0.9 Hz, 1H), 9.00

Elemental analysis for C ₁₈ H ₁₂ ClN ₃ OS

Calculated: C, 61.10; H, 3.42; N, 11.88.

Found: C, 60.92; H, 3.45; N, 11.90.

Example 275

5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazole-

Example 156 The product (0.15 g, 0.47 mmol) was suspended in 1,4-dioxane (3 mL) and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.50 mmol) was added. Stir the reaction mixture for 10 minutes it was dropwise added a solution of _{NaHCO 3 (0.04 g, 0.50 mmol} ) in water (1.4 mL). The colored reaction was stirred for 2 h then poured into saturated NaHCO ₃ (75 mL). The aqueous phase was extracted with 10% isopropanol / CHCl ₃ (4x25 mL). The organic extracts were combined, dried over sodium sulfate and concentrated to give a solid (0.13 g). A portion of the crude product was purified by HPLC over a gradient of 30% -70% acetonitrile / water + 0.1% TFA over 40 minutes to give the title compound as a brown solid.

mp 262-263 C;

MS (APCI) m / e: 345 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.15 (m, 2H), 7.47 (m, 2H), 7.52 (s, 1H), 7.60 (broad s, 2H), 8.24 (s, 1H), 9.17 ( s, 1H);

_{^{13 C NMR (DMSO-d 6}} ) δ 164.3, 155.6, 153.1, 146.6, 141.2, 137.0, 136.9, 134.0, 131.4, 130.1 (2C), 127.7, 119.5 (2C), 117.5;

IR (KBr) 3325, 3234, 3080, 1665, 1578, 1547, 1486, 1411, 1287, 1257, 1229, 1203 cm &lt; ^{-1 &} gt ;;

Elemental analysis for C ₁₅ H ₉ ClN ₄ O ₂ S

Calculated: C 52.26; H, 2.63; N, 16.25.

Found: C, 52.40; H, 2.68; N, 16.23.

Example 276

5- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-

The product (0.15 g, 0.47 mmol) was suspended in 1,4-dioxane (4 mL) and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.50 mmol) was added. Stir the reaction mixture for 10 minutes it was dropwise added a solution of _{NaHCO 3 (0.04 g, 0.50 mmol} ) in water (1.4 mL). The colored reaction was stirred for 2 h then poured into saturated NaHCO ₃ (75 mL). The aqueous phase was extracted with 10% IPA / CHCl ₃ (4 x 25 mL). The organic extracts were combined, dried over sodium sulfate and concentrated to give a solid. A portion of the crude product was purified by HPLC over a gradient of 30% -70% acetonitrile / water + 0.1% TFA over 40 minutes to give the title compound as a brown solid.

mp 270-273 占 폚;

MS (APCI) m / e: 389 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.08 (m, 2H), 7.52 (s, 1H), 7.56 (br s, 2H), 7.59 (m, 2H), 8.27 (s, 1H), 9.19 ( s, 1H);

Elemental analysis for C ₁₅ H ₉ BrN ₄ O ₂ S

Calculated: C, 46.29; H, 2.33; N, 14.39.

Found: C, 46.08; H, 2.59; N, 14.12.

Example 277

2,3-c] pyridin-2-yl] -4H-1,2,4-triazole-3-amine

A solution of 25% by weight NaOMe / MeOH (7.13 mL, 34.32 mmol) was slowly added to a dry flask containing 61A (0.33 g, 1.03 mmol) and aminoguanidine hydrochloride (3.45 g, 31.20 mmol). The reaction was stirred at ambient temperature for 1 hour, heated to 50 &lt; 0 &gt; C for 20 hours and then heated to 70 &lt; 0 &gt; C for 24 hours. The reaction was poured into water (200 mL) and the aqueous phase was neutralized with 3 N HCl (10 mL). The precipitate was collected by filtration, washed with water (2 x 20 mL) and then dried in a drier. The crude material was purified by HPLC over a gradient of 25% -65% acetonitrile / water + 0.1% TFA over 40 minutes. The product was neutralized with saturated NaHCO ₃ and the precipitate was collected by filtration and then dried in a drier to yield the title compound as a white solid (0.16 g, 45%).

mp &gt; 270 DEG C;

MS (APCI) m / e: 344 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6 0 δ 6.46 (br s, 2H), 7.27 (m, 2H), 7.58 (m, 2H), 7.67 (s, 1H), 8.31 (s, 1H), 9.21 ( s, 1H);

Elemental analysis for C ₁₅ H ₁₀ ClN ₅ OS

Calculated: C, 52.41; H, 2.93; N, 20.37.

Found: C, 52.21; H, 3.02; N, 20.45.

Example 278

5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3,4-thiadiazole-

Example 88 The product (0.36 g, 1.18 mmol) was suspended in thionyl chloride (4 mL) and the suspension was heated to 45 &lt; 0 &gt; C for 2 h. The reaction was concentrated and the residue was diluted with CH ₂ Cl ₂ ( ₂ x 5 mL) and then concentrated to give a colored solid. The crude solid was dissolved in DMF (5 mL), thiosemicarbazide (2.69 g, 29.50 mmol) was added and the reaction was stirred for 24 h. The reaction solution was poured into water (250 mL) and the aqueous suspension was treated with saturated aqueous NaHCO ₃ (10 mL) until pH was 7 or higher. Was obtained in ^{377 (M + H) +]} : Collect the precipitate and the product was washed with water (2x20 mL), and then cover-acyl semi that was dried in a dryer corresponding second bit solid (0.30 g) (MS (APCI ) m / e The crude material (0.20 g) was suspended in toluene (2 mL) and methanesulfonic acid (0.10 mL, 1.60 mmol) was added Reaction was heated at reflux for 4 hours then cooled to room temperature The heterogeneous mixture was extracted with hexane (5 mL) and the solvent was evaporated from the colored residue.The residue was triturated with hexane (2 x 10 mL) and dried under vacuum.The solid was suspended in water (15 mL) and NH ₄ OH The precipitate was collected and washed with water (2 x 5 mL) The crude material was partially purified by flash chromatography on silica gel using acetone as the eluent. Preliminary HPLC over 40 minutes with a gradient of nitrile / water + 01% TFA afforded further purification It was. A product was neutralized with saturated aqueous NaHCO ₃ and the precipitate was collected by filtration and then dried in a desiccator to give the title compound as a brown solid (0.04 mg, total yield 14%).

mp &gt; 270 DEG C;

MS (APCI) m / e: 361 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.15 (m, 2H), 7.46 (m, 2H), 7.68 (s, 1H), 7.75 (br s, 2H), 8.11 (s, 1H), 9.06 ( s, 1H);

Elemental analysis for C ₁₅ H ₉ ClN ₄ OS ₂

Calculated: C, 49.93; H, 2.51; N, 15.53.

Found: C, 49.82; H, 2.64; N, 15.58.

Example 279

Thieno [2,3-c] pyridine prepared in Step 2 of Example 1 was used in place of 4- (4-chlorophenoxy) -2- (5-methyl-

A solution of the product of example 249 (160 mg, 0.5 mmol) in pyridine (2.0 mL) was treated with acetyl chloride (50 mL, 0.55 mmol) at ambient temperature under nitrogen and heated to reflux for 15 h. The resulting thick yellow homogeneous solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ and brine, dried over magnesium sulfate, filtered through a plug of silica and concentrated to give 169 mg of a gray powder. The solid was flash chromatographed on a silica gel with 30-50% ethyl acetate / hexanes to give the title compound (150 mg, 87%).

mp 120-121 DEG C;

_{MS (APCI-NH 3) m} / e: 344 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.24 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.16 (d, 2H), 2.69 (s , 3H);

Elemental analysis for C ₁₆ H ₁₀ ClN ₃ O ₂ S

Calculated: C, 55.90; H, 2.93; N, 12.22.

Found: C, 56.10; H, 3.16; N, 12.01.

Example 280

Thieno [2,3-c] pyridin-2-yl} -1,3,4-oxadiazole-2-amine

The product was treated according to the procedure of Example 275 to give the title compound.

MS (APCI) m / e: 358.9 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.22 (d, 2H), 7.51 (s, 1H), 7.60 (s, 2H), 7.79 (d, 2H), 8.40 (s, 1H), 9.25 (s , 1H).

Example 281

2-yl] thieno [2,3-c] pyridine prepared in the same manner as in Example 1 using 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl)

Example 281A

Thiophene [2,3-c] pyridin-2-yl] -1,3,4-oxadiazole-2-thiol

The compound of Example 156 (100 mg, 0.31 mmol) was suspended in ethanol (2 ml) and cooled to 0 占 폚. Carbon disulfide (0.04 ml, 0.71 mmol) and potassium hydroxide (20 mg, 0.31 mmol) were added in turn. The reaction was stirred for 1 hour and the cold bath was removed. After 1 hour at ambient temperature, the reaction was stirred for 3 hours and then concentrated to a solid. The crude solid was triturated with chloroform (1 x 5 ml) and concentrated. The residue was dissolved in water (15 ml) and acidified with formic acid. The resulting precipitate was separated by filtration, washed with water (2 x 15 ml) and dried in a drier to give the title compound (106 mg, 94%).

mp 236-240 占 폚;

MS (ESI) m / e: 362 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CD ₂ Cl ₂ ) 隆 7.15 (m, 2H), 7.46 (m, 2H), 7.65 (m, 1H), 8.24 (s, 1H), 9.18

Elemental analysis for C ₁₅ H ₈ ClN ₃ O ₂ S ₂

Calculated: C, 47.89; H, 2.57; N, 11.17.

Found: C, 47.89; H, 2.49; N, 10.97.

Example 281B

2-yl] thieno [2,3-c] pyridine prepared in the same manner as in Example 1 using 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl)

To a stirred suspension of 281A (100 mg, 0.28 mmol) in THF (1 ml) at 0 <0> C was added 1 M aqueous sodium hydroxide solution (0.28 ml, 0.28 mmol). After 30 minutes all solids were dissolved and iodomethane (0.02 ml, 0.31 mmol) was slowly added dropwise. The reaction was stirred for 30 min and water (8 ml) was added. The solid was collected by filtration, washed with water (2 x 15 ml) and then dried in a drier to afford 80 mg of a light yellow solid. The crude product was purified by flash chromatography on silica gel using acetone / hexane as eluent to give the title compound as a solid (41 mg, 39%).

mp 158-160 DEG C;

MS (ESI) m / e: 376 (M + H) &lt; ⁺ &gt;;

_{^{1 H NMR (300MHz, CD 2}} Cl 2) δ 2.75 (s, 3H), 7.01 (m, 2H), 7.33 (m, 2H), 7.91 (s, 1H), 8.12 (s, 1H), 8.93 (s , 1H);

Elemental analysis for C ₁₆ H ₁₀ ClN ₃ O ₂ S ₂

Calculated: C, 51.13; H, 2.68; N, 11.18.

Found: C, 51.25; H, 3.02; N, 10.89.

Example 282

2,3-c] pyridin-4-ylmethyl) -2,3-dimethyl-lH-pyrrolo [2,3-

Example 282A

2- (l, 2,3,4-tetrazol-5-yl) thieno [2,3-c] pyridine

A solution of the compound of Example 248 (90 mg, 0.314 mmol) in toluene (1.5 mL) was treated with dibutyltin oxide (8 mg, 0.031 mmol) and trimethylsilyl azide (125 mL, 0.942 mmol) Was heated at reflux for 24 hours and then stirred at room temperature for an additional 2.5 days. The resulting heterogeneous mixture was concentrated and then flash chromatographed with 20% methanol / dichloromethane to give 105 mg of pale yellow powder. The resulting powder was dissolved in ethyl acetate and extracted with 10% NaHCO ₃ (2x). The aqueous extracts were combined and acidified to pH 2 with 6 N HCl, then extracted with ethyl acetate, dried with sodium sulfate and concentrated to give the title compound as a white powder (63 mg, 61%).

mp 250-254 占 폚;

_{MS (APCI-NH 3) m} / e: 330 (M + H) +;

¹ H NMR (300 MHz, DMSO- d ₆ )? 9.26 (s, IH), 8.27 (s, IH), 8.01 (s, IH), 7.48 (d, 2H), 7.19 (d, 2H);

Elemental analysis for C ₁₄ H ₈ ClN ₅ OS 0.25H ₂ O

Calculated: C, 50.30; H, 2.56; N, 20.95;

Found: C, 50.27; H, 2.69; N, 20.78.

Example 282B

2,3-c] pyridin-3-ylamino) -thiazol-2-one

A solution of the compound of Example 282A (100 mg, 0.3 mmol) in methanol (4 mL) was treated with diazomethane (diethyl ether and 40% solution in diethyl ether) in diethyl ether at room temperature under nitrogen, (Formed from N-methyl-N'-nitro-N-nitrosoguanidine in KOH) and stirred for an additional 15 minutes and then quenched by slow dropwise addition of glacial acetic acid until violet . The resulting pale yellow solid was filtered through a plug of silica gel with 5% methanol / dichloromethane and then purified by reverse phase silica gel (Dynamax 21.4 mm C) with 25-65% CH ₃ CN + 0.1% TFA / H ₂ O + 0.1% -18 &lt; / RTI &gt; column) gave the title compound as a white powder (40 mg, 39%).

mp 131-133 占 폚;

_{MS (APCI-NH 3) m} / e: 344 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.25 (s, 1H), 8.28 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.18 (d, 2H), 4.47 (s , 3H);

Elemental analysis for C ₁₅ H ₁₀ ClN ₅ OS 0.25H ₂ O

Calculated: C, 51.73; H, 3.04; N, 20.11.

Found: C, 51.74; H, 2.93; N, 19.93.

Example 283

2,3-c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazole-3-amine

Sodium hydride (60% in oil, 0.02 g, 0.42 mmol) was suspended in DMF (1 mL) at 0 &lt; 0 &gt; C. A solution of the product of Example 277 (0.11 g, 0.32 mmol) in DMF (1 mL) was added dropwise and the reaction was stirred for 20 minutes. Iodomethane (0.06 mL, 0.96 mmol) was added and after 30 min the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration and washed with water (1 x 20 mL) and 50% EtOAc / hexane (2 x 25 mL). The crude solid was dried to give a colored solid (0.11 g). The title compound was isolated by preparative HPLC over 40 minutes with a gradient of 25% -65% acetonitrile / water + 0.1% TFA. The product was neutralized with saturated aqueous NaHCO ₃ , filtered and the precipitate was collected and dried to give the title compound (31 mg, 27%).

mp 233-235 C;

MS (APCI) m / e: 358 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMF-} d 7) δ 3.75 (s, 3H), 6.58 (br s, 2H), 7.23 (m, 2H), 7.54 (m, 2H), 7.61 (s, 1H), 8.27 ( s, 1 H), 9.18 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₂ ClN ₅ OS

Calculated: C, 53.71; H, 3.38; N, 19.57.

Found: C, 54.00; H, 3.56; N, 19.68.

Example 284

3-yl] thieno [2,3-c] pyridine prepared in Step 1 was used in place of 4- (4-chlorophenoxy) -2- [5-

A solution of the product of example 249 (100 mg, 0.31 mmol) in pyridine (1.5 mL) was treated with trifluoroacetic anhydride (50 mL, 0.31 mmol) at room temperature under nitrogen and stirred for 20.5 h, And heated. The brown solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ and brine, dried over magnesium sulfate, concentrated and then filtered through a plug of silica gel with 50/50 hexane / ethyl acetate and concentrated to give 120 mg of a yellow residue Respectively. The residue was flash chromatographed twice over silica gel, with 20-33% ethyl acetate / hexanes and 0-1% methanol / CH ₂ Cl _2, to give the title compound as a white solid (67 mg, 54%).

mp 52-54 C;

_{MS (APCI-NH 3) m} / e: 398 (M + H) +, 416 (M + NH 4) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.30 (s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.48 (d, 2H), 7.20 (d, 2H);

Elemental analysis for C ₁₆ H ₇ ClF ₃ N ₃ O ₂ S 0.25H ₂ O

Calculated: C, 47.77; H, 1.88; N, 10.45.

Found: C, 48.15; H, 2.09; N, 10.14.

Example 285

5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2,4-oxadiazole-

A solution of the product of example 250 (100 mg, 0.3 mmol) in methanol (1.5 mL) was treated with hydroxylamine hydrochloride (40 mg, 0.45 mmol) and triethylamine (70 mL, 0.5 mmol) at ambient temperature under nitrogen And stirred for 18 h, then 4 mL of THF was added and stirred for 2 days and then the solvent was replaced with 50/50 dichloromethane / methanol. Additional hydroxylamine hydrochloride (100 mg, 1.4 mmol) and triethylamine (200 mL, 2.7 mmol) were then added and stirred at ambient temperature for 24 hours and then refluxed for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with dilute NaHCO ₃ and brine, dried over magnesium sulfate and concentrated to give 105 mg of a gray solid. This solid was purified by reverse-phase silica gel (Dynamax 21.4 mm C &lt;&quot;&gt;) in the order of 25-65% CH ₃ CN + 0.1% TFA / water + 0.1% TFA followed by 20-80% CH ₃ CN + 0.1% TFA / 18 column) gave the title compound as a white solid (26 mg, 25%).

mp 217-219 &lt; 0 &gt;C;

_{MS (APCI-NH 3) m} / e: 345 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.26 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.49 (d, 2H), 7.14 (d, 2H), 6.62 (br s, 2H);

Elemental analysis for C ₁₅ H ₉ ClN ₄ O ₂ S

Calculated: C 52.25; H, 2.63; N, 16.25.

Found: C, 51.94; H, 2.88; N, 15.98.

Example 286

2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazole-2-amine

The title compound (total yield 4%) was prepared as for Example 278 using 4-methylthiomecarbazide instead of thiosemicarbazide.

mp 226-229 [deg.] C;

MS (APCI) m / e 375 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.95 (d, J = 1.7Hz, 3H), 7.14 (m, 2H), 7.45 (m, 2H), 7.69 (s, 1H), 8.17 (s, 1H ), 8.19 (br m, 1 H), 9.07 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₁ ClN ₄ OS ₂

Calculated: C, 51.27; H, 2.96; N, 14.95.

Found: C, 51.24; H, 3.03; N, 14.85.

Example 287

2,3-c] pyridin-3-yl) thieno [2,3-c] pyridine

Example 287A

(4-chlorophenoxy) -N'- (diethoxymethoxy) thieno [2,3, -c] pyridine-2-carboximidamide

A solution of the product of example 249 (100 mg, 0.31 mmol) in triethylorthoformate (1.3 mL) was heated at 140 &lt; 0 &gt; C for 5 h under nitrogen, then heated to 160 &lt; 0 &gt; C for 2 h, . The resulting pale yellow oil (110 mg) was flash chromatographed on silica gel with 20-70% ethyl acetate / hexanes to give the title compound as a white solid (50 mg, 38%).

_{MS (APCI-NH 3) m} / e: 422 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.05 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.46 (d, 2H), 7.10 (d, 2H), 6.65 (br s, 2H), 5.66 (s, 1H), 3.62-3.71 (m, 4H), 1.15 (t, 6H).

Example 287B

2,3-c] pyridin-3-yl) thieno [2,3-c] pyridine

A solution of the product of Example 287A (50 mg, 0.119 mmol) in toluene (6 mL) was heated at reflux under nitrogen for 20 h, then cooled and concentrated. The yellow residue (46 mg) was flash chromatographed on silica gel with 25-50% ethyl acetate / hexanes to give the title compound as a white solid (39 mg, 100%).

Analytical HPLC: 4.6x250 mm C-18 column, 0.8 mL / min, 254 nm, CH ₃ CN in _{0.1% TFA: H 2 O,} 0: 100 (0-3 min), 90:10 (3-30 min.) , 90:10 (30-35 minutes), 0: 100 (35-40 minutes), Rt = 22.47 minutes (100% peak region)

mp 151-152 C;

_{MS (APCI-NH 3) m} / e: 330 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.86 (s, 1H), 9.26 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.48 (d, 2H), 7.19 (d , 2H).

Example 288

2- (1,3,4-oxadiazol-2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine

A solution of Example 183 (100 mg, 0.283 mmol) in triethylorthoformate (15 mL) was heated at reflux under a nitrogen atmosphere for 28 h. All volatiles were removed under reduced pressure. The resulting oil was purified by flash column chromatography eluting with hexane / ethyl acetate (2: 1) to give 65 mg (63%) of the title compound as colorless oil. This material turned solid when left to stand.

MS (ESI) m / e: 364 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CDCl ₃ )? 7.14 (d, 2H), 7.66 (s, IH), 8.05 );

Elemental analysis for C ₁₆ H ₈ N ₃ F ₃ O ₂ S

Calculated: C, 52.89; H, 2.22; N, 11.57.

Found: C, 53.03; H, 2.25; N, 11.48.

Example 289

2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine

Example 289A

Thieno [2,3-c] pyridin-2-yl] -5- (trichloromethyl-1,2,4-oxadiazole

A solution of the product of example 249 (50 mg, 0.156 mmol) in pyridine (2 mL) was treated with trichloroacetyl chloride (20 mL, 0.17 mmol) at ambient temperature under nitrogen and heated at reflux for 1.5 h. It was then cooled to room temperature and stirred overnight, then treated with additional trichloroacetyl chloride (100 mL, 0.86 mmol) and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with NaHCO ₃ and brine and dried over magnesium sulfate and concentrated. The resulting brown residue was flash chromatographed on silica gel with 25-50% ethyl acetate / hexanes to give the title compound as a clear residue (37 mg, 53%).

_{MS (APCI-NH 3) m} / e: 448 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 9.25 (s, IH), 8.24 (s, IH), 8.09 (s, IH), 7.46 (d, 2H), 7.18 (d, 2H).

Example 289B

2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine

A solution of the product of Example 289A (30 mg, 0.067 mmol) in methanol (6 mL) with 2.0 M ammonia in a pressure tube was heated to 60 &lt; 0 &gt; C for 15 h, then cooled to ambient temperature and the flask was rinsed with methanol and distilled water Respectively. The excess methanol was removed in vacuo and the cloudy white mixture was filtered and washed with distilled water. The resulting tan solid was purified twice by flash chromatography on reversed phase silica gel (Dyanamax C-18, 21.4 mm column) with 25-65% CH ₃ CN followed by 20-80% CN ₃ CN + 0.1% TFA / water + 0.1% TFA To give the title compound as a white solid (4 mg, 17%).

Analytical HPLC: 4.6x250 mm C-18 column, 0.8 mL / min, 254 nm, CH ₃ CN in _{0.1% TFA: H 2 O,} 0: 100 (0-3 min), 90:10 (3-30 min.) , 90:10 (30-35 minutes), 0: 100 (35-40 minutes), Rt = 22.47 minutes (100% peak region)

mp 268-270 占 폚;

_{MS (APCI-NH 3) m} / e: 345 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.21 (s, 1H), 8.27 (s, 1H), 8.22 (br s, 2H), 7.67 (s, 1H), 7.47 (d, 2H), 7.15 ( d, 2H).

Example 290

Phenoxy] thieno [2,3-c] pyridine prepared in the same manner as in Example 1, except for using 2- (5-methyl-1,3,4-oxadiazol-

The title compound was prepared as described in Example 288 using triethylorthoacetate as the solvent. And refluxed for 5 days to obtain a yield of 29.

MS (APCI) m / e: 377 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, CDCl ₃ )? 2.65 (s, 3H), 7.13 (d, 2H), 7.65 (d, 2H), 7.94 ).

Example 291

4- (4-chlorophenoxy) -2- (2-furyl) thieno [2,3-c] pyridine

A solution of Example 270A (0.30 g, 0.98 mmol), 2,5-dibromofuran (0.66 g, 2.94 mmol), cesium fluoride (0.45 g, 2.94 mmol) and triethylamine (0.14 mL, (0.16 g, 0.20 mmol) was added to a mixture of [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex . The reaction was heated to reflux for 4 h and then stirred overnight at ambient temperature. The reaction was diluted with EtOAc (100 mL) and filtered. The organic layer was washed with saturated NaHCO ₃ (3 x 50 mL) and brine (75 mL), partially dried over sodium sulphate and then concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give a colored oil (0.12 g, 0.30 mmol) [MS (APCI) m / e 406 (M + H) ⁺ ]. This material was dissolved in EtOH (10 mL) and 5% Pd / C (3 mg, 0.02 mmol) was added. Hydrogen gas was applied and the reaction solution was stirred at ambient temperature for 3 days. The reaction was filtered through celite and the celite was washed with MeOH (10 mL) and dichloromethane (10 mL). The filtrate and washings were combined and concentrated to give a colored wet bubble. The crude material was purified by preparative HPLC over 40 minutes with a gradient of 30-70% acetonitrile / water + 0.1% TFA. The product was neutralized with saturated NaHCO ₃ and the precipitate was collected by filtration and then turgidized in a dryer to afford the title compound as a brightly colored solid (15 mg, 5% total yield).

mp 75-77 [deg.] C;

MS (APCI) m / e: 328 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 6.70 (dd, J = 3.4,1.7Hz, 1H), 7.12 (m, 2H), 7.24 (d, J = 3.4Hz, 1H), 7.46 (m, 2H ), 7.59 (s, IH), 7.88 (d, J = 1.7 Hz, IH), 8.16 (s, IH), 9.08 (s, IH).

Example 292

4- (4-chlorophenoxy) -2- (2-thienyl) thieno [2,3-c] pyridine

The title compound (50 mg, 22%) was prepared as described in Example 272A using 2-iodothiophene instead of l-iodo-4-nitrobenzene.

mp 101-103 C;

MS (APCI) m / e: 344 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.14 (m, 2H), 7.19 (dd, J = 5.0, 3.4Hz, 1H), 7.46 (m, 2H), 7.54 (d, J = 0.9Hz, 1H ), 7.67 (dd, J = 3.4, 1.3 Hz, 1H), 7.73 (dd, J = 5.0 Hz, 1H), 8.14 (s, 1H), 9.05

Elemental analysis for C ₁₇ H ₁₀ ClNOS ₂ 0.2H ₂ O

Calculated: C, 58.77; H, 3.02; N, 4.03.

Found: C, 58.74; H, 2.84; N, 3.72.

Example 293

2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-

Example 293A

Ethyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-

Ethyl bromopyruvate (390 mL, 2.30 mmol) was mixed with the product of example 146 (672 mg, 2.09 mmol) and anhydrous ethanol (100 mL) and the orange solution was heated to 60 &lt; 0 &gt; C. After 48 hours the mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash silica gel chromatography (15% acetone in hexanes) afforded the title compound (297 mg, 34% yield) as a white solid.

_{MS (DCI / NH 3) m} / e: 417 (35 Cl) / 419 (37 Cl);

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.94 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.36 (d, J = 8.8Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.45 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7 Hz, 3H).

Example 293B

2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-

Example 293A The product (32 mg, 77 mmol) was mixed with ammonia in methanol (4 mL in a 2.0 M solution) and the solution was heated to 40 &lt; 0 &gt; C in a sealed tube. After 16 hours, the homogeneous solution was cooled to room temperature and concentrated to give a brown solid. This solid was loaded onto a flash silica gel and eluted sequentially with 20% acetone in hexanes and 40% acetone in hexanes to give the title compound (8 mg, 27% yield).

mp 215-218 [deg.] C;

_{MS (DCI / NH 3) m} / e: 388 (M + H) / 405 (M + NH 3), 407 (37 Cl + NH 3);

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 5.67 (br s, 2H), 7.06 (d, J = 8.5Hz, 2H), 7.38 (d, J = 8.8Hz, 2H), 8.09 (s, 1H), 8.25 (s, 1 H), 8.94 (s, 1 H).

Example 294

Tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazol-

The product of Example 293 was converted to the corresponding carboxylic acid following a method analogous to that described in Example 18. Diphenylphosphoryl azide (25 uL, 0.10 mmol) was added to a mixture of carboxylic acid (40 mg, 0.10 mmol), t-butanol (10 mL) and triethylamine (20 uL, 0.10 mmol) Lt; / RTI &gt; After 18 h the solution was cooled and concentrated. The yellow solid was dissolved in CH ₂ Cl ₂ (30 mL) and washed sequentially with 0.5 N aqueous HCl (40 mL), saturated aqueous NaHCO ₃ (25 mL) and brine (25 mL). The combined aqueous washings were extracted with CH ₂ Cl ₂ ( ₂ x 25 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a yellow residue. Flash chromatography on silica gel (15% acetone in hexanes) afforded the title compound (13 mg, 28% yield) as a pale yellow solid.

MS (APCI) m / e: 460 ( ³⁵ CI) / 462 ( ³⁷ C);

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.91 (s, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.9Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 3.97 (d, J = 11.4 Hz, 2H), 1.54 (s, 9H).

Example 295

2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazol-

Trifluoroacetic acid (0.5 mL) was added to the product of Example 294 (9.0 mg, 20 umol) in CHCl 3 (1.5 mL) at 0 ° C. After 1 hour the volatiles were removed and the organic residue was dissolved in 0.5 N aqueous HCl (35 mL). The aqueous phase was washed once with Et ₂ O (10 mL) and the ether washings were extracted with 1 N HCl (2 x 20 mL). The acidic layers were combined and saturated aqueous potassium carbonate was added until the solution was basic (pH &gt; 12). The alkaline phase was extracted with EtOAc (3 x 40 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to give a dark brown solid (9 mg). Purification by flash silica gel column chromatography (20% acetone in hexanes) afforded the title compound as a light yellow solid (6.8 mg, 97% yield).

mp 168-170 占 폚;

MS (APCI) m / e: 360 ( ³⁵ CI) / 362 ( ³⁷ CI);

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 8.90 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.35 (d, J = 9.2Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.07 (s, 1 H), 3.89 (br s, 2H).

Example 296

2- (1,3-oxazol-2-yl) thieno [2,3-c] pyridine

Diazabicyclo [5.4.0] undec-7-ene (DBU) (0.09 mL, 0.57 mmol) was added to a solution of the product of example 150 (0.14 g, 0.38 mmol) in anhydrous dichloromethane . The reaction was stirred for 24 hours and an excess of morpholine (0.2 mL) was added to react with the starting material of the residue. The reaction was stirred for 4 hours then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with diluted NaH ₂ PO ₄ (100 mL), saturated NaHCO ₃ (100 mL) and brine (100 mL), then partially dried over sodium sulfate and concentrated to give a solid. The crude product was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a solid (0.07 g, 55%).

mp 158-160 占 폚 (decomposition);

MS (APCI) m / e: 331 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.01 (t, J = 9.6Hz, 2H), 4.48 (t, J = 9.6Hz, 2H), 7.14 (m, 2H), 7.47 (m, 2H), 7.62 (s, 1 H), 8.24 (s, 1 H), 9.19 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₁ ClN ₂ O ₂ S

Calculated: C, 58.09; H, 3.35; N, 8.47.

Found: C, 58.16; H, 3.31; N, 8.27.

Example 297

2- (1,3-oxazol-2-yl) thieno [2,3-c] pyridine

Ishibashi, Y., et al., Tetrahedron Lett. 1996, 37 (17), 2997-3000), the title compound can be prepared from Example 296.

Example 298

LH-imidazol-2-yl) thieno [2,3-c] pyridine

A suspension of the product of example 154 (0.15 g, 0.43 mmol) and calcium oxide (0.12 g, 2.15 mmol) in phenyl ether (10 mL) was heated to 220-250 占 폚. The reaction was stirred over 45 min. At this time, the capacity of the reactants decreased due to the evaporation of the solvent. The reaction was cooled to room temperature, diluted with 10% MeOH / dichloromethane (25 mL) and then filtered. The filtrate was concentrated and the residue was purified by preparative HPLC with 30-90% acetonitrile / water + 0.1% TFA for 40 min. Combine the fractions containing product and neutralized with saturated NaHCO _3. The product crystallized when left standing for 3 days. This was collected by filtration and dried in a drier to afford the title compound as a brown needle (23 mg, 16%).

mp 154-155 占 폚;

MS (APCI) m / e: 330 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.46 (td, J = 9.9, 1.7Hz, 2H), 3.83 (t, J = 9.9Hz, H), 7.12 (m, 2H), 7.34 (br s, 1H), 7.46 (m, 2H), 7.81 (s, 1H), 8.17 (s, 1H), 9.11 (s, 1H);

Elemental analysis for C ₁₆ H ₁₂ ClN ₃ OS

Calculated: C, 58.27; H, 3.67; N, 12.74.

Found: C, 58.15; H, 3.50; N, 12.73.

Example 299

2- (1H-imidazol-2-yl) thieno [2,3-c] pyridine

The title compound can be prepared from Example 298 according to the method of Zimmerman, S. C., et al. (J. Org. Chem., 1989, 54 (6), 1256-1264).

Example 300

Chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide

The title compound was prepared from the corresponding 4-chloromethyl ester isolated as a by-product from Example 125A as described in Example 125.

_{MS (DCI / NH 3) m} / e: 227 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.55 (s, 3H), 6.95 (d, 2H), 7.57 (d, 2H), 7.90 (b, 1H), 8.00 (b, 1H), 8.27 (s , &Lt; / RTI &gt; 1H), 9.15 (s, 1H).

Example 301

3-Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide

Methyl 3-amino-4-chlorothieno [2,3-c] pyridine-2-carboxylate was isolated from the crude product mixture of Example 131B. The mixture was hydrolyzed as described in Example 18 and the resulting acid was mixed with ammonium chloride according to the procedure of Example 92. [ The reaction mixture was poured into 5% sodium bicarbonate solution and precipitated, and the product was isolated by filtration and washed with water.

_{MS (DCI / NH 3) m} / e: 228 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.01 (br s, 2H), 7.49 (br s, 2H), 8.42

Example 302

4 ', 5'] thieno [3,2-d] pyrimidine-2,4- (1H, 3H) -dione

To a suspension of the product of Example 131D (70 mg, 0.22 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1,1-carbonyldiimidazole (71 mg, 0.44 mmol) and triethylamine (60 uL, 0.44 mmol) Under a nitrogen atmosphere. The reaction mixture was stirred at reflux for 48 hours and then at ambient temperature for an additional 24 hours. The reaction mixture water: was collected by filtration and the resulting solid was poured into a solution of 1: 1 of saturated NH ₄ Cl. This material was purified by flash chromatography on silica gel eluting with 20% acetone-hexane. The desired fractions were combined, evaporated and slurried in hot EtOAc to give the title compound (39 mg) in 51% yield.

MS (APCI) m / e: (MH) ^- 344;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.32 (m, 2H), 7.55 (m, 2H), 7.92 (s, 1H), 9.09 (s, 1H), 11.22 (br s, 1H), 11.72 ( br s, 1 H);

HPLC: Supelco C-18 column, water: acetonitrile 0:90 to 90: 0 elution (30 min), flow rate 0.8 ml / min, rt 20.33 min.

Example 303

4- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine- 2- carboxamide

The title compound was prepared from the product of Example 125A.

_{MS (DCI / NH 3) m} / e: 333 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.55 (s, 3H), 2.80 (d, 3H), 7.05 (d, 2H), 7.45 (d, 2H), 8.20 (s, 1H), 8.55 (b , &Lt; / RTI &gt; 1H), 9.18 (s, 1H);

Example 304

4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide

The title compound was prepared by treating the product of Example 17A and 4-bromophenol as in Example 125.

mp 177-178 [deg.] C;

_{MS (DCI / NH 3) m} / e: 364 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.55 (s, 3H), 6.95 (d, 2H), 7.57 (d, 2H), 7.90 (m, 1H), 8.00 (m, 1H), 8.27 (s , &Lt; / RTI &gt; 1H), 9.15 (s, 1H);

Elemental analysis for C ₁₅ H ₁₁ BrN ₂ O ₂ S

Calculated: C, 49.60; H, 3.05; N, 7.71.

Found: C, 49.36; H, 3.24; N, 7.61.

Example 305

Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide

Example 305A

Methyl 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylate, N-

The title compound was prepared from the product of Example 125A following the procedure of Example 123A.

_{MS (DCI / NH 3) m} / e: 350 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.78 (s, 3H), 3.88 (s, 3H), 7.28 (m, 2H), 7.51 (m, 2H), 7.68 (br s, 1H), 8.92 ( br s, 1H).

Example 305B

Methyl 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine- 2- carboxamide

The product was treated according to the procedure of Example 1C to provide the title compound.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min), detection at 254 nm, flow rate 0.8 mL / min, RT 31.64 min;

_{MS (DCI / NH 3) m} / e: 368 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.78 (s, 3H), 3.92 (s, 3H), 7.18 (m, 2H), 7.48 (m, 2H), 8.01 (s, 1H).

Example 305C

7- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylic acid

The title compound was prepared by treating the product of Example 305B following the procedure of Example 18 using tetrahydrofuran instead of isopropanol.

HPLC: Supelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min) detection at 254 nm, flow rate 0.8 mL / min, RT 27.25 min;

MS (APCI) m / e: 354 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO- d ₆ )? 2.72 (s, 3H), 7.16 (m, 2H), 7.49 (m, 2H), 8.01

Example 305D

Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide

The product of Example 305C was treated according to Example 92 to provide the title compound.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min) detection at 254 nm, flow rate 0.8 mL / min, RT 24.75 min;

_{MS (DCI / NH 3) m} / e: 353 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.58 (s, 3H), 7.10 (m, 2H), 7.47 (m, 2H), 8.0 (br s, 1H), 8.02 (s, 1H), 8.03 ( br s, 1H).

Example 306

2,3-c] pyridine-3-carboxylate &lt; / RTI &gt;

Example 306A

Tert-butyl 3,5-dichloropyridine-4-oxalate

Example 17A was performed using t-butyl chlorooxalate in place of methyl formate to give the title compound.

_{MS (DCI / NH 3) m} / e: 241 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.5 (s, 9H), 8.85 (s, 2H).

Example 306B

2,3-c] pyridine-3-carboxylate &lt; / RTI &gt;

Example 306A &lt; Desc / Clms Page number 33 &gt; The product and 4-chlorophenol were carried as in Example 61 to give the title compound.

_{MS (DCI / NH 3) m} / e: 420 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.42 (s, 9H), 3.95 (s, 3H), 7.18 (d, 2H), 7.50 (d, 2H), 8.05 (s, 1H), 9.20 (s , 1H).

Example 306C

2,3-c] pyridine-3-carboxylate &lt; / RTI &gt;

Example 306B The product was treated as in Example 217 to give the title compound.

_{MS (DCI / NH 3) m} / e: 405 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 1.35 (s, 9H), 7.10 (d, 2H), 7.45 (d, 2H), 7.95 , &Lt; / RTI &gt; 1H), 9.18 (s, 1H).

Example 306D

2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine-

To a cold solution of trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was added the product of Example 306C (0.08 g, 0.2 mmol) and stirred for 1 hour. The solution was evaporated and treated slowly with a cold solution of sodium bicarbonate (20 mL) and then the mixture was extracted with ethyl acetate (3 x 20 mL). The ethyl acetate extract was dried and evaporated to give the title compound.

_{MS (DCI / NH 3) m} / e: 349 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 7.05 (d, 2H), 7.45 (d, 2H), 7.95 (b, 1H), 8.05 (m, 1H), 8.15 (s, 1H), 9.20 (s, 1H).

Example 307

Methyl-4- (4-toluidino) thieno [2,3-c] pyridine-2- carboxamide

(170 mg, 1.4 mmol), 18-crown-6 (370 mg, 1.4 mmol), Pd &lt; RTI ID = 0.0 & A mixture of ₂ (dba) ₃ (46 mg, 5 mol%) and BINAP (31 mg, 5 mol%) was placed in a cedar round bottom flask equipped with a condenser, internal temperature probe and N ₂ inlet. It was poured under nitrogen and anhydrous tetrahydrofuran (5 mL) was added. The reaction mixture was warmed to 45 &lt; 0 &gt; C for 3 days and the solid material was filtered through celite and washed with a mixture of ethyl acetate and acetone. The filtrate was diluted with ethyl acetate (100 mL), washed with brine (2 x 50 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure. Flash chromatography on silica gel eluting with 30% acetone-hexanes gave the title compound in 29% yield (86 mg).

_{MS (DCI / NH 3) m} / e: 298 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.25 (s, 3H), 2.80 (d, J = 6Hz, 3H), 7.02 (d, J = 9Hz, 2H), 7.10 (d, J = 9Hz, 2H ), 8.13 (s, IH), 8.26 (s, IH), 8.36 (m, IH), 8.76 (br s, IH);

^{13 C NMR (75MHz, DMSO-} d 6) δ 20.4 (CH 3), 26.4 (CH 2), 118.2 (CH), 118.2 (CH), 122.1 (CH), 129.8 (CH), 130.0 (C), 130.6 (CH), 130.7 (C), 135.9 (C), 136.5 (CH), 137.1 (C), 140.3 (C), 142.3 (C), 161.6 (CO).

Example 308

4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine-2- carboxamide

(500 mg, 84%) was prepared by carrying out the procedure of Example 307 using 4-chloroaniline (510 mg, 4 mmol) instead of 4-methylaniline and heating the reaction solution to 60 ° C for 20 hours. Respectively.

MS (APCI) m / e: 318 (M + H) &lt; ⁺ & gt ^; , 352 (M + Cl) ^- ;

^{1 H NMR (400MHz, DMSO-} d 6) δ 2.83 (d, J = 4Hz, 3H), 7.07 (d, J = 9Hz, 2H), 7.32 (d, J = 9Hz, 2H), 8.11 (s, 1H ), 8.38 (s, 1H), 8.67 (s, 1H), 8.85 (d, J = 4 Hz, 1H), 8.91 (s, 1H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 26.3 (CH 3), 118.1 (2xCH), 121.7 (CH), 123.6 (C), 129.1 (2xCH), 133.0 (CH), 134.4 (C), 137.1 ( C), 137.2 (C), 138.2 (CH), 142.6 (C), 143.2 (C), 161.4 (C).

Example 309

Methyl-4- (4-morpholinyl) thieno [2,3-c] pyridine-2- carboxamide

The title compound (105 mg, 38%) was prepared as for example 308 using morpholine (0.175 mL, 2 mmol) instead of 4-chloroaniline.

MS (APCI) m / e: 278 (M + H) ⁺ , 312 (M + Cl) ^- ;

¹ H NMR (400 MHz, DMSO-d ₆ )? 2.91 (d, J = 4 Hz, 3H), 3.23 (m, 4H), 3.91 , 8.96 (s, 1 H), 8.99 (d, J = 4 Hz, 1 H);

^{13 C NMR (100MHz, DMSO-} d 6) δ 26.1 (CH 3) 51.6 (2xCH 2), 66.3 (CH 2), 121.2 (CH), 131.6 (CH), 137.1 (C), 137.9 (C), 139.0 (C), 143.3 (C), 143.9 (C), 161.3 (CO).

Example 311

Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 311A

Methyl 7-chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-

The product was treated as in Example 1C to give the title compound.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min), detection at 254 nm, flow rate of 0.8 mL / min, RT 30.35 min;

_{MS (CDI / NH 3) m} / e: 354 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 3.91 (s, 3H), 7.14 (m, 2H), 7.45 (m, 2H), 7.91 (s, 1H); 8.24 (s, 1 H), 9.21 (s, 1 H).

Example 311B

Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

The title compound was prepared by treating the product of Example 311A as in Example 44. LCMS

_{MS (DCI / NH 3) m} / e: 339 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.20 (m, 2H), 7.58 (m, 2H), 7.94 br s, 1 H);

Elemental analysis for C ₁₄ H ₈ Cl ₂ O ₂ S

Calculated: C, 56.42; H, 3.28; N, 10.12.

Found: C, 56.31; H, 3.22; N, 10.01.

Example 312

7-chloro-4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide

Example 311A was processed as described in example 171 to provide the title compound.

_{MS (DCI / NH 3) m} / e: 353 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 2.80 (d, 3H); 1H), 8.14 (s, 1H), 9.04 (brs, 2H).

Example 313

7- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide

The title compound was prepared according to the procedure of Example 114 by treating the product of Example 311A.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min) detection at 254 nm, flow rate 0.8 mL / min, RT 23.49 min;

mp 129-132 占 폚;

_{MS (DCI / NH 3) m} / e: 382 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.33 (m, 2H), 3.51 (m, 2H), 4.82 (t, 1H), 7.19 (m, 2H), 7.48 (m, 2H), 8.08 (s , 8.27 (s, 1H), 9.12 (br t, 1H), 9.18 (s, 1H), 12.81 (br s, 1H).

Example 314

7- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

Example 314A

Methyl 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-

The title compound was prepared by treating the product of Example 123A as in Example 1C with phosphorous oxybromide instead of phosphorus oxychloride.

MS (ESI) m / e: 400 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO- d ₆ )? 3.91 (s, 3H), 7.22 (m, 2H), 7.48 (m, 2H), 8.19 (s,

Example 314B

7- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 314A was treated according to Example 44 to afford the title compound.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min), detection at 254 nm, flow rate of 0.8 mL / min, RT 24.95 min;

_{MS (DCI / NH 3) m} / e: 385 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 7.22 (m, 2H), 7.44 (m, 2H), 7.95 (s, 1H), 8.02 (s, 1H), 8.29 (s, 1H), 8.51 (br s , 1H).

Example 315

7- Bromo-4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide

The title compound was prepared by treating the product of Example 314A following the procedure in Example 171. [

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min), detection at 254 nm, flow rate 0.8 mL / min, RT 25.40 min;

_{MS (DCI / NH 3) m} / e: 397 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) 2.81 (d, 3H), 3.97 (s, 3H), 7.19 (m, 2H), 7.48 (m, 2H), 8.04 (s, 1H), 8.21 (s, 1H), 9.05 (br s, 1H).

Example 316

4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2- carboxamide

The title compound was prepared by treating the product of Example 316 as in Example 311 with 4-bromophenol instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e: 383,385 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.14 (d, 2H, J = 8.9Hz), 7.61 (d, 2H, J = 8.8Hz), 7.98 (br s, 1H), 8.05 (s, 1H) , 8.22 (s, 1 H), 8.52 (br s, 1 H);

Elemental analysis for C ₁₄ H ₈ N ₂ O ₂ SBrCl 0.5H ₂ O

Calculated: C, 42.82; H, 2.31; N, 7.10.

Found: C, 42.62; H, 2.26; N, 6.82.

Example 317

4- (4-bromophenoxy) -7-chloro-N-methylthieno [2,3-c] pyridine- 2- carboxamide

The title compound was prepared by treating the product of Example 317 as in Example 312 using 4-bromophenol instead of 4-chlorophenol.

_{MS (DCI / NH 3) m} / e: 397,399 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (d, 3H), J = 4.7Hz), 7.13 (d, 2H, J = 9.2Hz), 7.60 (d, 2H, J = 9.2Hz), 8.07 (s, 1 H), 8.13 (s, 1 H), 9.03 (q, 1 H, J = 4.7 Hz);

Elemental analysis for C ₁₅ H ₁₀ N ₂ O ₂ SBrCl

Calculated: C, 45.30; H, 2.53; N, 7.04.

Found: C, 45.25; H, 2.31; N, 6.86.

Example 318

7-chloro-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide

The title compound was prepared by treating the product of Example 17A and 4-trifluoromethylphenol as in Example 311.

mp 175-176 &lt; 0 &gt;C;

_{MS (DCI / NH 3) m} / e: 373 (M + H) +;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.30 (d, 2H), 7.80 (d, 2H), 8.00 (s, , 1H);

Elemental analysis for C ₁₆ H ₁₀ CIF ₃ N ₂ O ₂ S

Calculated: C, 48.33; H, 2.16; N, 7.52.

Found: C, 48.26; H, 2.25; N, 7.40.

Example 319

7-chloro-N-methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine-

The product of Example 17A and 4-trifluoromethylphenol were treated as in Example 312 to give the title compound.

mp 178-179 C;

_{MS (DCI / NH 3) m} / e: 387 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.80 (s, 3H), 7.30 (d, 2H), 7.80 (d, 2H), 8.00 (s, 1H), 8.25 (s, 1H), 8.55 (m , 1H);

Elemental analysis for C ₁₆ H ₁₀ ClF ₃ N ₂ O ₂ S

Calculated: C, 49.68; H, 2.61; N, 7.24.

Found: C, 49.58; H, 2.54; N, 6.94.

Example 320

7- chloro-N- (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide

The title compound was prepared according to the procedure in Example 319 substituting aminoethanol for methylamine.

mp 96-97 C;

_{MS (ESI / NH 3) m} / e: 415 (M + H) +;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 3.66 (t, 2H, J = 4.8Hz), 3.87 (t, 2H, J = 4.8Hz), 6.63 (m, 1H), 7.11 (d, 2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.72 (s, 1H), 8.02 (s, 1H).

Example 321

4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine- 2- carboxamide

Example 321A

Methyl 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine-

Except that methylboronic acid was used instead of 4- (trifluoromethyl) phenylboronic acid, dichlorobis (tricyclohexylphosphine) palladium was used instead of tetrakis (triphenylphosphine) palladium, NMP was used instead of DME, The title compound was prepared by treating the product of Example 311A as in 95A.

_{MS (DCI / NH 3) m} / e: 334 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.74 (d, 3H), 3.91 (s, 3H), 7.14 (m, 2H), 7.44 (m, 2H), 7.91 (s, 1H), 8.22 (s , 1H).

Example 321B

4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine- 2- carboxamide

The product of Example 321A was treated according to the procedure of Example 171 to yield the title compound.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min) detection at 254 nm, flow rate 0.8 mL / min, RT 20.70 min;

_{MS (DCI / NH 3) m} / e: 334 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.82 (d, 3H), 7.04 (m, 2H), 7.41 (m, 2H), 8.04 (s, 1H), 8.11 (s, 1H), 8.92 (br s, 1H).

Example 322

Preparation of 4- (4-chlorophenoxy) -7-methoxy-ethyno [2,3-c] pyridine-

Example 322A

7- (4-chlorophenoxy) -7-methoxy-etheno [2,3-c] pyridine-

Example 311A The product (100 mg, 0.28 mmol) was dissolved in methanol (10 mL) containing 25% sodium methoxide and warmed to 60 [deg.] C in a pressure tube for 3 days. The solvent was removed under reduced pressure and the residue was redissolved in methylene chloride and acidified with formic acid. The organic layer was washed with water and brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give the title compound (50 mg, 54%) as a gray solid.

MS (DCI) m / e 336 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.18 (s, 3H), 6.92 (m, 2H), 7.31 (m, 2H), 7.54 (s, 1H), 7.69 (s, 1H).

Example 322B

Preparation of 4- (4-chlorophenoxy) -7-methoxy-ethyno [2,3-c] pyridine-

Treatment of Example 322A product (40 mg, 0.12 mmol) according to the procedure of example 92 gave the title compound (23 mg, 0.58 mmol) as a white solid.

mp &gt; 250 DEG C;

_{MS (DCI / NH 3) m} / e: 335 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 4.08 (s, 3H), 7.01 (m, 2H), 7.38 (m, 2H), 7.82 (br s, 1H), 7.90 (s, 1H), 8.04 ( s, 1 H), 8.43 (s, 1 H).

Example 323

4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3-c] pyridine- 2- carboxamide

Example 323A

Methyl 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3-c] pyridine-

A solution of the product of example 311A (200 mg, 0.597 mmol) in acetic anhydride (20 mL) was heated at reflux for 18 hours. The reaction was cooled and poured into ice. The mixture was stirred for 1 hour and then CH ₂ Cl ₂ (100 mL) was added. The organic extracts were washed with 1 N NaOH (100 mL), water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and rotoevaporated to give a crude brown residue. The residue was treated with K ₂ CO ₃ and then directly dissolved in DMF (20 mL) and water (3 mL) and was warmed for 2 hours at 60 ℃. The reaction solution was cooled to room temperature and then roto-evaporated. The crude residue was purified by column chromatography on silica gel, eluting with a gradient of 10% ethyl acetate / hexanes to 50% ethyl acetate / hexanes to give the title compound.

_{MS (DCI / NH 3) m} / e: 336 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.82 (s, 3H), 7.09 (m, 2H), 7.38 (m, 2H), 7.42 (s, 1H), 7.52 (s, 1H), 11.84 (br s, 1H).

Example 323B

4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3-c] pyridine- 2- carboxamide

The product was prepared as described in example 323A.

HPLC: Shupelco C-18 column, gradient elution 0.1% aqueous TFA: acetonitrile 0: 90-90: 0 (for 30 min) detection at 254 nm, flow rate 0.8 mL / min, RT 18.61 min;

mp &gt; 250 DEG C;

MS (APCI) m / e: 321 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.04 (m, 2H), 7.38 (m, 2H), 7.40 (s, 1H), 7.75 (s, 1H), 8.32 (br s, 1H).

Example 324

7- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [2,3- c] pyridine-

Example 311A (27 mg, 76 mmol) was treated according to the procedure of Barraclough, et al. (J. Med. Chem. 1990, 33, 2231) to give the title compound (12 mg, 45% yield) .

_{MS (DCI / NH 3) m} / e: 348 (35 Cl) / (37 Cl);

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 2.98 (d, 3H), 3.16 (d, 3H), 4.65 (d, 1H), 6.56 (d, 1H), 6.83 (d, 2H), 7.27 (d, 2H ), 7.47 (s, 1 H), 7.86 (s, 1 H).

Example 325

Methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4- c] pyridine- 2- carboxamide

The title compound (1.5 mg, 75%) was obtained as a white solid.

_{MS (DCI / NH 3) m} / e: 300 (M + H) +, 317 (M + NH 3) +;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 2.39 (s, 3H), 3.07 (d, J = 5.1Hz, 3H), 7.06 (d, J = 8.8Hz, 2H), 7.23 (d, J = 8.5Hz, 2H), 7.52 (d, J = 5.5 Hz, 1H), 8.18 (s, 1H), 9.02 (s, 1H).

Example 327

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide

Example 327A

Ethyl 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxylate

To a solution of 4-chlorophenol (1.08 g, 8.7 mmol) in anhydrous tetrahydrofuran (25 mL) was added a solution of potassium t-butoxide (1.0 M solution in THF, 8.7 mL, 8.7 mmol) . The reaction mixture was stirred and heated to 65 [deg.] C for 2 hours, then cooled to 0 [deg.] C and treated with the product of Example 17A (1.0 g, 5.7 mmol) in anhydrous tetrahydrofuran (10 mL) . The reaction was cooled to 0 <0> C and ethyl glycolate (1.07 mL, 11.4 mmol) and cesium carbonate (3.0 g, 9.2 mmol) were added and the mixture was heated to 65 <0> C for 3 h. The reaction was cooled and concentrated, then the residue was diluted with ethyl acetate (50 mL), washed with brine (3 x 50 mL) and dried over magnesium sulfate. Ethyl acetate was evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane gave the title compound (0.110 g, 6.1%) as a glassy residue.

_{MS (DCI / NH 3) m} / e: 318 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.35 (t, 2H, CH 2), 4.4 (q, 3H, CH 3), 7.2 (d, J = 9Hz, 2H), 7.5 (d, J = 9Hz , 2H), 8.09 (s, IH), 8.23 (s, IH), 9.25 (s, IH).

Example 327B

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxylic acid

To a solution of lithium hydroxide monohydrate (0.0113 g, 0.5 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added the product of example 327A (0.1 g, 0.3 mmol) and the mixture was heated to 50 & And heated. The mixture was cooled and formic acid was added until acidic. The mixture was extracted with ethyl acetate (50 mL) and the extract was washed with brine (2 x 20 mL), dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with 20% acetone-hexane gave the title compound as a glassy residue.

_{MS (DCI / NH 3) m} / e: 290 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.4 (br s, 1H), 7.2 (d, J = 9Hz, 2H), 7.5 (d, J = 9Hz, 2H), 8.09 (s, 1H), 8.23 (s, 1 H), 9.25 (s, 1 H).

Example 327C

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide

DMF (10 mL) Example 327B (0.15 g, 0.5 mmol) solution of 1-hydroxybenzotriazole hydrate (0.104 g, 0.66 mmol), NH 4 Cl (0.0948 g, 0.017 mmol) and 4-methylmorpholine in a (0.141 g, 0.14 mmol). The solution was cooled to 0 ℃ and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, and then, saturated NaHCO ₃ and then warmed to room temperature and stirred overnight treated with (0.115 g, 0.6 mmol) , Filtered, washed with brine (3 x 20 mL), dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with 20% acetone-hexane gave 0.030 g (21%) of the title compound as a glassy residue.

_{MS (DCI / NH 3) m} / e: 289 (M + H) +;

^{1 H NRM (300MHz, DMSO-} d 6) δ 7.18 (d, 2H), 7.29 (s, 1H), 7.5 (d, 2H), 7.82 (br s, 1H), 8.25 (s, 1H), 8.35 ( br s, 1 H), 8.95 (s, 1 H);

Example 328

4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide

To a solution of the product of example 327 (0.06 g, 0.2 mmol) in toluene (5 mL) was added Loewe's reagent (0.1 g, 0.2 mmol). The reaction was refluxed for 1 h, cooled, evaporated and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (3 x 15 mL), dried over magnesium sulphate and then evaporated. Purification by flash chromatography on silica gel eluting with 20% acetone-hexane gave 0.022 g (37%) of the title compound as a light yellow solid.

_{MS (DCI / NH 3) m} / e: 305 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.20 (d, 2H), 7.29 (s, 1H), 7.5 (d, 2H), 8.25 (s, 1H), 8.82 (s, 1H), 9.95 (b , 2H).

Example 329

4- (2-phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 329A

2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

To a stirred solution of diethylbenzylphosphonate (0.08 mL, 0.38 mmol) in dichloromethane (2 mL) at -78 ° C was added a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene (0.84 mL, 0.42 mmol) . After 45 minutes, a solution of the product of Example 237E (0.10 g, 0.38 mmol) in dichloromethane (3 mL) was slowly added and the reaction was stirred for 1 hour. The bath was removed and the reaction was stirred for 20 minutes. The reaction mixture was quenched with diluted aqueous solution of NaHCO _3. The aqueous phase was extracted with dichloromethane (2 x 25 mL) and ethyl acetate (2 x 25 mL). All organic phases were combined, dried over sodium sulfate and concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexanes as eluent. The mixture of the stereoisomers was dried in a drier to give a solid (0.07 g, 55%): MS (APCI) m / e: 338 (M ⁺

Example 329B

E-4- (2-phenylethenyl) thieno [2,3-c] pyridine-2- carboxamide

Embodiment was dissolved in the product Example 329A (0.07 g, 0.21 mmol) of 10% H ₂ SO ₄ / MeOH solution (10 mL) of. The solution was heated to reflux for 6 hours and then stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and basified with saturated NaHCO ₃ (50 mL). The aqueous phase was extracted with dichloromethane (2 x 50 mL) and the organic extracts were combined. The organic layer was washed with dilute brine solution (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a colored residue. The residue was dissolved in methanol (8 mL) and chloroform (1 mL). Ammonia gas was applied and the reaction was heated to &lt; RTI ID = 0.0 &gt; 35 C &lt; / RTI &gt; The reaction was concentrated and the residue was purified by HPLC over a gradient of 25% -65% acetonitrile / water + 0.1% TFA over 40 minutes. The product was neutralized with saturated NaHCO ₃ to give the title compound (27 mg, 46%) and incidentally the corresponding Z-isomer (14 mg, 24%).

mp 257-258 C;

_{MS (DCI / NH 3) m} / e: 281 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.34 (dd, J = 7.6, 7.2Hz, 1H), 7.46 (dd, J = 7.6, 7.2Hz, 2H), 7.55 (d, J = 16.5Hz, 1H ), 7.64 (d, J = 16.5 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.88 (br s, 1H), 8.37 (br s, 1 H), 9.18 (s, 1 H);

Elemental analysis for C ₁₆ H ₁₂ N ₂ OS 0.2 H ₂ O:

Calculated: C, 67.68; H, 4.40; N, 9.87.

Found: C, 67.47; H, 4.18; N, 9.84.

Example 330

4- (4-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide

Example 330A

4- (4-chlorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (160 mg, 53%) was prepared according to Example 95A using 4-chlorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 304 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO- d ₆ )? 3.92 (s, 3H), 7.69 (m, 4H), 8.30 (s, 1H), 8.60 (s, 1H), 9.42

Example 330B

4- (4-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide

Example 330A was performed as in Example 44 to give the title compound (60 mg, 60%).

MS (APCI) m / e: 289 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (400MHz, DMSO-} d 6) 7.63 (d, J = 8Hz, 2H), 7.69 (d, J = 8Hz, 2H), 7.77 (s, 1H), 8.19 (s, 1H), 8.41 (s , &Lt; / RTI &gt; 1H), 8.51 (s, 1H), 9.30 (s, 1H).

Example 331

4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide

Example 331A

4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxylate

The title compound (100 mg, 30%) was prepared according to Example 95A using 4- (trifluoromethyl) phenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 338 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO-d ₆ )? 3.92 (s, 3H), 7.81-7.93 (m, 4H), 8.01 (s, 1H), 8.67 (s, 1H), 9.46

Example 331B

4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide

The product of Example 331A was treated according to Example 44 to give the title compound (90 mg, 94%).

MS (APCI) m / e: 323 (M + H) &lt; ⁺ &gt;;

¹ H NMR (400 MHz, DMSO-d ₆ )? 7.85 (s, 1H), 7.90-7.97 (m, 4H), 8.25 (s, 1 H).

Example 332

4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 332A

4- (3-chlorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (130 mg, 43%) was prepared according to Example 95A using 3-chlorophenylboronic acid instead of 4-chlorophenylboronic acid.

MS (APCI) m / e: 304 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.92 (s, 3H), 7.59-7.68 (m, 3H), 7.75 (s, 1H), 8.02 (s, 1H), 8.62 (s, 1H), 9.43 (s, 1 H).

Example 332B

4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 332A was treated according to Example 44 to give the title compound (82 mg, 86%).

MS (APCI) m / e: 288 (M + H) &lt; ⁺ &gt;;

¹ H NMR (400 MHz, DMSO-d ₆ )? 7.58-7.62 (s, IH), 7.62 (s, (s, 1 H), 9.31 (s, 1 H).

Example 333

4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 333A

Thieno [2,3-c] pyridine-2-carboxylate

The title compound (148 mg, 42%) was prepared according to Example 95A using 4-borophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 305 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.91 (s, 3H), 7.61 (d, J = 7.5Hz, 2H), 7.77 (d, J = 7.5Hz, 2H), 8.02 (s, 1H), 8.57 (s, 1 H), 9.40 (s, 1 H).

Example 333B

4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 333A was processed according to Example 44 to give the title compound (118 mg, 88%).

MS (APCI) m / e: 333, 335 (1: 1) (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ7.63 (d, J = 7.5Hz, 2H), 7.79 (d, J = 7.5Hz, 2H), 7.84 (s, 1H), 8.22 (s, 1H) , 8.46 (s, 1 H), 9.33 (s, 1 H).

Example 334

4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 334A

Thieno [2,3-c] pyridine-2-carboxylate &lt; / RTI &gt;

The title compound (90 mg, 32%) was prepared according to Example 95A using 3-aminophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 285 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.92 (s, 3H), 5.34 (s, 2H), 6.67-6.76 (m, 2H), 6.81 (m, 1H), 7.22 (t, J = 7.5Hz , &Lt; / RTI &gt; 1H), 8.07 (s, 1H), 8.53 (s, 1H), 9.36 (s,

Example 334B

4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 334A was treated according to Example 44 to give the title compound (83 mg, 98%).

MS (APCI) m / e 270 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 5.30 (s, 2H), 6.67-6.82 (m, 3H), 7.22 (t, J = 7.5Hz, 1H), 7.79 (s, 1H), 8.23 (s , 8.43 (s, 1 H), 8.51 (s, 1 H), 9.25 (s, 1 H).

Example 335

4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 335A

4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (90 mg, 27%) was prepared according to Example 95A using 3,5-dichlorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 338 (M + H) &lt; ⁺ &gt;;

Example 335B

4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 335A was processed according to Example 44 to give the title compound (21 mg, 24%).

MS (APCI) m / e: 323 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.73 (d, J = 2.25Hz, 2H), 7.80 (m, 1H), 7.88 (s, 1H), 8.20 (s, 1H), 8.53 (s, 1H ), 8.56 (s, 1 H), 9.36 (s, 1 H).

Example 336

4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 336A

4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (100 mg, 30%) was prepared according to Example 95A using 2,4-dichlorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 338 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.38 (s, 3H), 7.59 (s, 1H), 7.61 (d, J = 2.25Hz, 1H), 7.70 (s, 1H), 7.86 (d, J = 2.25 Hz, 1 H), 8.49 (s, 1 H), 9.45 (s, 1 H).

Example 336B

4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 336A was treated according to Example 44 to provide the title compound.

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.60 (s, 1H), 7.64 (m, 1H), 7.81 (br s, 1H), 7.87 (s, 1H), 7.91 (m, 1H), 8.37 ( br s, 1 H), 8.45 (s, 1 H), 9.37 (s, 1 H).

Example 337

4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 337A

4- (3,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (130 mg, 39%) was prepared according to Example 95A using 3,4-dichlorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 338 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.94 (s, 3H), 7.67-7.76 (m, 1H), 7.85 (m, 1H), 7.79 (d, J = 2.25Hz, 1H), 8.06 (s , &Lt; / RTI &gt; 1H), 8.63 (s, 1H), 9.44 (s, 1H).

Example 337B

4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 337A was treated according to Example 44 to give the title compound.

MS (APCI) m / e: 323 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 7.65-7.68 (m, 1H), 7.84-7.87 (m, 2H), 8.96 (d, J = 2.25Hz, 1H), 8.21 (s, 1H), 8.47 (s, 1 H), 8.56 (s, 1 H), 9.35 (s, 1 H).

Example 338

4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide

Example 338A

4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (130 mg, 42%) was prepared according to Example 95A using 2,4-difluorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 306 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.90 (s, 3H), 7.26 (m, 1H), 7.45 (m, 1H), 7.63 (m, 1H), 7.81 (d, J = 3Hz, 1H) , 8.55 (s, 1 H), 9.44 (s, 1 H).

Example 338B

4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide

The product of Example 338A was treated according to Example 44 to provide the title compound.

MS (APCI) m / e: 291 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO-d ₆ )? 7.30 (m, 1H), 7.49 (m, 1H), 7.66 , &Lt; / RTI &gt; 1H), 8.47 (s, 1H), 9.34 (s, 1H).

Example 339

4- (4-fluorophenyl) thieno [2,3-c] pyridine-2- carboxamide

Example 339A

4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxylate

The title compound (100 mg, 35%) was prepared according to Example 95A using 4-fluorophenylboronic acid instead of 4- (trifluoromethyl) phenylboronic acid.

MS (APCI) m / e: 288 (M + H) &lt; ⁺ &gt;;

^{1 H NMR (300MHz, DMSO-} d 6) δ 3.89 (s, 3H), 7.38-7.48 (m, 2H), 7.55-7.64 (m, 1H), 7.78 (d, J = 3Hz, 1H), 8.57 ( s, 1 H), 9.44 (s, 1 H).

Example 339B

4- (4-fluorophenyl) thieno [2,3-c] pyridine-2- carboxamide

The product of Example 339A was treated according to Example 44 to provide the title compound.

MS (APCI) m / e: 273 (M + H) &lt; ⁺ &gt;;

¹ H NMR (300 MHz, DMSO- d ₆ )? 7.40-7.50 (m, 2H), 7.57-7.65 (m, 2H), 7.81 , 8.51 (s, 1 H), 9.36 (s, 1 H).

Example 340

Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

Example 340A

2,3,5-trichloro-4-formylpyridine

A solution of lithium diisopropylamide (7.3 mL, 1.5 M in cyclohexane, 11 mmol) in 10 mL of anhydrous THF was added at -78 <0> C under nitrogen to a solution of 2,3,5-trichloropyridine (2 g, 11 mmol) for 30 minutes and stirred for an additional 30 minutes and then slowly added methylformate (1.4 mL, 1.3 g, 22 mmol) in 14 mL of THF to the brown solution over 15 minutes, then slowly warmed to room temperature Lt; / RTI &gt; The resulting dark brown solution was poured onto ice and saturated NaHCO ₃ , extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. Flash chromatography on silica gel eluting with a brown oil eluting with 20-33% ethyl acetate / hexanes gave the title compound (1.7 g, 74%).

_{MS (APCI-NH 3) m} / e: 211 (M + H) +, 229 (M + NH 4) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 10.26 (s, 1H), 8.70 (s, 1H).

Example 340B

2-Chloro-3,5-bis (4-bromophenoxy) -4-pyridinecarboxaldehyde

A solution of 4-bromophenol (1.04 g, 6 mmol) in 4 mL of THF was treated via syringe with potassium t-butoxide (4 mL, 1 M in THF, 4 mmol) at 0 C and warmed to room temperature After stirring for 1 hour and cooling to 0 ° C, the product of Example 340 A (390 mg, 2 mmol) in 2 mL of THF was added and the reaction was heated to 60 ° C for 2 hours and then cooled to room temperature . The reaction mixture was diluted with ethyl acetate, washed with 1 N NaOH, dried over sodium sulfate and concentrated. The brown residue was flash chromatographed on silica gel eluting with 1-2% methanol / dichloromethane then 5-20% ethyl acetate / hexane to give the title compound (235 mg, 24%).

_{MS (APCI-NH 3) m} / e: 483 (MH) -, 517 (M + Cl) -;

^{1 H NMR (300MHz, DMSO-} d 6) δ 10.20 (s, 1H), 8.24 (s, 1H), 7.63 (m, 2H), 7.53 (m, 2H), 7.24 (m, 2H), 6.99 (m , 2H).

Example 340C

Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate

THF 2 mL of 340B product (227 mg, 0.47 mmol) methyl thioglycolate (50 uL, 0.52 mmol) and a solution of and powdered _{Cs 2 CO 3 (179 mg,} 0.55 mmol) to the process, and the mixture was stirred for 21 hours at room temperature , Heated to 60 &lt; 0 &gt; C for 15 minutes and then cooled to room temperature. The reaction was diluted with ethyl acetate and distilled water, washed with 1 M K ₂ CO ₃ and brine, dried over magnesium sulfate and concentrated. While the eluting the residue with 5-20% ethyl acetate / hexanes, flash chromatography, eluting with the following gradient of _{30-90% CH 3 CN / H 2} O + 0.1% TFA over silica gel to give the HPLC (C-18) The title compound (6 mg, 3%) was obtained.

_{MS (APCI-NH 3) m} / e: 400 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 9.20 (s, 1H), 7.78 (s, 1H), 7.51 (d, 2H), 6.93 (d, 2H), 3.90 (s, 3H).

Example 340D

Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide

A solution of 340C product (5 mg, 0.013 mmol) in 1 mL methanol and 1 mL dichloromethane was treated with 2 M ammonia in methanol (3 mL, 6 mmol) in a pressure tube and heated to 60 C for 4 h Then cooled to room temperature and concentrated. By eluting the residue with dichloromethane / methanol 95/5 filtered through a plug of silica, concentrated and then _{20-75% CH 3 CN / H 2} O + was purified by reverse phase HPLC, eluting with 0.1% TFA the title compound (4.2 mg, 84%).

_{MS (APCI-NH 3) m} / e: 385 (M + H) +;

^{1 H NMR (300MHz, DMSO-} d 6) δ 8.98 (s, 1H), 7.9 (s, 1H), 7.49 (d, 2H), 6.83 (d, 2H).

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the compounds. Variations and changes apparent to those skilled in the art will be within the scope and nature of the invention as defined in the appended claims.

Claims (23)

A compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof. Formula I In the formula (I) --- represents a single bond or a double bond, provided that when only one bond is a double bond, the adjacent bond is a single bond, E, F and G are (1) carbon, (2) nitrogen, and (3) N ⁺ -O ^- to be selected from, However, E, F and G are at least one of the nitrogen or N ⁺ -O ^-, and at least one of E, F and G are carbon atoms, and Y and Z are each (1) carbon, (2) nitrogen, (3) oxygen, and (4) S (O) _t (wherein t is an integer of 0 to 2) Provided that at least one of Y and Z is other than carbon, L _A is (1) covalent bonding, (2) -O-, (3) -S (O) _t- , (4) -NR ₆ - (Wherein R &lt; ₆ &gt; is (a) hydrogen, (b) C1 to C10 alkyl optionally substituted with one or two substituents each independently selected from (i) aryl, and (ii) C3 to C10 cycloalkyl, (c) alkanoyl having an alkyl moiety of C1 to C10, and (d) cycloalkyl of C3 to C10, (5) -C (W) -, wherein W is selected from (a) O and (b) S, and (6) alkenylene, X _A is (1) halo, (2) (a) (b) C3 to C10 cycloalkyl, (c) from -CO ₂ R ₇ (where, R ₇ is (i) hydrogen and (ii) aryl, and C3 to optionally alkyl-substituted C1 to C10 with one or two substituents selected from among cycloalkyl, each of C10 Selected), (d) -NR ₈ R ₉ wherein R ₈ and R ₉ are each (i) hydrogen, (ii) -OH, aryl, heterocycle, C3 to C10 cycloalkyl and -NR _A R _B , , R _A and R _B are each selected from the group consisting of hydrogen and C 1 to C 6 alkyl optionally substituted with one or two OH), (iii) a C 1 to C 6 alkyl optionally substituted with one or two substituents each independently selected from (Vi) a heterocycle, and (vii) an aryl, wherein (vi) and (vii) are independently selected from the group consisting of C1 to C10 alkyl, alkenyl having an alkyl moiety of C1 to C10, (iv) cycloalkyl of C3 to C10, (v) alkoxy, C6 alkyl &lt; / RTI &gt; and halo, each of which is optionally substituted with one or two substituents each independently selected from halogen, (e) -C (W) R ₁₀ wherein W is as defined above and R ₁₀ is (i) hydrogen, (ii) one or two substituents each selected from aryl and C3 to C10 cycloalkyl Optionally substituted C 1 to C 10 alkyl, (iii) -NR ₈ R ₉ and (iv) -OR ₇ ), (f) -OH, (g) aryl, and (h) from the heterocycle (here, (g) and (h) are (i) C1 to C20 _{alkyl, (ii) -NR 8 R 9} , (iii) alkoxy of C1 to C10, (iv) C1 to C10 (Vi) C1 to C3 perfluoroalkyl, (vii) C2 to C10 alkenyl, (viii) C1 to C10 alkoxy and -OH, each of which is optionally substituted with one or two optionally substituted C1 to C10 alkyl with a _{substituent, (ix) -CO 2 R 7} , (x) aryl, and (xi) optionally substituted with 1, 2, 3, 4, or 5 substituents respectively selected from -CHO C 1 -C 10 alkyl, which may be optionally substituted with one, two or three substituents each selected from halogen, (3) C3 to C10 cycloalkyl, (4) aryl, (5) Heterocycles [wherein, (4) and (5) (a) a C1 to C20 alkyl, (b) (i) from -OR ₁₁ {Here, R ₁₁ is hydrogen, -C (W) R ₁₂ (where, R ₁₂ is C1 to alkyl, cycloalkyl, aryl and heterocyclyl of C3 to C10 in the C10 And optionally substituted with one, two, three or four substituents each independently selected from C1-C6 alkyl and-OH optionally substituted with one or two OH, (ii) alkoxy (Iii) spiroalkyl of C3 to C10, and (iv) halo, each of which is optionally substituted with one or two substituents each independently selected from lower alkyl, lower alkoxy and alkoxyalkoxy, Gt; C1-C10 &lt; / RTI &gt; alkyl, (c) a C1 to C10 alkoxy optionally substituted with one or two substituents each independently selected from (i) alkoxy, and (ii) alkoxyalkoxy, (d) C1 to C10 thioalkoxy, (e) halo, (f) perfluoroalkyl of C1 to C3, (g) (i) -C ( W) R 10 , and (ii) -C (W) R 12 of any substituted C2 to C10 with one or two substituents each selected from alkenylene, (h) -CO ₂ R _7, (i) -NR &lt; ₈ &gt; R &lt; ₉ & (j) aryl, (k) -C (W) R ₁₂ , (1) -CHO, (m) -C (O) NR &lt; ₈ &gt; R &lt; ₉ & (n) -CN, (o) a heterocycle optionally substituted with one or two substituents each independently selected from (i) C1 to C10 alkyl and (ii) C1 to C3 perfluoroalkyl, (p) -C (W) R 10, (q) ethylene dioxy, and 2, 3, 4 or 5 substituents each independently selected from (r) -OCF ₃ , (6) -OR ₇ , (7) hydrogen and (8) -NR &lt; ₈ &gt; R &lt; _{9 &} gt ;; L _B is (1) covalent bonding, (2) -O-, (3) -S (O) _t- , (4) -NR ₆ -, (5) -C (W) - and _{(6) -C (= NR 13} ) - [ where, R ₁₃ is (a) hydrogen, (b) -NO _2, (c) -CN, and (d) -OR ₁₄ wherein R ₁₄ is selected from the group consisting of (i) hydrogen, (ii) aryl and (iii) aryl and -C (O) R ₁₅ wherein R ₁₅ is hydrogen, -OH, alkoxy and NR _{&Lt; /} RTI &gt; R &lt; _B &gt;), each of which is optionally substituted with one or two substituents each independently selected from C1-C10 alkyl; X _B is (1) hydrogen, _{(2) (a) -CO 2} R 7, (b) -NR ₈ R ₉ , (c) -C (W) NR 8 R 9, (d) heterocycle, (e) (i) C1 to C10 alkyl, (ii) -NO _2, and (iii) aryl optionally substituted with one or two substituents each selected from among -NR _A R _B, (f) -OR ₁₆ wherein R ₁₆ is selected from (i) hydrogen and (ii) -C (W) NR _A R _B ; and (g) -NR _A C (W) NR &lt; ₈ &gt; R &lt; ₉ & (3) (a) -C (W) NR _A R _B , (b) -CO ₂ R _7, and (c) C2-C6 alkenyl optionally substituted with one or two substituents each independently selected from a heterocycle, (4) -NR ₁₇ R ₁₈ [where, R ₁₇ and R ₁₈ are each (a) hydrogen, (b) (i) -OH, (ii) -C (W) R 10, (iii) -NR A C (= NR 13) NR B R 19 ( Here, R _A, R _B and R ₁₃ are described above (Iv) heterocycle, (v) aryl, (vi) halo, and (vii) -NR _A R _B , wherein R ₁₉ is selected from hydrogen, C 1 to C 10 alkyl and -NO ₂ C1 to C10 alkyl optionally substituted with one, two or three substituents selected from &lt; RTI ID = 0.0 &gt; (c) alkoxy, (d) optionally substituted with 1, 2 or 3 substituents each independently selected from (i) halo, (ii) C1 to C10 alkyl, (iii) C1 to C10 alkoxy, (iv) C1 to C3 perfluoroalkyl Substituted aryl, (e) heterocycle, (f) -NR _A R _B , (g) -C (O) R ₂₀ wherein R ₂₀ is selected from (i) hydrogen, (ii) C 1 to C 10 alkyl, (iii) -OR ₁₂ and (iv) -NR _A R _B ) , (h) C3 to C10 cycloalkyl and (i) -OH, (5) alkoxy, (6) -OH, _{(7) -NR A C (=} NR 13) NR B R 19, (8) -C (W) NR 8 R 19, (9) aryl, (10) Heterocycles [wherein, (9) and (10) (a) halo, (b) (i) halo, (ii) C1 to C10 alkoxy, (iii) -NR _A R _B , (iv) -OH, (v) -CO ₂ R ₇ , _A R _B, and (vii) aryl, each of which is optionally substituted with 1, 2, or 3 substituents each selected from C1- (c) -NR _A R _B , (d) C1 to C10 alkoxy, (e) C1 to C10 thioalkoxy, (f) perfluoroalkyl of C1 to C3, (g) -OH, (h) -C (W) NR 8 R 9, (i) -CO ₂ R _7, (j) -NR _A C (W) OR ₂₁ wherein R _A is as defined above and R ₂₁ is (i) optionally substituted with one or two substituents selected from aryl and C 3 to C 10 cycloalkyl C1 to C10 alkyl, (ii) aryl and (iii) C3 to C10 cycloalkyl), (k) C2 to C10 alkenyl, (l) heterocycle, (m) aryl, and (n) -NO _2] , or a pharmaceutically acceptable salt thereof, (11) -CN, (12) -CHO, (13) halo, and (14) -B (OR _A ) (OR _B ) With the proviso that when R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are hydrogen or absent, -L _A - is a covalent bond and -L _B - is a covalent bond, one of X _A and X _B is Other than hydrogen, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are absent, (1) hydrogen, (2) (a) -OC (O) R ₂₂ wherein R ₂₂ is selected from (i) alkyl, (ii) alkoxy and (iii) NR _A R _B ) (b) alkoxy, (c) -OH, (d) -NR _A R _B , (e) heterocycle, and (f) C1 to C6 alkyl optionally substituted with one or two substituents each independently selected from aryl, (3) -CO ₂ R _7, (4) -C (O) NR _A R _B , (5) -SR &lt; ₂₃ &gt; wherein R &lt; _{23 &} (a) hydrogen, (b) C1 to C6 alkyl, (c) (i) aryl optionally substituted with one or two substituents selected from C1 to C6 alkyl and (ii) halo, (6) -NR _A R _B , (7) halo, (8) alkoxy, (9) perfluoroalkyl of C1 to C3, (10) -OH and (11) heterocycle, Provided that when E, F and Y are carbon, G is nitrogen, Z is sulfur, -L _A - is a covalent bond, and X _A is halo, then R ₁ is other than -CO ₂ R ₇ . The method of claim 1, wherein, F and Y are carbon, E and G are each N or N ⁺ -O ^-, and a, Z is S (O) _t compound. 3. The method of claim 2, Methyl 2 - [(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate, 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(2-methylethyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(phenylmethyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3-d] pyrimidine, Ethyl 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine- 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidin- Thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine, Thiadiazol-2-yl) thio] -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, and From the group consisting of 4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-ethyl- 2- (phenylmethyl) thieno [2,3- d] pyrimidine &Lt; / RTI &gt; According to claim 1, F, and Z is carbon, E and G are each N or N ⁺ -O ^- and a, Y is S (O) _t compound. 5. The method of claim 4, 7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine, Methyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [3,2-d] pyrimidine, Methyl-4 - [[5- (methylthio) -1,3,4-thiadiazol-2-yl] thio] thieno [3,2-d] pyrimidine, 4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -7-methylthieno [3,2-d] pyrimidine, 7-methyl-N - [(4- (methylthio) phenyl] thieno [3,2- d] pyrimidin- 7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine-6-carboxamide. The method of claim 1, wherein, E, G and Y are carbon, F is nitrogen or N ⁺ -O ^-, and the compound which Z is S (O) _t. The method according to claim 6, Methyl 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2- carboxamide, 4 - [(4-chlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, Methoxy-N-methyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, Methoxy-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, (4-chlorophenyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- (phenylmethyl) oxime, 2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid, &lt; 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, oxime, 2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide, 2- [ (E) -3 - [(4-methylphenyl) thio] thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] ethanone, 2- Benzoyl-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine, 2-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine, 2,3-c] pyridin-2-yl] ethanone, oxime, thiophene, (2,3-dihydroxypropyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxylic acid, hydrazide, N ² -4 - [(4- methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] carbonyl] -N ⁶ - [(nitro) methyl-imino] -L- lysine, methyl ester, (Aminoiminomethyl) -4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine, Methyl 4 - [(2-methoxy-2-oxoethyl) thio] thieno [2,3- c] pyridine- 4 - [(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-bromophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide, 4 - [[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2-methyl-3-furanyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [[(4-chlorophenyl) methyl] thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,4-dichlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-methoxyphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl acetate salt, 4-methylphenylsulfonyl chloride, 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 2- carboxamide, Methyl 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate, 4 - [(4-trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- [4- (1-methylethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (2-bromo-4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-ethynylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,2-dihydroxyethyl) 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [2- (2,3-dihydroxypropyl) Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 1-oxide, 4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Ethyl 3 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate, 4-phenoxy-ethyno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4-methoxymethyl) 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, Thieno [2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate, Thieno [2,3-c] pyridine-2-methanol, 4- (4-chlorophenoxy) (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4-bromothieno [2,3-c] pyridine-2-carboxamide, Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylate, 4-chlorothieno [2,3-c] pyridine-2-carboxamide, 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxylate, Methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine- 2- carboxamide, 4-phenylthieno [2,3-c] pyridine-2-carboxamide, Methyl 4-phenylthieno [2,3-c] pyridine-2-carboxylate, 4 - ([1,1'-biphenyl] -4-ylthio) thieno [2,3-c] pyridine- 2- carboxamide, (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2- carboxamide, Ethyl 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate, 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4- yl] oxy] benzoic acid, 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxalate, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide, N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) N, N-diethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridin-2-yl] carbonyl] pyrrolidine, Thieno [2,3-c] pyridin-2-yl] carbonyl] piperidine, Thieno [2,3-c] pyridin-2-yl] carbonyl] morpholine, Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine, Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine, 2,3-c] pyridin-2-yl] carbonyl] -4- (phenylmethyl) -piperazine, 2,3-c] pyridin-2-yl] carbonyl] -4- (2-pyridinyl) -piperazine, (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide, (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -N- Lt; / RTI &gt; 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thieno [ (4-chlorophenoxy) -N- [l, l-bis (hydroxymethyl) ethyl] thieno [2,3- c] pyridine- 2- carboxamide, (D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl) thieno [2,3- c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2- carboxamide, Thieno [2,3-c] pyridine-2-carboxylic acid, N-oxide, Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, N- (4-chlorophenoxy) -2- (2-methoxyphenyl) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylate, Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine- Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboethioamide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2- carboxamide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl) 2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3- dihydroxypropyl) (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide, (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3- c] pyridine- 2- carboxamide, (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- 2,3-c] pyridin-2-yl] carbonyl} amino) acetic acid, (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno [2,3- c] pyridine- 2- carboxamide, (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine- 2- carboxamide, (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid, Thieno [2,3-c] pyridine-2-carboxamide (100 mg) was obtained in the same manner as in Example 1, , (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid, (2R) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid, 2,3-c] pyridine-2-carboxamide, 2,3-dimethyl-lH- (2S) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid, 2,3-c] pyridine-2-carboxamide, 2,3-c] pyridine-2-carboxamide, Thieno [2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide, 2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide, (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide, Methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,3,4-Trifluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, 4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, Methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (hydroxymethyl) Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (methoxymethyl) 4- {4 - [(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-c] pyridine- 2- carboxamide, Methyl} phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [ Ethoxy] methyl} phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4 - {[ Methyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4 - {[2- (2-methoxyethoxy) ethoxy] Pyridin-2-yloxymethyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide, Methyl-4- {4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3- c] pyridine- 2,3-c] pyridin-4-yl] oxy} benzyl 2-furoate, 4 - {[2- (aminocarbonyl) thieno [ 2-yl] oxy} methyl) phenoxy) -2,3-dihydroxy-6- (hydroxymethyl) ] -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Carboxyphenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4-fluorophenyl) Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- ({[2- (4-morpholinyl) ethyl] Phenoxy} thieno [2,3-c] pyridine-2-carboxamide, 4- {4 - [(E) -3- (4-morpholinyl) 3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine Carboxamide, Methyl-4- [4 - ((E) -3 - {[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3 -c] pyridine-2-carboxamide, Thieno [2,3-c] pyridin-2 (1 H) -quinolin-2- - carboxamide, Amino] -3-oxo-1-propenyl} phenoxy) -N-methylthieno [2,3-c] quinolin-2- ] Pyridine-2-carboxamide, Amino] -3-oxo-1-propenyl) phenoxy] -N-methyl thieno [3, 2,3-c] pyridine-2-carboxamide, Amino] ethyl} -3-oxo-1-propenyl] phenoxy} -N-methylthieno [ [2,3-c] pyridine-2-carboxamide, Amino] -3-oxo-1-propenyl] phenoxy} thieno [2,3-b] -c] pyridine-2-carboxamide, [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H- 2-yl] phenoxy} thieno [2,3-c] pyridine-2-carbaldehyde Vox amide, Methyl-thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4,5-dihydro-1H-imidazol- Methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4 - ([1,1'-biphenyl] -4-yloxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, Methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxaldehyde amides, Methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 2,3-c] pyridin-2-yl} - (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] thieno [ 1,3,4-oxadiazole-2-amine, Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,1-difluoro-2- 2,3-c] pyridine-1-carboxylic acid ethyl ester was used in place of 4- (4- {2- [2- (2- ethoxyethoxy) ethoxy] -1,1- difluoroethyl} phenoxy) 2-carboxamide, 2,3-c] pyridine-1-carboxylic acid ethyl ester, which was prepared in accordance with the general method of example 1 from 2- 6-Ium, Methyl] carbonyl] thieno [2,3-c] pyridine prepared in Step 1 was added to a solution of 4- (4-bromophenoxy) -6 - {[(2,2- dimethylpropanoyl) oxy] 6-ium, 2,3-c] pyridin-6-ynyl) -2, 3-dihydro- 4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide, 4 - [(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, N ⁴ - (4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide, Thieno [2,3-c] pyridin-2-yl] methanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime, Thieno [2,3-c] pyridine-2-carbaldehyde O-Methyloxime, 2,3-c] pyridin-2-yl] -1-ethanone O-Methyloxime, 2,3-c] pyridin-2-yl] -1-ethanone O-Methyloxime, L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] Thiophene [2,3-c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile, 2,3-c] pyridine-2-carboximidamide, 4- (4-chlorophenoxy) -N'- C] pyridin-2-carboximidamide, 4- (4-chlorophenoxy) -N'-cyanothieno [2,3- c] 2,3-c] pyridin-2-yl] (2-nitrophenyl) methanol, Thieno [2,3-c] pyridin-2-yl] (2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] (3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methyl carbamate, 2,3-c] pyridin-2-yl] methyl} urea, N - {[4- (4-chlorophenoxy) (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin- (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] -2,3-dihydroxy-N-methylpropanamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylformamide, 2,3-c] pyridin-2-yl] urea, N- [4- (4-chlorophenoxy) Thiophene [2,3-c] pyridin-2-yl] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-sulfonamide, Thieno [2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl) (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2-sulfonamide, Thieno [2,3-c] pyridin-2-yl] phenol, Thieno [2,3-c] pyridin-2-yl] aniline, Thieno [2,3-c] pyridin-2-yl] aniline, Thieno [2,3-c] pyridine, 2,4-dihydro-2H-pyridin- Thieno [2,3-c] pyridin-2-yl] -3-pyridineamine, Thieno [2,3-c] pyridin-2-yl] -2-pyridinamine, Thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazole-2-amine, Thiophene [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-2-ylamine, 2,3-c] pyridin-2-yl] -4H-1,2,4-triazole-3-amine, 2,3-c] pyridin-2-yl] -1,3,4-thiadiazole-2-amine, 2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c] 2,3-c] pyridin-2-yl} -1,3,4-oxadiazole-2-amine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [ 2-yl] thieno [2,3-c] pyridine, which was obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) 2,3-c] pyridine, 2,3-dicarboxylic acid ethyl ester, 2- 2,3- c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazole-3-amine, 3-yl] thieno [2,3-c] pyridine, which is obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) Thiophene [2,3-c] pyridin-2-yl] -1,2,4-oxadiazole-3-amine, 2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazole-2-amine, 2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c] 2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, 2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine, 2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, Methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole- 2,3- c] pyridin-2-yl] -1,3-thiazole-4-carboxamide, 2- [4- (4-chlorophenoxy) 2,3-c] pyridin-2-yl] -1,3-thiazol-4-ylcarbamate, Thieno [4,3-c] pyridin-2-yl] -1,3-thiazol-4- 4-chloro-3-methylthieno [2,3-c] pyridine-2- carboxamide, Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide, N- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine- 2- carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, 7- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, 2,3-c] pyridine-3-carboxylate, 3-tert-butyl 2- (aminocarbonyl) -4- (4- chlorophenoxy) N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamide, 7- chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 7-chloro-4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, 7-bromo-4- (4-chlorophenoxy) -N-methylthieno [2,3, - C] pyridine- 2- carboxamide, 4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) -7-chloro-N-methylthieno [2,3-c] pyridine- 2- carboxamide, 7- chloro-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -7-methoxy-ethyno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [2,3- c] pyridine- 2- carboxamide, 4 - [(E) -2-phenylethenyl] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide, and (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-2-carboxamide. The method of claim 1, wherein, E, F and Y are carbon, G is nitrogen or N ⁺ -O ^-, and the compound which Z is S (O) _t. 9. The compound according to claim 8, which is 4 - [(4-methylphenyl) thio] thieno [2,3- b] 4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- 2- carboxamide, 4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine- Ethyl 4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3- b] pyridine-5- Methyl 6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine-2-carboxylate, and Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate. The method of claim 1, wherein, E, F and Z is carbon, G is nitrogen or N ⁺ -O ^-, and the compound Y is S (O) _t. The compound according to claim 10, which is 7 - [(4-methylphenyl) thio] thieno [3,2-b] pyridine-2- carboxamide. According to claim 1, F, G and Y are carbon, E is nitrogen or N ⁺ -O ^-, and the compound which Z is S (O) _t. The compound according to claim 12, which is 2-bromo-4- [(4-methylphenyl) thio] thieno [3,2- c] 4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine- 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2- carboxamide, and (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonitrile. According to claim 1, and E and G are carbon, F and Y are each nitrogen or N ⁺ -O ^-, and the compound which Z is S (O) _t. 15. The method of claim 14, Methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine- 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-2- carboxamide, and The compound is selected from the group consisting of N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4- c] pyridine-2- carboxamide. According to claim 1, and E and G are carbon, F is nitrogen or N ⁺ -O ^- and, Y and Z is nitrogen a compound. The method of claim 1, wherein, G and Y are carbon, E and F are each N or N ⁺ -O ^-, and the compound which Z is S (O) _t. The method of claim 1, wherein, E, G and Z is carbon, F is nitrogen or N ⁺ -O ^-, and the compound Y is S (O) _t. According to claim 1, and E and G are carbon, F is nitrogen or N ⁺ -O ^-, and Y is nitrogen, Z is oxygen compounds. The method of claim 1, wherein, E, G and Y are carbon, F is nitrogen or N ⁺ -O ^-, and Z is an O compound. 21. The compound according to claim 20, which is 4- (4-chlorophenoxy) furo [2,3-c] pyridine- 2- carboxamide and 4- (4-chlorophenoxy) -2-carbothioamide. &Lt; / RTI &gt; Methyl 2 - [(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate, 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(2-methylethyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(phenylmethyl) thio] thieno [2,3-d] pyrimidine, 6-ethyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3-d] pyrimidine, Ethyl 6-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3-d] pyrimidine- 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidin- Thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine, Thiadiazol-2-yl) thio] -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, Thiadiazol-2-yl) thio] -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine, Methyl-4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [3,2-d] pyrimidine, Methyl-4 - [[5- (methylthio) -1,3,4-thiadiazol-2-yl] thio] thieno [3,2-d] pyrimidine, 4 - [(5-amino-1,3,4-thiadiazol-2-yl) thio] -7-methylthieno [3,2-d] pyrimidine, 7-methyl-N - [(4- (methylthio) phenyl] thieno [3,2- d] pyrimidin- 7-methyl-4 - [(4-methylphenyl) thio] thieno [3,2-d] pyrimidine- Methyl 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2- carboxamide, 4 - [(4-chlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, Methoxy-N-methyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, Methoxy-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, (4-chlorophenyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- (phenylmethyl) oxime, 2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid, &lt; 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, O- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxaldehyde, oxime, 2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide, 2- [ (E) -3 - [(4-methylphenyl) thio] thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] ethanone, 2- Benzoyl-4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine, 2-ethyl-4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine, 2,3-c] pyridin-2-yl] ethanone, oxime, thiophene, (2,3-dihydroxypropyl) -4 - [(4-methylphenyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine-2- carboxylic acid, hydrazide, N ² -4 - [(4- methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] carbonyl] -N ⁶ - [(nitro) methyl-imino] -L- lysine, methyl ester, (Aminoiminomethyl) -4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine, Methyl 4 - [(2-methoxy-2-oxoethyl) thio] thieno [2,3- c] pyridine- 4 - [(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-bromophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide, 4 - [[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3-methylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2,4-dimethylphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(2-methyl-3-furanyl) thio] thieno [2,3- c] pyridine- 2- carboxamide, 4 - [[(4-chlorophenyl) methyl] thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(3,4-dichlorophenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4 - [(4-methoxyphenyl) thio] thieno [2,3-c] pyridine- 2- carboxamide, 4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl acetate salt, 4-methylphenylsulfonyl chloride, 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 2- carboxamide, Methyl 4 - [(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine- 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate, 4 - [(4-trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- [4- (1-methylethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (2-bromo-4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-ethynylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,2-dihydroxyethyl) 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [2- (2,3-dihydroxypropyl) Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 1-oxide, 4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2- carboxamide, Ethyl 3 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate, 4-phenoxy-ethyno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4-methoxymethyl) 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, Thieno [2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate, Thieno [2,3-c] pyridine-2-methanol, 4- (4-chlorophenoxy) (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4-bromothieno [2,3-c] pyridine-2-carboxamide, Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylate, 4-chlorothieno [2,3-c] pyridine-2-carboxamide, 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxylate, Methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine- 2- carboxamide, 4-phenylthieno [2,3-c] pyridine-2-carboxamide, Methyl 4-phenylthieno [2,3-c] pyridine-2-carboxylate, 4 - ([1,1'-biphenyl] -4-ylthio) thieno [2,3-c] pyridine- 2- carboxamide, (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2- carboxamide, Ethyl 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl] oxy] benzoate, 4 - [[2- (aminocarbonyl) thieno [2,3-c] pyridin-4- yl] oxy] benzoic acid, 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-carboxalate, 4 - [(4-methylphenyl) thio] thieno [2,3-c] pyridine- 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide, N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) N, N-diethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridin-2-yl] carbonyl] pyrrolidine, Thieno [2,3-c] pyridin-2-yl] carbonyl] piperidine, Thieno [2,3-c] pyridin-2-yl] carbonyl] morpholine, Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine, Thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine, 2,3-c] pyridin-2-yl] carbonyl] -4- (phenylmethyl) -piperazine, 2,3-c] pyridin-2-yl] carbonyl] -4- (2-pyridinyl) -piperazine, (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide, (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -N- Lt; / RTI &gt; 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thieno [ (4-chlorophenoxy) -N- [l, l-bis (hydroxymethyl) ethyl] thieno [2,3- c] pyridine- 2- carboxamide, (D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl) thieno [2,3- c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2- carboxamide, Thieno [2,3-c] pyridine-2-carboxylic acid, N-oxide, Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, N- (4-chlorophenoxy) -2- (2-methoxyphenyl) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, Methyl 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2-carboxylate, Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine- Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid, 4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine, 4 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- 2- carboxamide, 4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine- Ethyl 4 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3- b] pyridine-5- 7 - [(4-methylphenyl) thio] thieno [3,2-b] pyridine- 2- carboxamide, Methyl 6 - [(4-methylphenyl) thio] thieno [2,3-b] pyridine- Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate, 2-bromo-4 - [(4-methylphenyl) thio] thieno [3,2- c] pyridine, 4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine- 2- carboxamide, 4 - [(4-methylphenyl) thio] thieno [3,2-c] pyridine- 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2- carboxamide, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonitrile, 7- (4-methylphenoxy) [l, 3] thiazolo [5,4- c] pyridine- 2- carboxamide, Methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboethioamide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2- carboxamide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl) 2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3- dihydroxypropyl) (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2- carboxamide, (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3- c] pyridine- 2- carboxamide, (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide, 2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- 2,3-c] pyridin-2-yl] carbonyl} amino) acetic acid, (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno [2,3- c] pyridine- 2- carboxamide, (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3- c] pyridine- 2- carboxamide, (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid, Thieno [2,3-c] pyridine-2-carboxamide (100 mg) was obtained in the same manner as in Example 1, , (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid, (2R) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid, 2,3-c] pyridine-2-carboxamide, 2,3-dimethyl-lH- (2S) -2 - {[4- (4-chlorophenoxy) thieno [2,3- c] pyridin- 2- yl] carbonyl} amino) propanoic acid, 2,3-c] pyridine-2-carboxamide, 2,3-c] pyridine-2-carboxamide, Thieno [2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide, 2,3-c] pyridin-2-ylmethyl) -2- (4-fluorophenyl) Carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide, (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide, Methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,3,4-Trifluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, 4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, Methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (hydroxymethyl) Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (methoxymethyl) 4- {4 - [(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-c] pyridine- 2- carboxamide, Methyl} phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [ Ethoxy] methyl} phenoxy) thieno [2,3-c] pyridine-2-carboxamide, 4- (4 - {[ Methyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [ Pyridin-2-yloxymethyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide, Methyl-4- {4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3- c] pyridine- 2,3-c] pyridin-4-yl] oxy} benzyl 2-furoate, 4 - {[2- (aminocarbonyl) thieno [ 2-yl] oxy} methyl) phenoxy) -2,3-dihydroxy-6- (hydroxymethyl) ] -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Carboxyphenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4-fluorophenyl) Amino] carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- ({[2- (4-morpholinyl) ethyl] Phenoxy} thieno [2,3-c] pyridine-2-carboxamide, 4- {4 - [(E) -3- (4-morpholinyl) 3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine Carboxamide, Methyl-4- [4 - ((E) -3 - {[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3 -c] pyridine-2-carboxamide, Thieno [2,3-c] pyridin-2 (1 H) -quinolin-2- - carboxamide, Amino] -3-oxo-1-propenyl} phenoxy) -N-methylthieno [2,3-c] quinolin-2- ] Pyridine-2-carboxamide, Amino] -3-oxo-1-propenyl) phenoxy] -N-methyl thieno [3, 2,3-c] pyridine-2-carboxamide, Amino] ethyl} -3-oxo-1-propenyl] phenoxy} -N-methylthieno [ [2,3-c] pyridine-2-carboxamide, Amino] -3-oxo-1-propenyl] phenoxy} thieno [2,3-b] -c] pyridine-2-carboxamide, [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,3- c] pyridine- 2- carboxamide, Thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H- 2-yl] phenoxy} thieno [2,3-c] pyridine-2-carbaldehyde Vox amide, Methyl-thieno [2,3-c] pyridine-2-carboxamide, 4- [4- (4,5-dihydro-1H-imidazol- Methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4 - ([1,1'-biphenyl] -4-yloxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, Methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Phenoxy} -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] Methyl] phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxaldehyde amides, Methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 2,3-c] pyridin-2-yl} - (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] thieno [ 1,3,4-oxadiazole-2-amine, Phenoxy] -N- methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1,1-difluoro-2- 2,3-c] pyridine-1-carboxylic acid ethyl ester was used in place of 4- (4- {2- [2- (2- ethoxyethoxy) ethoxy] -1,1- difluoroethyl} phenoxy) 2-carboxamide, 2,3-c] pyridine-1-carboxylic acid ethyl ester, which was prepared in accordance with the general method of example 1 from 2- 6-Ium, Methyl] carbonyl] thieno [2,3-c] pyridine prepared in Step 1 was added to a solution of 4- (4-bromophenoxy) -6 - {[(2,2- dimethylpropanoyl) oxy] 6-ium, 2,3-c] pyridin-6-ynyl) -2, 3-dihydro- 4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide, 4 - [(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, N ⁴ - (4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide, Thieno [2,3-c] pyridin-2-yl] methanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime, Thieno [2,3-c] pyridine-2-carbaldehyde O-Methyloxime, 2,3-c] pyridin-2-yl] -1-ethanone O-Methyloxime, L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] Thiophene [2,3-c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile, 2,3-c] pyridine-2-carboximidamide, 4- (4-chlorophenoxy) -N'- C] pyridin-2-carboximidamide, 4- (4-chlorophenoxy) -N'-cyanothieno [2,3- c] 2,3-c] pyridin-2-yl] (2-nitrophenyl) methanol, Thieno [2,3-c] pyridin-2-yl] (2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] (3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c] pyridin- 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, L- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] L- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methyl carbamate, 2,3-c] pyridin-2-yl] methyl} urea, N - {[4- (4-chlorophenoxy) (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin- (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin- 2,3-c] pyridin-2-yl] -2,3-dihydroxy-N-methylpropanamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylformamide, 2,3-c] pyridin-2-yl] urea, N- [4- (4-chlorophenoxy) Thiophene [2,3-c] pyridin-2-yl] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2-sulfonamide, Thieno [2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2,3- dihydroxypropyl) (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2-sulfonamide, Thieno [2,3-c] pyridin-2-yl] phenol, Thieno [2,3-c] pyridin-2-yl] aniline, Thieno [2,3-c] pyridin-2-yl] aniline, Thieno [2,3-c] pyridine, 2,4-dihydro-2H-pyridin- Thieno [2,3-c] pyridin-2-yl] -3-pyridineamine, Thieno [2,3-c] pyridin-2-yl] -2-pyridinamine, Thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazole-2-amine, Thiophene [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-2-ylamine, 2,3-c] pyridin-2-yl] -4H-1,2,4-triazole-3-amine, 2,3-c] pyridin-2-yl] -1,3,4-thiadiazole-2-amine, 2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c] 2,3-c] pyridin-2-yl} -1,3,4-oxadiazole-2-amine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [ 2-yl] thieno [2,3-c] pyridine, which was obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) 2,3-c] pyridine, 2,3-dicarboxylic acid ethyl ester, 2- 2,3- c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazole-3-amine, 3-yl] thieno [2,3-c] pyridine, which is obtained in the same manner as in Example 1, except for using 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) Thiophene [2,3-c] pyridin-2-yl] -1,2,4-oxadiazole-3-amine, 2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazole-2-amine, 2,3-c] pyridine, 2,4-dihydro-4H-pyrrolo [2,3-c] 2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, 2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine, 2-yl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, Methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole- 2,3- c] pyridin-2-yl] -1,3-thiazole-4-carboxamide, 2- [4- (4-chlorophenoxy) 2,3-c] pyridin-2-yl] -1,3-thiazol-4-ylcarbamate, Thieno [4,3-c] pyridin-2-yl] -1,3-thiazol-4- 4-chloro-3-methylthieno [2,3-c] pyridine-2- carboxamide, Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide, N- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine- 2- carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, 7- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2- carboxamide, 2,3-c] pyridine-3-carboxylate, 3-tert-butyl 2- (aminocarbonyl) -4- (4- chlorophenoxy) N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamide, 7- chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2- carboxamide, 7-chloro-4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, 7- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenoxy) -7-chloro-N-methylthieno [2,3-c] pyridine- 2- carboxamide, 7- chloro-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, Methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2- carboxamide, (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -7-methoxy-ethyno [2,3-c] pyridine- 2- carboxamide, 7- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3-c] pyridine- 2- carboxamide, Methyl-7- (4-chlorophenoxy) -N-methyl- (7-methylamino) thieno [2,3- c] pyridine- 2- carboxamide N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4- c] pyridine- 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide, 4 - [(E) -2-phenylethenyl] thieno [2,3-c] pyridine- 2- carboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2- carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2- carboxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide, and (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-2-carboxamide. A method of treating reperfusion injury and inflammatory disease, comprising administering an effective amount of a compound of claim 1.