JP2002517396A - Anti-inflammatory compounds that inhibit cell adhesion - Google Patents

Abstract

(57) SUMMARY Compounds having formula (I) are useful for treating inflammation. Also disclosed are drug compositions containing the compounds of formula (I) and methods for inhibiting / treating inflammatory diseases in mammals. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to compounds useful for treating inflammatory diseases, drug compositions containing the compounds and methods of inhibiting inflammation in mammals.

BACKGROUND OF THE INVENTION Inflammation results from a multi-step event involving vasodilation with increased vascular permeability and exudation of body fluids and plasma proteins. This destruction of the vascular prototype proceeds with or occurs simultaneously with the infiltration of inflammatory cells. Inflammatory mediators that occur at the site of the initial lesion function to recruit inflammatory cells to the site of injury. These mediators (IL
-8, MCP-1, MIP-1 and RANTES, chemokinesis such as complement fragments and lipid mediators) have leukocyte chemotactic activity and attract inflammatory cells towards inflamed lesions . These chemotactic mediators that localize circulating leukocytes to sites of inflammation require cells to cross the vascular endothelium at precise locations. This leukocyte recruitment involves a process called cell adhesion.

[0003] Cell adhesion is achieved by a series of coordinately regulated steps that cause leukocytes to first adhere to specific areas of the vascular endothelium and then travel across the endothelial barrier toward inflamed tissue. Occur (Springer, TA, 1994, "Communications Signals for Lymphocyte Recirculation and Leukocyte Migration: A Multistep Paradigm (Traff
ic Signals for Lymphocyte Recirculator
ion and Leukocyte Emigration: The Mu
ltest Step Paradigm) ", Cell, Vol. 76, No. 301-30.
Page 4; Lawrence, M .; B. And Springer, T .; A. , 1991
"Rotation of leukocytes to selectin at physiological flow rates: discrimination from adhesion by integrins and prerequisites therefor (Leukocytes' Roll on
a Selectin at Physiological Flow Rates
: Distraction from and Prerequisite
for Adhesion Through Integrins) ", Cel
1, 65, 859-873; von Adrian, U.S.A. , Chamb
ers, J. et al. D. McEnvoy, L .; M. Bargatze, R .; F. ,
Arfos, K .; E. FIG. And Butcher, E .; C. 1991, "Two-Step Model of Leukocyte-Endothelial Cell Interaction in Inflammation.
of Leukocyte-Endothelial Cell Intera
actions in Inflammation) ", Proc. Natl. A
cad. Sci. USA, 88, 7538-7542; and Ley,
K. Gaehgens, P .; Fennie, C .; Singer, M .; S
. Lasky, L .; H. And Rosen, S.M. D. 1991, "Lectin-like cell adhesion molecule 1 mediates rotation in mesenteric venules in vivo (Le
ctin-like Cell Adhesion Molecule 1 M
edites Rolling in Mesentelic Venule
s in vivo) ", Blood, 77, 2555-2555).
These steps are mediated by a family of adhesion molecules, such as integrins, members of the Ig supergene family and selectins, which are expressed on the surface of circulating leukocytes and on vascular endothelial cells. The first step consists of leukocyte rolling along the vascular endothelial cell lining in the area of inflammation. This rolling step is performed using leukocyte surface oligosaccharides such as sialylated Lewis-X antigen (Slex
)) And the selectin molecule expressed on the surface of endothelial cells in the area of inflammation. Selectin molecules are not normally expressed on the surface of endothelial cells, but rather are induced by the action of inflammatory mediators such as TNF-α and interleukin-1. Rolling reduces the speed of circulating leukocytes in the area of inflammation, causing the cells to adhere more tightly to endothelial cells. This tight adhesion involves the interaction of integrin molecules present on the surface of rolling leukocytes with their opposing receptor-Ig superfamily molecules on the surface of endothelial cells. Ig superfamily molecules or CAMs (cell adhesion molecules) are not expressed or are expressed at low levels on normal vascular endothelial cells. CAM, like selectin, has TNF-α
And induced by the action of inflammatory mediators such as IL-1. The final event in the adhesion process is the migration of leukocytes along the chemotactic gradient of leukocytes through the endothelial cell barrier to sites of extravasation and inflammation. This transfer is mediated by the conversion of leukocyte integrins from a low avidity state to a high avidity state. The adhesion process relies on the inducible expression of selectins and CAMs on the surface of vascular endothelial cells to mediate leukocyte rotation and tight adhesion to vascular endothelium.

[0004] Inducible expression of selectins and CAMs is mediated by the transcription factor NFkB.
NFkB is a family of dimeric transcription factors made from monomers containing a 300 amino acid Rel domain. These factors can bind to DNA, interact with each other, and bind to inhibitor molecules at the IkB terminus (Verma).
a, I. M. Stevenson, J .; K. Schwarz, E .; M. , A
ntwerp, D .; V. And Miyamoto, S .; , 1995, "Rel /
NFIB / IkB family: a detailed story of association and dissociation (Rel / NFIB / I
KB Family: Initiate Tales of Associate
and Dissociation) ", Genes Dev. 9, pp. 2723-2735 and Baldwin, A .; S. , 1996, "
NFkB and IkB proteins: new discoveries and insights (The NFkB an
d IkB proteins: New Discoveries and
Insights) ", Annu. Rev .. Immunol. , Volume 14, Volume 6
49-681). NFkB has been found in the cytoplasm complexed with IkB.
Activation of NFkB occurs in response to inflammatory mediators such as TNF-α, IL-1 and lipopolysaccharide. Activation of NFkB requires phosphorylation of IkB, followed by ubiquitinylation of the IkB molecule and subsequent degradation by the proteosomes. N from meeting with IkB
The release of FkB results in a translocation of the dimer to the nucleus, where it contains specific DNA
May be associated with the sequence. The e-selectin gene and CAM contain an NFkB recognition sequence upstream from their coding region. DNA-binding NFkB, which works with other proteins in the transcription complex, is directed, inter alia, to the expression of e-selectin and CAM genes controlled by this transcription factor.

[0005] The present invention discloses compounds that inhibit the expression of e-selectin and ICAM-1 on VCAM-1. These compounds are useful for treating or preventing a disease caused by expression of an adhesion molecule. These diseases include those in which leukocyte migration plays a role, markedly acute and chronic inflammatory diseases, autoimmune diseases, tumor metastases,
Allograft rejection as well as reperfusion injury are included.

SUMMARY OF THE INVENTION In one embodiment of the present invention, structural formula I:

[0007]

Embedded imageOr a pharmaceutically acceptable salt or prodrug thereof
Is disclosed. In the structural formula I,-----Is a single bond or a double bond;
However, when one bond is a double bond, the adjacent bond is a single bond, and E, F, and G are (1) carbon, (2) nitrogen, and (3) N⁺-O⁻Independently selected from, wherein at least one of E, F or G is nitrogen or N⁺-O⁻And more
Wherein at least one of E, F or G is carbon, and Y and Z are (1) carbon, (2) nitrogen, (3) oxygen, and (4) S (O)_t(T is an integer from 0 to 2), independently selected from the group consisting of: wherein at least one of Y or Z is other than carbon;_AIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆− (R₆Is optionally substituted with one or two substituents independently selected from: (a) hydrogen, (b) (i) aryl and (ii) cycloalkyl of 3 to 10 carbons. (C) alkanoyl wherein the alkyl moiety is 1 to 10 carbons, and (d) cycloalkyl of 3 to 10 carbons), (5) -C (W X) is selected from: (a) O and (b) S, and (6) alkenylene;_A(1) halo, (2) (a) oxo, (b) cycloalkyl of 3 to 10 carbons, (c) -CO₂R₇(R₇Is selected from: (i) hydrogen and (ii) aryl and cycloalkyl of 3 to 10 carbons, 1 to 10 carbons optionally substituted with one or two substituents independently selected from And (d) -NR₈R₉(R₈And R₉Is selected from: (i) hydrogen, (ii) -OH, aryl, heterocycle, cycloalkyl of 3 to 10 carbons, and -NR_AR_B(R_AAnd R_BIs independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted with one or two substituents selected from hydrogen and -OH), independently selected from 1-6 alkyl optionally substituted with one or two substituents, (iii) alkanoyl wherein the alkyl moiety is 1-10 carbon atoms, (iv) cycloalkyl of 3-10 carbons. Alkyl, (v) alkoxy, (vi) heterocycle, and (vii) aryl, wherein (vi) and (vii) are alkyl of 1 to 6 carbon atoms And halo, substituted with one or two substitutions independently selected from:), (e) -C (W) R₁₀(W is as defined above, and R₁₀Represents 1 to 10 carbon atoms optionally substituted with one or two substituents independently selected from: (i) hydrogen, (ii) aryl and cycloalkyl of 3 to 10 carbons Alkyl of (iii) -NR₈R₉And (iv) -OR₇(F) —OH, (g) aryl, and (h) heterocycle, 1 to 10 optionally substituted with 1, 2 or 3 substituents independently selected from Wherein (g) and (h) are: (i) alkyl of 1 to 20 carbons, (ii) -NR₈R₉(Iii) alkoxy of 1 to 10 carbons, (iv) thioalkoxy of 1 to 10 carbons, (v) halo, (vi) perfluoroalkyl of 1 to 3 carbons, (vii) 2 to 10 Alkenyl of 1 carbon, (viii) alkoxy of 1 to 10 carbons and alkyl of 1 to 10 carbons optionally substituted with 1 or 2 substituents independently selected from -OH, (Ix) -CO₂R₇, (X) aryl, and (xi) -CHO, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: (10) cycloalkyl of 10 carbons, (4) aryl, (5) heterocycle, wherein (4) and (5) are (a) alkyl of 1 to 20 carbons, (b) (i) -OR₁₁(R₁₁Is hydrogen, -C (W) R₁₂(R₁₂Is selected from alkyl of 1 to 10 carbons, cycloalkyl of 3 to 10 carbons, aryl, and heterocycle), and 1 or 2 substituents selected from -OH and -OH Selected from alkyl of 1 to 6 carbons, optionally substituted with; heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from: ii) alkoxy and alkoxyalkoxy, 1 to 10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (iii) 3 to 10 carbon spiroalkyl, And (iv) alkyl of 1 to 10 carbons, optionally substituted with 1, 2, or 3 substituents independently selected from halo, (c) (i) alkoxy and (ii) alkyl Xyalkoxy, 1-10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (d) 1-10 carbon thioalkoxy, (e) halo, (F) perfluoroalkyl of 1 to 3 carbons, (g) (i) -C (W) R₁₀And (ii) -C (W) R₁₂Alkenyl of 2 to 10 carbons optionally substituted with one or two substituents independently selected from: (h) -CO₂R₇, (I) -NR₈R₉, (J) aryl, (k) -C (W) R₁₂, (L) -CHO, (m) -C (O) NR₈R₉(N) -CN, (o) (i) alkyl of 1 to 10 carbons and (ii) perfluoroalkyl of 1 to 3 carbons, with one or two substituents independently selected from Optionally substituted heterocycle, (p) -C (W) R₁₀, (Q) ethylenedioxy, and (r) -OCF₃, Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from), (6) -OR₇, (7) hydrogen, and (8) -NR₈R₉L is selected from_BIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆-, (5) C (W)-, and (6) -C (= NR₁₃)-(R₁₃Are (a) hydrogen, (b) -NO₂, (C) -CN, and (d) -OR₁₄(R₁₄Is selected from: (i) hydrogen, (ii) aryl, and (iii) aryl and -C (O) R_Fifteen(R_FifteenIs hydrogen, -OH, alkoxy, and NR_AR_BX selected from 1 to 10 alkyls optionally substituted with 1 to 2 substituents, independently selected from_BAre (1) hydrogen, (2) (a) -CO₂R₇, (B) -NR₈R₉, (C) -C (W) NR₈R₉(D) heterocycle, (e) (i) alkyl of 1 to 10 carbons, (ii) -NO₂And (iii) -NR_AR_BAryl optionally substituted with one or two substituents independently selected from:, (f) -OR₁₆(R₁₆Is (i) hydrogen and (ii) -C (W) NR_AR_BAnd (g) -NR_AC (W) NR₈R₉1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (3) (a) -C (W) NR_AR_B, (B) -CO₂R₇And (c) a heterocycle, an alkenyl of 2 to 6 carbons optionally substituted with one or two substituents independently selected from: (4) -NR₁₇R₁₈(R₁₇And R₁₈(A) hydrogen, (b) (i) -OH, (ii) -C (W) R₁₀, (Iii) -NR_AC (= NR₁₃) NR_BR₁₉(R_A, R_B  And R₁₃Is already defined and R₁₉Is hydrogen, alkyl of 1 to 10 carbons, and -NO₂  (Iv) heterocycle, (v) aryl, (vi) halo, and (vii) -NR_AR_B(C) alkoxy; (d) (i) halo; (ii) 1-alkyl of 1 to 10 carbons optionally substituted with 1, 2 or 3 substituents independently selected from (Iii) 1 to 10 carbon alkoxy, and (iv) 1 to 3 carbon perfluoroalkyl, 1, 2, or 3 substitutions independently selected from: Aryl optionally substituted with a group, (e) heterocycle, (f) -NR_AR_B, (G) -C (O) R₂₀(R₂₀Is (i) hydrogen, (ii) alkyl of 1 to 10 carbons, (iii) -OR₁₂And (iv) -NR_AR_B(H) cycloalkyl of 3 to 10 carbons, and (i) independently selected from -OH), (5) alkoxy, (6) -OH, (7) -NR_AC (= NR₁₃) NR_BR₁₉, (8) -C (W) NR₈R₉(9) aryl, (10) heterocycle, wherein (9) and (10) are (a) halo, (b) (i) halo, (ii) alkoxy of 1 to 10 carbons, iii) -NR_AR_B, (Iv) -OH, (v) -CO₂R₇, (Vi) -C (W) NR_AR_BAnd (vii) aryl, 1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (c) -NR_AR_B(D) alkoxy of 1 to 10 carbons, (e) thioalkoxy of 1 to 10 carbons, (f) perfluoroalkyl of 1 to 3 carbons, (g) -OH, (h) -C (W) NR₈R₉, (I) -CO₂R₇, (J) -NR_AC (W) OR₂₁(R_AIs already defined and R₂₁Is (i) aryl and 1-10 carbon alkyl optionally substituted with one or two substituents selected from 3-10 carbon cycloalkyl, (ii) aryl, and (iii) (K) cycloalkyl of 3 to 10 carbons, (k) alkenyl of 1 to 10 carbons, (l) heterocycle, (m) aryl, and (n) -NO₂Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(11) -CN, (12) -CHO, (13) halo, and (14) -B (OR_A) (OR_B), Where R₁, R₂, R₃, R₄, And R₅Is hydrogen or lacking
, -L_A-Is a covalent bond, -L_B-Is a covalent bond, X_AOr X_BOne of them is
Other than hydrogen, R₁, R₂, R₃, R₄, And R₅Is missing or (1) hydrogen, (2) (a) -OC (O) R₂₂(R₂₂Is (i) alkyl, (ii) alkoxy, and (iii) NR_AR_B(B) alkoxy, (c) -OH, (d) -NR_AR_B(E) a heterocycle, and (f) aryl, alkyl of 1 to 6 carbons optionally substituted with one or two substituents independently selected from: (3) -CO₂R₇, (4) -C (O) NR_AR_B, (5) -SR₂₃(R₂₃Is one or two substituents selected from: (a) hydrogen, (b) alkyl of 1 to 6 carbons, (c) (i) alkyl of 1 to 6 carbons, and (ii) halo. Selected from aryl optionally substituted with), (6) -NR_AR_B(7) halo, (8) alkoxy, (9) perfluoroalkyl of 1 to 3 carbons, (10) -OH and (11) heterocyclic ring, with the proviso that E, F, and When Y is carbon, G is nitrogen and Z is sulfur
, -L_A-Is a covalent bond, X_AIs halo and R₁Is -CO₂R₇Other than
].

In another aspect of the present invention, a method for treating a disease comprising administering an effective amount of a compound having formula I is disclosed.

In yet another aspect of the present invention, there is disclosed a pharmaceutical composition comprising a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms As used herein, the term “alkanoyl” refers to an alkyl group attached to the parent molecular group through a carbonyl group.

As used herein, the term “alkenyl” refers to a group of 2 to 12 carbon atoms containing at least one carbon-carbon double bond derived from an alkene by removal of one hydrogen atom. Refers to a monovalent linear or branched group of carbon atoms.

As used herein, the term “alkenylene” refers to a 2-10 carbon atom containing a carbon-carbon double bond derived from an alkene by removal of two hydrogen atoms. Refers to a divalent linear or branched group.

As used herein, the term “alkoxy” refers to an alkyl group attached to the parent molecular group through an oxygen atom.

As used herein, the term “alkoxyalkoxy” refers to an alkoxy group attached to the parent molecular group through another alkoxy group.

As used herein, the term “alkoxycarbonyloxy” is defined herein as attached to the parent molecular moiety through a carbonyloxy group, as defined herein. Refers to such an alkoxy group.

As used herein, the term “alkoxycarbonyloxymethylene” is defined herein as attached to the parent molecular moiety through a methylene group as defined herein. Refers to such an alkoxycarbonyloxy group.

As used herein, the term “alkyl” refers to a saturated linear or branched group of 1 to 20 carbon atoms derived from an alkane by removal of one hydrogen atom. Point.

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

As used herein, the term “alkylcarbonyloxy” is as defined herein appended to the parent molecular moiety through a carbonyloxy group as defined herein. Refers to such an alkyl group.

As used herein, the term “alkylcarbonyloxymethylene”
Refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.

The term “alkylene” refers to a divalent group derived from a straight or branched chain hydrocarbon group of 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited _{to, -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 C
_{H 2 CH 2 CH 2 -,} - CH 2 CH (CH 3) CH 2 - and the like are included.

As used herein, the term “amino” refers to —NR₈₀R₈₁Group (wherein R ₈₀ And R₈₁Independently selected from hydrogen and alkyl).

As used herein, the term “aminocarbonyl” as defined herein, appended to the parent molecular moiety through a carbonyl group as defined herein Refers to an amino group.

As used herein, the term “aminocarbonyloxy” is as defined herein, appended to the parent molecular moiety through an oxy group as defined herein. An aminocarbonyl group.

As used herein, the term “aminocarbonyloxymethylene” is defined herein as attached to the parent molecular moiety through a methylene group as defined herein. Refers to such an aminocarbonyloxy group.

As used herein, the term “aryl” refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings. This aryl group may be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of the present invention may be optionally substituted.

The term “carbonyl,” as used herein, refers to a —C (O) — group.

As used herein, the term “carbonyloxy” as defined herein attached to the parent molecular moiety through an oxy group as defined herein Refers to a carbonyl group.

As used herein, the term “cycloalkyl” refers to a monovalent saturated cyclic hydrocarbon group of 3 to 12 carbons derived from cycloalkane by removal of one hydrogen atom. Point to.

As used herein, the term “ethylenedioxy” refers to a —O (CH ₂ ) ₂ O— group. Here, the oxygen atom of the ethylenedioxy group is bonded to the parent molecular moiety through one carbon atom to form a five-membered ring, or the oxygen atom of the ethylenedioxy group is two adjacent carbon atoms. It bonds to the parent molecular moiety through an atom to form a 6-membered ring.

As used herein, the term “halo” or “halogen” refers to F, Cl, B
Refers to r or I.

The term “heterocycle” refers to 4-, 5-, 6- or 7- containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Represents a member ring. The 4- and 5-membered rings have zero to two double bonds, and the 6- and 7-membered rings are
It has zero to three double bonds. The term “heterocycle” includes bicyclic, tricyclic and tetracyclic groups (provided that all of the above heterocyclic rings are aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene rings) Or fused to one or two rings independently selected from other monocyclic heterocyclic rings).
Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolinyl, imidazolinyl , Isoquinolyl, isothiazolidinyl, isothiazolyl,
Isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxadiazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, quinolinyl, quinolinyl Includes tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl and the like.

Further, the heterocyclic ring includes

[0034]

Embedded image Also included are bridged bicyclic groups, wherein a monocyclic heterocyclic group is bridged by an alkylene.

Further, the heterocyclic ring has the formula

[0036]

Embedded image (Wherein X ^* is selected from —CH ₂ —, —CH ₂ O— and —O—, and Y ^* is
—C (O) — and — (C (R ″) ₂ ) _v —, wherein R ″ is hydrogen or a group having 1 to 1 carbon atoms.
And v is 1 to 3). These heterocycles include 1,3-benzodioxolyl,
4-benzodioxanyl and the like. The heterocyclic groups of the present invention may be optionally substituted.

As used herein, the term “oxo” refers to ＝ O.

As used herein, the term “oxy” refers to —O—.

As used herein, the term “methylene” refers to a —CH ₂ — group.

As used herein, the term “perfluoroalkyl” refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms.

As used herein, the term “phenyl” refers to a monocyclic carbocyclic ring system having one aromatic ring. Further, the aryl group may be fused to a cyclohexane ring or a cyclopentane ring. The phenyl groups of the present invention may be optionally substituted.

As used herein, the term “pharmaceutically acceptable prodrug” refers to human and lower animals that have adverse toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment. These prodrugs of the compounds of the invention and, where possible, the invention are suitable for use in contact with tissue, which correspond to a reasonable effect / risk ratio and are effective for their intended use. Represents the zwitterionic form of the compound

As used herein, the term “prodrug” refers to a compound that is rapidly transformed in vivo, for example, by hydrolysis in blood, to a parent compound of the above formula. A thorough study is provided by T.W. Higuchi and V.M. Stella, "Prodrugs as Novell Deliv as a Novel Delivery System
ery Systems) ", A.I. C. S. Volume 14 of the symposium series and Edward B. Roche, “Bioreversible Carriers in Drug Design (B
ioreversable Carriers in Drug Design
) ", American Pharmaceutical Association
locations and Pergamon Press
1987), both of which are incorporated herein by reference.

As used herein, the term “spiroalkyl” means that two carbon atoms of the alkylene group are bonded to one carbon atom of the parent molecular group, thereby forming 3-11 carbon atoms. Refers to an alkylene group that forms a carbocyclic ring of atoms.

As used herein, “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule, in which case two or more structures Different compounds are in equilibrium with each other.

As used herein, the term “thioalkoxy” refers to an alkyl group attached to the parent molecular group through a sulfur atom.

The compounds of the present invention may exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers,

[0048]

Embedded image Is specified. The individual stereoisomers of the compounds of the invention can be synthesized from commercially available starting materials containing an asymmetric or chiral center or can be prepared by preparing a racemic mixture followed by resolution known to those skilled in the art. it can. These resolution methods include (1) coupling of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and isolation of an optically pure product from the auxiliary. Or (2) exemplified by the direct separation of a mixture of optical enantiomers on a chiral chromatography column.

[0049] Geometric isomers may be present in the compounds of the present invention. The present invention relates to carbon-
Various geometric isomers and mixtures thereof resulting from the configuration of substituents around a carbon double bond or the configuration of substituents around a carbocyclic ring are contemplated. Substituents around a carbon-carbon double bond are designated as being in a Z or E configuration. in this case,
The term "Z" refers to a substituent on the same side of the carbon-carbon double bond and the term "E"
Represents a substituent on the opposite side of the carbon-carbon double bond. The configuration of the substituents around the carbocyclic ring is designated as cis or trans. In this case, the term "cis" refers to a substituent on the same side of the plane of the ring, and the term "trans" refers to a substituent on the opposite side of the plane of the ring. Mixtures of compounds in which the substituents are located both on the same side and on the opposite side of the plane of the ring are designated cis / trans.

Also, tautomers may be present in the compounds of the present invention. The present invention provides for a proton shift from one atom to another atom of the same molecule, which is in equilibrium with each other.
Tautomers are contemplated that result in giving rise to a variety of different compounds.

Compounds of the present invention include, but are not limited to:

Methyl 2-[(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio
Acetate, 6-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-d] pyri
Midine, 6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine, 6-ethyl-4-[(2-methylethyl) thio] thieno [2,3-d] pyrimidin
Gin, 6-ethyl-4-[(phenylmethyl) thio] thieno [2,3-d] pyrimidi
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-carboxylate, 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidine-4-
Amine, 6-ethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) thio
Eno [2,3-d] pyrimidin-4-amine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6
Ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine
Midine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-
Ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyrimidine
Midine, 7-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)
Thio] thieno [3,2-d] pyrimidine, 7-methyl-4-[[5- (methylthio) -1,3,4-thiadiazole-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] pyrimidine
Limidin-7-amine, 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyri
Midine-6-carboxamide, methyl 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-carboxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubonic acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2-carboxa
Imide, 4-[(4-chlorophenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxamide, N-methoxy-N-methyl-4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, N-methoxy-4-[(4-methylphenyl) thio] thieno [2,3-c] pi
Lysine-2-carboxamide, N- (4-chlorophenyl) -4-[(4-methylphenyl) thio] thieno [
2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-methyloxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O- (phenylmethyl) oxime, 2-[[[4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
4-N-ylmethylene] amino] oxy] acetic acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-phenyl oxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, oxime, 2-[[[4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
2-Ethylmethylene] amino] oxy] acetamide, (E) -3-[(4-methylphenyl) thio] thieno [2,3-c] pyridine
-2-yl] -2-propenamide, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, 2-benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c]
Pyridine, 2-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pyri
Gin, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, oxime, N- (2,3-dihydroxypropyl) -4-[(4-methylphenyl) thio
Thieno [2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubonic acid, hydrazide, N ² -4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] carbonyl] -N ⁶ -[(Nitroamino) iminomethyl] -L-lysi
, Methyl ester, N- (aminoiminomethyl) -4-[(4-methylphenyl) thio] thieno [
2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubothioamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine, methyl 4-[(2-methoxy-2-oxoethyl) thio] thieno [2,3-c
] Pyridine-2-carboxylate, 4-[(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridi
2-carboxamide, 4-[(4-bromophenyl) thio] thieno [2,3-c] pyridine-2-ca
Luboxamide, 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-ca
Ruboxamide, 4-[(3-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxamide, 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] pyridi
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-carboxa
Mido, 4-[(4-methylphenyl) thio] -N- [3- (4-morpholinyl) pro
Pyl] thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl
Luacetate salt, 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine
-2-carboxamide, methyl 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pi
Lysine-2-carboxylate, 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 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-carboxy
Samide, 4- (4-ethenylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, 4- [2- (2,3-dihydroxypropyl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, 1-oxide, 4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-
4-yl] oxy] benzoate, 4-phenoxythieno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2-carbox
Samide, 4- (4- (methoxymethyl) phenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic
Acid, N- (4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
) -O- (3-tetrahydrofuranyl) carbamate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-methanol
(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenoic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Aldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenamide, 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] pi
Lysine-2-carboxylate, N-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] pyri
Gin-2-carboxamide, 4- (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2-ca
Ruboxamide, ethyl 4-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-
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-carboxy
Samide, methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-meth
Tanol, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N, N-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -N, N-diethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pi
Lysine-2-carboxamide, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] pyrrolidine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] piperidine, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] morpholine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4-methylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4-phenylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4- (phenylmethyl) piperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4- (2-pyridinyl) piperazine, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-carboxamide, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide
, Trifluoroacetate salt, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thio
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1,1-bis (hydroxymethyl) e
Tyl] thieno [2,3-c] pyridine-2-carboxamide, (D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl
) Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thi
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfone
Amide, 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine-2-
Carboxamide, methyl 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine
-2-carboxylate, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, N-oxide, methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbo
Acid, N-oxide, 4- (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] pyri
Gin-2-carboxylate, 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c] pyridi
2-Carboxamide, methyl 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c]
Pyridine-2-carboxylate, 4- (4-chlorophenoxy) -3- (1-methylethoxy) thieno [2,3
-C] pyridine-2-carboxamide, 3-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3 -Carbon
Acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3-carboxy
Samide, 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-carboxamide, methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyri
Gin-2-carboxylate, 3-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-ca
Ruboxamide, 4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5
-Carboxamide, ethyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio
Thieno [2,3-b] pyridine-5-carboxylate, 7-[(4-methylphenyl) thio] thieno [3,2-b] pyridine-2-ca
Ruboxamide, methyl 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-
2-carboxylate, methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxy
Silate, 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-2-ca
Ruboxamide, 2-bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyri
Gin, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-ca
Ruboxamide, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-ca
Rubonitrile, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboxy
Samide, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboni
Tolyl, 7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2-cal
Boxamide, Methyl 7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2
-Carboxylate, 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-
2-carboxamide, methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyri
Gin-2-carboxylate, 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2
-Carboxamide, methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridi
2-carboxylate, 4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carbo
Oxamide, 4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carbo
Acid, 7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carbamic acid
7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid
Acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Oamide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3-dihydroxypropyl) thiye
[2,3-c] pyridine-2-carboxamide, N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-carboxamide, 4- (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide, N- (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy
[Thi] thieno [2,3-c] pyridine-2-carboxamide, N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxyl
Drazide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohi
Drazide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carbohydrazide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridi
2-Carboxamide, 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl @ amino) acetic acid, N- (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thiye
No [2,3-c] pyridine-2-carboxamide, N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thiye
No [2,3-c] pyridine-2-carboxamide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl @ amino) -3-hydroxypropanoic acid, N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl
] -4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) -3-hydroxypropanoic acid, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methyl
Amino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxa
Amide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1S) -1-methyl-2- (methyl
Amino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)
-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)
-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-
c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-
Carboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pi
Lysine-2-carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine
-2-carboxamide, N-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, N-methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3
-C] pyridine-2-carboxamide, 4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2-carbox
Samide, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine
-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] -N-methylthieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (methoxymethyl) phenoxy] -N-methylthieno [2,3-c
Pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} thieno [2,3
-C] pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} -N-methylthio
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy
) Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy
) -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] fe
Nonoxydithieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy)
Methyl] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4-{[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl
] Oxy} benzyl-2-furoate, 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6-
(Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl
) Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxami
, 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine
-2-carboxamide, 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide, N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno
[2,3-c] pyridine-2-carboxamide, 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) f
Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} ca
Rubonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propeni
L] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino}-
3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- [4-((E) -3-{[2- (4-morpholinyl) ethyl]
] Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c]
Pyridine-2-carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3
-Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3
-Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pi
Lysine-2-carboxamide, 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
] Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [
2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] "
Ethyl {amino) -3-oxo-1-propenyl] phenoxy} -N-methylthio
Eno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-(} 2- [bis (2-hydroxyethyl) amino]
Ethyl {amino) -3-oxo-1-propenyl] phenoxy} thieno [2,3
-C] pyridine-2-carboxamide, 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno
[2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) phene
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxa
Diazol-3-yl] phenoxydithieno [2,3-c] pyridin-2-cal
Boxamide, 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy
] -N-methylthieno [2,3-c] pyridine-2-carboxamide, N-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, N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) phene
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] phenoxy} -N-
Methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclic
L-propyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-ca
Ruboxamide, N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,
3-c] pyridine-2-carboxamide, 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl]
{Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl}-
1,3,4-oxadiazol-2-amine, 4- [4- (1,1-difluoro-2-hydroxyethyl) phenoxy] -N
-Methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1-diif
Fluoroethyl {phenoxy) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-chlorophenoxy) -6-{[(2,2-dimethylpropanoyl)
Oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c]
Pyridine-6-ium, 4- (4-bromophenoxy) -6-{[(2,2-dimethylpropanoyl)
Oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c]
Pyridine-6-ium, 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(iso
Propoxycarbonyl) oxy] methyldithieno [2,3-c] pyridine-6-
Iium, 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-carboxy
Samide, [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl]
Methanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde oxime, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Aldehyde O-methyl oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone O-methyloxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone O-methyloxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1] -propanone, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -1-propanone oxime, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboni
Tolyl, 4- (4-chlorophenoxy) -N′-hydroxythieno [2,3-c] pyri
Gin-2-carboximidamide, 4- (4-chlorophenoxy) -N'-cyanothieno [2,3-c] pyridine
-2-carboximidamide, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(2-nitrophenyl) methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanone, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanol, 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine -2-b
L] -1,2-ethanediol, 1- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-i
] -1,2-ethanediol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
Methanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
Methyl carbamate, N-{[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] methyldiurea, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenamide, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine
-2-yl] -N-methyl-2-propenamide, 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
] -2,3-dihydroxy-N-methylpropanamide, 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
L] -2,3-Dihydroxypropanamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamido
4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylform
Muamide, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Ru] urea, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-sulfonamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thiye
No [2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-sulfonamide, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Phenol], 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] aniline, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Ru] aniline, 4- (4-chlorophenoxy) -2- (5-nitro-2-pyridinyl) thieno
[2,3-c] pyridine, 6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -3-pyridineamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -2-pyridineamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1,3,4-oxadiazol-2-amine, 5- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
1,3,4-oxadiazol-2-ylamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
] -4H-1,2,4-triazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (5-methyl-1,2,4-oxadia
Zol-3-yl) thieno [2,3-c] pyridine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c]
Pyridin-2-yl {-1,3,4-oxadiazol-2-amine, 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3
, 4-oxadiazol-2-yl) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (2-methyl-2H-1,2,3,4-
Tetraazol-5-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
4-Methyl-4H-1,2,4-triazol-3-amine, 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) -1,2
, 4-oxadiazol-3-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,2,4-oxadiazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] -N-methyl-1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (1,2,4-oxadiazole-3-
Yl) thieno [2,3-c] pyridine, 2- (1,3,4-oxadiazol-2-yl) -4- [4- (trifluoro
L-methyl) phenoxy] thieno [2,3-c] pyridine, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -1,2,4-oxadiazol-5-amine, 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4-
(Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -1,3-thiazole-4-carboxylate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,3-thiazole-4-carboxamide, tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] -1,3-thiazol-4-ylcarbamate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] -1,3-thiazol-4-amine, 4- (4-chlorophenoxy) -2- (1,3-oxazol-3-yl) thio
Eno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (1H-imidazol-3-yl) thiye
No [2,3-c] pyridine, 4-chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide
3-amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide
4- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-
2-carboxamide, 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c
Pyridine-2-carboxamide, tert-butyl 2- (aminocarbonyl) -4- (4-chlorophenoxy)
) Thieno [2,3-c] pyridine-2-carboxylate, N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- (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-chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide, 7-bromo-4- (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, 7-chloro-N-methyl-4- [4- (trifluoromethyl) phenoxy] thio
Eno [2,3-c] pyridine-2-carboxamide, 7-chloro-N- (2-hydroxyethyl) -4- [4- (trifluoromethyl
Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,
3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [
2,3-c] pyridine-2-carboxamide, 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-
2-carboxamide, N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4-c
] Pyridine-2-carboxamide, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide
Mido, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothio
Amide, 4-[(E) -2-phenylethenyl] thieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine
-2-carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxy
Samide, and 4- (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-
2-carboxamide.

Determination of Biological Activity The pooled primary human umbilical vein endothelial cells (HUVEC) (Clonetics) between passages 3 and 7 were placed in a 96-well plate and treated with hydrocortisone. In the presence, Clonetics EBM / 2% FBS /
In EGF / bovine brain extract / gentamicin were placed in 100 [mu] L / well, 5 × 10 ⁴ cells / mL. The next day, the compound of the present invention was added to 10 μL / well medium,
Incubated at 37 ° C. for 24 hours after compound addition. TNF (Gibco / BRL) in 10 μL / well medium was added to a final concentration of 5 ng / mL and the cells were incubated for an additional 6 hours at 37 ° C. The medium was then removed and the plate was washed once with D-PBS (Gibco / BRL),
-First antibody (Becton Dickinson, City, Becton Dickinson, PBS / 2% BSA (Sigma) /0.01% azide)
(City)), 100 μL / well. An initial concentration of 1 mg / mL primary antibody was used at the following dilutions. Anti-ELAM-1, 1: 2000, anti-ICAM-
1, 1: 2000 and anti-VCAM, 1: 3000. The plates were stored overnight at 4 ° C., washed three times with D-PBS, and the second antibody (Jackson Labs)
on Labs)), 100 μL / well, 1: 8000 dilution, D-PBS / 2
Treated with HRP-conjugated donkey anti-mouse IgG (H + L) in% BSA. Plates were incubated for a minimum of 1 hour at room temperature, washed three times with D-PBS, and treated with 100 μL per well of ortho-phenylenediamine.2HCl reagent. The plate was allowed to develop for about 15 minutes and neutralized with 100 μL / well of 1N sulfuric acid. The absorbance was read at 490 nm. Inhibitory titers for representative compounds of the present invention are shown in Table 1.

[0054]

[Table 1] Thus, the compounds of the present invention act as anti-inflammatory agents at a titer of less than 1 μM and are therefore useful for treating inflammatory diseases.

Pharmaceutical Compositions and Methods of Treatment The present invention also provides pharmaceutical compositions comprising a compound of the present invention formulated with one or more non-toxic pharmaceutically acceptable carriers. The drug compositions may be particularly formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The drug formulations of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally (as by powder, ointment or drop). B) topically, orally, or as an oral or nasal spray. The term “parenteral” administration as used herein refers to intravenous, intramuscular,
Refers to modes of administration including intraperitoneal, intrasternal, subcutaneous and intraarterial injection and infusion.

The parenterally-injected pharmaceutical compositions of the present invention include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions immediately before use. Sterile powder reconstituted into a neat solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and olein. Injectable organic esters such as ethyl acid are included. The appropriate liquidity is, for example,
It can be maintained by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersion, and by using a surfactant.

[0058] Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microbial activity can be reliably prevented by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay the absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material that has poor water solubility. In that case, the absorption rate of the drug depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0060] Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0061] Injectable formulations can be prepared, for example, by filtration through a bacteria-retaining filter.
Alternatively, sterilization can be accomplished by incorporating the bactericide in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0062] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound comprises at least one
Two inert pharmaceutically acceptable excipients or carriers (such as citric acid or dicalcium phosphate) and / or a) fillers or bulking agents (starch, lactose, sucrose, glucose, mannitol and silicic acid) B) binder (
For example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), c) humectants (such as glycerol), d) disintegrants (agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicas) Acid salts and sodium carbonate), e) dissolution retarders (such as paraffin), f) absorption enhancers (such as quaternary ammonium compounds)
G) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl. Sodium sulfate, and mixtures thereof). In the case of capsules, tablets and pills, the dosage form also contains buffering agents.

Solid compositions of a similar type may also include excipients such as lactose or lactose,
It can be used as a filler in soft-filled gelatin capsules or hard-filled gelatin capsules using high molecular weight polyethylene glycol or the like.

Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Such dosage forms may optionally contain an opacifying agent, and may contain only the active ingredient (s) or preferentially the active ingredient (s) to identify the intestinal tract. Can be made from compositions that release in a delayed manner, if desired. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions,
Suspensions, syrups and elixirs are included. In addition to the active compound, liquid dosage forms can contain inert diluents, solubilizing agents and emulsifying agents that are widely used in the art, such as, for example, water or other solvents. Such solubilizers and emulsifiers include, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, Peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0067] In addition to the inert diluents, the oral compositions can also include adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

Suspensions may contain, in addition to the active compounds, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum aluminum hydroxide, bentonite, agar. And gum tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories. Such suppositories may render the compound of the present invention solid at room temperature, liquid at body temperature, and therefore suitable nonirritating excipients or carriers that melt in the rectal or vaginal cavity to release the active compound. body(
Cocoa butter, polyethylene glycol or suppository wax).

The compounds of the present invention can also be administered in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-lamellar or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins).

[0071] Methods for forming liposomes are well known in the art. For example, Prescott
Hen, Methods in Cell Biology, Volume XIV, Acad
emic Press, New York, N.M. 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. "Pharmaceutically acceptable salts" are intended for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment. Appropriate and reasonable effect /
A salt corresponding to the risk ratio is meant. Pharmaceutically acceptable salts are well-known in the art. For example, M. Berge et al. Disclose pharmaceutically acceptable salts. P
The details are described in Pharmaceutical Sciences, 1977, 66: 1 et seq. Such salts can be prepared during the final isolation and purification of the compounds of the present invention or separately by reacting the free base function with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, citric acid, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate , Digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate Salt), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate,
Persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,
Includes but is not limited to bicarbonate, p-toluenesulfonate and undecanoate. In addition, basic nitrogen-containing groups include lower alkyl halides (methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl and butyl bromide, methyl iodide, ethyl iodide, Propyl iodide and butyl iodide, etc.); dialkyl sulfates (dimethyl sulfate, diethyl sulfate,
Long chain halides (decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, decyl iodide, lauryl iodide, iodide) It can be quaternized with agents such as myristyl and stearyl iodide, etc .; arylalkyl halides such as benzyl bromide and phenethyl bromide. A water-soluble or oil-soluble or dispersible product is thereby obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and oxalic, maleic, succinic and Organic acids such as citric acid are included.

The base addition salt may be used for the final isolation and purification of the compounds of the present invention, while the carboxylic acid-containing moiety is being replaced with a pharmaceutically acceptable hydroxide, carbonate or metal cation. It can be prepared by reacting with a suitable base such as bicarbonate, or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include lithium, sodium, potassium,
Cations based on alkali or alkaline earth metals such as calcium, magnesium and aluminum salts, and non-toxic compounds including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like Includes, but is not limited to, quaternary ammonia and amine cations. Other representative organic amines useful for forming base addition salts include ethylenediamine,
Ethanolamine, diethanolamine, piperidine, piperazine and the like are included. Preferred salts of the compounds of the present invention include phosphate, Tris and acetate.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
Ophthalmic formulations, eye ointments, powders and solutions are also included as being within the scope of this invention.

The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention will depend on the particular patient,
The composition and mode of administration can be varied to provide an effective amount of active compound (s) to achieve the desired therapeutic response. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and previous medical history of the patient being treated. However, it is within the skill of the art to start doses of the compounds at lower levels than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. is there.

In general, dosage levels of about 1 mg to about 50 mg, more preferably about 5 mg to about 20 mg, of active compound per kg of body weight per day are orally administered to a mammalian patient. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, for example, two to four separate doses per day.

Preparation of Compounds of the Invention Abbreviations The abbreviations used in the description of the schemes and examples below are shown below. BH ₃ : borane, BH ₃ .DMS: borane dimethylsulfide complex, BINA
P: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, BF ₃ OEt ₂ : boron trifluoride diethyl ether complex, n-BuLi: n-butyl lithium, 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: dimethylsulfoxide, DIPEA : Diisopropylethylamine, DPPA: diphenylphosphoryl azide, EDCl or EDC: 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, Et ₃ N: triethylamine, E
t ₂ O: diethyl ether, EtOAc: ethyl acetate, EtOH: ethanol,
K ₂ CO ₃ : potassium carbonate, LiAlH ₄ : lithium aluminum hydride, LD
A: lithium diisopropylamide, MeOH: methanol, NaOMe: sodium methoxide, NaOH: sodium hydroxide, HCl: hydrochloric acid, NMP: 1-
_{Methyl-2-pyrrolidinone,} H 2 / Pd: hydrogen and a palladium catalyst, iPrO
H: isopropyl alcohol, PPh ₃ : triphenylphosphine, THF: tetrahydrofuran, THP: tetrahydropyran, TFA: trifluoroacetic acid,
pyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium =
Hexafluorophosphate.

Synthetic Methods The compounds and processes of the present invention are better understood with the following synthetic schemes which illustrate how the compounds of the present invention may be prepared. Moreover, all references in this case are incorporated by reference.

[0079]

Embedded image Scheme 1 describes a thieno [2,2 from an ester of general formula 1 according to a published procedure.
3 shows the preparation of 3-d] pyrimidines. 4-chlorothieno [2,3-d of the general formula 3
The pyrimidines were substituted with thiols to obtain the 4-thioethers of general formula 4 or with amines to obtain the 4-aminothieno [2,3-d] pyrimidines of general formula 5.

[0080]

Embedded image Scheme 2 shows the preparation of 2-carboxy-substituted thieno [2,3-d] pyrimidines. The pyrimidinones of the general formula 1 are reacted with phosphoryl chloride to form the general formula 6
Which was then substituted with a thiol to give the thioether of general formula 7.

[0081]

Embedded image Scheme 3 shows the thieno [3,2 derived from chloropyrimidines of general formula 8
-D] shows the preparation of pyrimidines. The thioether of general formula 9 was obtained by substituting this chloride with thiol. By substituting the chloride with an amine, aminopyrimidines of the general formula 10 were obtained.

[0082]

Embedded image Analogs having a 2-carboxamide group in thieno [3,2-d] pyrimidine were prepared as shown in Scheme 4. The 2-position of thiophene was deprotonated with a strong base such as lithium diisopropylamide, and the corresponding carbanion was treated with carbon dioxide to give the acid of general formula 11. This acid was converted to the corresponding amide of general formula 12 via the intermediate acid chloride.

[0083]

Embedded image Scheme 5 shows a 6-alkyl-substituted thieno with an alkylthio group at the 4-position [2,
3 shows the preparation of 3-d] pyrimidines. Using known procedures, 2-aminothiophene 13 is acylated to amide 14, which is cyclized to thienopyrimidinone 1
It was set to 5. This pyrimidinone was converted to chloride 16 and further converted to thioether 17 by standard procedures.

[0084]

Embedded image A general process for preparing 2,4-disubstituted thieno [2,3-c] pyridines is shown in Scheme 6. Commercially available 3,5-dichloropyridine was added in an anhydrous solvent,
Treatment with a strong base such as lithium diisopropylamide at low temperature followed by reaction with methyl formate (or dimethylformamide) gave the known pyridine-4-carboxaldehyde 18. The aldehyde 18 is then substituted with one equivalent of a thiol (R ¹ = substituted or unsubstituted aryl, alkyl or heterocycle) to give a compound of general formula 1
9 chloroaldehydes were obtained. 19 is treated with methyl thioglycolate and a base (such as cesium carbonate or potassium carbonate) to give a 4-thioether of general formula 20 [
2,3-c] thienopyridine ester was obtained. This ester was converted to the corresponding acid of general formula 21 by, for example, base hydrolysis using lithium, sodium or potassium hydroxide in a mixture of water and alcohol or tetrahydrofuran. The acid of general formula 21 can also be treated first with oxalyl chloride or thionyl chloride, and then with a selected amine (R ² , R ³ can be substituted or unsubstituted alkyl, aryl, heterocycle). Can be converted to an amide of the general formula 22 or 23 via an intermediate acid chloride. Alternatively, the acid 21 can be a carbodiimide (eg, N-ethyl-N ′-(3-dimethylamino) propylcarbodiimide hydrochloride (EDC)), a mixed anhydride (derived from treatment of pivaloyl chloride or isobutyl chloroformate), And active ester (
The amides 22 or 23 can be converted by other coupling methods such as, for example, N-hydroxysuccinimide, derived from p-nitrophenol).

[0085]

Embedded image Scheme 7 illustrates a similar preparation of 4-ether substituted thienopyridines of general formula 30. Substitution of aldehyde 18 with an alcohol (R ¹ = substituted or unsubstituted aryl, heterocycle) under basic conditions (eg, anhydrous tetrahydrofuran or dimethylformamide containing potassium tert-butoxide or cesium carbonate) yields a compound of general formula The pyridine-ethers of 24 were then reacted further with methyl thioglycolate to give thieno [2,3-c] pyridine esters of general formula 25. This ester can be converted to the corresponding primary amide of general formula 26 by heating in a methanolic ammonia solution. Alternatively, general formula 2
The ester of 5 can be reacted with a mono- or disubstituted amine in a polar solvent such as dimethylformamide or methanol. The ester of general formula 25 was hydrolyzed to the carboxylic acid of general formula 28 by base hydrolysis using sodium hydroxide or lithium hydroxide in aqueous methanol or aqueous tetrahydrofuran. The acid was then converted to an amide of general formula 30 by reacting the corresponding acid chloride of general formula 29 with an amine. Alternatively, acid 30 was coupled to the amine by standard peptide coupling conditions as described in Scheme 6 for amide 22 or 23.

[0086]

Embedded image A similar method is shown in Scheme 8, as shown in 4-bromothieno [2,
3-c] pyridine 32 can be used. 3,5-Dibromopyridine was converted to aldehyde 31 by the procedure described in Scheme 6 for the preparation of compound 18. The reaction of 31 with methyl thioglycolate was performed, for example, in DMF in the presence of cesium carbonate to give 4-bromothieno [2,3-c] pyridine ester 32. The bromide 32 is a starting material for preparing 4-aryl, 4-heterocyclic, 4-alkyl or 4-alkenyl derivatives of general formula 33 using Suzuki coupling methodology as shown. Used as a substance. Bromide 32 also contains Sanogash
ira method (Sanogashira, K .; Tohda, Y .; Hagihar)
a, N .; Tetrahedron Lett. 1975, 4467-70) can be coupled with a terminal alkyne to obtain an alkynyl derivative (R ¹ = alkynyl). The ester of general formula 33 is converted to 26 in scheme 7,
Conversion to the amide of general formula 34 by the procedure described for 27 or 30.

[0087]

Embedded image Scheme 9 illustrates the conversion of an acid of general formula 21 to an aldehyde or ketone derived compound. For example, an aldehyde of general formula 36 was obtained by reducing N-methyl-N-methoxylamides of general formula 35. The amide of general formula 35 also reacted with the Grignard reagent to give an asymmetric ketone of general formula 39.
Aldehydes of general formula 36 and ketones of general formula 39 were utilized to obtain oximes of general formula 37 or 40 by reaction with hydroxylamine derivatives. The aldehyde of general formula 36 was reacted with a phosphorane (or phosphonoacetate salt) to give a 2-alkenyl substituted derivative of general formula 38. The ketone of general formula 39 was reduced to the corresponding alkane of general formula 41 by treatment with hydrazine and a strong base such as potassium hydroxide. The 2-position analog derivative of the thienopyridine ether of general formula 28 in Scheme 7 follows a similar synthetic route as described in Scheme 9. Thus, acid 28 can be converted to an aldehyde, ketone, oxime, alkene or alkane substituent at the 2-position.

[0088]

Embedded image An amide of general formula 34 (or 26, 27 or 30) can be converted to the corresponding thionoamide of general formula 42 by treatment with a Lawesson reagent, as shown in Scheme 10.

[0089]

Embedded image As shown in Scheme 11, 4-sulfoxide of general formula 43 is obtained by reacting a thioether of general formula 20 with an oxidizing agent such as m-chloroperoxybenzoic acid under controlled conditions. Was done.

[0090]

Embedded image Another functional group was introduced at the 2-position of the thienopyridines of general formula 44 by metallization at the 2-position followed by reaction with a suitable electrophile, as shown in Scheme 12. Formula 21 acid (L A _X A ₌ thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) (optionally in the presence of copper powder) to a high temperature by decarboxylation, of the general formula 44 The 2-unsubstituted derivative was obtained. The compound of general formula 44 is deprotonated with a strong organic base such as n-butyllithium and then subjected to standard procedures (Ma
Sakatsu, N .; Kazuhiro, N .; Ichiro, M .; ; Iwa
o, W. Chem. Lett. 1983, 6, 905-908) with an electrophile such as borate, cyanoformate, aldehyde or trialkyltin chloride.

[0091]

Embedded image Scheme 13 illustrates another method for preparing 2-carboxaldehydes of general formula 36 or 47. Esters of general formula 20 or 25 (R ¹ = thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocycle) were reduced to the corresponding alcohols of general formula 46 using calcium borohydride. The alcohol was then oxidized to aldehyde using Swern conditions. The aldehyde was then reacted with the Wittig reagent. For example, reaction with phosphoranes gave acrylate derivatives of general formula 48 (Jung, ME and Ki).
ankarami, M .; J. Org. Chem. 1998, 63, 2968-2
974).

[0092]

Embedded image As shown in Scheme 14, thienopyridines of general formula 27 or 30 are converted to alkyl iodides (or alkyl bromides or alkyl triflates).
Alkylation at the pyridine nitrogen using afforded the pyridinium salt of general formula 49. For example, R can be alkylcarbonyloxymethylene, aminocarbonyloxymethylene, alkoxycarbonyloxymethylene, or alkyl. Such derivatives can be used as prodrug forms of thienopyridine amide 27 or 30.

[0093]

Embedded image Various 2-aminothienyl [2,3-c] pyridine derivatives can be obtained starting from a 2-carboxylic acid of general formula 21 or 28, as shown in Scheme 15, where R ¹ can be thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocycle. According to Curtius rearrangement, general formula 5
An isocyanate of 0 was obtained, which was reacted with an alcohol (alkyl, aryl, heterocycle or dialkylaminoalkyl) to give a carbamate of the general formula 51. Isocyanate 50 can be reacted with an amine (ammonia, primary alkyl or secondary alkyl) to form a urea of general formula 52. Further, 50 can be reacted with an alkyl magnesium halide, an aryl magnesium halide or an alkyl lithium salt to give an amide of the general formula 53. The isocyanate 50 was hydrolyzed under aqueous conditions to give the 2-amino derivative of general formula 54.

[0094]

Embedded image This position was further derivatized by reacting the amine of general formula 54 with a suitable electrophile. Thus, by reacting 54 with an arylsulfonyl chloride or an alkylsulfonyl chloride (R ² = alkyl, aryl, heterocycle) or by reacting with a sulfamoyl chloride (R ² = NH ₂ , monoalkylamino or dialkylamino) The sulfonamide of the general formula 55 was obtained. Amino derivative 54 also reacted with an acyl chloride (R ² = alkyl, heterocycle or aryl) to give the amide of general formula 53, as shown in Scheme 16.

[0095]

Embedded image The functional groups present on the aryl ring bonded to the 4-position of the thieno [2,3-c] pyridines can be further reacted effectively, as illustrated in Scheme 17. For example, 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 displaced by an arylboronic acid under palladium catalyst under Suzuki conditions to yield the biaryl derivative of general formula 59. Alternatively, the alkoxycarbonylation with palladium catalysis efficiently yielded the ester of general formula 61.

[0096]

Embedded image Scheme 19 shows that a boric acid derivative is used to functionalize the 4-position of thieno [2,3-c] pyridines. The chemistry shown is bromostyrene 6
It can be applied to a wide range of aryl olefins similar to 2. Where indicated, bromostyrene 62 is converted to boric acid 63 under standard conditions,
Then, the boronic acid was converted to 4-bromothienopyridine 32 under Suzuki conditions.
To give styryl analog 64. Esters 64 can be prepared as previously described (Miyara, N and Suzuki, A. Chem. Rev.
1995, 95, 2457-2463). The olefin group can then be converted to an epoxide 66. This can undergo a reaction with a nucleophile at the less sterically hindered position of the epoxide to give an analog of general formula 67. Alternatively, styryl derivative 65 can be converted to diol 68 by standard methods.

[0097]

Embedded image Another method for introducing a substituent at the 4-position of thieno [2,3-c] pyridines is shown in Scheme 20. Bromide 32 can be converted to the corresponding cuprate by an intermediate zinc bromide reagent, which is then reacted with a suitable electrophile (acid chloride, alkyl halide, aldehyde, ketone). To give a substituted compound of the general formula 69 (Zhu.L .; Wehmeyer, RM; Rieke, RD).
. J. Org. Chem. 1991, 56, 1445-1453).

[0098]

Embedded image Scheme 21 illustrates the preparation of a 5-halothienopyridine derivative, as exemplified by the preparation of the 5-chloro analog 75. 2,3,5 lithiated
Aldehyde 72 was obtained by formylation of trichloropyridine with methyl formate. Replacement of 3 and 5 chlorine by excess 4-bromophenol,
And by reaction with methyl thioglycolate, 5-chlorothienopyridine 74 was obtained in low yield together with the main product 73. The 5-chloro isomer was treated with ammonia in methanol in a pressure tube to give amide 75. It should be noted that this chemistry can be applied using various phenols or hydroxy heterocycles instead of 4-bromophenol.

[0099]

Embedded image The 2-position of the thienopyridines was substituted with an aryl, vinyl, acetylenic or alkyl group using the procedure shown in Scheme 22. Scheme 1
The boronic acid of general formula 79 prepared according to 2 was coupled with an aryl halide under a palladium catalyst to give the 2-aryl derivative of general formula 80.

[0100]

Embedded image Scheme 23 illustrates the preparation of 4-acyl derivatives of thieno [2,3-c] pyridines. Carboxylic acid 85 was converted to amide 86 by acid chloride. The hydroxyamide 86 is then cyclized via thionyl chloride-mediated oxazoline 87
(Meyers, AI; Stoianova, DJ Org. Ch.
em. 1997, 62, 5219-5221). Ester 88 was obtained by palladium mediated alkoxycarbonylation of 87 (Heck, RF et al., J. Am.
Org. Chem. 1974, 39, 3318). Ester 88 can be converted to Weinreb amide 89 by standard methods. Amide 89 was reacted with a suitable Grignard reagent to give the desired 4-acyl product of general formula 90. The desired product of general formula 91 was obtained by hydrolyzing oxazoline and converting the resulting carboxylic acid to an amide.

[0101]

Embedded image Scheme 24 shows a proposed method for obtaining 4-hydroxy-substituted thieno [2,3-c] pyridines. Reaction of phenol 92 with dihydropyran under acidic conditions gives tetrahydropyranyl ether 93 (Gr.
ant, H .; N. Et al., Helv. Chim. Acta. 1963, 46, 41)
. The aldehyde 9 can be prepared by lithiation of 93 followed by treatment with methyl formate.
4 is obtained. Displacement of this chloride with methyl thioglycolate followed by cyclization with cesium carbonate gives ester 95. Removal of the tetrahydropyranyl ether with aqueous HCl gives hydroxypyridine 96. This can be converted to an amide as described previously.

[0102]

Embedded image Scheme 25 proposes that a 4-hydroxy group be used to introduce a functional group at the 4-position of the thieno [2,3-c] pyridines. The 2-carboxylic acid group is first protected as oxazoline 99 (via the intermediate amide 98) and then the hydroxy group is converted to the aryl triflate 100 by standard conditions. Triflate 100 can then be converted to N-methyl-N-methoxyamide 89 under conditions similar to those for bromide 87. It should be noted that 4-triflate 100 can be used as a coupling partner in various transition metal-mediated couplings with suitable nucleophile partners (e.g., boronic acids, boranes, alkyl zinc reagents or aryl zinc reagents). No.

[0103]

Embedded image Compounds with amino substitution at the 3-position of thieno [2,3-c] pyridines were prepared according to the procedure outlined in Scheme 26. Aldehyde 18 was converted to cyanopyridine 107 by treatment with hydroxylamine under dehydrating conditions.
Cyanopyridine 107 was sequentially substituted with phenols and methyl thioglycolate in a manner similar to the reaction involving aldehyde 18 to give 3-aminothieno [2,3-c] pyridines of general formula 108. The ester of general formula 108 was then converted to the amide of general formula 109 by standard procedures.

[0104]

Embedded image Scheme 27 illustrates additional derivatives that can be derived from amino esters of general formula 108 or aminoamides of general formula 109. For example, an aminoamide of general formula 109 can be treated with 1,1'-carbonyldiimidazole to form a cyclic imide of general formula 110. A 3-amino group can be added (e.g., with acid chlorides and weak bases or by coupling with acids using carbodiimides).
Acylation afforded the diamide of general formula 111. The 3-amino group can be alkylated to an alkylated amine of general formula 112 under reducing conditions using an aldehyde and a reducing agent (such as triacetoxyborohydride).

[0105]

Embedded image Scheme 28 illustrates the preparation of compounds having an alkyl substituent at the 3-position of thieno [2,3-c] pyridines. Using similar chemistry as described for compound 30, 3,5-dichloropyridine is deprotonated with a strong base (eg, lithium diisopropylamide) and then acylating agent (ester, N-methyl-N
-Methoxyamide, acylpyrazole, etc.) to give ketone 113.
Alternatively, reacting the anion with an aldehyde (eg, acetaldehyde)
The product can then be oxidized (eg, with tetrapropylammonium perruthenate) to ketone 113. The dichloroketone was reacted sequentially with phenols and then with methyl thioglycolate according to the protocol outlined for Example 30 to give the cyclic product of general formula 114. The ester of general formula 114 can be converted to various derivatives as outlined previously.

[0106]

Embedded image Scheme 29 describes a similar method used to obtain derivatives with an alkoxy group at the 3-position of thieno [2,3-c] pyridines. Substitution and cyclization of ester 116 provided the 3-hydroxy analog of general formula 117. The hydroxy group can be left unsubstituted to form an amide of general formula 118 (or other derivative). Alternatively, the hydroxy ester of general formula 117 can be alkylated by standard procedures to a 3-alkoxy derivative of general formula 119, which can then be amide to a compound of general formula 120.

[0107]

Embedded image Scheme 30 shows the procedure used to convert commercially available furo [2,3-b] pyridine 121 to amide 122.

[0108]

Embedded image Scheme 31 proposes the preparation of a thienopyridine derivative containing an amide group at the 3-position. The thienopyridines of the general formula 44 are converted to an electrophilic halide source (eg, N
- bromosuccinimide, and halogenated using I _2), 3 of the general formula 123
-Halothienopyridines were obtained. Metal-halogen exchange followed by capture with carbon dioxide gives the acid of general formula 124. The acid can be converted to the amide of general formula 125 by standard procedures, or (e.g., Arndt-Eis
(by the procedure of ert). The ester of general formula 126 can then be converted to an amide or other functional group in the manner described above.

[0109]

Embedded image Scheme 32 describes the method used to prepare various thieno [2,3-b] pyridines starting from the known 4-chloro-5-ester 127. The substitution of chlorine at 127 proceeds with a thiol in the presence of potassium carbonate to give a compound of the general formula 12
This resulted in the 4-thioether of 8. Ester 127 was also hydrolyzed to acid 129, which was subsequently converted to the amide of general formula 130 by standard coupling conditions.

[0110]

Embedded image Scheme 33 illustrates the conversion of a thioether of general formula 128 to a 2,4-disubstituted analog. The corresponding acid of general formula 131 is thermally decarboxylated to give 5 of general formula 132
-Unsubstituted analogs can be obtained. The compound of the general formula 132 is treated with a strong base (for example, n-butyllithium), reacted with carbon dioxide,
A carboxylic acid was obtained. This acid was then converted to the amide of general formula 134 by procedures previously described.

[0111]

Embedded image Scheme 34 illustrates the preparation of thieno [3,2-b] pyridines. The chloride 135 was converted by a group of conditions similar to those described in Scheme 33 to give the acid of general formula 139 and the amide of general formula 140.

[0112]

Embedded image Scheme 35 illustrates the preparation of thieno [3,2-c] pyridines. Starting from thienopyridone 141, 4-oxo-4,5-dihydrothieno [3,2-c]
Pyridine-2-nitrile 144 was prepared according to literature methods (Eloy, F. et al.
Deryckere, A .; Bull. Soc. Chim. Belg. 1970,
79, 301; Troxler, F .; Wiscott, E .; US Patent No. 3,9
98,835). Treatment of thienopyridone 144 with phosphoryl chloride at 130 ° C. afforded chloride 145, which when exposed to thiols under basic conditions, provided the thioether of general formula 146. Hydrolysis of the nitrile group with polyphosphoric acid gave the corresponding amide of general formula 147.

[0113]

Embedded image Scheme 36 shows that the ether of general formula 149 was prepared in a similar manner as described previously in Scheme 35.

[0114]

Embedded image Scheme 37 illustrates the preparation of an intermediate of general formula 151 useful for preparing another 2-derivative. Treatment of a known 2-bromo-4-chlorothieno [3,2-c] pyridine 150 with one equivalent of thiol gives 2-bromothieno [
[3,2-c] pyridines were obtained.

[0115]

Embedded image Scheme 38 shows an example of the preparation of a related class of inhibitors based on the oxazolopyridine structure. Commercially available 3-chloropyridine is oxidized to N-oxide 152 with peracetic acid, which is then nitrated in a mixture of concentrated nitric acid, sulfuric acid and fuming sulfuric acid to give the 4-nitro derivative 153. The chlorine of 153 is then replaced with the sodium salt of p-cresol and the resulting biaryl ether 154 is hydrogenated (Raney nickel catalyzed) to reduce both the nitro function and the N-oxide to give 155. The amino group of 155 was protected with an N-trimethylacetyl group, and the 5-hydroxyl group was treated with the procedure of Chu-Moyer and Berger (J. Org. Che.
m. 1995, 60, 5721), by introduction of the dianion of 156, treatment with trimethylborate and oxidation of the intermediate boronate ester, followed by hydrolysis with basic hydrogen peroxide to give the hydroxypyridine 157. The amide is hydrolyzed with hydrochloric acid to 158, which is condensed with methyl oxalyl chloride to give oxazolopyridine 158. The methyl ester at 159 is then converted to a primary amide by treatment with ammonia in methanol to give the desired compound 160.

[0116]

Embedded image Scheme 39 shows an example of the preparation of a similar thiazolopyridine-based inhibitor. Although the scheme shows the use of paracresol-substituted pyridine as a starting material, the synthesis can be generalized to other aryl, heterocyclic, or alkyl esters. The dianion of 4- (N-trimethylacetyl) -amino-3- (4-methylphenoxy) -pyridine is quenched with tetramethylthiuram disulfide to introduce a 5-mercapto group into the substituted pyridine ring as dithiocarbamate 161. The amine is subsequently deprotected under acidic conditions and the free aniline 162 is acylated with methyl oxalyl chloride to give oxalamide 163. The thiazolopyridine bicyclic nucleus 164 is then prepared by treatment with a mild acid (eg, formic acid at reflux). The ester functionality was converted to the corresponding amide 165 by the amine solution in methanol with warming.

[0117]

Embedded image Related compounds, the imidazopyridines, can be prepared from the intermediates shown in Scheme 40. 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. C).
hem. 1960, 25, 214). After removing the pivaloyl group of 166 with hydrochloric acid, the obtained diaminopyridine 167 can be condensed with methyl oxalyl chloride to give imidazopyridine 168. The ester functionality can then be converted to the amide 169 by treatment with ammonia in methanol as described above.

[0118]

Embedded image Scheme 41 is a diagram of the preparation of thienopyridazine-containing inhibitors. Deprotonating protected thiophenic acid 170 with a strong base (eg, n-butyllithium);
It was reacted with a formylating reagent. The obtained oxazoline aldehyde 171 was hydrolyzed and cyclized with hydrazine to obtain hydroxythienopyridazine 172. The hydroxyl group was converted to chloride 173 by the action of phosphorus oxychloride, followed by substitution with alkoxide to give ether 174. The amide group was introduced into the thienopyridine in a manner similar to that described above to give the amide 176.

[0119]

Embedded image The synthesis of the water-soluble glycosylamide derivative of the general formula 178 is shown in Scheme 42.
With the aid of PyBOP, a thienopyridinecarboxylic acid of general formula 21 or 28 and 2
Tributylphosphine-mediated coupling with 3,3,4,6-tetra-acetyl-D-glucopyranosyl azide afforded a protected glycosylamide of general formula 177. No other isomer was detected in the reaction. Cleavage of the acetyl group with methylamine provided the compound of general formula 178.

[0120]

Embedded image Scheme 43 illustrates the preparation of 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxamide using a modification of the pathway described in Scheme 7. A two-step series was employed to build the thienopyridine nucleus in the synthesis of 182. Treatment of dichloropyridine aldehyde with one equivalent of N-BOC-protected 4-hydroxyaniline provided compound 179, which was cyclized to give ester 180. Conversion to the amide 181 was carried out as described above, and the Boc-group was removed by treatment with trifluoroacetic acid. Aniline 182 acts as a starting material for a Sandmeyer reaction via a diazonium salt, whose amino groups can be converted to various functional groups, including the halogen, hydroxy, cyano groups of other standard sandmeier products. Note what you can do.

[0121]

Embedded image Scheme 44 is based on the methodology described by Buchwald et al. (Wolfe
Buchwald, Stephen L., J .; J. Org. Chem
. 1997, 62, 6066) using 4-substituted aminophenoxythieno [2
1 illustrates a general method for preparing [3-c] pyridine. The iodide 183 prepared by the method described above can be used in the presence of bis (dibenzylideneacetone) dipalladium and BINAP in the presence of a disubstituted amine (such as morpholine described in the above example).
And substituted aniline 184 was obtained.

[0122]

Embedded image Scheme 45 describes the preparation of 4- (4-hydroxymethylphenyl) thieno [2,3-c] pyridine 188 using a modification of the pathway shown in Formula 7. Starting with mono-tritylated 4-hydroxybenzyl alcohol, condensed with dichloroaldehyde 18 and cyclized with methylthioglycolate to give protected benzyl alcohol 188.

[0123]

Embedded image Scheme 46 describes the preparation of protected benzyl alcohol 190, starting from mono-tetrahydropyran-protected hydroxybenzyl alcohol 189. Also, benzyl alcohol analog 188 can be obtained by standard acid-catalyzed hydrolysis of THP groups.

[0124]

Embedded image Also, as shown in Scheme 47, benzyl alcohol 188 can be derivatized to an ester using, for example, the carbodiimide conditions described above, or standard coupling procedures using acid chlorides. Further, the alcohol can be converted to a carbamate (R = N by treatment with isocyanate or carbamoyl chloride).
H ₂ , monosubstituted amino or disubstituted amino).

[0125]

Embedded image The glycoside of benzyl alcohol 187 can be produced using the procedure described in Scheme 48. Alcohol 187 and tri-O-acetyl-D
-Treatment of glucar with stoichiometric scandium triflate gave stereospecific protected glycoside 192, which was deprotected with methylamine to give free glycoside 193.

[0126]

Embedded image Stille coupling of the iodophenyl derivative 194 (or its corresponding bromophenyl analog) with tributylethoxyvinyltin allows the introduction of an acetyl group on the phenyl ether at the 4-position, as shown in Scheme 49. The acetophenone derivative 195 is obtained by hydrolyzing the intermediate vinyl ether during the reaction conditions. Addition of methylmagnesium bromide to ketone 195 at -50 ° C did not give the desired adduct, but conversely isolated aldol adduct 196 in 40% yield. Palladium-catalyzed carbonylation of bromophenoxymethyl ester 197 in an aqueous medium affords acid 198 in moderate yields.
was gotten. PyBOP or EDC mediated coupling with an amine (exemplified above with morpholine) followed by amination of the 2-methyl ester provided the diamide 199.

[0127]

Embedded image Scheme 50 describes the preparation of a cinamide ether. Bromophenoxymethyl ester 197 using tolylphosphine as ligand
Cinnamate 200 in good yield by Heck reaction of
was gotten. Hydrolysis of the t-butyl ester with trifluoroacetic acid followed by PyBOP, or EDC-mediated coupling with an amine followed by amination of the methyl ester gave diamide 201.

[0128]

Embedded image Scheme 51 illustrates the preparation of a 4-heterocyclic phenoxythienopyridine. When the para-cyanophenyl derivative 202 is treated with hydroxyamine in a mixture of DMF and ethanol, hydroxyimidamide 203 is obtained smoothly and oxadiazole 204 is obtained by heating with trifluoroacetic anhydride in pyridine. Was. The cyano derivative 202 was converted to imidazoline 205 under the conditions described above. Still of iodine compound 194 and tributylstannylthiophene
Attachment of other heterocycles using known Stille, Suzuki or Heck conditions as exemplified by e-coupling provided compound 205A. The aryl coupling reactions described above can be applied to compounds using various substituents at C-2 of thienopyridine in addition to the methyl amide illustrated in Scheme 51.

[0129]

Embedded image By the methods described in Scheme 52 and Scheme 53, cyclopropylcarbinyl alcohol derivatives of 4-phenyl ether can be prepared. Commercial phenylcyclopropanecarboxylic acid is converted to the corresponding alcohol 206 by LAH reduction, followed by demethylation of the hydroxymethyl group and selective protection to give phenol 207. Using the procedure of Scheme 7, phenol 2
07 was condensed with dichloroaldehyde 18 and then with methylthioglycolate to give thienopyridine 208. Conversion of the standard yielded the desired compounds 209 and 21
0 was obtained.

[0130]

Embedded image Alcohol 206 was alkylated to give polyether phenol 211 and converted to cyclopropylcarbinyl polyether 212 using a similar procedure described in Scheme 52, as shown in Scheme 53. Such alkylation chemistry is:
It can be done widely by substituting the diether tosylate shown by other alkyl halide or sulfonate esters.

[0131]

Embedded image In Scheme 54, the difluoroacetic acid derivative 213 was synthesized by copper-mediated coupling of iodide 194 and ethyl iododifluoroacetate in the presence of phenol, which was found to significantly inhibit side effects. Ester 21
The reduction of 3 gave difluoroethyl alcohol 214. Alkylation of alcohol 214 with ethoxyethyl tosylate in the presence of sodium hydride and 15-crown-5 provided polyether 215.

[0132]

Embedded image Scheme 55 shows a 4-alkoxythieno [2, via phenolic alkylation
3-c] describes an alternative synthesis of pyridine. Mitsunobu alkylation of 5-chloro-3-hydroxypyridine provided benzyl ether 216, which was deprotonated with an alkyl lithium base and the resulting anion was treated with methyl formate to give pyridinecarboxaldehyde 217. The thienopyridine nucleus was constructed by condensation with methyl thioglycolate under the conditions described above to give ester 218. The method can be applied to other alkyl ethers similar to 216 to obtain various 4-alkoxyl derivatives related to 218. The ester 218 was then converted to another active derivative, such as an amide, using the methods described above. Benzyl ether 218 was hydrocracked to phenol 219 and converted to the corresponding amide 220 by standard procedures. Phenol 219 also acts as a partner in the Mitsunobu reaction with various primary or secondary alcohols to give alkyl ethers of general formula 221 (Huang, F. et al.
J. Med. Chem. 1998, 41, 4216-4223). General formula 221
Was converted to the amide of general formula 222 by treatment with a methanolic amine solution under standard conditions of reflux.

[0133]

Embedded image Thienopyridine analogs having one 4-carbonyl group can be prepared by the procedure described in Scheme 56. Under the conditions described above, dichloropyridine aldehyde 18 was treated with methyl thioglycolate to give 4-chlorothienopyridine ester 223. Transesterification to the acid 224 by base catalyzed hydrolysis and tertiary butyl esterification to 225 was carried out under O-
Performed using t-butyl trichloroacetimidate. Palladium catalyzed carboethoxylation was performed under the conditions described above to give diester 226. Aldehyde 227 was obtained by reduction / oxidation reaction and then condensed with an arylmagnesium halide reagent (exemplified above with 4-chlorophenyl magnesium chloride) to give alcohol 228. Ester 228 can be directly converted to various 2-substituted thienopyridine analogs or can be oxidized to the corresponding 4-keto derivative 230. The synthesis is complete by standard conversion of ester 230 to amide 231. Ester 226 is the first alkaline hydrolysis of the ethyl ester,
It should be noted that coupling to an amine, acidic hydrolysis of a tertiary butyl ester, final coupling to another amine, can be selectively converted to the amide derivative to give 308.

[0134]

Embedded image Various 2-substituted thieno [2,3-c] pyridines have the general formula 20 and 25-2
-Available from esters. Scheme 57 illustrates the products obtainable from the hydroxymethyl derivative of general formula 232. General formula 20 or 25
Reduction of the ester of the formula to calcium borohydride provided the alcohol of general formula 232. Aldehydes of general formula 233 were obtained neatly by Swern oxidation. As exemplified by the preparation of 2-vinylthienopyridine of general formula 234, this versatile intermediate can be converted to an olefin by standard Wittig conditions (Hibino, SJ Org. Chem. 1984, 49, 50).
06-5008). ) Additional modifications to the dihydroxyethyl compound 235 were made by using osmium tetroxide catalyzed with 4-methylmorpholine N-oxide as the stoichiometric oxidant.

[0135]

Embedded image Scheme 58 illustrates the conversion of aldehyde 233 to acrylate 236, which is a Horner-Emmo using trimethylphosphonoacetate.
ns condensation (Jung, ME and Kiankarami,
M. J. Org. Chem. 1998, 63, 2968-2974). The described method can be extended to analogs with various C-4 substituents, including aryloxy, alkoxy, arylamino, aryl, alkyl. Next, the derivative ester 236 was hydrolyzed to obtain an acid 237. Carboxylic acid 237 was subjected to standard coupling conditions to give amide 238. The derivative acrylate of general formula 239 can be oxidized to the corresponding diol of general formula 240 using osmium tetroxide in the presence of 4-methylmorpholine-N-oxide.

[0136]

Embedded image Scheme 59 uses starting materials in the preparation of oxime derivatives of general formula 241
And L_AX_A= Using aldehyde 233 with aryloxy
Explain. The outlined method generally involves various L_AX_AAnalogs with substituents
Applicable to In addition, the aldehyde of the general formula 233 is converted to an organic magnesium
Or an organolithium) reagent to give a secondary alcohol, which is represented by the general formula 2
Oxidized to the corresponding ketone of 42. Oxidation was performed under standard Swern conditions (low temperature CH ₂ C1₂DMSO and oxalyl chloride, and
Treatment with a tertiary amine such as amine).
(Tetra-n-propyltetraoxolthenium (VII) salt, man dioxide
Gun). Thereafter, the ketone is converted to the general formula 243 by the method described above.
Oxime.

[0137]

Embedded image The preparation of the 2-heterocyclic thienopyridine of general formula 249 is illustrated in Scheme 60. Treatment of a primary amide of general formula 26 with an excess of trifluoroacetic anhydride in pyridine affords a smooth nitrile of general formula 244, which acts as a useful intermediate in the preparation of amidine and azole derivatives. Therefore, the general formula 244
Was converted to the amidoxime of general formula 245 by treatment with hydroxylamine hydrochloride and triethylamine. Reaction of the amidoxime of general formula 245 with acetyl chloride, trifluoroacetic anhydride, triethyl orthoformate or trichloroacetyl chloride in pyridine, general formula having a variable site of X determined by the choice of acylating or dehydrating reagent 246 oxadiazoles were obtained. The trichloromethyloxadiazole of the general formula 246 (X = CCl ₃ ) is heated together with ammonia in a sealed tube to give 5-amino-1,4 of the general formula 247.
Converted to 2,4-oxadiazole. When DBU is used as a base and reacted with an excess of cyanamide in THF, the nitrile of the general formula 244 is converted to a compound of the general formula 248
Was converted to cyanoamidine. Thereafter, the cyanoamidine of the general formula 248 is treated with hydroxylamine hydrochloride and triethylamine in methanol to obtain a compound of the general formula 2
49 3-amino-1,2,4-oxadiazole was obtained.

[0138]

Embedded image Scheme 61 illustrates the preparation of a 2-arylcarbonylthienopyridine. The thienopyridine of general formula 44 was deprotonated with an alkyl lithium base and condensed with nitrobenzaldehyde to give benzyl alcohol of general formula 250. General formula 25
Tin (II) -induced reduction of nitrophenyl to the aniline 1 was performed by selective alcohol oxidation using pyridinium chlorochromate. Further, the nitrobenzyl alcohol of general formula 250 was converted to the corresponding ketone of general formula 253 under Swern conditions (eg, treatment with low temperature oxalyl chloride / DMSO / CH ₂ Cl ₂ , and further with an amine base).

[0139]

Embedded image Scheme 62 describes the preparation of 2-carbamate thienopyridine and 2-urea thienopyridine. The alcohol of general formula 232 was converted to amines of general formula 254 by Mitsunobu reaction with phthalimide and further deprotection with hydrazine. The amine of general formula 254 was converted to the corresponding urea derivative of general formula 255 by reaction with potassium isocyanate under acidic conditions. Similarly, the alcohol of general formula 232 was converted to the corresponding carbamate of general formula 256. This chemistry is generally applicable to the use of substituted isocyanates or carbamoyl chlorides, resulting in mono- or disubstituted carbamate or urea derivatives.

[0140]

Embedded image Scheme 63 shows the 2-aminothienopyridine of general formula 54,
2 illustrates the preparation of thiourea thienopyridine. Reaction of 54 with the substituted isothiocyanate in pyridine at reflux provided the thiourea of general formula 257.

[0141]

Embedded image Scheme 64 illustrates the synthesis of a sulfonamide at the 2-position of a thienopyridine. 4 shows an improved method for the decarboxylation of thienopyridine-2-carboxylic acid, wherein a thienopyridine of general formula 44 is obtained in high yield by heating an acid of general formula 21 at 210 ° C. in diphenyl ether. Compound 44 was deprotonated with a strong base and then treated with sulfur dioxide to give the intermediate sulfinic acid. Addition of N-chlorosuccinimide affords the sulfonyl chloride of general formula 258, which is then reacted with ammonia, primary or secondary amine in the presence of diisopropylethylamine in a protic solvent such as methanol, and then reacted with general formula 25
Nine different sulfonamides were prepared (Prough, JD et al., J. Med.
Chem. 1991, 34, 1805-1818; Davidsen, S .; K
. Et al. Med. Chem. 1998, 41, 74-95).

[0142]

Embedded image Scheme 65 provides an overview on the synthesis of new 2-arylthienopyridines having an amino or hydroxyl group on the aryl ring. Suzuki of nitro-substituted aryl iodides with boronic acids of general formula 79 using the method of Scheme 24
Coupling provided the biaryl of general formula 260. The biaryl of general formula 260 was reduced with tin (II) chloride to the aminophenyl derivative of general formula 261. The methyl ether of general formula 262 is prepared from boronic acid 79 by coupling with methoxyiodobenzene and converted to the hydroxy derivative of general formula 263 by using boron tribromide to demethylate the methyl ether. did.

[0143]

Embedded image Schemes 66-71 illustrate the synthesis for an additional 5-membered heterocycle at the 2-position of the thienopyridine. Scheme 66 outlines a method for producing 1,3,4-oxadiazole. The hydrazide of general formula 264 was prepared by treating an ester of general formula 20 or 25 with hydrazine in methylene chloride. The hydrazide is reacted with cyanogen bromide to give 5-amino-1 of the general formula 265.
, 3,4-oxadiazole. The hydrazide of the general formula 264 can be converted to the 5-unsubstituted-1,1 of the general formula 266 by condensation with an orthoester under reflux conditions.
It can be converted to 3,4-oxadiazole or 5-alkyl-substituted-1,3,4-oxadiazole.

[0144]

Embedded image Scheme 67 illustrates a method for preparing a 1,3,4-triazole from a methyl ester of general formula 20 or 25. By condensation with aminoguanidine under basic conditions (eg sodium methoxide in methanol),
67 2-amino-1,3,4-triazoles were obtained. Non-specific methylation is carried out using sodium hydride and methyl iodide using 1,3,4 of the general formula 267.
Carried out with a triazole, a monomethyltriazole of the general formula 268, a general formula 26
9 and trimethyltriazole of the general formula 270 were obtained, which were separable by chromatography.

[0145]

Embedded image Scheme 68 illustrates a method for preparing a 1,3,4-thiadiazole of general formula 272. Reaction of an acid chloride derived from an acid of general formula 21 or 28 with thiosemicarbazide or a substituted thiosemicarbazide provides an intermediate acylated thiosemicarbazide of general formula 271 and acid catalysis (eg, methanesulfone at toluene reflux). Cyclization under acid) gave the thiadiazole of general formula 272.

[0146]

Embedded image Scheme 69 comprises 1,3,4-oxadiazole-2-thione and general formula 2
Methods are provided for the preparation of 74 derived alkylthio substituted oxadiazoles. General formula 2
Treatment of 64 hydrazides with potassium disulfide in potassium hydroxide dissolved in an aqueous ethanol solution gave the cyclic thiocarbamates of general formula 273. The thiocarbonyl group was alkylated with an alkyl halide in low yield to obtain alkylthio 1,3,4-oxadiazole of the general formula 274.

[0147]

Embedded image Scheme 70 illustrates the preparation of tetrazole at the 2-position of thienopyridine.
The 2-cyano derivative of general formula 244 was converted to a tetrazole of general formula 275 using trimethylsilyl azide in the presence of dibutyltin oxide as a catalyst. Tetrazole was converted to the N-methyl derivative of general formula 276 using a diazomethane solution in methanol.

[0148]

Embedded image Scheme 71 illustrates the synthesis of 2-oxazole and 2-imidazole thienopyridine. The chloroethylamide of general formula 277 was prepared by chlorination of the corresponding hydroxyethylamide and then cyclized to an oxazoline of general formula 278 under a base catalyst (eg, diazabicycloundecane in dichloromethane). Oxazolines of general formula 278 can be converted to oxazoles of general formula 278 by dehydrogenation according to the method of Meyer et al. (Meyers,
A. I. J. et al. Amer. Chem. Soc. 1975, 97, 7383).
The aminoethylamide of general formula 280 was cyclized to imidazoline of general formula 281 by treatment with calcium oxide in diphenyl ether at elevated temperature. Imidazolines of general formula 281 can be converted to imidazoles of general formula 282 by literature methods (Hughey, JL et al., Synthesi).
s [SYNTBF] 1980, (6), 489).

[0149]

Embedded image Scheme 72 illustrates an improved method for preparing 3-alkyl-substituted thienopyridines of general formula 115. Aldehyde 18 was condensed with preformed potassium phenoxide to give a mixture of mono- and disubstituted aryloxyaldehydes. Next, this mixture was reacted with a desired Grignard reagent, and then the obtained mixture of secondary alcohols was subjected to a Swern oxidation treatment to obtain a desired aryloxy ketone compound. Further, the mixture of aryloxy ketones is reacted with methylthioglycolate in the presence of cesium carbonate to form 2,3,3 of the general formula 114
The 4-trisubstituted thieno [2,3-c] pyridine ester was obtained. These esters were converted to the corresponding acids by hydrolysis with lithium hydroxide and then coupled with various amines, for example, with carbodiimide, to give the desired amide of general formula 115.

[0150]

Embedded image Scheme 73 provides for the synthesis of 3-carboxythienopyridine. Using a methodology similar to that described for the preparation of 20 or 25, 3,5-dichloropyridine is treated at low temperature with a strong base such as lithium diisopropylamide in anhydrous ethereal solvent, followed by t-butylchlorooxoacetate. Was added to give the 4-tert-butyl-2-ketoester of 3,5-dichloropyridine 283. The ester 283 was then reacted at room temperature with 1.25 equivalents of preformed potassium phenoxide to give the monoaryloxy derivative as the major product.
Without purification, the monoaryloxy ester is treated with methyl thioglycolate and a base such as potassium t-butoxide or cesium carbonate to give the desired compound of general formula 2
84 thienopyridine diester was obtained. Thereafter, the diester of general formula 284 was treated with a methanolic amine to give the corresponding 3-t-butyl ester amide of general formula 285. The t-butyl ester amide of general formula 285 was converted to the corresponding acid amide of general formula 287 by solvolysis using trifluoroacetic acid. further,
The diester of general formula 284 can be converted to the acid of general formula 286 by a similar solvolysis reaction.

[0151]

Embedded image Scheme 74 shows a scheme for preparing 4-amino-substituted thienopyridine derivatives.
It describes the use of bromothienopyridine 32. Ester 32 is converted to the amide of general formula 288 by standard methods and then variously catalyzed using palladium (0) catalysis as described by Buchwald (J. Org. Chem. 1997, 62, 6066-6068). Coupling to various amines, general formula 2
The 4-amino derivative of 89 was obtained.

[0152]

Embedded image Scheme 75 outlines the preparation and reaction of 7-chlorothienopyridine and 7-bromothienopyridine derivatives. Analogs serve as synthetic intermediates for various 7-substituted thienopyridines and are useful for preparing active derivatives. The ester of the general formula 25 is metachloroperbenzoic acid and is represented by the general formula 29
Oxidized to 0 pyridine-N-oxide. The N-oxide was rearranged to a 7-halogen derivative of the general formula 291 by heating in phosphorus oxychloride or phosphorus oxybromide. The resulting 7-halide can be converted to the amide derivative of general formula 292 by standard methods without reaction of the 7-chloro or 7-bromo component. However, under further forcing conditions, replacement of the chloro or bromo group with an amine or alcohol provides a 7-amino derivative of general formula 293,
And a 7-alkoxy derivative of the general formula 294 can be obtained. The ester of general formula 294 was converted to the amide of general formula 295 using standard methods. The 7-hydroxy analog of general formula 296 was prepared from the derivative of 291 using acetic anhydride, followed by hydrolysis with water. Further, the 7-halogen derivative 2
91, especially the 7-Moromo derivative, was an effective educt in the Suzuki reaction with arylboronic acids, as described in Scheme 19 and Scheme 65.

[0153]

Embedded image Scheme 76 describes the preparation of a furopyridine analog such as 299 (Example 327). By a procedure analogous to that of the preparation of 20 or 25, low yields of furopyridine esters are obtained by successively reacting dichloropyridinecarboxaldehyde 18 with potassium phenoxide and then with ethyl glycolate and further cyclizing under basic conditions. 298 were obtained. Amide 299 was obtained by standard hydrolysis and coupling conditions. The amide was converted to thioamide 300 by treatment with Lawesson's reagent in heated toluene.

[0154]

Embedded image Scheme 77 illustrates the preparation of N-alkyl 5-amino-1,3,4, -oxadiazole. Treatment of 265 with refluxing trimethyl orthoformate and further reduction of the eneamine intermediate with sodium borohydride in refluxing ethanol provides N-alkylated 5-amino-1,3,4, -oxadiamides of general formula 301. An azole is obtained.

[0155]

Embedded image Scheme 78 illustrates the synthesis of a substituted vinyl moiety at the 4-position of a thienopyridine. Aldehyde 2 in the presence of potassium bis (trimethylsilyl) amide
Treatment of 27 with the appropriate diethylphosphonate provided 302.
Thereafter, treatment of compound 302 with sulfuric acid in methanol provided methyl ester 303, followed by standard amide formation using ammonia and methanol to give 4-vinyl-substituted thienopyridine of general formula 304. The introduction of substituted vinyls can also be achieved by using Wittig phosphorane chemistry.

[0156]

Embedded image Scheme 79 illustrates the preparation of a 4-substituted alkyl thienopyridine. The alcohol 228 was subjected to palladium on carbon in acetic acid to produce the methylene derivative 305. Treatment of 305 with sulfuric acid in methanol gave 306. Amide formation was performed by treating 306 with ammonia in methanol to give 307.

[0157]

Embedded image Scheme 80 illustrates the preparation of a thiazole derivative at the 2-position of a thienopyridine. The thioamide of general formula 309 was alkylated and cyclized with ethyl bromopyruvate to give the thiazole ester of general formula 310. Standard amide formation provided the amide of general formula 311. Other amines can be used to obtain various substituted amides. Further, the ester of general formula 310 is an intermediate acid Cu
It can be converted to a carbamate of the general formula 312 via the rtius rearrangement. The t-butyl carbamate of the general formula 312 was converted to a primary amine of the general formula 313 by the action of trifluoroacetic acid.

[0158]

Embedded image Scheme 81 outlines an alternative method of preparing 3-substituted thienopyridines, where Ar is unsubstituted aryl or substituted aryl, or heterocycle, and R is alkyl, alkoxy, substituted alkyl, aryl, arylalkyl It is. Reaction of aldehyde 18 with the appropriate organomagnesium halide provided the intermediate secondary alcohol, which was oxidized to the corresponding ketone 314. The method of oxidation was the Swern method, but other standard oxidation methods of this type can also be used (eg, PCC, TPAP). The above method was then performed on the 3-unsubstituted analog to give ester 315. The ester 315 then served as the starting material in the preparation of amide or other heterocyclic derivatives at the 2-position of thienopyridine.

[0159]

Embedded image Scheme 82 describes a method for producing a cyclic derivative between the 2- and 3-positions of thienopyridine. The 3-methyl derivative 115 was treated with N-bromosuccinimide (or N-chlorosuccinimide) in carbon tetrachloride to obtain a bromomethyl (or chloromethyl) compound 316 (X = Br, Cl). Then
Compound 316 can be reacted with a primary amine via alkylation and acylation to give tricyclic lactam 317. Further treatment of compound 316 with sodium alkoxide or sodium aryl oxide (R ² = alkyl, aryl or heterocycle) provided the 3-position extended alkoxymethyl derivative 318. These esters can be reacted sequentially with a substituted amine to give the corresponding amide 319.

The compounds and processes of the present invention may be better understood with reference to the following examples. However, the examples are intended to illustrate the scope of the present invention,
It does not limit the scope of the invention.

Example 1 Methyl 2-[(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate Example 1A 6-ethyl-3,4-dihydro-4-oxothieno [2,3 -D] Methyl pyrimidine-2-carboxylate The desired compound is described in Heterocyclic Chem. 1987, 24,
Prepared as described in 581-587.

Example 1B 6-ethylthieno [2,3-d] pyrimidin-4 (3H) -one Example 1A (35 g, 140 m) in DMSO (80 mL) and water (8 mL)
mol) and LiCl (6.5 g, 153 mmol) were heated to 150 ° C. for 18 hours, cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated to give the specified compound.

Example 1C Example 1B (3.97 g, 22.0 mmol) in 4-chloro-6-ethylthieno [2,3-d] pyrimidine POCl ₃ (22 mL) was heated to reflux for 2 hours and cooled Then, poured on ice, diluted with water, made alkaline with concentrated ammonium hydroxide and extracted with ethyl acetate. The extract is dried (Mg
SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate-hexane to give the specified 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 treated sequentially 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 hours,
Cooled, poured into water, diluted with brine and extracted with dichloromethane. The extract was washed with water and brine, dried (MgSO _4), filtered, and concentrated.
The residue was triturated and washed with 10% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 269 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33 (t, 3H);
99 (q, 2H), 3.75 (s, 2H), 4.26 (s, 3H), 7.23 (
s, 1H), 8.76 (s, 1H).

Example 2 Example 1D except that thiocresol was used in place of methyl 6-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-d] pyrimidine thioglycolate
Treated Example 1C as described in the title compound to afford the title compound.

MS (DCI / NH ₃ ) m / z 286 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.32 (t, 3H);
38 (s, 3H), 2.99 (q, 2H), 7.20 (s, 1H), 7.33 (
m, 2H), 7.52 (m , 2H), 8.63 (s, 1H); Calcd for analysis _{C 15 H 14 N 2 S 2} : 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 Performed as in Example 1D, except that methyl 2-mercaptopyridine was used instead of methyl thioglycolate. Treatment of Example 1C provided the title compound.

MS (DCI / NH ₃ ) m / z 274 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (t, 3H);
99 (q, 2H), 7.18 (s, 1H), 7.46 (dt, 1H), 7.81
(D, 1H) 7.90 (dt, 1H) 8.60 (m, 1H), 8.74 (s, 1
H).

Example 4 6-Ethyl-4-[(2-methylethyl) thio] thieno [2,3-d] pyrimidine As in Example 1D, except that isobutylmercaptan was used in place of methyl thioglycolate. To Example 1C to give the title compound.

MS (DCI / NH ₃ ) m / z 253 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.08 (d, 6H);
39 (t, 3H), 2.03 (hep, 1H), 2.95 (q, 2H), 3.2
8 (d, 2H), 7.01 (s, 1H), 8.71 (s, 1H); Calcd for analysis _{C 12 H 16 N 2 S 2} : 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 Performed as in Example 1D, except that benzyl mercaptan was used instead of methyl thioglycolate. Treatment of Example 1C provided the title compound.

MS (DCI / NH ₃ ) m / z 287 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
96 (q, 2H), 4.65 (s, 2H), 7.16 (s, 1H), 7.21 to 21
7.36 (m, 3H), 7.46 (m, 2H), 8.83 (s, 1H); Calcd for analysis _{C 15 H 14 N 2 S 2} : 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)
Example 1C was treated as in Example 1D, except that 5-methyl-1,3,4-thiadiazole-2-thiol was used instead of methyl thio] thieno [2,3-d] pyrimidine thioglycolate. do it,
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 295 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (t, 3H);
82 (s, 3H), 3.05 (q, 2H), 7.42 (s, 1H), 8.88 (
s, 1H); Calculated for C ₁₁ H ₁₀ N ₄ S ₃ : 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-6-carboxylate Example 1A was treated as in Examples 1C and 2. To give the title compound.

MS (DCI / NH ₃ ) m / z 359 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26 (t, 3H);
31 (t, 3H), 2.39 (s, 3H), 3.02 (q, 2H), 4.27 (
q, 2H), 7.17 (s, 1H), 7.33 (m, 2H), 7.57 (m, 2
H); Calcd for analysis _{C 18 H 18 N 2 O 2} S 2: C, 60.31, H, 5.0
6, N, 7.81. Found: C, 60.44; H, 4.88; N, 7.65.

Example 8 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidine-4-
Example 1C (0.27 g, 1.37 mm) in amine isopropanol (1.5 mL)
ol) was treated with benzylamine (0.19 mL, 1.71 mmol) and sodium carbonate (0.24 g, 2.3 mmol), stirred at room temperature overnight, filtered and concentrated. The residue was purified by flash chromatography on silica gel using 25% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 270 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
88 (q, 2H), 4.72 (d, 2H), 7.20 to 7.40 (m, 6H),
8.26 (s, 1H), 8.34 (t, 2H); Calcd for analysis _{C 15 H 15 N 3 S 2} : C, 66.89, H, 5.61,
N, 15.60. Found: C, 66.66, H, 5.43, N, 15.43.

Example 9 Example in 6-ethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine isopropanol (2 mL) 1C (0.20 g, 1.01 mmol
) Was dissolved in 2-amino-5-methyl-1,3,4-thiadiazole (0.15 g).
, 1.26 mmol) and sodium carbonate (0.18 g, 1.7 mmol) and stirred at room temperature for 48 hours, cesium carbonate (0.55 g, 1.7 mmol)
) And stirred under reflux for 24 hours, concentrated, treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was recrystallized using ethanol / water to give the title compound.

[0181] mp _{^{277~280 ℃; MS (DCI / NH}} 3) m / z278 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ1.33 (t, 3H), 2.
63 (s, 3H), 2.96 (q, 1H), 7.81 (br s, 1H), 8.
65 (s, 1H); Calcd for analysis _{C 11 H 11 N 5 S 2} : 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-ethylthiophen-3-carboxamide Heterocyclic Chem. 1987, 24,
Prepared as described in pp. 581-587.

Example 10B 5-Ethyl-2-[(phenylacetyl) amino] -3-thiophenecarboxamide Example 10A was prepared as described in Bull. Soc. Chim. France 1975, p8
Treatment as described in 15 provided the specified compound.

Example 10C 6-Ethyl-2-phenylmethylthieno [2,3-d] pyrimidine-4 (3H
) - On dioxane / water, Example 10B was stirred in the presence of 10% _Na 2 CO _3,
The specified compound was obtained.

Example 10D 4-Chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine Example 10C was treated as in Example 1C to give the specified 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-1,3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound. I got

MS (DCI / NH ₃ ) m / z 386 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (t, 3H);
97 (q, 2H), 4.17 (s, 2H), 7.17 to 7.30 (m, 6H),
7.70 (br s, 2H); Calcd for analysis _{C 17 H 15 N 5 S 3} : C, 52.96, H, 3.92,
N, 18.17. Found: C, 53.10, H, 3.74, N, 18.03.

Example 11 Example 1D except that p-thiocresol was used in place of methyl 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyrimidine glycolate
Treatment of 3-methyl-7-chlorothieno [3,2-d] pyrimidine as in afforded the title compound.

MS (DCI / NH ₃ ) m / z 273 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.40 (s, 6H), 7.
36 (m, 2H), 7.57 (m, 2H), 8.04 (s, 1H), 8.88 (
s, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : C, 61.73, H, 4.44
, N, 10.28. Found: C, 61.73; H, 4.50; N, 10.21.

Example 12 7-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-
Treatment of 1,3,4-thiadiazole-2-thiol as in Example 1D provided the title compound.

MS (DCI / NH ₃ ) m / z 281 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.44 (s, 3H);
83 (s, 3H), 8.20 (s, 1H), 9.08 (s, 1H); Calcd for analysis _{C 10 H 8 N 4 S 3} : C, 42.84, H, 2.88, N
, 19.98. Found: C, 42.72; H, 2.83; N, 19.64.

Example 13 7-Methyl-4-[[5- (methylthio) -1,3,4-thiadiazole-2
-Yl] thio] thieno [3,2-d] pyrimidine Examples of 3-methyl-7-chlorothieno [3,2-d] pyrimidine and 5- (methylthio) -1,3,4-thiadiazole-2-thiol Treatment as in ID gave the title compound.

MS (DCI / NH ₃ ) m / z 313 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.45 (s, 3H);
83 (s, 3H), 8.22 (s, 1H), 9.11 (s, 1H); Calcd for analysis _{C 10 H 8 N 4 S 4} : 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-
Treatment of 1,3,4-thiadiazole-2-thiol as in Example 1D provided the title compound.

MS (DCI / NH ₃ ) m / z 282 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.43 (s, 3H), 7.
80 (br s, 2H), 8.15 (s, 1H), 9.02 (s, 1H); Calculated for C ₉ H ₇ N ₅ S ₃ : 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-4-amine of 3-methyl-7-chlorothieno [3,2-d] pyrimidine The ethanol solution was treated with 4- (methylmercapto) aniline, stirred under reflux for 45 minutes, cooled to room temperature and filtered, and the precipitate was recrystallized from ethanol / water to give the title compound.

MS (DCI / NH ₃ ) m / z 288 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (s, 3H);
48 (s, 3H), 7.29 (m, 2H), 7.76 (m, 2H), 7.87 (
br s, 1H), 8.60 (s, 1H), 9.63 (br s, 1H); Analysis Calculated for C ₁₄ H ₁₃ N ₃ S ₂ : 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- (methyl Phenyl) thio] thieno [3,2-d] pyrimidine-2-carboxylic acid A solution of LDA at −78 ° C. (0.1 M in THF, 9.6 mL) was prepared in Example 11 (0
. 26 g, 0.96 mmol), warm to 0 ° C. over 1 hour, pour constantly swirl onto dry ice, quench with saturated NH ₄ Cl, 3:
Extracted with 1 chloroform / isopropanol. Concentrate the extract and reduce the residue to 7%
Purification by flash chromatography on silica gel with methanol / dichloromethane provided the specified compound.

Example 16B 7-Methyl-4-[(4- (methylphenyl) thio] thieno [3,2-d] pyrimidine-2-carboxamide Suspension of Example 16A in dichloromethane (3.3 mL) To oxalyl chloride (
(0.03 mL, 0.33 mmol) and DMF (1 drop) and concentrated after acid chloride formation. The residue was suspended in THF (10 mL), transferred to a vigorously stirred 1: 1 ammonium hydroxide / water solution (10 mL) and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was recrystallized from ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.40 (s, 3H);
58 (s, 3H), 7.35 (m, 2H), 7.57 (m, 2H), 8.01 (
br s, 2H), 8.93 ( s, 1H); Calcd for analysis _{C 15 H 13 N 3 OS 2} : C, 57.12, H, 4.15
, N, 13.32. Found: C, 56.81, H, 4.06, N, 13.25.

Example 17 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-
Methyl carboxylate Example 17A 3,5-dichloropyridine-4-carboxaldehyde Diisopropylamine (15.6 mL, 0 mL in 0 ° C. dry THF (25 mL))
. 111 mol) with n-butyllithium (44.6 mL, 2.5 M in hexane, 0.111 mol) for 35 minutes, stir for 30 minutes, cool to -78 ° C., and dilute with THF (100 mL). 3,5- in THF (175 mL)
Dichloropyridine (15.0 g, 0.101 mol) was added slowly over 3.5 hours to keep the internal temperature below -74 ° C. The solution was stirred at −78 ° C. for 30 minutes, and methyl formate (12.5 mL, 0.20 mL) in THF (50 mL) was added.
(3 mmol) was added dropwise over 35 minutes while maintaining the internal temperature below -74 ° C, stirred at -78 ° C for 1.4 hours and quickly added to an ice-cold solution of saturated NaHCO ₃ with vigorous stirring. Cannulated, partitioned with ethyl acetate (500 mL), extracted sequentially with saturated NaHCO ₃ (2 × 100 mL) and brine ( ₃ × 150 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using 10% acetone / hexane.

MS (DCI / NH ₃ ) m / z 176, 178, 180 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 added to p.
-Thiocresol (3.56 g, 28.7 mmol) and potassium carbonate (4.5.
36 g, 31.6 mmol) and stirred at 0 ° C. for 0.5 h, then at room temperature for 1 h, poured into water, 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 designated compound.

Example 17C Methyl 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxylic acid The solution of Example 17B was treated as in Example 1D. The title compound was obtained.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
91 (s, 3H), 7.20 (m, 2H), 7.29 (m, 2H), 8.00 (
s, 1H), 8.44 (s, 1H), 9.36 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ N ₂ S ₂ .0.25H ₂ O: C, 60.07
, H, 4.25, N, 4.37. Obtained values: C, 60.04, H, 4.08, N,
4.27.

Example 18 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-
Example 17C (2.C) in carboxylic acid isopropanol (25 mL) and water (15 mL).
(G, 635 mmol) and a suspension of LiOH.H ₂ O (1.4 g, 32 mmol) were heated to 75 ° C. for 1 hour, cooled, 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.

MS (DCI / NH ₃ ) m / z 302 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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 Example 18 (0.535 g, 1.78) in dichloromethane (25 mL) at 0 ° C.
mmol) was treated sequentially with oxalyl chloride (0.34 g, 2.67 mmol) and DMF (1 drop), stirred at room temperature for 0.5 h, and concentrated. Residue T
Suspended in HF solution, THF (60 mL), water (30 mL) and concentrated NH ₄ O
Treated with H (30 mL) and stirred for 0.5 h. The THF layer was separated, washed with brine, partially dried (MgSO ₄ ), filtered and concentrated. 5% residue
Purification by flash chromatography on silica gel with methanol / dichloromethane and recrystallization from 95% ethanol gave the title compound.

[0209] mp _{^{198~199 ℃; MS (DCI / NH}} 3) m / z301 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.29 (s, 3H), 7.
20 (m, 2H), 7.30 (m, 2H), 7.89 (brs, 1H), 8.
26 (s, 1H), 8.35 (s, 1H), 8.54 (brs, 1H), 9.
16 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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 Example 17B, except that 2-mercaptopyridine was used instead of p-thiocresol in Example 17B. Example 17 as in 17C, 18 and 19
Treatment of A gave the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + NH ₄ ) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.99 (d, 1 H), 7.
17 (dd, 1H), 7.65 (dt, 1H), 7.85 (brs, 1H),
8.18 (s, 1H), 8.36 (m, 1H), 8.49 (br s, 1H),
8.69 (s, 1H), 9.23 (s, 1H); Calcd for analysis _{C 13 H 9 N 3 OS 2} : 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 Performed as in Example 17B, except that 4-chlorothiophenol was used instead of p-thiocresol. Example 17 as in Examples 17B, 17C, 18 and 19
Treatment of A gave the title compound.

[0213] mp _{^{239~241 ℃; MS (DCI / NH}} 3) m / z321 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ7.31 (m, 2H), 7.
43 (m, 2H), 7.89 (br s, 1H), 8.24 (s, 1H), 8.
54 (br s, 1H), 8.56 (s, 1H), 9.38 (s, 1H); Calcd for analysis _{C 14 H 9 ClN 2 OS 2} : C, 52.42, H, 2.8
3, N, 8.73. Found: C, 52.33, H, 2.80, N, 8.63.

Example 22 N-methoxy-N-methyl-4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide Example 18 (0.66 g, 2.2 mmol) in dichloromethane was treated sequentially with oxalyl chloride (0.29 mL, 3.3 mmol) and DMF (1 drop) to give 30 Stirred for minutes and concentrated. The residue was suspended in THF and transferred to a solution of N, O-dimethylhydroxylamine hydrochloride (0.32 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) in 1: 1 THF / water. Stir for 5 minutes. Separating the THF layer, dried (MgSO _4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 345 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
34 (s, 3H), 3.74 (s, 3H), 7.19 (m, 2H), 7.27 (
m, 2H), 8.02 (s , 1H), 8.46 (s, 1H); Calcd for analysis _{C 17 H 16 N 2 O 2} S 2: C, 59.28, H, 4.6
8, N, 8.13. Found: C, 58.76, H, 4.58, N, 8.06.

Example 23 N-methoxy-4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxamide O-methylhydroxyl hydrochloride in place of N, O-dimethylhydroxylamine hydrochloride Example 18 was treated as in Example 22 except using an amine to give the title compound.

MS (DCI / NH ₃ ) m / z 331 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
76 (s, 3H), 7.20 (m, 2H), 7.30 (m, 2H), 7.89 (
br s, 1H), 8.15 (s, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
1H); Analysis _{C 16 H 14 N 2 O 2} S 2 · 0.25H Calcd for ₂ O: C, 58.
16, H, 4.27, N, 8.48. Obtained: 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) and refluxed. For 20 minutes and concentrated. The residue was suspended in (3: 1) benzene / dichloromethane (4 mL), treated with trimethylamine (0.5 mL) and 4-chloroaniline (46 mg, 0.36 mmol), stirred under reflux overnight, and concentrated did. The residue was treated with water and extracted with dichloromethane. The extract is dried (Mg
SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 411 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.31 (s, 1H)
H), 10.90 (br s, 1H); Calcd for analysis _{C 12 H 15 ClN 2 OS 2} : C, 61.38, H, 3.
68, N, 6.2. Found: C, 61.22, H, 3.67, N, 6.79.

Example 25 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxaldehyde THF of Example 22 (3.33 g, 9.6 mmol) at -5 ° C. The solution was treated dropwise with 1M DIBAl-H in THF (14.5 mL, 14.5 mmol),
Stir for 45 minutes, pour into ice / HCL with constant stirring and extract 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 (300 MHz, 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 , 1H), 10.23 (s, 1H); Calcd for analysis _{C 15 H 11 NOS 2: 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-methyl oxime 1: 1 pyridine in ethanol (8 mL) Example 25 (0.22 g, 0.7
Methoxylamine hydrochloride (0.51 mL, 1.52 mmol)
), Stirred at room temperature for 3 hours, concentrated, treated with water, and extracted with dichloromethane. The extract was washed with 1N HCl, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
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 (s, 0.6H), 8.38 (s, 0.4H)
H), 8.68 (s, 0.6H), 9.20 (s, 0.6H), 9.30 (s, 0.6H).
0.4 H); Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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 The stirring time was changed from 3 hours to 18 hours Treated Example 25 and O-benzylhydroxylamine hydrochloride as in Example 26 to give the title compound.

MS (DCI / NH ₃ ) m / z 391 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
22 (s, 1.2H), 5.38 (s, 0.8H), 7.15 to 7.26 (m,
4H), 7.31 to 7.47 (m, 5H), 7.78 (s, 0.6H), 7.9
6 (s, 0.4H), 8.31 (s, 0.4H), 8.36 (s, 0.6H),
8.39 (s, 0.4H), 8.74 (s, 0.6H), 9.20 (s, 0.6H)
H), 9.30 (s, 0.4H ); Calcd for analysis _{C 22 H 18 N 2 OS 2} : C, 67.66, H, 4.65
, N, 7.17. Found: C, 67.45, H, 4.80, N, 7.13.

Example 28 2-[[[4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid Carboxy hemihydrochloride instead of methoxylamine hydrochloride Example 25 was treated as in Example 26 except using methoxylamine to give the title compound.

MS (DCI / NH ₃ ) m / z 359 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
71 (s, 2H), 7.19 (m, 2H), 7.25 (m, 2H), 7.84 (
s, 1H), 8.36 (s, 1H), 8.79 (s, 1H), 9.20 (s, 1)
H); Calcd for analysis _{C 17 H 14 N 2 O 3} S 2: C, 56.97, H, 3.9
4, 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-phenyloxime O-phenylhydroxylamine hydrochloride is used instead of methoxylamine hydrochloride. Example 25 was treated as in Example 26 except used to afford the title compound.

[0229] mp _{^{94~97 ℃; MS (DCI / NH}} 3) m / z337 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.38 (s, 3H), 7.
09 to 7.50 (m, 9H), 7.98 (s, 0.5H), 8.16 (s, 0.
5H), 8.39 (s, 0.5H), 8.42 (s, 0.5H), 8.71 (s
, 0.5H), 9.16 (s, 0.5H), 9.27 (s, 0.5H), 9.3
7 (s, 0.5H); Calcd for analysis _{C 21 H 16 N 2 OS 2} : 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 Except that hydroxylamine hydrochloride was used instead of methoxylamine hydrochloride. Example 25 was treated as in 26 to give the title compound.

[0231] mp _{^{209~210 ℃; MS (DCI / NH}} 3) m / z301 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.28 (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); Calcd for analysis _{C 15 H 12 N 2 OS 2} : C, 59.98, H, 4.03
, N, 9.33. Found: C, 59.80, H, 4.08, N, 9.30.

Example 31 2-[[[4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide Example 28 is in Example 19. To give the title compound.

MS (DCI / NH ₃ ) m / z 358 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
52 (s, 0.6H), 4.66 (s, 0.4H), 7.19 (m, 2H), 7
. 25 (m, 2H), 7.32 (brs, 1H), 7.40 (brs, 1H)
), 7.84 (s, 0.6H), 7.97 (s, 0.4H), 8.32 (s, 0H).
. 4H), 8.37 (s, 0.6H), 8.40 (s, 0.4H), 8.75 (
s, 0.6H), 9.21 (s , 0.6H), 9.32 (s, 0.4H); Analysis _{C 17 H 15 N 3 O 2} S calculated for ₂ · (1.25H ₂ O) Value: C, 5
7.12, H, 4.23, N, 11.76. Obtained: C, 56.19, H, 4.
48, N, 10.94.

Example 32 (E) -3-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] -2-propenamide Example 25 (10 mL) in chloroform (10 mL) 0.23 g, 1.27 mmol)
To carbamoylmethylenetriphenylphosphorane (0.41 g, 1.27 mmol
Treated with 1), heated to reflux for 30 hours, cooled and concentrated. The residue was purified by flash chromatography on silica gel using 2% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 327 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H), 6.
64 (d, 1H), 7.19 (m, 2H), 7.25 to 7.37 (m, 3H),
7.68 to 7.82 (m, 3H), 8.35 (s, 1H), 9.19 (s, 1H)
); Analysis _{C 17 H 14 N 2 OS 2} · H 2 Calculated for O: C, 62.55, H,
4.32, N, 8.58. Obtained: C, 59.78, H, 4.50, N, 8.2
0.

Example 33 1- [4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone A solution of Example 22 in THF (25 mL) at 0 ° C. was treated with methyl magnesium bromide (
Treat with 1.4 M in toluene / THF, 1.85 mL, 2.6 mmol), warm to room temperature, stir overnight, and add methylmagnesium bromide (1.4 in toluene / THF).
M, 0.7 mL, 1.3 mmol), stir for 1 h, and add ice / NH ₄ Cl
Poured in a continuous swirl over top and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.33 (s, 3H);
71 (s, 3H), 7.24 (m, 2H), 7.38 (m, 2H), 8.28 (
s, 1H), 8.31 (s, 1H), 9.29 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ NOS ₂ : C, 64.19, H, 4.38,
N, 4.68. Found: C, 64.11; H, 4.41; N, 4.61.

Example 34 2-Benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c]
Treatment of pyridine Example 22 and phenyllithium as in Example 33 provided the title compound.

MS (DCI / NH ₃ ) m / z 362 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Analysis C ₂₁ H ₁₅ NOS ₂ · 1.25H Calcd for ₂ O: C, 65.68
, H, 4.59, N, 3.64. Obtained: 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 in ethylene glycol (10 mL) was treated with hydrazine hydrate (
0.18 mL, 5.8 mmol), stir at 160 ° C. for 30 minutes, cool to room temperature, treat with potassium hydroxide, stir at 150 ° C. for 45 minutes, cool to room temperature, and add water Work up and extract with ethyl acetate. The extract is washed with water and 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 (300 MHz, DMSO-d ₆ ) δ 1.28 (t, 3H);
26 (s, 3H), 2.99 (q, 2H), 7.14 to 7.27 (m, 5H),
8.34 (s, 1H), 9.11 (s, 1H); Analysis C ₁₆ H ₁₅ NS ₂ · 0.25H Calcd for ₂ O: C, 67.33,
H, 5.30, N, 4.91. Obtained: C, 66.63, H, 5.38, N, 4
. 72.

Example 36 1- [4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, oxime Example 33 and hydroxylamine hydrochloride were treated as in Example 26 to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.22 (s, 1.5 H);
2.28 (s, 3H), 2.32 (s, 1.5H), 7.20 (m, 2H), 7
. 30 (m, 2H), 7.62 (s, 0.5), 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) ; Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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-2-carboxamide 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 methylene chloride. Treated with DCC (1.882 g, 9.13 mmol) in (15 mL), stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO _4), filtered, and concentrated. The residue was treated with 3-amino-1,2-propanediol (0.1%) in 3: 1 dioxane / methanol (20 mL).
(44 g, 1.6 mmol), stirred at room temperature for 18 hours, concentrated, dissolved in ethyl acetate, washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 6% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 375 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
19 (m, 1H), 3.4 (m, 1H), 3.65 (m, 1H), 4.62 (t
, 1H), 4.88 (d, 1H), 7.20 (m, 2H), 7.30 (m, 2H)
), 8.38 (s, 1H) , 9.1 (s, 1H), 9.28 (s, 1H); Analysis _{C 18 H 18 N 2 O 3} S 2 · 0.75H 2 Calculated for O: C, 57.
73, H, 4.84, N, 7.48. Obtained: C, 55.54, H, 5.23,
N, 6.7.

Example 38 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxylic acid, hydrazide Hydrazine was used instead of 3-amino-1,2-propanediol Example 18 was otherwise processed as in Example 37 to give the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
86 (br s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 8.
2 (s, 1H), 8.4 (s, 1H), 9.28 (s, 1H), 10.4 (br
s, 1H); Analysis _{C 15 H 13 N 3 OS 2} · 0.25H Calcd for ₂ O: C, 57.1
2, H, 4.15, N, 13.32. Obtained: C, 56.49, H, 4.19,
N, 12.29.

Example 39 N ^2-4 -[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] carbonyl] -N ⁶ -[(nitroamino) iminomethyl] -L-lysine, methyl ester N-ω-nitroarginine methyl ester hydrochloride and NaHCO ₃ in Example 3
Processed as in 7. The residue was purified by flash chromatography on silica gel with 5% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 517 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.60 (m, 2H);
85 (m, 2H), 2.29 (s, 3H), 3.20 (m, 2H), 3.68 (
s, 3H), 4.35 (t, 1H), 4.48 (m, 1H), 7.20 (m, 2
H), 7.30 (m, 2H), 8.32 (s, 1H), 8.48 (s, 1H),
8.52 (br s, 1H), 9.30 (s, 1H), 9.42 (d, 1H);
Analysis _{C 22 H 24 N 6 O 5} S 2 · 0.25H Calcd for ₂ O: 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 methanol solution of guanidine hydrochloride (0.095 g, 1 mmol) was treated with potassium t
Treated with butoxide (0.112 g, 1 mmol) and stirred at room temperature for 30 minutes, treated with Example 17 (0.1 g, 0.3 mmol) and warmed to room temperature for 16 hours,
Concentrated. The concentrate was dissolved in ethyl acetate (100 mL), washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 6% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 343 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.40 (s, 1H), 9.
24 (s, 1H).

Example 41 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-carbothioamide Example 19 (190 mg, 0.63 mmol) and Rosesson (15 mL) in toluene (15 mL) Lawsesson) reagent (383 mg, 9.48 mmol)
Was heated to room temperature for 5 hours and concentrated. The residue was purified by flash chromatography on silica gel with 4% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H), 7.
20 (m, 2H), 7.30 (m, 2H), 8.18 (brs, 1H), 8.
32 (s, 1H), 9.2 (s, 1H), 10.1 (br s, 1H), 10.
2 (br s, 1H); Analysis _{C 15 H 12 N 2 S 3} · 0.25H Calcd for ₂ O: C, 56.93
, H, 3.82, N, 8.85. Obtained: C, 55.89, H, 3.83, N,
8.48.

Example 42 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine Boiling Dowtherm A (2 mL) was treated with Example 18 (0.6 g, 1 g).
. 99 mmol) and copper powder (0.3 g), stirred for 5 minutes, cooled, diluted with hexane, and purified by flash chromatography on silica gel using 15% ethyl acetate / hexane. Thereafter, the product was recrystallized from hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 258 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 , 1H), 9.27 (s, 1H); Calcd for analysis _{C 14 H 11 NS 3: 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-2-carboxylate Methyl thioglycolate in place of p-thiocresol in Example 17B Example 93A was treated as in Examples 17B and 17C but using the title compound to provide the title compound.

MS (DCI / NH ₃ ) m / z 298 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.59 (s, 3H);
94 (s, 3H), 4.04 (s, 2H), 8.14 (s, 1H), 8.55 (
s, 1H), 9.27 (s, 1H).

Example 44 4-[(2-Amino-2-oxoethyl) thio] thieno [2,3-c] pyridine-2-carboxamide Example 43 was dissolved in 2M methanolic ammonia and placed in a sealed tube. At 45 ° C. for 18 hours. The precipitate was filtered, and methanol-diethyl ether (1: 1) was added.
) And dried under vacuum to give the title compound.

MS (APCI) m / z 268 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 2H), 7.
17 (br s, 1H), 7.59 (br s, 1H), 7.82 (br s, 1H)
1H), 8.29 (br s, 1H), 8.46 (s, 1H), 8.52 (br
s, 1H), 9.14 (s, 1H).

Example 45 4-[(4-Bromophenyl) thio] thieno [2,3-c] pyridine-2-carboxamide Except for using 4-bromothiophenol in place of p-thiocresol in Example 17B Example 1 as in Examples 17B and 17C and 44
Treatment of 7A provided the title compound.

MS (DCI / NH ₃ ) m / z 365 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.36 (s, 1H);
Calculated for analysis _{C 14 H 9 BrN 2 OS 2} : C, 46.04, H, 2.4
8, N, 7.67. Found: C, 45.86, H, 2.30, N, 7.51.

Example 46 4- (Phenylthio) thieno [2,3-c] pyridine-2-carboxamide Same as Example 17B, 17C and 44 except that thiophenol was used in place of p-thiocresol in Example 17B. Processing Example 17A as in
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 287 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.29 to 7.40 (m, 5)
H), 7.86 (br s, 1H), 8.25 (s, 1H), 8.46 (s, 1)
H), 8.52 (br s, 1H), 9.31 (s, 1H); Calcd for analysis _{C 14 H 10 N 2 OS 2} : 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 α, α, α- in place of p-thiocresol in Example 17B Treatment of Example 17A as in Examples 17B, 17C and 44 except using trifluorothiocresol provided the title compound.

MS (DCI / NH ₃ ) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.31 (d, 2H), 7.
65 (d, 2H), 7.85 (brs, 1H), 8.19 (s, 1H), 8.
50 (br s, 1H), 8.68 (s, 1H), 9.44 (s, 1H); Calcd for analysis _{C 15 H 9 F 3 N 2} OS 2: C, 50.84, H, 2 .5
6, 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 Except for using 2-methylthiophenol in place of p-thiocresol in Example 17B. Example 1 as in Examples 17B and 17C and 44
7A was processed. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 7.
04 (dd, 1H), 7.15 (dt, 1H), 7.27 (dt, 1H), 7.
38 (br d, 1H), 7.86 (br s, 1H), 8.20 (s, 1H)
, 8.23 (s, 1H), 8.53 (br s, 1H), 9.28 (s, 1H)
; Calculated for analysis _{C 15 H 12 N 2 OS 2} : 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 Except for using 3-methylthiophenol in place of p-thiocresol in Example 17B Example 1 as in Examples 17B and 17C and 44
7A was processed. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H), 7.
06 to 7.13 (m, 2H), 7.21 to 7.27 (m, 2H), 7.89 (b
rs, 1H), 8.26 (s, 1H), 8.42 (s, 1H), 8.55 (b
r s, 1H), 9.30 ( s, 1H); Analysis _{C 15 H 12 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 59.0
8, H, 4.13, N, 9.19. Obtained: C, 59.10, H, 4.16, N
, 9.11.

Example 50 4-[(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 3,4-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.09 (s, 3H);
11 (s, 3H), 7.05 (m, 2H), 7.19 (s, 1H), 7.81 (
br s, 1H), 8.12 (d, 2H), 8.49 (br s, 1H), 9.
15 (s, 1H); Analysis _{C 16 H 14 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 60.2
5, H, 4.58, N, 8.78. Obtained: C, 60.34, H, 4.52, N
, 8.75.

Example 51 4-[(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 3,5-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.13 (s, 6H), 6.
83 (s, 1H), 6.92 (s, 1H), 7.81 (brs, 1H), 8.
21 (s, 1H), 8.30 (s, 1H), 8.50 (brs, 1H), 9.
19 (s, 1H); Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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 Example 17A was treated as in Examples 17B and 17C and 44 except that 2,4-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
38 (s, 3H), 7.02 (d, 1H), 7.13 (d, 1H), 7.20 (
s, 1H), 7.91 (br s, 1H), 8.05 (s, 1H), 8.58 (
br s, 1H), 9.22 ( s, 1H); Analysis _{C 16 H 14 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 60.2
5, H, 4.58, N, 8.78. Obtained: C, 60.40, H, 4.52, N
, 8.72.

Example 53 4-[(2-methyl-3-furanyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 2-methyl-3-furanthiol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 291 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 6.
68 (d, 1H), 7.74 (d, 1H), 7.93 (brs, 1H), 8.
19. (s, 1H), 8.38 (s, 1H), 8.60 (brs, 1H), 9.
15 (s, 1H); Analysis _{C 13 H 10 N 2 O 2} S 2 · 0.25H Calcd for ₂ O: C, 52.
95, H, 3.59, N, 9.50. Obtained values: C, 52.57, H, 3.41,
N, 9.30.

Example 54 4-[[(4-Chlorophenyl) methyl] thio] thieno [2,3-c] pyridine-2-carboxamide Using 4-chlorobenzylmercaptan in place of p-thiocresol in Example 17B Example 17A was treated as in Examples 17B and 17C and 44 except where noted. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 335 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.15 (s, 1H); Calcd for analysis _{C 15 H 11 ClN 2 OS 2} : 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 treated as in Examples 17B and 17C and 44 except that 3,4-dichlorothiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.10 (dd, 1 H), 7
. 55 (d, 1H), 7.59 (d, 1H), 7.91 (brs, 1H), 8
. 21 (s, 1H), 8.53 (br s, 1H), 8.62 (s, 1H), 9
. 41 (s, 1H); Calcd for analysis _{C 14 H 8 Cl 2 N 2} OS 2: 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 Example 17A was treated as in Examples 17B and 17C and 44 except that 4-methoxythiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.76 (s, 3H), 6.
7. 99 (d, 2H), 7.46 (d, 2H), 7.89 (brs, 1H),
8. 17 (s, 1H), 8.30 (s, 1H), 8.54 (brs, 1H), 9.
18 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S 2: C, 56.94, H, 3.8
2, N, 8.85. Found: C, 56.80, H, 3.78, N, 8.79.

Example 57 4- (Cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide Examples 17B and 17C and 44 except that cyclohexylmercaptan was used in place of p-thiocresol in Example 17B. Example 17A was processed as described above. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 293 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.14-1.43 (br
m, 6H), 1.51 to 1.61 (br m, 1H), 1.66 to 1.78 (b
rm, 2H), 1.83 to 1.98 (br m, 2H), 7.90 (br s
, 1H), 8.33 (s, 1H), 8.52 (s, 1H), 8.57 (br s
, 1H), 9.22 (s, 1H); Calcd for analysis _{C 14 H 16 N 2 OS 2} : C, 57.50, H, 5.51
, N, 9.58. Found: C, 57.53, H, 5.39, N, 9.51.

Example 58 4-[(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 warmed at 70 ° C. for 4 hours, diluted with acetonitrile (6 mL), and treated with 20% purification by C-18 reverse phase HPLC using a gradient of acetonitrile / water to 100% _CH 3 CN containing 0.1% trifluoroacetic acid to give the title compound.

MS (APCI) m / z 428 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.95 (m, 2H);
08 (m, 2H), 3.18 (m, 2H), 3.36 (m, 2H), 3.43 (
m, 2H), 3.68 (m, 4H), 7.20 (d, 2H), 7.28 (d, 2
H), 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-2-carboxylic acid Example 17C (144 mg, 0.46 in dichloromethane (10 mL) at 0 ° C.
mmol) of 3-chloroperoxybenzoic acid (57-86%, 82 mg).
And warmed to room temperature for 4 hours, treated with dichloromethane (50 mL), washed sequentially with 1 N NaOH, water, and brine, dried (MgSO ₄ )
, Filtered and concentrated. The residue was purified by flash chromatography on silica gel using 50% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 332 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
84 (s, 3H), 7.38 (d, 2H), 7.65 (d, 2H), 8.41 (
s, 1H), 9.0 (s, 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 (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 7.
38 (d, 2H), 7.79 (d, 2H), 7.94 (brs, 1H), 8.
43 (s, 1H), 8.62 (br s, 1H), 8.85 (s, 1H), 9.
43 (s, 1H).

Example 60 4- (4-Methylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 60A Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2 -Carboxylic acid Treatment of Example 17A as in Examples 17B and 17C, except that p-thiocresol was used instead of p-thiocresol in Example 17B, gave the title compound.

[0293] mp _{96~98 ℃; MS (DCI / NH} 3) m / z317 (M + NH 4) +, 300 (M + H) +;
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.32 (s, 3H);
91 (s, 3H), 7.05 (m, 2H), 7.24 (m, 2H), 7.95 (
s, 1H), 8.12 (s, 1H), 9.17 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ NO ₃ S: 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.

MS (DCI / NH ₃ ) m / z 285 (M + H) ⁺ , 302 (M + NH ₄ ) ⁺ ;
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 7.
7. 04 (m, 2H), 7.25 (m, 2H), 7.82 (brs, 1H),
00 (s, 1H), 8.21 (s, 1H), 8.42 (brs, 1H), 9.
07 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S: 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 -Carboxylic acid 4-chlorophenol (2.63 g, 20.5 g) in THF (20 mL) at 0 ° C.
mmol) in a solution of potassium t-butoxide (1.0 M solution in THF, 20.
4 mL, 20.5 mmol) was added dropwise, stirred at 25 ° C. for 1 hour, and cooled to 0 ° C.
And cooled Example 17A (3.54 g, 20.23 mm) in THF (40 mL).
ol), warmed at 60 ° C. for 0.5 h, cooled to 0 ° C., and treated with methyl thioglycolate (1.989 mL, 22.25 mmol) and Cs ₂ CO ₃ (
6.59 g, 20.23 mmol), warmed at 60 ° C. for 0.25 hours, cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate, washed sequentially with water and brine, dried (MgSO _4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 4% acetone / hexane provided the title compound.

Melting point 99-100 ° C; MS (APCI) m / z 320 (M + H)⁺;¹ 1 H NMR (300 MHz, DMSO-d₆) 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, 1H);¹³ C NMR (100 MHz, DMSO-d₆) Δ 56.45 (OCH₃),
120.19 (CH), 123.06 (Ar-CH), 128.04 (Ar-C
H), 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); Analysis C_FifteenH₁₀ClNO₃Calculated value for S: C, 56.34, H, 3.1
5, 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 treated as in Example 44 to give the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Analysis _{C 14 H 9 ClN 2 O 2} S · 0.25H Calcd for ₂ O: C, 54.
37, H, 3.10, N, 9.06. Obtained: C, 54.44, H, 2.74,
N, 9.06.

Example 62 4- [4- (Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Except that 4- (trifluoromethyl) phenol was used instead of 4-chlorophenol Treated Example 17A as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 339 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.24 (d, 2H), 7.
77 (d, 2H), 7.88 (br s, 1H), 8.10 (s, 1H), 8.
33 (s, 1H), 8.45 (br s, 1H), 9.24 (s, 1H); Analysis _{C 15 H 9 F 3 N 2} O 2 Calculated for S: C, 53.26, H, 2.6
8, 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 are treated as in Example 61 to give the title compound. Was.

MS (DCI / NH ₃ ) m / z 383 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.07 (br s, 1H), 8.92 (br s, 1H)
); Analysis C ₂₂ H ₂₆ N ₂ O ₂ Calculated for S: 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 in Example 61 Workup as in to give the title compound.

MS (DCI / NH ₃ ) m / z 313 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21 (d, 6H);
92 (septet, 1H), 7.05 (d, 2H), 7.30 (d, 2H),
7.82 (br s, 1H), 8.03 (s, 1H), 8.21 (s, 1H),
8.44 (br s, 1H), 9.09 (s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.18 (d, 1 H), 7.
49 (dd, 1H), 7.90 (brs, 1H), 7.98 (s, 2H), 8
. 23 (s, 1H), 8.49 (br s, 1H), 9.14 (s, 1H); Analysis C ₁₄ H ₈ BrClN ₂ O ₂ Calculated for S: C, 43.83, H, 2
. 10, N, 7.30. Obtained: 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. Obtained.

MS (DCI / NH ₃ ) m / z 299 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, 3H);
62 (q, 2H), 7.05 (dt, 2H), 7.26 (dt, 2H), 7.8
1 (br s, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.4
3 (br s, 1H), 9.08 (s, 1H); Analysis Calculated for C ₁₆ H ₁₄ N ₂ O ₂ S.CH ₃ OH: C, 63.71.
H, 4.69, N, 9.14. Obtained: C, 63.34, H, 4.51, N, 9
. 51.

Example 67 4- (4-Ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 67A 4-Vinylphenol A solution of 4-vinylphenol in propylene glycol is treated with water and treated with diethyl ether. Extraction with ether removed the propylene glycol to give the specified compound in diethyl ether.

Example 67B 4- (4-Ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and Example 67A were treated as in Example 61 to give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 297 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.24 (d, 1 H);
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 (br s, 1H), 9.13 (s, 1H); Analysis Calculated for C ₁₆ H ₁₂ N ₂ O ₂ S.0.25 CH ₃ OH: C, 64
. 13, H, 4.06, N, 9.20. Obtained: C, 64.40, H, 4.12
, N, 9.27.

Example 68 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c
Example 67B (35 mg, 0.118 mmol) in pyridine-2-carboxamide pyridine (5 mL) solution was treated with _OsO 4 (90mg, _0.354mmol) of was stirred for 5 hours, 1
Treated with 0% NaHSO ₃ aqueous solution, stirred for 5 h, treated with brine, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 1:10 methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 331 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.44 (t, 2H);
55 (q, 1H), 4.73 (t, 1H), 5.27 (d, 1H), 7.08 (
d, 2H), 7.39 (d, 2H), 7.85 (brs, 1H), 8.03 (
s, 1H), 8.21 (s, 1H), 8.47 (br s, 1H), 9.10 (
s, 1H); Analysis Calculated for C ₁₆ H ₁₄ N ₂ O ₄ S.0.25 CH ₃ OH: C, 57
. 68, H, 4.24, N, 8.28. Obtained: C, 57.92, H, 4.34
, 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 (300 MHz, DMSO-d ₆ ) δ 3.43 (d, 2H);
01 (m, 1H), 5.05 (m, 1H), 5.98 (m, 1H), 7.00 (
dd, 1H), 7.27 (m, 2H), 7.39 (dd, 1H), 7.82 (s
, 1H), 7.88 (br s, 1H), 8.27 (s, 1H), 8.49 (b
r s, 1H), 9.05 ( s, 1H); Analysis C ₁₇ H ₁₄ N ₂ O ₂ Calculated for S: 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 (300 MHz, DMSO-d ₆ ) δ 2.60 (dd, 1 H), 2
. 88 (dd, 1H), 3.29 (t, 2H), 3.76 (m, 1H), 4.5
5 (t, 1H), 4.63 (d, 1H), 6.94 (dd, 1H), 7.22 (
m, 2H), 7.45 (dd, 1H), 7.84 (s, 1H), 7.88 (br
s, 1H), 8.26 (s, 1H), 8.46 (br s, 1H), 9.04
(S, 1H); Analysis C ₁₇ H ₁₆ N ₂ O ₄ Calculated for S: C, 59.29, H, 4.68
, N, 8.13. Found: C, 59.16, H, 4.51, N, 8.06.

Example 71 Example 62 (26 mg) in 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 1-oxide (1 mL) and dichloromethane (5 mL) , 0.
077 mmol) in m-CPBA (80-85%, 30 mg, 0.14 m
mol), stirred at 0 ° C. for 1 hour and at room temperature for 10 hours. The precipitate formed was collected by filtration and washed with dichloromethane. HPLC analysis of the material (C-18, reverse phase) showed a mixture of the desired sulfoxide and starting tiefen in a ratio of 8: 1. The mixture was recrystallized from DMF / methanol / dichloromethane to give the title compound (97.5% pure by HPLC analysis).

MS (HPCI / NH ₃ ) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.39 (d, 2H), 7.
79 (br s, 1H), 7.18 (d, 2H), 8.02 (s, 1H), 8.
05 (d, 1 H), 8.36 (br s, 1 H), 9.02 (s, 1 H); Analysis Calculated for C ₁₅ H ₉ F ₃ NO ₃ S.0.25 CH ₃ OH: C, 50
. 55, H, 2.57, N, 7.73. Obtained values: 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 (300 MHz, DMSO-d ₆ ) δ 0.84 (t, 3H);
20 to 1.28 (m, 24H), 1.54 (m, 2H), 2.57 (t, 2H)
, 6.92 (m, 1H), 6.97 (t, 1H), 7.03 (d, 1H), 7.
7. 33 (t, 1H), 7.85 (br s, 1H), 8.03 (s, 1H),
23 (s, 1H), 8.44 (br s, 1H), 9.09 (s, 1H); Analysis Calculated for C ₂₉ H ₄₀ N ₂ O ₂ S: 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 potassium t-butoxide solution (1 M solution in THF, 28.6 mL, 28.
6 mmol) was added dropwise under a nitrogen atmosphere to a solution of 4-bromophenol (4.94 g, 28.55 mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes, after which anhydrous tetrahydrofuran (20 mL
) Was added and refluxed for 8 hours. The reaction mixture was cooled to 25 ° C. and methyl thioglycolate (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 and extracted with an ice-cold solution of 1 N NaOH (3 ×
75 mL). The organic layer was washed with brine (3 x 100 mL), dried (MgS
O ₄ ) and the solvent were removed under reduced pressure to give a crude product (4.2 g). 10% of this
Purification by flash chromatography on silica gel, eluting with acetone-hexane, gave the title compound (1.81 g) in 44% yield.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7
. 10 (d, J = 9 Hz, 2H), 7.59 (d, J = 9 Hz, 2H), 7.9
4 (s, 1H), 8.25 (s, 1H), 9.24 (s, 1H); MS (APCI) m / e 364, 366 (M + H) ^<+> .

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. Obtained.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.10 (m, 1 H), 7.
30 (m, 2H), 7.45 (b, 1H), 7.95 (b, 1H), 8.20 (
d, 1H), 8.30 (s, 1H), 8.6 (b, 1H), 9.30 (s, 1H)
).

Example 75 4- (4-t-Butylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 4-t-butylphenol were treated as in Example 61. The title compound was obtained.

MS (DCI / NH ₃ ) m / z 327 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.3 (s, 9H), 7.1
0 (d, 2H), 7.45 (d, 2H), 7.85 (brs, 1H), 8.0
5 (s, 1H), 8.20 (s, 1H), 8.45 (brs, 1H), 9.1
(S, 1H).

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 (300 MHz, 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, 1H), 8.19 (s, 1H), 8.45
(Br s, 1H), 9.15 (s, 1H).

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 (300 MHz, 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, 1H), 8.25 (s, 1H), 8.45
(Br s, 1H), 9.15 (s, 1H).

Example 78 4- (4-Methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 4-methoxyphenol were treated as in Example 61 to give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.05 (s, 1H)
1H).

Example 79 Ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-4
-Yl] oxy] benzoic acid Example 17A and ethyl 3-hydroxybenzoate were treated as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 343 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
30 (s, 3H), 7.40 (dd, 1H), 7.60 (m, 2H), 7.80
(Dd, 1H), 7.85 (b, 1H), 8.15 (s, 1H), 8.20 (s)
, 1H), 8.42 (b, 1H), 9.17 (s, 1H).

Example 80 4-phenoxythieno [2,3-c] pyridine-2-carboxamide Example 17A and phenol were treated as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 271 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.15 (s, 1H)
1H).

Example 81 4- (3-Flomophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 3-bromophenol were treated as in Example 61 to give the title compound. I got

MS (DCI / NH ₃ ) m / z 349, 351 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.07 (dt, 2 Hz, 1
H), 7.36-7.39 (m, 3H), 7.87 (brs, 1H), 8.1
5 (s, 1H), 8.20 (s, 1H), 8.45 (brs, 1H), 9.1
7 (s, 1H); Analysis C ₁₄ H ₉ N ₂ O ₂ Calculated for _{S · CH 3 OH: C,} 47.26, H
, 2.64, N, 7.35. Obtained: 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 give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 289 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 give the title compound.

MS (DCI / NH ₃ ) m / z 299 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.10 (s, 1)
H).

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 (300 MHz, DMSO-d ₆ ) δ 2.35 (s, 3H), 7.
00 (dd, 1H), 7.25 (d, 1H), 7.45 (d, 1H), 7.85
(B, 1H), 8.15 (s, 1H), 8.20 (s, 1H), 8.45 (b, 1H)
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 give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 397 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.94 (d, 2H), 7.
7. 74 (d, 2H), 7.86 (brs, 1H), 8.13 (s, 1H),
17 (s, 1H), 8.44 (br s, 1H), 9.16 (s, 1H); Analysis C ₁₄ H ₉ IN ₂ O ₂ Calculated for S: 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.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.30 (s, 3H);
41 (s, 2H), 7.10 (d, 2H), 7.37 (d, 2H), 7.86 (
s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), 8.45 (br
s, 1H), 9.12 (s, 1H).

Example 87 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridinium, iodide Example 61 (0.11 g, 0.0033 mol) was treated with methyl iodide (0.2 mL, 0.0033 mmol) under reflux for 2 hours and filtered. The precipitate was washed with ether, dried and recrystallized from acetonitrile to give the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.70 (br s, 1H),
9.70 (s, 1H).

Example 88 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid Example 61A (354 mg, 1.11) in 3: 1 methanol / water (4 mL).
mmol), lithium hydroxide monohydrate (98 mg, 2.33 mmol) was stirred at room temperature for 20 hours, acidified with 90% formic acid (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 ) δ 7.26 (m, 2H), 7.
47 (m, 2H), 7.83 (s, 1H), 8.23 (s, 1H), 9.21 (
s, 1H); Calculated for C ₁₄ H ₈ ClNO ₃ S: C, 55.00, H, 2.64.
, N, 4.58. Found: C, 54.77, H, 2.60, N, 4.44.

Example 89 N- (4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate Example 88 in toluene (2 mL) (100 mg, 0.327 mmol) was treated with ethyldiisopropylamine (63 mg, 0.49 mmol) and diphenylphosphoryl azide (109 mg, 0.394 mmol) at 63 ° C., stirred for 1 hour, and stirred at 110 ° C. (± ) -3-Hydroxytellorahydrofuran (130
mg, 1.47 mmol), stirred for 18 h, and concentrated. 30 residue
Purification by flash chromatography on silica gel using% ethyl acetate / hexane and recrystallization from ethyl acetate gave the title compound.

MS (APCI) m / z 391 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.93 to 2.04 (m, 1
H), 2.13 to 2.28 (m, 1H), 3.29 to 3.34 (m, 1H plus HOD), 3.70 to 3.86 (m, 4H), 5.33 (m, 1H). 1H), 6.5
6 (s, 1H), 7.02 (dt, 2H), 7.43 (dt, 2H), 8.14
(S, 1H), 8.91 ( s, 1H); Analysis C ₁₈ H ₁₅ ClN ₂ O ₄ Calculated for S: 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 Example 61A (254 mg, 0.793 mmol in anhydrous ethanol (4 mL)
l) was treated with anhydrous CaCl ₂ (177 mg, 1.59 mmol) to give 1
Stir for hours, cool to 0 ° C., treat with NaBH ₄ (123 mg, 3,25 mmol), stir at 0 ° C. for 4 hours, stir at room temperature for 18 hours, treat with water, and extract with dichloromethane . The extract was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by silica gel using 30% ethyl acetate / hexane to give the title compound.

MS (APCI) m / z 292, 294 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ -d ₆ ) 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, 1H), 8.89 (s, 1
H); Analysis C ₁₄ H ₁₀ ClNO ₂ Calculated for S: C, 57.64, H, 3.4
5, N, 4.80. Found: C, 57.50, H, 3.58, N, 4.66.

Example 91 (E) -3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenoic acid Example 91A 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde -DMSO (77 mg, 0.99m
oxalyl chloride (109 mg, 0.86 mmol) was added dropwise to the solution, stirred for 5 minutes, and stirred for 2 minutes with Example 90 (123 mg) in 2 mL of dichloromethane.
, 0.420 mmol) was added dropwise, stirred at -78 ° C for 1 hour, treated with ethyldiisopropylamine (326 mg, 2.53 mmol), warmed to -20 ° C, stirred for 1.5 hours, Partitioned and extracted between 10 mL of dichloromethane and 5 mL of water. Wash the extract with water (5 mL) and brine (5 mL),
Dry (MgSO ₄ ) and filter. The residue was rotary evaporated and dried under high vacuum to give the title compound.

MS (APCI) m / z 290, 292 (M + H) ^<+> .

Example 91B Methyl 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenoic acid (E) Example 91A (138 mg, 0.42 mmol) in dichloroethane (2 mL)
) And methyltriphenylphosphoranylidene acetate (210 mg, 0.628 m
mol) was stirred at 65 ° C. for 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 25% ethyl acetate / hexane to give the title compound.

MS (APCI) m / z 346, 348 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.83 (s, 3H), 6.
43 (d, 1H), 7.00 (dt, 2H), 7.35 (dt, 2H), 7.4
8 (s, 1H), 7.84 (d, 1H), 8.11 (s, 1H), 8.88 (s
, 1H); Analysis C ₁₇ H ₁₇ ClNO ₃ Calculated for S: C, 59.05, H, 3.5
0, 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-2-yl] -2-propenoic acid Example 91B was as in Example 88. To give the title compound.

MS (ESI-) m / z 330, 332 (M-H) ^- ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.46 (d, 1 H), 7.
14 (dt, 2H), 7.46 (dt, 2H), 7.83 (s, 1H), 7.9
2 (d, 1 H), 8.15 (s, 1 H), 9.10 (s, 1 H); Analysis Calculated for C ₁₇ H ₁₇ ClNO ₃ S: C, 59.05, H, 3.5.
0, 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 Performed at 0 ° C. in DMF (1 mL). Example 91C (51.5 mg, 0.155 mmol
1), N-hydroxybenzotriazole monohydrate (34.5 mg, 0.225
mmol), 4-methylmorpholine (47 mg, 0.464 mmol) and N
A solution of H ₄ Cl (31.6 mg, 0.591 mmol) was added to EDC (45.0 mg).
, 0.235 mmol), stirred at 0 ° C. for 4 hours, stirred at room temperature for 10 hours, treated with chloroform (5 mL), washed successively with 1 M NaHCO ₃ and brine, and dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 5% methanol / dichloromethane to give the title compound.

[0366] mp ^{176~178 ℃; MS (ESI) m} / z331,333 (M + H) +; 1 H NMR (300MHz, CDCDl 3 -d 6) δ5.60 (br s, 2
H), 6.46 (d, 1H), 7.01 (m, 2H), 7.35 (m, 2H),
7.46 (s, 1H), 7.84 (d, 1H), 8.11 (s, 1H), 8.8
8 (s, 1H); Calculated for C ₁₆ H ₁₁ ClN ₂ O ₂ S: 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 Diisopropylamine (6. 6 mL, 46.4
3 mmol) in n-butyllithium (2.
. 50M solution, 18.6 mL, 46.43 mmol), stir at 0 ° C. for 30 min, dilute with THF (200 mL), cool to −78 ° C. and 95 min in THF (110 mL). 3,5-dibromopyridine (10 g, 42.
21 mmol) and stirred at -78 ° C for 30 minutes to give methyl formate (5.2).
mL, 84.42 mmol) was added dropwise, stirred at -78 ° C for 2 hours, transferred into an ice-cold saturated NaHCO ₃ solution, stirred for 15 minutes and extracted with diethyl ether. The extract was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 10% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 266 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.91 (s, 2H), 10
. 09 (s, 1H).

Example 93B Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylic acid Treatment of Example 93A as in Example 17C except running at 0-25 ° C. to give the title compound Obtained.

MS (DCI / NH ₃ ) m / z 274 (M + H) ⁺ ; ¹ H NMR (500 MHz, 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 ) δ 7.97 (br s, 1H)
, 8.11 (s, 1H), 8.33 (brs, 1H), 8.43 (s, 1H)
, 9.24 (s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.93 (br s, 1H,
NH), 8.28 (s, 1H), 8.55 (brs, 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 Example 93B (272 mg, 1 mmol), 4- (trifluoromethyl) phenylboronic acid (209 mg, 1.1 mmol) and cesium fluoride (347 mg, -3,3-c] pyridine-2-carboxylic acid in DME (5 mL). 2.1 mmol) was degassed for 15 minutes and tetrakis (triphenylphosphine) palladium (0) (35 mg, 0.03 m
mol), warmed at 80 ° C. for 6 hours, stirred at room temperature for 12 hours, and celite (
(Trademark) and concentrated. The residue was purified by flash chromatography on silica gel using 5% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 338 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
94 (m, 4H), 8.06 (s, 1H), 8.66 (s, 1H), 9.47 (
s, 1H).

Example 95B 4- [4- (Trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxamide Example 95A is treated as in Example 44 to give the title compound. Was.

MS (APCI) m / z 323 (M + H) ⁺ , 321 (M−H) ⁻ , and 3
57 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (brs, 1H).
, 7.93 (m, 4H), 8.24 (s, 3H), 8.45 (br s, 1H)
, 8.59 (br s, 1H), 9.37 (br s, 1H).

Example 96 N-methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-
c] Pyridine-2-carboxamide Example 95A was treated as in Example 44 except that methylamine (2.0 M in methanol) was used instead of methanolic ammonia to give the title compound.

MS (APCI) m / z 337 (M + H)⁺, 335 (MH)⁻, And 3
71 (M + Cl)⁻;¹ 1 H NMR (400 MHz, DMSO-d₆6.) δ 2.82 (d, 3H);
90 (d, 2H), 7.94 (d, 2H), 8.17 (s, 1H), 8.58 (
s, 1H), 8.93 (br d, 1H), 9.36 (s, 1H);¹³ C NMR (100 MHz, DMSO-d₆) Δ26.1 (CH₃), 12
1.6 (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-carboxylic acid Example 93B and phenylboronic acid Was treated as in Example 95 to give the specified compound.

MS (DCI / NH ₃ ) m / z 338 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
94 (m, 4H), 8.06 (s, 1H), 8.66 (s, 1H), 9.47 (
s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.52 to 7.69 (m, 5)
H), 7.78 (br s, 1H), 8.23 (s, 1H), 8.44 (br
s, 1H), 8.52 (s , 1H), 9.30 (s, 1H); Calcd for analysis _{C 14 H 10 N 2 OS:} 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 as in Example 95 After workup and purification, repurification by HPLC (C18 reverse phase, 0-90% acetonitrile gradient in water containing 0.1% TFA) provided the title compound.

MS (DCI / NH ₃ ) m / z 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.36 to 7.48 (m, 5)
H), 7.63-7.68 (m, 4H), 7.91 (brs, 1H), 8.3
0 (s, 1H), 8.54 (s, 1H), 8.57 (brs, 1H), 9.3
6 (s, 1H).

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-2-carboxylic acid 3- Hydroxytetrahydrofuran (0.043 mL, 0.53 mmol),
Triphenylphosphene (138 mg, 0.53 mmol) and diethyl azodicarboxylate (0.083 mL, 0.53 mmol) at room temperature and under an atmosphere of nitrogen in Example 236E (110 mg, 0
. 53 mmol). After 22 hours, the reaction mixture was stirred in ethyl acetate
00 mL), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40S) eluting with 10% acetone-hexane to give the title compound in 22% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.05 to 2.18 (m,
1H), 2.26 to 2.49 (m, 1H), 3.61 to 3.77 (m, 2H),
3.93 (s, 2H), 4.25 to 4.31 (m, 2H), 5.32 to 5.39
(M, 1H), 8.10 (s, 1H), 8.26 (s, 1H), 8.99 (s, 1H)
1H); MS (APCI) m / e 280 (M + H) ^<+> .

Example 99B Methyl 4- [3- (2,3,4,5-tetrahydrofuranyl) oxy] thieno [2,3-c] pyridine-2-carboxamide The title compound (5.7 mg, 19%) , Example 99A (30 mg, 0.108
mmol) was prepared as described in Example 171. By C-18 reverse-phase HPLC, eluting with a gradient of _{20% CH 3 CN-H 2} O containing 0.1% trifluoroacetic acid, the product was isolated.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.05 to 22.13 (m
, 1H), 2.30 to 2.40 (m, 1H), 2.81 (d, J = 5 Hz, 3H)
), 3.78-3.84 (m, 1H), 3.90-4.01 (m, 3H), 5.
32 to 5.37 (m, 1H), 8.13 (s, 1H), 8.21 (s, 1H),
8.90 (s, 1 H), 8.55 (d, J = 5 Hz, 1 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 26.2 (CH ₃ );
_{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] pyridine-4-
Il] oxy] benzoic acid Example 73 (120 mg in DMF (6 mL) and ethanol (3 mL)
0.33 mmol), palladium (II) acetate (11 mg, 0.05 mmol)
, 1,3-bis (diphenylphosphino) propane (20.6 mg, 0.05 m
mol), and a solution of triethylamine (100 mg, 0.99 mmol) was purged with carbon monoxide, heated at 105 ° C. under a carbon monoxide atmosphere (balloon) for 12 h, treated with ether, and brine and water. Wash sequentially and dry (N
a ₂ SO ₄ ), filtered and concentrated. The residue was subjected to flash chromatography (20
(% Ethyl acetate / hexane) 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 Example 100 (50 mg) in DMF (5 mL) and ethanol (10 mL)
) Was treated with a solution of NaOH (200 mg) in water (0.5 mL) to give 1
Stir for 3 hours, treat sequentially with acetic acid (500 mg) and water, and filter. The residue was recrystallized from DMF / water to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.13 (dt, 1.8 Hz)
, 2H), 7.86 (brs, 1H), 7.98 (dt, 2H), 8.09 (
s, 1H), 8.31 (s, 1H), 8.44 (br s, 1H), 9.22 (
s, 1H); Analysis C ₁₅ H ₁₀ N ₂ O ₄ Calculated for S: 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-α-boronic acid α-α in diethyl ether (30 mL) at −78 ° C. Bromostyrene (5.5 g
, 30 mmol) with a solution of t-butyllithium (1.7 M solution, 21.2).
mL, 36 mmol), stirred at -78 ° C for 0.5 h, treated with triisopropyl borate (8.31 mL, 36 mmol) for 48 min, stirred for 1 h, and allowed to reach room temperature over 18 h. Warm, dilute with diethyl ether (100 mL), treat with 1M HCl (100 mL), stir at room temperature for 5 h, concentrate and add T
The HF was removed, brought to pH 14 with 1N NaOH, washed with hexane and 1M H
The mixture was adjusted to pH 1 with Cl 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) δ5.75 (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-carboxylic acid Example 93B and styrene-α-boronic acid were treated as in Example 95. To give the title compound.

MS (APCI) m / z 296 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.84 (s, 3H);
56 (s, 1H), 5.95 (s, 1H), 7.31 (m, 2H), 7.36 (
m, 3H), 7.47 (s, 1H), 8.5 (s, 1H), 9.40 (s, 1H)
); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 53.03 (OCH ₃ ),
118.37 _(CH 2 vinyl), 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), 13
9.59 (C), 141.88 (C), 142.97 (3-CH), 144.0
3 (C), 145.39 (CH), 161.69 (CO).

Example 102C 4- (1-Phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide Example 102B was treated as in Example 44 to give the title compound.

MS (DCI) m / z 281 (M + H) ⁺ ; ¹ H NMR (400 MHz, 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, 1H), 8.33 (s, 1H), 8.37 (
br s, 1H), 9.29 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 118.0 (CH ₂ ), 1
23.10 (CH), 126.73 (Ar-CH), 128.22 (CH), 1
28.60 (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-2-methanol NaBH ₄ (28 mg, 0.74 in 2: 3 THF / ethanol (2 mL)
3 mmol) was stirred at 0 ° C. for 10 minutes, and CaCl ₂ (41.2 mg, 0
. 37 mmol), stir for 15 minutes, and add 2: 3 THF / ethanol (
Treat with a solution of Example 17C (117 mg, 0.37 mmol) in 3 mL), stir at 0 ° C. for 4 h, treat with 20% aqueous acetic acid (5 mL), and concentrate to remove low boiling solvents. . The resulting mixture was brought 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 column chromatography on silica gel eluting with 15% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 288 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
80 (s, 2H), 5.90 (br s, 1H), 7.14 (d, 2H), 7.
18 (d, 2H), 7.32 (s, 1H), 8.36 (s, 1H), 9.15 (
s, 1H).

Example 103A 4- (4-Chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-Carboxamide Example 61A (100 mg, 0.3135 mmol in THF (2 mL) at 0 ° C.
l) and methylamine (2M solution in THF, 0.467 mL, 0.941 m
mol) was treated with NaH (12 mg, 0.47 mmol) at room temperature.
Stirred for hours, treated with water (0.1 mL) and concentrated. 20% acetone /
Purification by flash chromatography on silica gel with hexane provided the title compound.

MS (APCI) m / z 319 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 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. ,
The title compound was obtained.

MS (APCI) m / z 333 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.03 (br s, 3H).
3.12 (brs, 3H), 7.17 (d, 2H), 7.46 (d, 2H)
, 7.62 (s, 1H), 8.18 (s, 1H), 9.15 (s, 1H).

Example 105 4- (4-Chlorophenoxy) -N, N-diethylthieno [2,3-c] pyridine-2-carboxamide Example 61A and diethylamine were treated as in Example 103A.
The title compound was obtained.

MS (APCI) m / z 361 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (m, 6H);
42 (m, 4H), 7.15 (d, 2H), 7.45 (d, 2H), 7.49 (
s, 1H), 8.74 (s, 1H), 9.17 (s, 1H).

Example 106 4- (4-Chlorophenoxy) -N-sillopropylthieno [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) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.85 (m, 1 H), 7.
12 (d, 2H), 7.46 (d, 2H), 8.11 (s, 1H), 8.13 (
s, 1H), 8.93 (d, 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) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.83 to 1.93 (m, 4
H), 3.53 (t, 2H), 3.71 (t, 2H), 7.17 (d, 2H),
7.47 (d, 2H), 7.70 (s, 1H), 8.16 (s, 1H), 9.1
2 (s, 1H).

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) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.52 (m, 3H);
62 (m, 2H), 3.53 (m, 5H), 7.14 (d, 2H), 7.46 (
d, 2H), 7.47 (s, 1H), 8.20 (s, 1H), 9.14 (s, 1)
H).

Example 109 4-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
[Ill] carbonyl] morpholine Example 61A and morpholine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 375 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.6 (m, 8H), 7.1
4 (d, 2H), 7.45 (d, 2H), 7.55 (s, 1H), 8.17 (s
, 1H), 9.14 (s, 1H).

Example 110 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine Example 61A and methylpiperazine were added to Example 103A. Workup as in to give the title compound.

MS (APCI) m / z 388 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 3H), 2.3
2 (br s, 4H), 8.58 (br s, 4H), 7.15 (dd, 1 H)
, 7.47 (dd, 1H), 7.49 (s, 1H), 8.2 (d, 1H), 9.
15 (s, 1H).

Example 111 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine Example 61A and phenylpiperazine in Example 103A Workup as in to give the title compound.

MS (APCI) m / z 450 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.18 (br s, 4H).
3.73 (brs, 4H), 6.81 (t, 1H), 6.95 (d, 2H)
, 7.15 (d, 2H), 7.24 (d, 2H), 7.46 (d, 2H), 7.
57 (s, 1H), 8.20 (s, 1H), 9.17 (s, 1H).

Example 112 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-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) ⁺ ; ¹ H NMR (500 MHz, 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, 1H), 8.
91 (s, 1H), 9.13 (s, 1H).

Example 113 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
Il] carbonyl] -4- (2-pyridinyl) piperazine Example 61A and 2-pyridylpiperazine were treated as in Example 103A to give the title compound.

[0423] ^{MS (APCI) m / z451 (} M + H) +; 1 H NMR (500MHz, CDCl 3 -d) δ3.65 (br s, 4H)
3.85 (brs, 4H), 6.70 (m, 2H), 7.07 (d, 2H)
, 7.34 (d, 2H), 7.50 (s, 1H), 7.54 (m, 1H), 8.
15 (s, 1H), 8.29 (m, 1H), 8.96 (s, 1H).

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 (400 MHz, DMSO-d ₆ ) δ 3.33 (m, 2H);
51 (m, 2H), 5.76 (t, 1H), 7.12 (d, 2H), 7.26 (
d, 2H), 8.17 (s, 2H), 8.98 (br.t, 1H), 9.14 (
s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ42.3 (N-CH ₂ );
_{59.4 (O-CH 2),} 119.2 (CH), 119.3 (Ar-CH), 1
27.6 (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-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide, trifluoroacetic acid (salt) Example 61A and N-isopropylpiperazineacetamide were prepared in Example 103.
Treatment as in A provided the title compound. 20% CH ₃ CN / water and 0.1%
The residue was purified by C-18 reverse phase HPLC using a gradient of 100% _CH 3 CN containing trifluoroacetic acid to yield the title compound.

MS (APCI) m / z 473 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.09 (m, 6H);
05 (br s, 4H), 3.43 (s, 2H), 3.87 (br s, 4H)
, 7.16 (d, 2H), 7.67 (d, 2H), 7.68 (s, 1H), 8.
20 (s, 1H), 9.18 (s, 1H).

Example 116 4- (4-Chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and DL-2-amino-1 -Propanol was treated as in Example 103A to give the title compound.

MS (APCI) m / z 363 (M + H) ⁺ , 361 (M−H) ⁻ , 397 (
M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.14 (d, 3H);
36 to 3.40 (m, 1H), 3.43 to 3.5 (m, 1H), 3.97 to 4.
04 (m, 1H), 4.77 (t, 1H), 7.15 (d, 2H), 7.48 (
d, 2H), 8.14 (s, 1H), 8.26 (s, 1H), 8.67 (d, 1)
H), 9.14 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 16.87 (CH ₃ ), 4
_{7.74 (CH), 64.06 (CH} 2 OH), 119.16 (3-CH), 1
19.46 (2xAr-CH), 127.72 (C), 130.08 (2xAr
-CH), 132.84 (5-CH), 137.51 (C), 137.91 (C
), 141.20 (7-CH), 146.62 (C), 147.28 (C), 1
55.53 (C), 160.01 (CO).

Example 117 4- (4-chlorophenoxy) -N- [1,1-bis (hydroxymethyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and 2-amino- Treatment of 2-methyl-1,3-propanediol as in Example 103A provided the title compound.

MS (APCI) m / z 393 (M + H) ⁺ , 391 (M−H) ⁻ , 393 (
M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (s, 3H);
56 to 3.66 (m, 4H), 4.71 (t, 2H), 7.16 (d, 2H),
7.48 (d, 2H), 7.92 (s, 1H), 8.11 (s, 1H), 8.3
1 (s, 1H), 9.12 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 18.45 (CH ₃ ), 5
9.80 (C), 63.08 (CH ₂ ), 119.46 (CH), 119.74
(2xAr-CH), 127.83 (C), 130.09 (2xAr-CH),
132.53 (CH), 137.43 (C), 137.84 (C), 140.9
9 (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-2-carboxamide Examples 61A and DL-1- Treatment of amino-2-propanol as in Example 103A provided the title compound.

MS (APCI) m / z 363 (M + H) ⁺ , and 397 (M + Cl) ⁻ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.08 (d, 3H);
21 (m, 2H), 3.75 to 3.84 (m, 1H), 4.8 (br s, 1H)
), 7.14 (d, 2H), 7.48 (d, 2H), 8.17 (s, 1H), 8
. 22 (s, 1H), 8.98 (br s, 1H), 9.15 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 21.13 (CH ₃ ), 4
_{7.24 (CH 2), 64.84 (} CH), 119.30 (3-CH), 119
. 42 (2xAr-CH), 127.66 (C), 130.04 (2xAr-C
H) 133.05 (CH), 137.48 (C), 137.92 (C), 14
1.30 (CH), 146.37 (C), 147.16 (C), 155.58 (
C), 160.59 (CO).

Example 119 4- (4-Chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and 4- (2-amino Ethyl) monophorine was treated as in Example 103A to give the title compound.

MS (APCI) m / z 418 (M + H) ⁺ , 452 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.41 (t, 4H);
48 (m, 2H), 3.40 (m, 2H), 3.56 (t, 4H), 7.15 (
d, 2H), 7.47 (d, 2H), 8.13 (s, 1H), 8.17 (s, 1H)
H), 8.94 (t, 1H), 9.04 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 36.73 (N-CH ₃ )
, 53.21 (morpholine ring _{2xN-CH 2), 57.07 (} N-CH 2),
66.12 (morpholine ring _{2x-OCH 2), 119.14 (} 3-CH), 1
19.50 (2xAr-CH), 127.73 (C), 130.06 (2xAr
-CH), 132.96 (pyridyl ring CH), 137.35 (C), 137.
91 (C), 141.29 (pyridyl ring 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 t-butyllithium (1.7 M solution in hexane, 0.647 under nitrogen atmosphere)
mL, 1.1 mmol) of Example 124A in anhydrous THF (5 mL) at -78 ° C.
(261 mg, 1 mmol). The reaction mixture was stirred at −78 ° C. for 15 minutes and SO ₂ gas was bubbled through the solution for 15 minutes. Then, change this to -7
The mixture was stirred at 2 ° C for 2.5 hours and then at 0 ° C for 4 hours. The reaction mixture was diluted with hexane (10 mL), evaporated and the resulting residue was suspended in _CH 2 _Cl 2 (5mL), at 0 ° C. N-chlorosuccinimide (214 mg, 1.6 mmol)
Processed. After 2 hours, at ambient temperature, dilute the reaction mixture with CH ₂ Cl ₂ and add
NaHSO ₃ aqueous solution (3 × 25 mL) followed by brine (
3x25mL). The dried (MgSO ₄ ) organic layer was evaporated under reduced pressure to dryness to give the crude sulfonyl chloride as an oil. This was dissolved in acetone (5 mL) and treated at 0 ° C. with an ice-cold solution of NH ₄ OH (5 mL). After 2 hours, the reaction mixture was evaporated from toluene at 0 ° C. to give the crude product as an oil. Flash chromatography on silica gel, eluting with 20% acetone-hexane, followed by 40% acetone-hexane, gave the title compound (57 g, 16%).
I got

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.21 (d, J = 9 Hz)
, 2H), 7.51 (d, J = 9 Hz, 2H), 7.79 (s, 1H), 8.1
4 (br.s, 2H), 8.30 (s, 1H), 9.27 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 119.65 (CH), 1
20.88 (CH), 127.94 (C), 130.12 (CH), 133.6
7 (CH), 135.61 (C), 141.65 (CH), 152.11 (C)
MS (APCI) m / z 341 (M + H) ⁺ , 339 (M−H) ⁻ , 375 (M
+ Cl) ^- .

Example 121 4-[(4-Methylphenyl) methyl] thieno [2,3-c] pyridine-2-
Carboxamide Example 121A Methyl 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine-2-carboxylic acid Example 121A is described in J. Am. Org. Chem, 1988, 53, pp. 2392
Processed as described in ~ 2394. For example, 1,2-dibromoethane (0
. Zn powder (5 mL, 0.054 mmol) in THF (2 mL) containing
(92 mg, 1.4 mM) was heated at 65 ° C for 2 minutes, cooled to 25 ° C,
Treat with trimethylsilyl chloride (0.009 mL, 0.043 mM), stir at room temperature for 25 minutes, cool to 0 ° C., and add 4-methylbenzyl bromide (0.248 mL, 1.0 mmol) in THF (5 mL) And slowly treated with a solution of
Warm to 0 ° C., cool to −10 ° C., and add CuCN (106 ml) in THF (10 mL)
g, 1.18 mM) and LiCl (100 mg, 2.35 mM)
Stir at 0 ° C. for 30 minutes and prepare Example 93B (272 mg, 1 m) in THF (5 mL).
mol), stirred at 0 ° C. for 3 hours, and
Warm to 5 ° C., treat with ethyl acetate, wash sequentially with saturated NH ₄ Cl and brine, dry (MgSO ₄ ), filter and concentrate. The residue was purified by flash chromatography on silica gel 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- (morpholino) thieno [2,3-c] pyridine-2-carboxamide 1,4-dioxo-8-azaspiro [4,5] instead of 4-methylaniline
Example 122 (241 mg, 72%) was prepared as described in Example 308 using decane (0.256 mL, 2 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.91 (m, 4H), 2
. 85 (d, J = 4 Hz, 3H), 3.25 (m, 4H), 3.96 (s, 4H)
), 8.10 (s, 1H), 8.12 (s, 1H), 8.87 (s, 1H), 8
. 96 (d, J = 4 Hz, 1 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 26.1 (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 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, N-oxide Example 123A Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine -2-Carboxylic acid, N-oxide A solution of methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate (319 mg, 1 mmol) in dichloromethane (15 mL) at 0 ° C. Treated with chloroperoxybenzoic acid (302 mg, 1.75 mmol), stirred at 0 ° C. for 0.5 h, stirred at room temperature for 4 h, washed successively with water, saturated sodium bicarbonate, water, and brine , dried _(Na 2 _SO 4), filtered, and concentrated to give the title compound.

[0443] _{^{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- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, N-oxide Example 123A is treated as in Example 44 to give the title compound. Was.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.30 (m, 2H), 7
. 52 (m, 2H), 7.74 (d, 1H), 7.81 (brs, 1H), 8
. 10 (s, 1H), 8.34 (br s, 1H), 8.93 (s, 1H).

Example 124 4- (4-Chlorophenoxy) -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) is added at 210 ° C. to a solution of diphenyl ether (55 mL). At this temperature for 10 hours. The cooled reaction mixture was purified directly by flash chromatography on silica gel, eluting with hexane, followed by 10% acetone-hexane to give the title compound (3.83 g, 99.5%).

Mp 87-89 ° C. MS (DCI / NH ₃ ) m / e 262 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.09 (d, J = 9 Hz,
2H), 7.35 (d, J = 6 Hz, 1H), 7.45 (d, J = 9 Hz, 2H)
), 8.13 (d, J = 6 Hz, 1H), 8.18 (s, 1H), 9.15 (s
, 1H); Analysis _{C 13 H 8 Cl 1 N 1} O 1 calculated for _{S 1: C, 59.66, H} , 3
. 08, N, 5.35. Obtained: C, 59.52, H, 3.08, N, 5.15
.

Example 124B 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-boronic acid To a solution of s-butyllithium (0.92 mmol) in THF (2 mL) at −78 ° C. Treat Example 124A dropwise in THF (1 mL) and treat at −78 ° C. for 30 minutes.
Stir for 5 min, treat dropwise with tributyl borate, stir at −78 ° C. for 5 min, stir at room temperature for 45 min, treat with 2M NaOH (3 mL), stir for 5 min, and hexane Washed and acidified to pH 2 with 6M HCl. The precipitate formed was collected and dried under vacuum to give the title compound.

MS (APCI) m / z 262, 264 (M + H-B (OH) ₂ ) ⁺ 340
, And 342 (M + Cl−) ⁻ ; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.29 (d, 2H), 7.53
(D, 2H), 8.08 (s, 1H), 8.11 (s, 1H), 9.40 (s, 1H)
1H).

Example 124C 4- (4-Chlorophenoxy) -2- (2-methoxyphenyl) thieno [2,
3-c] pyridine Example 124B was prepared as in Example 95 except that 2-iodoanisole was used instead of Example 93B and Example 124B was used instead of 4- (trifluoromethyl) phenylboronic acid. Work-up provided the title compound.

Example 125 4- (4-Chlorophenoxy) -3-methylthienol [2,3-c] pyridine-2-carboxamide Example 125A Methyl 4- (4-chlorophenoxy) -3-methylthienol [2,3-c]
Pyridine-2-carboxylic acid 4-chlorophenol was dissolved in THF (20 mL), treated with 1 M 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 ° C. for 4 hours and cooled to room temperature. It was poured into water, diluted with brine and extracted with ethyl acetate. Thereafter, the ethyl acetate was washed (3 ×
20 mL), dried and evaporated. The residue was dissolved in THF (20 mL), cooled in an ice bath, and to this was added 3M methylmagnesium bromide in ethyl ether (4 mL, 12 mmol). The reaction was stirred overnight at room temperature. Excess Grignard reagent was decomposed with a saturated ammonium chloride solution (25 mL) and then extracted with ethyl acetate (3 × 25 mL). Wash the ethyl acetate with brine (3 × 25 mL
), Dried and evaporated to give the desired phenoxy alcohol. Thereafter, the alcohol was Swern oxidized using the following conditions. Oxalyl chloride (1.1 mL, 12 mL) in anhydrous methylene chloride (20 mL) cooled to -78 ° C.
dimethylsulfoxide (1.85 mL, 24 mmol) in a solution of
Added over 0 minutes. Thereafter, a solution of the above phenoxy alcohol in methylene chloride (20 mL) was added over 15 minutes. Triethylamine (7.5 mL)
Was added and the reaction was allowed to come to room temperature over 2 hours. Thereafter, ice water was added and the mixture was extracted with ethyl acetate. Wash the ethyl acetate with brine (3x
20 mL), dried and evaporated. To a 0 ° C. solution of this residue in THF (20 mL) was added methyl thioglycolate (0.88 mL, 10 mmol) and cesium carbonate (3.2 g, 10 mmol). Thereafter, the reaction was heated at 70 ° C. for 1 hour.
Heated for hours, cooled, poured into water, diluted with brine and extracted with ethyl acetate. Thereafter, the ethyl acetate was washed with 1N NaOH (2 × 20 mL), washed with brine (3 × 20 mL), dried and evaporated to give an oil. This oil was triturated with methanol to give the desired compound.

MS (DCI / NH ₃ ) m / e 334 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (s, 3H);
90 (s, 3H), 7.22 (d, 2H), 7.45 (d, 2H), 8.12 (
s, 1H), 9.15 (s , 1H); Analysis _{C 16 H 12 ClNO 3 S ·} 0.5H Calcd for ₂ O: C, 56.0
6, H, 3.82, N, 4.09. Obtained: C, 56.03, H, 3.43, N
, 3.71.

Example 125B 4- (4-Chlorophenoxy) -3-methylthienol [2,3-c] pyridine-2-carboxylic acid Example 125A in THF (20 mL) and H ₂ O (10 mL) 1.1g
, 3.3 mmol) and a solution of LiOH.H ₂ O (0.30 g, 6.9 mmol) were heated at 50 ° C. for 1 hour, then cooled, acidified with formic acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3 × 15 mL) and then dried,
Evaporation gave the desired product as a white solid.

MS (DCI / NH ₃ ) m / e 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.76 (s, 3H);
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-methylthienol [2,3-c] pyridine-2-carboxamide Example 125B was treated as in Example 92 to afford the title compound. Obtained.

Mp 174-175 ° C MS (DCI / NH ₃ ) m / e 319 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H);
05 (d, 2H), 7.45 (d, 2H), 7.90 (m, 1H), 7.95 (
m, 1H), 8.15 (s , 1H), 9.12 (s, 1H); Analysis C ₁₅ H ₁₁ ClN ₂ O ₂ Calculated for S: 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-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 126A Ethyl 3,5-dichloropyridine-4-carboxylic acid at −78 ° C. Lithium diisopropylamide (45 mL, 150 mL THF)
A stirred solution of 1.5M in THF, 67.6 mmol) was added to 3,5 in 40 mL of THF.
-Dichloropyridine (10 g, 67.6 mmol) was added and treated over 1.5 hours, stirred at -78 ° C for 1 hour, and ethyl chloroformate (9.5 mL, 100 ml) was added.
mol), stirred for 2 hours, and saturated sodium bicarbonate (200 mL) at 0 ° C.
) And treated with diethyl ether (200 mL) and extracted with ethyl ether (2 x 100 mL). The extract was washed with saturated sodium bicarbonate solution (2 × 100 mL
), Washed sequentially with brine (2 × 100 mL), dried (MgSO _4), and concentrated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate to give the title compound.

Example 126B Methyl 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c] pyridine-2-carboxylate Example 126A was treated as in Example 61A to give the title compound. I got

Example 126C 4- (4-Chlorophenoxy) -3-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 126B was treated as in Example 61B to give the title compound. Was.

Example 127 4- (4-Chlorophenoxy) -3- (1-methylethoxy) thieno [2,3
-C] pyridine-2-carboxamide Example 127 is described in J. Am. Medicinal. Chem. 1992, 35, p.
Treated as described in 958. Example 126C (0 in 50 mL THF)
. 10 g, 0.3 mmol) and cesium carbonate (1.0 g, 0.1 mmol)
Was treated with 2-bromopropane (0.37 g, 0.3 mmol), heated for 2 hours, poured onto ice, extracted with ethyl ether, washed successively with 1N aqueous sodium hydroxide and brine, and concentrated. . The residue was purified by flash chromatography on silica gel with hexane-acetone (7: 3) to give the title compound.

Example 128 3-Bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine Archiv For Kemi (1970-74), 32, p. 249 can be applied. Example 124A in thionyl chloride at 90 ° C
For 4 hours with bromine to give the title compound.

Example 129 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-3-carboxylic acid Arkiv For Kemi (1970-74), 32, p. 249 can be applied. Example 128, cooled to -78 ° C, was treated with ethyllithium followed by reaction with carbon dioxide to give the title compound.

Example 130 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-3-carboxamide Example 129 can be treated as in Example 19 to give the title compound.

Example 131 3-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 added to hydroxylamine hydrochloride (1.04 g, 11.4 mmol) and concentrated. Sulfuric acid (0.05m
L), stirred under reflux for 18 hours and concentrated. The residue 1: 1 ethyl acetate - was partitioned extracted between water, saturated sodium bicarbonate, washed successively with water, brine, dried (Na 2 _{SO 4),} and concentrated. The residue was recrystallized from hexane to give the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s); IR (KBr, νcm ⁻¹ ) 1710, 1525, 1400, 1250, 119
0, 1100, 920, 820, 800, 750.

Example 131B Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid 4-chlorophenol (1.12 g) in THF (20 mL) at 0 ° C. , 8.72
mmol) in a solution of potassium t-butoxide (8.72 mL, 8.72 m2).
mol, 1M in THF), stir at 0 ° C. for 1 hour, and add THF (10
Treated with Example 131A (1.5 g, 8.72 mmol) in acetic acid (mL), warmed to room temperature, stirred overnight, concentrated, and extracted by partitioning between 1: 1 ethyl acetate-water. . The extract was washed with brine, dried _(Na 2 _SO 4), and concentrated. D at 0 ° C
A solution of the concentrate in MF (50 mL) was treated with potassium carbonate (2.42 g, 17.51 m).
mol) and methyl thioglycolate (778 μL, 8.72 mmol), warmed to room temperature, stirred overnight, and poured into ether (400 mL). The organic layer was washed with brine, dried _(Na 2 _SO 4), and concentrated. 0-5% residue
Purification by flash chromatography on silica gel with acetone-hexane of the title compound afforded the title compound.

MS (APCI) m / z 335 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 6.
86 (br s, 2H), 7.22 to 7.32 (m, 2H), 7.45 to 7.5
6 (m, 2H), 7.88 (s, 1H), 8.89 (s, 1H); Analysis C ₁₅ H ₁₁ ClN ₂ O ₂ Calculated for S: C, 53.81, H, 3.
31, N, 8.36. Found: C, 53.80, H, 3.27, N, 8.27.

Example 131C 3-Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-Carboxylic acid The title compound was prepared from Example 131B using the procedure of Example 18.

Mp 173-176 ° C (decomposition); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.29 (m, 2H), 7.
52 (m, 2H), 7.88 (s, 1H), 8.89 (s, 1H); MS (ESI) m / e321 (M + H) +; Analysis _{C 14 H 9 ClN 2 O 3} 0.25H 2 Calculated value for O: C, 51.7
0; H, 2.94; N, 8.61. Actual value? ? .

Example 131D 3-Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-Carboxamide Example 131C (96 mg, 0.3 mmol) in DMF (2 mL) was added to 1
-Hydroxybenzotriazole hydrate (67 mg, 0.44 mmol), NH ₄ Cl (61 mg, 1.14 mmol) and 4-methylmorpholine (100 μμ
L, 0.9 mmol), cooled to 0 ° C., and treated with 1- [3- (dimethylamino)
Propyl] -3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol)
, Warm to room temperature, stir overnight, and add saturated NaHCO₃Pour into, collect, with water
Washed and dried. Recrystallization of the residue from methanol / toluene / hexane
The title compound is obtained.

MS (APCI) m / z 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.84 (br s, 2H).
, 7.21-7.30 (m, 2H), 7.39 (brs, 2H), 7.47-
7.56 (m, 2H), 7.88 (s, 1H), 8.90 (s, 1H); Analysis C ₁₄ H ₁₀ ClN ₃ O ₂ Calculated for S: C, 52.58; H, 3 .
15; N, 13.14. Found: C, 52.63; H, 3.18; N, 13.1.
2.

Example 132A Ethyl 4-chlorothieno [2,3-b] pyridine-5-carboxylate Heterocyclic Chem. 1977, 1
4, p. Treatment as in 807-812 afforded the title compound.

MS (DCI / NH ₃ ) m / z 259 (M + H) ⁺ ; 242 (M + NH ₄ ) ⁺ ;
3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37 (t, 3H);
41 (q, 2H), 7.64 (d, 1H), 8.17 (d, 1H), 8.95 (
s, 1H); Analysis C ₁₀ H ₈ ClNO ₂ Calculated for S: C, 49.69; H, 3.33
N, 5.79; S, 13.26. Found: C, 49.46; H, 3.13; N
5.52; S, 13.42.

Example 132B Ethyl 4-[(4-methylphenyl) -thio] thieno [2,3-b] pyridine-5-carboxylate Example 132A and thiocresol were treated as in Example 2. To give the title compound.

MS (DCI / NH)₃) M / z 347 (M + NH₄)⁺And 330 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆1.) δ 1.30 (t, 3H);
28 (s, 3H), 4.26 (q, 2H), 7.00 (d, 1H), 7.17 (
m, 2H), 7.24 (m, 2H), 7.91 (d, 1H), 8.81 (s, 1
H); Analysis C₁₇H_FifteenNO₂S₂For 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.

MS (DCI / NH)₃) M / z 275 (M + NH₄)⁺And 258 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆5.) δ 2.39 (s, 3H);
66 (d, 1H), 7.38 (m, 2H), 7.46 (d, 1H), 7.53 (
m, 2H), 7.46 (d, 1H), 7.53 (m, 2H), 7.95 (d, 1H)
H); 8.12 (d, 1H); analysis C₁₄H₁₁NS₂For 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 diisopropylamine (0.056 g, 0.56 mmol) in THF (10 m
L) The solution was added at −78 ° C. with n-butyllithium (0.22 mL, 0.56 mmol).
l, 2.5M in hexane), stirred for 15 minutes, and treated with Example 132C (0.1
(3 g, 0.51 mmol) in THF (5 mL), stir for 0.5 h, warm to 0 ° C. in 1 min, re-cool to −78 ° C., pour onto solid CO ₂ , add 0.
Stir for 5 h, dilute with saturated NH ₄ Cl, and extract with ethyl acetate. The extract was washed with brine, dried (MgSO _4), and concentrated to give the title compound.

280-282 ° C .; MS (DCI / NH₃) M / z 318 (M + NH₄)⁺And 301 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆5.) δ 2.41 (s, 3H);
62 (d, 1H), 7.40 (m, 2H), 7.57 (m, 2H), 7.77 (
br s, 1H), 8.26 (s, 1H), 8.36 (d, 1H), 8.43 (
brs, 1H); Analysis C_FifteenH₁₂N₂OS₂For C: 59.97; H, 4.02.
N, 9.32. Found: C, 59.83; H, 4.03; N, 9.11.

Example 133 4-Chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5
- carboxamide Example 132A, as in Examples 18 and 19, however, is treated by replacing the 4-chloroaniline with concentrated _NH 4 OH in Example 19, the title compound was obtained.

Mp 199-202 ° C; MS (DCI / NH₃) M / z 340 (M + NH₄)⁺, 342 (M + NH₄) ⁺ , 323 (M + H)⁺, 325 (M + H)⁺;¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 7.6 (m, 2H), 7.6
2 (d, 1H), 7.77 (m, 2H), 8.19 (d, 1H), 8.79 (s
, 1H); Analysis C₁₄H₈Cl₂N₂OS₂For 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-carboxylate Example 132A and 5-methyl-1,3,4-thiadiazole-2-thiol were treated as in Example 17B to give the title compound.

MS (DCI / NH)₃) M / z 355 (M + NH₄)⁺And 238 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆1.) δ 1.32 (t, 3H);
66 (s, 3H), 4.36 (q, 2H), 7.34 (d, 1H), 8.13 (
d, 1H), 9.00 (s, 1H); Analysis C₁₃H₁₁N₃O₂S₂For C: 46.27; H, 3.2.
8; 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
Treatment as in Examples 17B, 18 and 19 provided the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 6.
83 (d, 1H), 7.37 (m, 2H), 7.56 (m, 2H), 7.83 (
br s, 1H), 8.25 (s, 1H), 8.41 (br s, 1H),
53 (d, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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-
2-Carboxylate Example 136A 2,6, Dichloro-3-pyridinecarbonitrile Example 136B Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate Example 136A and methylthioglycolate Treatment as in Example 1D afforded the specified compound.

Example 136C Methyl 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-
2-carboxylate 75% H of Example 136B (32 g, 1.34 mmol)₂SO₄(7.4m
L) The solution was added at 0 ° C with NaNO₂Water (0.24 g / 1.5 mL, 3.5 mmol
), Stirred for 30 minutes, cold 50% H₂PO₃(11.8 mL)
, Stirred for 30 minutes, stored at 0 ° C. for 60 hours, warmed to room temperature, NaHCO 3 ₃ And extracted with ether. Dry the extract (MgSO 4₄) Then filter and concentrate
Shrank. Dissolve the residue in methanol (7 mL), heat to 50 ° C., ₃ (0.08 g, 1.45 mmol) and p-thiocresol (0.18 g,
(1.45 mmol), stirred at room temperature for 18 hours and concentrated. Residue
Was treated with 10% citric acid and extracted with dichloromethane. Dry the extract (MgS
O₄), Filtered and concentrated. The residue is purified using 25% ethyl acetate / hexane
Purification by silica gel flash chromatography provided the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) 2.39 (s, 3H), 3.8
9 (s, 3H), 7.02 (d, 7.36 (m, 2H), 7.57 (m, 2H)
, 8.13 (s, 1H), 8.23 (d, 1H); Calcd for analysis _{C 16 H 13 NO 2 S 2} : 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 Example 136C using the procedure of Example 44. .

Example 138 2-Bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyri
Gin para-thiocresol (500 mg, 4 mmol) in DMF (10 mL)
At room temperature with potassium t-butoxide (451 mg, 4 mmol),
After 5 minutes, the mixture was cooled to 0 ° C., and 2-bromo-4-chlorothieno [3,2-c] pyridyl was added.
(F. Eloy and A. Deryckere (Bull. Soc. Chim)
. Belg. 1970, 79, 301) (prepared in 6 steps) (1.0
g, 4.0 mmol) and stirred at 0 ° C. for 2 hours and at room temperature for 12 hours,
And extracted with diethyl ether. The extract is washed with water and dried (Na₂SO ₄ ) And dried under vacuum. The residue was washed with 1:20 ethyl acetate-hexane.
Purification by Ricagel flash chromatography provided the title compound.

MS (DCI / NH ₃ ) m / z 336, 338 (M + H) ⁺ ; ¹ H NMR (300 Hz, CDCl ₃ ) δ 2.36 (s, 3H), 7.18 (
d, 2H), 7.40 (d, 2H), 7.48 (brs, 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 F . Eloy and A.J. Deryckere, Bull. Soc. Chim.
Belg. 4-oxo-4,5-dihydrothieno [3,2-c] pyridine-2-nitrile prepared as in 1970, 79, 301 (500 mg, 2.84 mm
ol) and phosphoryl chloride (5 mL) were heated at reflux for 1 hour. The red solution formed was poured on ice and extracted with methylene chloride (2 × 150 mL). The dichloromethane solution was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Residue 1: 1
Purification by flash chromatography using 0 EtOAc / hexane gave the title compound.

MS (DCI / NH ₃ ) m / z 195 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, 1 H), 8.10
(S, 1H), 8.41 (d, 1H).

Example 139B 4-[(4-Methylphenyl) thio] thieno [3,2-c] pyridine-2-carbonitrile para-thiocresol (192 mg, 1.54 mmol) in DMF (5 mL)
The solution was added at room temperature with potassium tert-butoxide (173 mg, 1.54 mmol).
), Stirred for 15 minutes, cooled to 0 ° C., and treated with Example 139A (200 mg,
1.03 mmol), stirred initially at 0 ° C. and then at room temperature for 48 hours, treated with water and extracted with dichloromethane. The extract is dried (MgSO ₄ ), filtered,
Concentrated. The residue was purified by silica gel flash chromatography using 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 / z 283 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 ); Calcd for analysis _{C 15 H 10 N 2 S 2} : 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) is prepared as 110 Heated at 3O 0 C for 3 hours, cooled, treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel flash chromatography using 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 (brs, 1H), 7.
84 (d, 1H), 8.19 (d, 1H), 8.34 (s, 1H), 8.46 (
br s, 1H); Calcd for analyzing _{C 15 H 12 N 2 OS 2} : 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); Calcd for analysis _{C 15 H 10 N 2 OS:} C, 67.65; H, 3.78;
N, 10.52. 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, 1H), 8.38 (br s, 1H), 8.
41 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S: 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 prepared as described in Caldwell and Martin (J. Hetero).
cyclic Chem. , 1980, 17, 989). 3-Chloropyridine (15.0) with cooling to maintain the internal temperature below 30 ° C.
g, 132 mmol) in acetic anhydride (75 mL) was treated with hydrogen peroxide (75 mL of a 30% aqueous solution), stirred at room temperature for 3 hours, heated at 60 ° C. for 18 hours, and treated with water (
(200 mL), concentrated, solid sodium bisulfite was added portionwise until peroxide was no longer detectable (by the enzymatic peroxide test) and the remaining solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The wash was filtered and concentrated to give the specified compound.

Example 141B 4-Nitro-3-chloropyridine-N-oxide Example 141B was prepared as described in Caldwell and Martin (J. Hetero).
cyclic Chem. , 1980, 17, 989). Example 141A (16.8 g, 130 mmol) sulfuric acid (25 mL, 98%) of fuming sulfuric acid _{(30% SO 3, 10mL)} , and nitric acid (60 mL, 90%) solution, 1
Heat at 20 ° C. for 2 hours, cool to room temperature, pour into ice water (200 mL), add solid ammonium carbonate to bring the solution to pH = 9, and extract with methylene chloride (4 × 100 mL). The extracts were dried _(Na 2 SO _4), and concentrated. The residue was treated with ethyl acetate-
Recrystallization from hexane gave a clean first group of the title compound. A second group of recrystallizations provided a mixture of the title compound and by-products.

[0504] ^{_{MS (DCI / NH 3) m}} / z194 (37 Cl) / 192 (35 Cl), (
M + NH ₄ ) ⁺ ; 177 ( ³⁷ Cl) / 175 ( ³⁵ Cl), (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (d, 1H), 8.14
(Dd, 1H), 8.32 (d, 1H).

Example 141C 4-Nitro-3- (4-methylphenoxy) pyridine-N-oxide A solution of NaH (834 mg, 34.8 mmol) in DMF (20 mL) was added at room temperature to p-cresol (3.57 g, 33). 1.0 mmol) Example 141B (5.75)
g, 32.9 mmol), stirred at room temperature for 10 minutes, and 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 ₂ SO ₄ ) and concentrated. Recrystallization from diethyl ether gave the title compound.

MS (DCI / NH ₃ ) m / z 264 (M + NH ₄ ) ⁺ , 247 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.39 (s, 3H), 7.02
(D, 2H), 7.26 (d, 2H), 7.78 (d, 1H), 7.89 (dd
, 1H), 7.98 (d, 1H).

Example 141D 3- (4-Methylphenoxy) -4-pyridineamine Example 141C (3.65 g, 14.8 mmol) in methanol (100 mL)
), Treated with Raney nickel (1.00 g), flushed with hydrogen, pressurized to 4 atm at 37 ° C. for 2.5 hours, and filtered. The filtrate was concentrated to give the title compound.

MS (DCI / NH ₃ ) m / z 201 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.32 (s, 3H), 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 treated with methylene chloride (50 m
L), cooled to 0 ° C., and triethylamine (1.78 g, 17.6 mm
ol) and trimethylacetyl chloride (1.86 g, 15.4 mmol), stir at room temperature for 15 hours, and add a little sodium chloride in water (100 ml).
L). The organic layer was separated, treated with activated carbon, filtered through Celite®, washed with saturated sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated,
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 285 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 8.42 (d,
1H).

Example 141F 5-Hydroxy-4- (N-trimethylacetyl) amino-3- (4-methylphenoxy) pyridine Chu-Moyer and Berger (J. Org. Chem. 1995;
60, 5721). Example 141E (5.50 g, 19.3 m
mol) was dissolved in diethyl ether and cooled to -78 ° C. Tert-butyllithium (24.0 mL of a 1.7 M solution in 1.7 M pentane, 40.8 mmol) was added dropwise and stirring was continued at -78 ° C for 2 hours. Trimethyl borate (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 30% aqueous hydrogen peroxide (5.8 m).
L) was added. The reaction was stirred at room temperature for 2 hours, then poured into 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 is washed once with water, once with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a mixture of the two compounds, where a higher R _f is desired. The mixture is applied to a 40M Biotage cartridge (Biotage ca
rtridge), purified by flash silica chromatography using a 1.5% methanol in CH ₂ Cl ₂ eluent to give 0.15 mmol (15% yield) of the desired product and 0.73 mmol (73%) The title compound was obtained.

MS (DCI / NH ₃ ) m / e 301 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 10.2
6 (br s, 1H).

Example 141G 5-Hydroxy-4-amino-3- (4-methoxyphenoxy) pyridine Example 141F (850 mg, 2.83 mmol) was suspended in 3N aqueous HCl and stirred at 90 ° C. for 18 hours. The reaction was then cooled to 0 ° C. and 6N NaO
Neutralized with H water 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 (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
16 (s, 2H), 6.81 (d, 2H), 7.12 (d, 2H), 7.50 (
s, 1H), 7.71 (s, 1H), 8.14 (s, 1H), 9.55 (br
s, 1H).

Example 141H Methyloxazolo [5,4-c] -4- (4-methylphenoxy) pyridine-
2-Carboxylate To a DMF solution of Example 141G (1.00 mmol) was added pyridine (1.10 m).
mol) and methyl oxalyl chloride (1.10 mmol) are added and the resulting solution is stirred overnight at room temperature. The reaction is then partitioned between methylene chloride and 1N aqueous HCl, the organic layer is 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) pyridine Example 141E (284 mg, 1.00 mmol) in diethyl ether (12
The solution was treated dropwise at −78 ° C. with tert-butyllithium (1.3 mL of a 1.7 M solution in pentane, 2.21 mmol, Aldrich), followed by 3 mL.
Stirred at -78 ° C for hours. Tetramethylthiuram disulfide (529 mg, 2
. 20 mmol) was added to the resulting dianion and stirring and temperature increase were continued for 18 hours. The reaction was quenched with water and extracted with _CH 2 Cl _2. Dry the organic phase (N
a ₂ SO ₄ ) and concentrated under reduced pressure. The title compound (50 mg, 12% yield) was obtained
Isolated by flash silica gel column chromatography.

MS (DCI / NH ₃ ) m / e 404 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.32 (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, 1H), 8.45 (s, 1H)
.

Example 142B 5- (N, N-dimethylthiuram) sulfide-4-amino-3- (4-methylphenoxy) pyridine Example 142A (270 mg, 0.67 mmol) was added to formic acid (96 mL of 96% in 20 mL).
, Aldrich) and stirred at 90 ° C for 72 hours. The reaction was then cooled to room temperature and the formic acid was removed under reduced pressure. The resulting residue is purified by flash silica gel chromatography (70% EtOAc in hexane) to give the title compound (96 mg, 45% yield).

MS (DCI / NH ₃ ) m / e 320 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.33 (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, 1H), 8.12 (s,
1H).

Example 142C 5- (N, N-dimethylthiuram) sulfide-4-methyloxamate-3
- (4-methylphenoxy) pyridine Example 142B (90 mg, 0.28 mmol) _to, CH ₂ Cl ₂ (7.0m
L). Triethylamine (0.39 mL, 2.2 mmol) was added,
Then, methyl oxalyl chloride (120 mL, 1.30 mmol, Aldrich) was added. After 6 hours, the mixture was combined with saturated aqueous sodium bicarbonate 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 , 300 MHz) δ 2.33 (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, 1H), 8.41 (s, 1H)
, 9.20 (br s, 1H).

Example 142D Methyl 4- (4-methylphenoxy) thiazolo [5,4-c] -pyridine-2
-Carboxylate Example 142C (50 mg, 0.12 mmol) was added to formic acid (14 mL, 96%,
Aldrich) and heated to reflux. After 4 hours, the reaction was cooled and volatiles were removed. Flash silica gel column chromatography (6 in hexane)
(0% EtOAc) provided 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 , 300 MHz) δ 2.39 (s, 3H), 4.10
(S, 3H), 7.08 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8
. 5 Hz, 2H), 8.14 (s, 1H), 9.00 (s, 1H).

Example 142E 4- (4-Methylphenoxy) thiazolo [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 , 300 MHz) δ 2.39 (s, 3H), 5.66
(Br s, 1H), 7.06 (d, J = 8.2 Hz, 2H), 7.22 (d,
J = 7.8 Hz, 2H), 7.32 (brs, 1H), 8.20 (s, 1H)
, 9.04 (s, 1H).

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) is suspended in ammonium hydroxide (28%), saturated with sulfur dioxide, heated to 150 ° C in a pressure vessel for 27 hours, cooled and treated with ethyl acetate. Extracted. Concentrate the extract to give the title compound.

Example 143B 5- (4-Methylphenoxy) -3,4-pyridinediamine Example 143A (1.00 mmol) is suspended in HCl (3N aqueous) and 90 ° C.
For 18 hours, cooled to 0 ° C., neutralized with 6N aqueous NaOH, and water was removed.
The residue obtained is triturated with methanol. Concentrate the wash to give the title compound.

Example 143C Methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2-carboxylate A solution of Example 143B (1.00 mmol) in DMF was treated with pyridine (1.10 m
mol) and methyl oxalyl chloride (1.10 mmol), stir at room temperature overnight, and partition 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 can be 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 is described in Prugh et al. (J. Med. Chem.
1805). Dibromothiophene (14 g, 58 mmol)
In THF (100 mL) at −78 ° C. in n-butyllithium (24 mL, 5 mL).
9 mmol), stir for 15 minutes, dry DMF (6.8 mL, 87 mmol)
1), stirred at -78 ° C for 10 minutes, slowly warmed to 0 ° C over 15 minutes, poured into cold 1N aqueous HCl and extracted with diethyl ether. Extract 1N
Washed with aqueous HCl, water and saturated sodium bicarbonate. The washing 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 on silica gel with 5% ethyl acetate / hexane to give the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.16 (d, 1H), 7.7
4 (d, 1H), 10.0 (s, 1H).

Example 144B 3-Bromo-2- (2-dioxolanyl) thiophene Example 144B is described in Prugh et al. (J. Med. Chem. 1991, 34;
1805). In a three-necked flask equipped with a Dean-Stark trap, Example 144A (5.24 g, 27.4 mmol), ethylene glycol (6.2 mL, 110 mmol), pyridinium tosylate (276 mg)
, 1.10 mmol) and toluene (30 mL), heat to reflux for 14 hours, cool to room temperature, pour into water and extract with diethyl ether. The organic layer was washed with water and saturated sodium bicarbonate, dried (MgSO _4), filtered, and concentrated.
The residue is purified by flash chromatography on silica gel with 5% ethyl acetate / hexane to give the title compound.

[0534] ^{_{MS (DCI / NH 3) m}} / z252 (79 Br) / 254 (81 Br), (
M + NH ₄ ) ⁺ ; 235 ( ⁷⁹ Br) / 237 ( ⁸¹ Br), (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 4.11-4.02 (m, 4H)
, 6.14 (s, 1H), 6.97 (d, 1H), 7.30 (d, 2H).

Example 144C Ethyl-2- (2-dioxiranyl) thiophene-3-carboxylate Example 144C was prepared according to Prugh et al. (J. Med. Chem. 1991, 34;
1805). Example 144B (1.00 g, 4.25 mmol
l) in THF (12 mL) was treated with n-butyllithium (1.7 mL, 4.25 mmol) while maintaining the temperature between -105 and -95 ° C, and diethyl carbonate (0.57 mL, 4 mL). .68 mmol) and warm to room temperature. The solution is poured into water and extracted with diethyl ether. The extract was washed with brine and dried (M
gSO ₄ ), filter and concentrate under reduced pressure. The residue is purified by flash chromatography on silica gel 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 combined with 1N
Treat with aqueous sodium hydroxide solution (100 mmol), stir for 1 h, bring to pH = 5 by adding glacial acetic acid, stir for 1 h, dilute with water and extract with ethyl acetate.
The combined extracts were washed with brine, washed with saturated sodium bicarbonate and dried (Mg
SO ₄ ), filter and concentrate. The specified compounds are used without further purification.

Example 144E 4-Oxothieno [2,3-d] pyridazine Example 144D is described in Bull. Soc. Chim. Fr. 1967, 2495
Process as follows.

Example 144F 4-Chlorothieno [2,3-d] pyridazine Example 144E is described in Bull. Soc. Chim. Fr. 1967, 2495
Process as follows.

Example 144G 4- (4-Chlorophenoxy) thieno [2,3-d] pyridazine Robba and others (Bull. Soc. Chim. Fr., 1967, 42).
Example 144F (100 mg, 0.59 mmol) was obtained by employing the method of 20).
Combined with 4-chlorophenol (1.0 mL, 10.0 mmol) and sodium metal (21 mg, 0.90 mmol). The mixture was heated at 100 ° C. for 14 hours. After cooling to room temperature, the residue was diluted with chloroform and washed once with 2N aqueous sodium hydroxide and once with brine. The organic layer was dried (MgSO ₄ ), filtered,
Concentrated under reduced pressure. Recrystallization from diethyl ether gave the title compound (124 mg
, 85%) as a white solid.

MS (DCI / NH ₃ ) m / e: 363 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.27 (d, J = 8.9 Hz,
2H), 7.42 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 5.5H)
z, 1H), 7.88 (d, J = 5.2 Hz, 1H), 9.41 (s, 1H).

Example 144H 4- (4-Chlorophenoxy) thieno [2,3-d] pyridazine-2-carboxylic acid A solution of Example 144G (1.0 mmol) in THF (1.0 mL) at -78 ° C. Treat with n-butyllithium (1.0 mmol), stir for 15 min, saturate with CO ₂ , slowly warm to room temperature, partition between 1N aqueous sodium hydroxide and diethyl ether, separate, ice Acetic acid is added to the aqueous layer until pH = 5. The acidic solution is extracted three times with methylene chloride. The extracts are combined, 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 is described in Desai and Stramiello (Tetrahe).
(Dron Lett, 1993, 34, 7665). Example 144H (1.0 mmol), 1-hydroxybenzotriazole (1.4 mm
ol), N-methylmorpholine (12 mmol), and DMF (1.0 mL)
And cooled to 0 ° C., treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.4 mmol), stirred at 0 ° C. for 1 hour, and treated with methylene chloride and saturated sodium bicarbonate. Distribute between and separate. Dry the extract (Mg
SO ₄ ), filter and concentrate. Recrystallization from hot methanol gives the title compound.

Example 145 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carbamide Example 145A 2,5-Dibromo-3-thiophenecarboxaldehyde . Soc. Chem.
Fr. , 1974, 3040 to give the title compound.

Example 145B Dimethylacetyl- (2,5-dibromo-3-thienyl) carboxyiminoethane Example 145A was prepared according to Bull. Soc. Chem. Fr. , 1974, 304
Treat as 0 to give the title compound.

Example 145C 6,7-Dihydro-7-oxothieno [3,2-c] pyridine Example 145B was prepared according to Bull. Soc. Chem. Fr. , 1974, 304
Treat as 0 to give the title compound.

Example 145D 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine Example 145D was prepared from Lindley (Tetrahedron, 1983, 1).
433). Example 145C (1.0 mmol) and DMF
(2.0 mL) at 0 ° C. was treated with sodium hydride (1.0 mmol), slowly warmed to room temperature, and treated with 1-chloro-4-iodobenzene (1.0 mm).
ol) and copper iodide (0.1 mmol), heat at 80 ° C. overnight and cool. The solution is poured into water and extracted with diethyl ether. Combine the extracts and dry (
MgSO ₄ ), filter and concentrate. Recrystallization from ethyl acetate / hexane gives the title compound.

Example 145E 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid The specified compound is treated as described in Example 144H.

Example 145F 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carboxamide The specified compound is treated as described in Example 144I.

Example 146 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbothioamide Example 61 (50 mg, 0.16 mmol) and Lawesson (Lawess)
on) Reagent (73 mg, (0.18 mmol)) in toluene (2 mL)
Heat to reflux for 4 hours. Removal of the solvent under reduced pressure gives the crude product (150 mg) as a yellow residue. Purified title compound (24 mg, 47%) was obtained by flash chromatography on silica gel, eluting with 10% methanol in dichloromethane.

MS (DCI / NH ₃ ) m / e: 321 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (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 Example 61A (200 mg, 0.627 mmol) was added to ethylamine (1 ml).
, 17.65 mmol) was replaced with methylamine to give the title compound (209 mg, 100%).

MS (DCI / NH ₃ ) m / e 333 (M + H) ⁺ , 303; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.14 (t, J = 8 Hz,
3H), 3.30 (m, 2H), 7.14 (d, J = 9 Hz, 2H), 7.47
(D, J = 9 Hz, 2H), 8.13 (s, 1H), 8.17 (s, 1H), 8
. 91 (t, J = 6 Hz, 1H), 9.15 (s, 1H).

Example 148 4- (4-Chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno [2,3-c] pyridine-2-carboxamide Example 148 comprises 3-amino-1,2 -Propanediol (60 mL, 0.7
82 mmol) and Example 61A (250 mg, 0.782 mmol) were prepared in an analogous manner to Example 103A to give the title compound (133 mg).
, 45% yield) as a white solid.

MS (DCI / NH ₃ ) m / e: 379 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.16 (m, 2H);
38 (m, 2H), 3.63 (m, 1H), 4.56 (t, J = 5.7 Hz, 1
H), 4.81 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 9.2, 2
H), 7.47 (d, J = 9.2 Hz, 2H), 8.18 (s, 1H), 8.2
1 (s, 1H), 8.95 (t, J = 5.7 Hz, 1H), 9.16 (s, 1H)
); Analysis _{C 17 H 15 ClN 2 O 4} S 2 0.25H 2 O Calculated: C, 53.27;
H, 4.08; N, 7.31. Found: C, 53.19; H, 4.22; N, 6
. 22.

Example 149 4- (4-Bromophenoxy) -N- (2,3-dihydroxypropyl) thieno [2,3-c] pyridine-2-carboxamide Example 149 shows methyl 4- (4-bromo Phenoxy) -thieno [2,3-c
Prepared following the procedure for Example 114, substituting Example 61A for pyridine-2-carboxylate.

MS (DCI / NH ₃ ) m / e: 423, 425 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.12 (m, 2H);
41 (m, 3H), 3.63 (m, 2H), 7.06 (d, 2H, J = 8.8H)
z), 7.59 (d, 2H, J = 8.8 Hz), 8.20 (s, 1H), 8.2
2 (s, 1H), 8.99 (t, 1H, J = 5.5 Hz), 9.18 (s, 1H)
).

Example 150 N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] Pyridine-2-carboxamide To a solution of Example 114 (0.32 g, 0.92 mol) in anhydrous THF (5 mL)
Slowly, thionyl chloride (0.34 mL, 4.60 mmol) was added. reaction
Heat the material to 50 ° C. for 18 hours, cool to room temperature, and add saturated NaHCO 3₃And neutralized.
The aqueous suspension was extracted with dichloromethane (100 mL) and the organic layer was diluted with dilute NaHCO₃ (2 × 100 mL), diluted with brine (50 mL) and partially dried (Na₂SO ₄ ) And concentrated to a solid. The crude product was eluted with EtOAc / hexane.
Purified by flash chromatography on silica gel using the title compound
Was obtained as a solid (0.27 g, 80%).

MS (DCI-NH ₃ ) m / e: 367 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.60 (m, 2H), 3 .
75 (t, J = 6.1 Hz, 2H), 7.15 (m, 2H), 7.48 (m, 2H)
H), 8.18 (s, 1H), 8.18 (s, 1H), 9.17 (s, 1H),
9.26 (m, 1H); Analysis _{C 16 H 12 Cl 2 N 2} O 2 Calculated for S: 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 Example 151 was prepared according to the procedure of Example 114 using methyl 4- (4-bromophenoxy) -thieno [2,3-c] pyridine-2-carboxylate as Example 61.
Prepared in place of A.

MS (DCI / NH ₃ ) m / e: 393, 395 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.32 (m, 2H);
51 (m, 3H), 4.79 (t, 1H, J = 5.9 Hz), 7.06 (d, 2
H, J = 8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 8.17 (s)
, 1H), 8.20 (s, 1H), 9.02 (t, 1H, J = 5.5), 9.1
7 (s, 1H).

Example 152 4- (2-Bromo-4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide Example 152 was prepared according to the procedure of Example 114, substituting 4-chlorophenol for 2-bromo-4-chlorophenol.

MS (DCI / NH ₃ ) m / e: 428 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.86 (q, 1 H, J = 5)
. 4 Hz), 3.34 (m, 2H), 3.55 (m, 2H), 7.15 (d, 1
H, J = 8.8 Hz), 7.48 (dd, 1H, J = 2.4, 8.8 Hz), 7
. 97 (d, 1H, J = 2.7 Hz), 8.02 (s, 1H), 8.25 (s,
1H), 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 Example 62A (322 mg, 0.912 mmol) Was treated with 226 mg (3.65 mmol) of ethanolamine. The solution was heated at reflux for 4 hours. Crystals formed upon cooling. Recrystallization from ethyl acetate gave 170 mg (48.8%) of white crystals.

MS (DCI / NH ₃ ) m / e: 383 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3-3.4 (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); Analysis _{C 17 H 13 F 3 N 2} O 3 Calculated for S: 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 Example 88 (0.50 g, 1.64 mmol) in anhydrous methylene chloride (15 mL)
) The suspension was added with N, N-diisopropylethylamine (0.57 mL, 3.28 m
mol) was added. The reaction was cooled in an ice bath and pivaloyl chloride (0.24 mL, 1
. 97 mmol) was added slowly. After 10 minutes, the ice bath was removed and the reaction was stirred at ambient temperature for 1.5 hours. The reaction contents were slowly transferred via cannula to a solution of anhydrous ethylenediamine (0.33 mL, 4.92 mmol) in methylene chloride (5 mL) at 0 ° C. over 5 minutes. The reaction was stirred for 15 minutes and the cold bath was removed. The reaction was stirred for 1 hour and then partitioned between CHCl ₃ / sat. NaHCO ₃ . The organic layer was washed with dilute aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated to give a light yellow foam. The crude product was reduced to 25% over 40 minutes.
Purified by preparative HPLC using a gradient of -65% acetonitrile / water + 0.1% TFA. The product was neutralized with saturated aqueous NaHCO ₃ and the precipitate was collected by filtration and dried in a desiccator to give the title compound as a white solid (0.45 g,
79%).

MS (ACPI) m / e: 348 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.69 (t, J = 6.4 H).
z, 2H), 3.25 (t, J = 6.4 Hz, 2H), 7.14 (m, 2H),
7.47 (m, 2H), 8.16 (s, 1H), 8.18 (s, 1H), 9.1
5 (s, 1H).

Example 155 4- (4-Chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 155 is a compound of Example 88 (161 mg, 0.527 mmol) and hydroxylamine hydrochloride. Prepared as in Example 92 by combining the salts (37.0 mg, 0.527 mmol) to give the title product (40 mg, 24% yield) as a white solid.

MS (DCI / NH ₃ ) m / e: 321 (M + H) ⁺ ; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.11 (d, J = 9.2 Hz;
2H), 7.42 (d, J = 9.2 Hz, 2H), 7.90 (s, 1H), 8.
05 (s, 1H), 9.01 (s, 1H); IR (KBr) 3200-2800 (m), 1660 (s), 1640 (s),
1560 (m), 1485 (s ), 1420 (s) cm -1; Analysis _{C 14 H 9 ClN 2 O 3} S + 0.25H calcd for ₂ O: 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-carboxyhydrazide Example 61A (0.50 g, 1.56 mmol) was treated with dichloromethane (10 mL).
) And anhydrous hydrazine (1 mL) was added. After 24 hours, the precipitate was collected by filtration and washed with dichloromethane (2 × 25 mL) and water (2 × 50 mL). The product was dried in a desiccator to give the title compound as a white solid (0.
35 g, 70%).

MS (APCI) m / e: 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.62 (broad s, 2H
), 7.12 (m, 2H), 7.46 (m, 2H), 8.03 (s, 1H), 8
. 19 (s, 1H), 9.15 (s, 1H), 10.24 (br s, 1H);
Analysis Calculated for C ₁₄ H ₁₀ ClN ₃ O ₂ S: C, 52.59; H, 3.
15; N, 13.14. Found: C, 52.59; H, 3.12; N, 13.1.
8.

Example 157 4- (4-Bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide Example 73A (0.21 g, 0.58 mmol) in dichloromethane (2 mL)
And anhydrous hydrazine (1 mL) was added. After 18 hours, the precipitate was collected by filtration, dichloromethane (2 × 5 mL), water (2 × 5 mL), acetonitrile (
(2 x 5 mL) to give a white solid. The washes were combined, diluted with saturated NaHCO ₃ (100 mL) and extracted with dichloromethane (4 × 25 mL). The organic extracts were combined, partially dried (Na ₂ SO ₄ ) and concentrated to give a white solid, which was combined with the collected precipitate and dried in a desiccator (0.21 g, 99%).

MS (APCI) m / e: 364 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.62 (br s, 2H).
, 7.06 (m, 2H), 7.58 (m, 2H), 8.02 (s, 1H),
21 (s, 1H), 9.16 (s, 1H), 10.24 (br s, 1H); Analysis C ₁₄ H ₁₀ BrN ₃ O ₂ Calculated for S: C, 46.17; H, 2.
77; N, 11.54. Found: C, 46.08; H, 2.90; N, 11.4.
One.

Example 158 4- [4- (Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide Example 62A is treated according to the procedure of Example 157 to give the title compound. Obtained.

MS (ESI) m / e: 353.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.18 (d, 2H);
11 (t, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.78 (
s, 1H), 8.36 (s, 1H), 9.21 (s, 1H).

Example 159 2-({[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl @ amino) acetic acid Example 159A 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid Example 61A (354 mg, 1.11 mmol) in 3 mL methanol and 1
The suspension mL water, lithium hydroxide monohydrate (98 mg, 2.33 mmol) was treated with the resulting mixture at room temperature _{(N 2} under) was stirred for 20 h. The reaction was treated with 0.
Acidified with 13 mL of 90% formic acid, the white suspension was stirred for 5 minutes, then the solid was isolated by suction filtration. The solid was washed successively with 15 mL of water and 5 mL of diethyl ether, then 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 ) δ 7.15 (m, 2H), 7.
47 (m, 2H), 7.82 (s, 1H), 8.23 (s, 1H), 9.21 (
s, 1H), 13-15 (vbr s, 1H); Analysis C ₁₇ H ₈ ClNO ₃ Calculated for S: C, 55.00; H, 2.64
N, 4.58. Found: C, 54.77; H, 2.60; N, 4.44.

Example 159B Methyl 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) acetate The title compound was obtained from Example 159A in Example Prepared as in 92, but replacing glycine methyl ester hydrochloride with ammonium chloride.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 1 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (APCI) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.68 (s, 3H);
05 (d, J = 6 Hz, 2H), 7.13 (m, 2H), 7.49 (m, 2H)
, 8.19 (s, 1H), 8.21 (s, 1H), 9.19 (s, 1H), 9.
50 (brt, J = 6 Hz, 1H); Calculated for C ₁₇ H ₁₃ ClN ₂ O ₄ S: C, 54.19; H, 3.
48; N, 7.43. Found: C, 53.92; H, 3.61; N, 7.52.

Example 159C 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl {amino) acetic acid The title compound was prepared from Example 159B using the procedure of Example 18.
The title compound was obtained.

MS (APCI) m / e: 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.95 (d, J = ₆ Hz,
2H), 7.13 (m, 2H), 7.48 (m, 2H), 8.19 (s, 1H)
, 8.21 (s, 1H), 9.19 (s, 1H), 9.41 (brt, J = 6)
Hz, 1H), 12.77 (br s, 1H); Analysis _{C 16 H 11 ClN 2 O 4} S · 1H 2 O Calcd for: 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-2-carboxamide The title compound was obtained from Example 159C to Example 92. Prepared as in

MS (APCI) m / e: 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.82 (br s, 2H).
, 7.12 (m, 2H), 7.49 (m, 2H), 8.19 (s, 1H),
21 (s, 1H), 9.20 (s, 1H), 9.29 (br s, 1H); Analysis Calculated for C ₁₆ H ₁₂ ClN ₃ O ₃ S.1.35H ₂ O: C, 49
. 77; H, 3.84; N, 10.88. Found: C, 49.86; H, 3.7.
9; N, 10.59.

Example 161 N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 161A Methyl N- (2-amino- 2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxylate Example 73A was hydrolyzed according to the procedure of Example 18. The derived carboxylic acid was coupled to glycine methyl ester hydrochloride as in Example 92.

MS (DCI / NH ₃ ) m / e: 421 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 370 (s, 3H), 4.1
1 (br d, 2H), 7.11 (br d, 2H), 7.61 (br d, 2H)
H), 8.22 (br d, 2H), 9.19 (s, 1H), 9.51 (br
t, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 41.15, 51.84,
104.95, 115.57, 119.74, 119.97, 132.93, 1
33.32, 137.36, 138.04, 141.45, 145.06, 14
7.03,156.10,161.09,169.80; Analysis C ₁₇ H ₁₃ BrN ₂ O ₄ Calculated for S: C, 48.47; H, 3.
11; N, 6.65. Found: C, 48.16; H, 3.27; N, 6.65.

Example 161B 2-({[4- (4-bromophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl {amino) acetic acid The title compound was prepared from Example 161A using the procedure of Example 18.
The title compound was obtained.

MS (DCI / NH ₃ ) m / e: 407 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.11 (br d, 2H)
, 7.10 (br d, 2H), 7.60 (br d, 2H), 8.21 (br
d, 2H), 9.19 (s, 1H), 9.40 (brt, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 41.50, 115.85.
, 120.00, 120.09, 133.25, 133.67, 137.76,
138.34, 141.79, 145.74, 147.29, 156.46, 1
61.28,171.05; Analysis _{C 16 H 11 BrN 2 O 4} S · H 2 O Calculated for: 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-2-carboxamide The title compound was obtained from Example 161B to Example 92. Prepared as in

MS (APCI) m / e: 406 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.81 (br d, J = 6).
Hz, 2H), 7.08 (m, 2H), 7.10 (brs, 1H), 7.60
(M, 2H), 8.19 (s, 1H), 8.22 (s, 1H), 9.20 (s,
1H), 9.28 (br t, J = 6Hz, 1H); Analysis _{C 16 H 12 BrN 3 O 3} S · 0.3H Calcd for ₂ O: C, 46.
68; H, 3.09; N, 10.21. Found: C, 46.68; H, 3.30.
N, 10.16.

Example 162 N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl] -4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 162A (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid Prepared as in Example 92, replacing L-serine ethyl ester hydrochloride with ammonium chloride. Then, the intermediate ester was prepared in Example 1.
Hydrolysis according to the procedure of 8 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, APCI m / e: 392 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.70 (m, 2H);
43 (brt, 2H), 5.04 (brs, 1H), 7.13 (m, 3H)
, 7.49 (m, 3H), 8.18 (s, 1H), 8.37 (s, 1H),
98 (br s, 1H), 9.18 (s, 1H).

Example 162B N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl] -4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 162B was prepared from Example 162A in the same manner as Example 92.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, APCI m / e: 392 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.70 (m, 2H);
43 (brt, 2H), 5.04 (brs, 1H), 7.13 (m, 3H)
, 7.49 (m, 3H), 8.18 (s, 1H), 8.37 (s, 1H),
98 (br s, 1H), 9.18 (s, 1H).

Example 163 (2R) -2-({[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid Example 163 Was prepared as in 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, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, (ESI) m / e: 393 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.78 (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 4- (4-Chlorophenoxy) -N-[(1R) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 164A (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid Example 164A is the same as Example 92. Thus, D-alanine methyl ester hydrochloride was prepared using ammonium chloride instead. The derived ester is
Hydrolysis according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (DCI / NH ₃ ) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (d, J = 7 Hz;
3H), 4.41 (q, J = 7 Hz, 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 (brs, 1H).

Example 164B 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 164 was prepared as in Example 92, using D-alanine methyl ester hydrochloride instead of ammonium chloride. The derived ester was treated according to the procedure of Example 171 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
Min, RT17.46 _{^{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 (br d, 1H), 8.19 (s, 1H), 8.38 (
s, 1H), 9.13 (br d, 1H), 9.19 (s, 1H).

Example 165 4- (4-Chlorophenoxy) -N-[(1S) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 165A (2S) -2-({[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid Example 165A is the same as Example 92. As such, L-alanine methyl ester hydrochloride was prepared using ammonium chloride instead. The derived ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (DCI / NH ₃ ) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (d, J = 7 Hz,
3H), 4.41 (q, J = 7 Hz, 1H), 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 (brs, 1H);
¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 16.78, 48.46,
119.52, 119.80, 119.97, 127.84, 130.13, 1,
32.97, 137.54, 137.60, 138.09, 141.30, 14
5.59, 147.38, 155.59, 160.54, 173.68.

Example 165B 4- (4-chlorophenoxy) -N-[(1S) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 165B was prepared as in Examples 165A to 92 except that L-alanine methyl ester was replaced with ammonium chloride. Intermediate ester,
This was converted to the title compound according to the procedure of Example 171 using methanolic methylamine.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
Min, RT17.48 _{^{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 (br d, 1H), 8.18 (s, 1H), 8.36 (
s, 1H), 9.12 (br d, 1H), 9.19 (s, 1H).

Example 166 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide The title compound was prepared as in Example 164B using D-serine methyl ester. HPLC: Supelco C-18 column, eluent gradient of water: acetonitrile 0: 90-90: 0 was introduced in 30 minutes, detection 254 nm, flow rate 0.8 mL / min, retention time 16.10 minutes. MS (APCI) m / e: 404 (M-H) < ^- >. ¹ H NMR (300 MHz, 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, 1H), 8.18 (s,
1H), 8.49 (s, 1H), 9.01 (br d, 1H), 9.19 (s, 1H).
1H).

Example 167 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide The title compound was prepared in a similar manner to Example 164B using L-serine methyl ester. HPLC: Supelco C-18 column, eluent gradient of water: acetonitrile 0: 90-90: 0 was introduced in 30 minutes, detection 254 nm, flow rate 0.8 mL / min, retention time 16.18. MS (APCI) m / e: 404 (M-H) < ^- >. ¹ H NMR (300 MHz, 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, 1H), 8.18
(S, 1H), 8.49 (s, 1H), 9.01 (br d, 1H), 9.19
(S, 1H).

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. Obtained. _{MS (DCI / NH 3) m} / e: 272 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.50 (m, 2H), 7
. 85 (m, 1H), 8.20 (s, 2H), 8.45 (dd, 2H), 8.5
5 (d, 1H), 9.20 (s, 1H). Elemental _{analysis: C 13 H 9 N 3 O} 2 S0.25H 2 Calculated O; C 56.61, H
3.47, N 15.24. Obtained: C 57.01, H 3.50, N 1
5.16.

Example 171 Methyl 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 73A (2 g, 5.5 mmol) was prepared by dissolving methylamine in a methanol solution of methylamine (2
M solution, 15 mL) and refluxed under a nitrogen atmosphere for 1 hour. The solvent was then removed and the residue was purified by flash chromatography on silica gel, eluting with 30% acetone in hexane, to give the title compound (1.96 g, 98%). Melting point: 78-80C. _{MS (DCI / NH 3) m} / e: 363,365 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 7.06 (d, 2H, J = 8.8 Hz), 7.59 (d, 2H,
J = 8.8 Hz), 8.06 (s, 1H), 8.20 (s, 1H), 8.96 (
q, 1H, J = 4.8 Hz), 9.17 (s, 1H).

Example 172 4- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide Methyl 4- (4-bromophenoxy) -thieno [2 in Example 61A , 3-c]
Example 172 was prepared according to the procedure of Example 104, substituting pyridine-2-carboxylate. Melting point: 93-95C. _{MS (DCI / NH 3) m} / e: 377,379 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.02 (br s, 3H
), 3.13 (brs, 3H), 7.09 (d, 2H, J = 8.8 Hz), 7
. 5 (d, 2H, J = 8.8 Hz), 7.60 (s, 1H), 8.19 (s, 1
H), 9.15 (s, 1H) ppm.

Example 173 N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2
, 3-c] Pyridine-2-carboxamide In Example 61A, methyl 4- (4-trifluoromethylphenoxy) -thieno [
Example 173 was prepared according to the procedure of Example 104, substituting 2,3-c] pyridine-2-carboxylate. Melting point: 74-76 [deg.] C. _{MS (DCI / NH 3) m} / e: 367 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.17 (brs, 6H),
7.11 (d, 2H, J = 8.0 Hz), 7.45 (s, 1H), 7.63 (d
, 2H, J = 8.0 Hz), 8.24 (brs, 1H), 9.01 (brs
, 1H).

Example 174 4- (4-Chloro-3-fluorophenoxy) -N-methylthieno [2,3-c
Pyridine-2-carboxamide Example 174 was prepared as in Example 103, but replacing 4-chlorophenol with 4-chloro-3-fluorophenol, to give the title compound. Melting point: 62-64 [deg.] C. _{MS (DCI / NH 3) m} / e: 337 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.05 (d, 3H, J =
4.7 Hz), 6.24 (brs, 1H), 6.77 (d, 1H, J = 9.8)
Hz), 6.84 (dd, 1H, J = 2.4, 9.5 Hz), 7.26 (s, 2
H), 7.37 (t, 1H, J = 8.5 Hz), 7.69 (s, 1H), 8.2
1 (s, 1H), 9.00 (s, 1H). Elemental _analysis: Calculated for _{C 15 H 10 N 2 ClFO 2} S; 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 Example 175 was prepared as in Example 61, but replacing 4-chlorophenol with 4-chloro-3-fluorophenol, to give the title compound. Melting point: 227-228 ° C. _{MS (DCI / NH 3) m} / e: 323 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.94 (m, 1 H), 7
. 34 (dd, 1H, J = 3.0, 10.5 Hz), 7.60 (t, 1H, J =
8.7 Hz), 7.87 (s, 1H), 8.11 (s, 1H), 8.26 (s, 1H)
1H), 8.44 (s, 1H), 9.19 (s, 1H). Elemental _analysis: Calculated for _{C 14 H 8 N 2 ClFO 2} S; C 52.10, H 2.5
0, 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 Example 17A and 4-chloro-3-ethylphenol were treated as in Example 61 to give the title compound. Melting point: 185-187 ° C. _{MS (DCI / NH 3) m} / e: 333 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.15 (t, 3H), 2
. 70 (q, 2H), 6.95 (dd, 1H), 7.20 (d, 1H), 7.4
5 (d, 1H), 7.85 (brs, 1H), 8.15 (s, 1H), 8.4
5 (m, 1H), 9.15 (s, 1H).

Example 177 4- (3-Fluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 177 was prepared according to the procedure of Example 61, substituting 3-fluorophenol for 4-chlorophenol. Prepared. Melting point: 215-216 ° C. _{MS (DCI / NH 3) m} / e: 289 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.90 (m, 1 H), 7
. 05 (m, 2H), 7.43 (q, 1H, J = 8.6 Hz), 7.86 (br
s, 1H), 8.14 (s, 1H), 8.20 (s, 1H), 8.45 (br
s, 1H), 9.17 (s, 1H).

Example 178 4- (2,3-Difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 178 was prepared by following the procedure of Example 61 and converting 4-chlorophenol to 2,3-difluoro Prepared in place of phenol. Melting point: 207-209 [deg.] C. _{MS (DCI / NH 3) m} / e: 307 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.97 (t, 1 H, J =
8.5 Hz), 7.22 (q, 1H, J = 8.5 Hz), 7.32 (q, 1H,
J = 8.5 Hz), 7.87 (brs, 1H), 8.18 (s, 1H), 8.
21 (s, 1H), 8.43 (brs, 1H), 9.17 (s, 1H).

Example 179 4- (2,3-Difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 179 was converted to 2-chlorophenol with 2, 3-
Prepared in place of difluorophenol. Melting point: 169-171 [deg.] C. _{MS (DCI / NH 3) m} / e: 321 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.88 (d, 3H, J =
4.4 Hz), 6.94 (t, 1H, J = 8.5 Hz), 7.21 (q, 1H,
J = 8.5 Hz), 7.31 (q, 1H, J = 8.5 Hz), 8.14 (s, 1
H), 8.21 (s, 1H), 8.95 (q, 1H, J = 4.5 Hz), 9.1
7 (s, 1H).

Example 180 4- (3-Fluorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-Carboxamide Example 180 was prepared according to the procedure of Example 103, substituting 3-fluorophenol for 4-chlorophenol. Melting point: 194-195 [deg.] C. _{MS (DCI / NH 3) m} / e: 303 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 6.87 (d, 1 H, J = 8.5 Hz), 7.05 (m, 2 H)
, 7.42 (q, 1H, J = 8.5 Hz), 8.05 (s, 1H), 8.23 (
s, 1H), 8.95 (q, 1H, J = 4.4 Hz), 9.17 (s, 1H).

Example 181 N-methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c
Pyridine-2-carboxamide Example 181 was prepared according to the procedure of Example 103 by converting 4-chlorophenol to 2,3
Prepared in place of 4-trifluorophenol. Melting point: 170-171 ° C. _{MS (DCI / NH 3) m} / e: 339 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.82 (d, 3H, J =
4.4 Hz), 7.13 (m, 1H), 7.35 (q, 1H, J = 8.5 Hz)
, 8.16 (s, 1H), 8.17 (s, 1H), 8.97 (q, 1H, J = 4)
. 5 Hz), 9.16 (s, 1H).

Example 182 4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-
2-Carboxamide Example 182 was prepared according to the procedure of Example 61 by converting 4-chlorophenol to 2,3,4
-Prepared in place of trifluorophenol. Melting point: 218-219 ° C. _{MS (DCI / NH 3) m} / e: 325 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.15 (m, 1 H), 7
. 38 (q, 1H, J = 8.5 Hz), 7.89 (brs, 1H), 8.15
(S, 1H), 8.23 (s, 1H), 8.45 (br s, 1H), 9.15
(S, 1H).

Example 183 N-methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-
c] Pyridine-2-carboxamide Example 183 was prepared according to the procedure of Example 103, substituting 4-trifluorophenol for 4-chlorophenol. Melting point: 157-158 [deg.] C. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.76 (d, 2H,
J = 8.5 Hz), 8.01 (s, 1H), 8.34 (s, 1H), 8.92 (
q, 1H, J = 4.4 Hz), 9.24 (s, 1H).

Example 184 4- [3- (Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 17A and 3-trifluoromethylolophenol were prepared in the same manner as in Example 183. Workup provided the title compound. Melting point: 175-176 ° C. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H), 7
. 35 (d, 1H), 7.20 (d, 1H), 7.60 (m, 3H), 8.10
(S, 1H), 8.30 (s, 1H), 9.00 (b, 2H), 9.25 (s, 1H)
1H). Elemental _analysis: Calculated for _{C 16 H 11 F 3 N 2} O 2 S0.25H 2 O; C 53.8
6, 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 Example 185 was converted to 4-chlorophenol according to the procedure of Example 104 to give 4-chlorophenol. -Prepared in place of vinylphenol. Melting point: 80-81 ° C. _{MS (DCI / NH 3) m} / e: 325 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.02 (br s, 3H
), 3.13 (brs, 3H), 5.24 (d, 1H, J = 11.4 Hz),
5.78 (d, 1H, J = 17.3 Hz), 6.74 (dd, 1H, J = 11.
4,17.3 Hz), 7.09 (d, 2H, J = 8.5 Hz), 7.53 (d,
2H, J = 8.5 Hz) 7.61 (s, 1H), 8.16 (s, 1H), 9.1
3 (s, 1H).

Example 186 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 186 was prepared as in Example 103, but replacing 4-chlorophenol with 4-cyanophenol, to give the title compound. _{MS (ESI / NH 3) m} / e: 310 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.89 (d, 2H,
J = 8.8 Hz), 7.97 (s, 1H), 8.37 (s, 1H), 8.94 (
q, 1H, J = 4.4 Hz), 9.26 (s, 1H). Elemental _{analysis: C 16 H 11 N 3 O} 2 S0.05CH 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 Example 187 as in example 61 but substituting 4-cyanophenol for 4-chlorophenol. Was prepared to give the title compound. Melting point: 255-257 ° C. _{MS (ESI / NH 3) m} / e: 296 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.20 (d, 2H, J =
8.8 Hz), 7.84 (s, 1H), 7.89 (d, 2H, J = 8.8 Hz)
, 8.05 (s, 1H), 8.36 (s, 1H), 8.41 (q, 1H, J = 4)
. 4 Hz), 9.26 (s, 1H). Elemental _{analysis: C 15 H 9 N 3 O} 2 S. Calculated 1.5CH ₃ OH; C 57.71
, H 3.08, N 12.24. Obtained: 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- (t-butyloxycarbonyl) amino) phenoxy-
Literature method (A. Vigroux, M. Bergon) in 4-pyridinecarboxaldehyde DMF (30 mL).
, C.I. Zedde; Med. Chem. 1995, 38, 3983), prepared according to Example 17A (2.0 g, 11.4 mmol) and t-butyl N- (
A solution of 4-hydroxyphenyl) carbamate (2.38 g, 11.4 mmol) was treated with CsCO ₃ (3.70 g, 11.4 mmol) at room temperature for 1 hour and then at 70 ° C.
It processed at 30 degreeC and 30 minutes. Brine (150 mL) was added and the mixture was extracted with ether / ethyl acetate (2 × 200 mL). The combined organic phases are dried (MgSO ₄ )
Concentrated. Flash chromatography of the residue on silica gel with 1: 6 ethyl acetate / hexane provided the specified 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 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 hour. After further treatment at room temperature for 1 hour, Cs ₂ CO ₃ (2.47 g, 7.58 mmol
) Was added. The reaction mixture was stirred at room temperature for 1 hour and further at 70 ° C. for 0.5 hour.
Brine (150 mL) was added and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 20% ethyl acetate in hexane to give the specified 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 Example 18 as in example 44 but substituting example 188B for example 43.
8C was prepared to give the title compound. _{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. The residual oil was treated with a mixture of ethyl acetate and aqueous NaHCO ₃ solution.The solid formed was collected by filtration, ethyl acetate, aqueous Na.
Washed sequentially with HCO ₃ solution, water, methanol and ethyl acetate and dried to give the title compound (492 mg, 86% from Example 188B) as a yellow solid. Melting point> 250 ° C. _{MS (DCI / NH 3) m} / e: 286 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 5.62 (br s, 2H
), 6.65 (d, 2H, J = 8.8 Hz), 6.93 (d, 2H, J = 8.8)
Hz), 7.86 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H)
, 9.00 (br s, 1H). Elemental _{analysis: C 14 H 11 N 3 O} 2 S. Calculated 0.5CH ₃ OH; C 57.7
9, 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 as in example 188C, but with t-butyl N- (4-hydroxyphenyl)
Example 189 was prepared by substituting 4- (acetylamino) phenol for the carbamate to give the title compound. _{MS (DCI / NH 3) m} / e: 328 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.04 (s, 3H), 7
. 10 (d, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 8.8 Hz)
, 7.82 (brs, 1H), 7.99 (s, 1H), 8.20 (s, 1H)
, 8.43 (br s, 1H), 9.06 (s, 1H), 9.99 (s, 1H)
. Elemental _{analysis: C 16 H 13 N 3 O} 3 S. Calculated 1.0CH ₃ OH; C 56.8
1, H 3.93, N 11.69. Measured value: C 56.51, H 3.93,
N 11.57.

Example 190 N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide Example 190A Methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-2-carboxylate Same as in Example 61A, except that 4-chlorophenol is used. Example 190A was prepared in place of 4-iodophenol to give the specified compound. _{MS (DCI / NH 3) m} / e: 412 (M + H) +.

Example 190B N-methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-2-carboxamide Example 190A (1.4 g, 3.4 mmol) methylamine /methanol(
(2.0 M solution, 70 mL) The solution was stirred at 45 ° C. for 15 hours and then concentrated in vacuo.
The residue was flash chromatographed on silica gel with EtOAc / hexane (1.5 / 1) to give the specified compound (1.3 g, 93%). _{MS (DCI / NH 3) m} / e: 411 (M + H) +.

Example 190C N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
Example 190B (150 mg, 0.37 mmol), NaOB
ut (71 mg, 0.74 mmol), Pd ₂ (dba) ₃ (14 mg, 0.
014 mmol), BINAP (27 mg, 0.044 mmol) and 18-
Filled with crown-6 (196 mg, 0.74 mmol) and purged with nitrogen.
Anhydrous degassed THF (10 mL) and morpholine (64 mg, 0.74 mmol) were added sequentially. The clear dark red solution was heated at 60 ° C. for 70 hours and quenched with brine. The mixture was extracted with methylene chloride. The organic phase was dried (MgSO _4), and concentrated. To the crude subjected to flash chromatography on silica gel (EtOAc / hexanes) to obtain the title compound further _{HPLC (C-18, CH 3} CN / H 2 O) (26mg). _{MS (DCI / NH 3) m} / e: 370 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.81 (d, 3H, J =
4.5 Hz), 3.1 (m, 2H), 3.74 (m, 2H), 6.99 (d, 2
H, J = 8.8 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7.92 (s)
, 1H), 8.20 (s, 1H), 8.98 (q, 1H, J = 4.8 Hz), 9
. 04 (s, 1H).

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-2-carboxylate As in Example 61A, but 4-chlorophenol was prepared according to the literature method (Frank
, R .; Doring, R .; , Tetrahedron 1988, 44, 60.
Example 1 in place of 4-trityloxymethylphenol prepared according to 31)
91A was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 558 (M + H) +.

Example 191B 4- {4-[(Trityloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide As in Example 61 but 4-chlorophenol was converted to 4-trityl Example 191A was prepared in place of oxymethylphenol to give the title compound. _{MS (DCI / NH 3) m} / e: 543 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 4.10 (s, 2H), 7
. 11 (d, 2H, J = 8.5 Hz), 7.26 to 7.46 (m, 17H), 7
. 87 (br s, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8
. 46 (br s, 1H), 9.12 (s, 1H) ppm. Elemental _analysis: Calculated for _{C 34 H 26 N 2 O 3} S; 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 Example 191A (5.05 g, 9 mmol) in chloroform (20 mL) and methanol ( 8 mL) with trifluoroacetic acid (10 mL) at 0 ° C.
After time processing, it poured into a mixture of ice and saturated NaHCO _3. The mixture was extracted with methylene chloride (2 × 200 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 66% EtOAc / hexane to give the specified 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 As in Example 61, but substituting Example 191C for Example 191C, Example 191D was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 301 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 4.50 (d, 2H, J =
5.8 Hz), 5.19 (t, 1H, J = 5.8 Hz), 7.10 (d, 2H,
J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 7.82 (br
s, 1H), 8.03 (s, 1H), 8.20 (s, 1H), 8.43 (br
s, 1H), 9.09 (s, 1H). Elemental _analysis: Calculated for _{C 15 H 12 N 2 O 3} S; 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 Example 192 was prepared as in Example 103, but substituting Example 191C for Example 61A, to give the title compound. Melting point: 195-196 ° C. _{MS (DCI / NH 3) m} / e: 315 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.5 Hz), 4.49 (d, 2H, J = 4.5 Hz), 5.19 (t, 1H,
J = 4.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H)
H, J = 8.5 Hz), 8.07 (s, 1H), 8.11 (s, 1H), 8.9
4 (q, 1H, J = 4.5 Hz), 9.10 (s, 1H). Elemental _{analysis: C 16 H 14 N 2 O} 3 S. Calculated 0.75CH ₃ OH; C 59.
45, H 4.39, N 8.28. Obtained: C 59.31, H 4.35,
N 8.49.

Example 193 4- [4- (Methoxymethyl) phenoxy] -N-methylthieno [2,3-c]
Pyridine-2-carboxamide As in Example 188C, but preparing Example 193, substituting 4-methoxymethylphenol for 4-t-butyloxycarbonylaminophenol and methylamine for ammonia, to give the title compound. Was. Melting point: 163-164C. _{MS (DCI / NH 3) m} / e: 329 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 3.29 (s, 3H), 4.40 (s, 2H), 7.08 (d,
2H, J = 8.5 Hz), 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 (s, 1H). Elemental _analysis: Calculated for _{C 17 H 16 N 2 O 3} S; 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 as in example 188C, but substituting 4- (2-methoxyethoxymethyl) phenol for 4-t-butyloxycarbonylaminophenol, Example 19
4 was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 359 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.40 (s, 3H), 3.6
0 (m, 2H), 3.65 (m, 2H), 4.56 (s, 2H), 7.02 (d
, 2H, J = 8.5 Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.80
(S, 1H), 8.13 (s, 1H), 8.94 (s, 1H). Elemental _analysis: Calculated for _{C 18 H 18 N 2 O 4} S; 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 As in Example 188C, but with 4-t Example 195 was prepared by replacing -butyloxycarbonylaminophenol with 4- (2-methoxyethoxymethyl) phenol and replacing ammonia with methylamine to obtain the title compound. Melting point: 133-134 [deg.] C. _{MS (DCI / NH 3) m} / e: 373 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.01 (d, 3H, J = 5.
1 Hz), 3.40 (s, 3H), 3.60 (m, 2H), 3.65 (m, 2H)
), 4.54 (s, 2H), 6.51 (q, 1H, J = 5.1 Hz), 7.00
(D, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.
73 (s, 1H), 8.14 (s, 1H), 8.94 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 20 N 2 O 4} S; C 61.27, H 5.41,
N 7.52. Found: C, 61.28; H, 5.35; N, 7.46.

Example 196 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
Thieno [2,3-c] pyridine-2-carboxamide As in Example 188C, but replacing 4-t-butyloxycarbonylaminophenol with 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol. Example 196 was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 403 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.38 (s, 3H), 3.5
7 (m, 2H), 3.63 to 3.70 (m, 6H), 4.55 (s, 2H), 7
. 02 (d, 2H, J = 8.5 Hz), 7.36 (d, 2H, J = 8.5 Hz)
, 7.71 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H).

Example 197 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
-N-methylthieno [2,3-c] pyridine-2-carboxamide Same as in Example 188C, except that 4-t-butyloxycarbonylaminophenol was converted to 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol. Example 197 was prepared by substituting methylamine for ammonia, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 417 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.02 (d, 3H, J = 4.
8 Hz), 3.38 (s, 3H), 3.57 (m, 2H), 3.63 to 3.70
(M, 6H), 4.54 (s, 2H), 6.45 (m, 1H), 7.00 (d,
2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.72 (
s, 1H), 8.15 (s, 1H), 8.94 (s, 1H).

Example 198 4- {4-[(2,3,4,5-tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 198A Methyl 4- {4-} [(2,3,4,5-tetrahydro-2H-pyran-2-yl) oxy] methyl} phenoxy} thieno [2,3-c] pyridine-2-carboxylate 188B, but 4-t-butyloxycarbonylaminophenol is converted to 4-[(2,3,4,5-tetrahydro-2H-pyran-2-yl)
Oxy] methylphenol (PA Grieco, et al, J. Org.
Chem. Example 198A was prepared in place of 1977, 42, 3772) to give the specified compound. _{MS (DCI / NH 3) m} / e: 400 (M + H) +.

Example 198B 4- {4-[(2,3,4,5-tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example Example 198B was prepared as in Example 61, but substituting Example 198A for Example 61A, to give the specified compound. Melting point: 95-96C. _{MS (DCI / NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.49 (m, 4H), 1
. 69 (m, 2H), 3.49 (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), 7.10 (d, 2H, J = 8.8 Hz), 7.41 (d
, 2H, J = 8.8 Hz), 7.87 (s, 1H), 8.08 (s, 1H), 8
. 20 (s, 1H), 8.46 (s, 1H), 9.12 (s, 1H). Elemental _{analysis: C 20 H 20 N 2 O} 4 S. Calculated _{CH 3 OH; C 60.56, H} 5.08, N 6.73. Obtained value: C 60.51, H 5.07, N6.
59.

Example 199 N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide As in Example 103 Similarly, Example 199 was prepared, substituting Example 198A for Example 61A, to give the specified compound. Melting point: 195-196 ° C. _{MS (DCI / NH 3) m} / e: 399 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.49 (m, 4H), 1
. 69 (m, 2H), 2.79 (d, 3H, J = 4.8 Hz), 3.50 (m, 2H)
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), 7.09 (d
, 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 8.11
(S, 1H), 8.12 (s, 1H), 8.97 (q, 1H, J = 4.8 Hz)
, 9.13 (s, 1H). Elemental _analysis: Calculated for _{C 21 H 22 N 2 O 4} S; 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 Example 191D (40 mg, 0.133 mmol) in DMF (5 mL) was treated with 2-furancarboxylic acid (45 mg, 0.4 mmol) and HOBt (54 mg, 0
. 4 mmol), EDC (77 mg, 0.4 mmol) 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 flash chromatographed on silica gel with 65% EtOAc / hexane,
The specified compound was obtained. Melting point: 180-182 [deg.] C. _{MS (DCI / NH 3) m} / e: 395 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 5.31 (s, 2H), 6
. 70 (dd, 1H, J = 1.7, 3.4 Hz), 7.14 (d, 2H, J = 8
. 5 Hz), 7.36 (d, 1H, J = 3.4 Hz), 7.50 (d, 2H, J
= 8.5 Hz), 7.84 (s, 1H), 8.00 (dd, 1H, J = 1.1,
3.7 Hz), 8.13 (s, 1H), 8.17 (s, 1H), 8.44 (s, 1H)
1H), 9.14 (s, 1H).

Example 201 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 201A Methyl 4- [4-({[(2R, 4R, 5S, 6R) -4,5-diacetoxy-
6- (acetoxymethyl) tetrahydro -2H- pyran-2-yl] oxy} methyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate Dry _CH 2 _Cl 2 (10 mL) Example in 191C ( 200mg, 0.63m
mol) and tri-O-acetyl-D-glycal (520 mg, 1.92 mmol)
1) with Sc (OTf) ₃ (380 mg, 0.75 mmol) at room temperature, 12
Temporation and flash chromatography directly on silica gel with 40% EtOAc / hexane provided the specified compound. _{MS (DCI / NH 3) m} / e: 528 (M-OAc) +.

Example 201B 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Example 201A (167) in a methanol solution (10 mL) of phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide methylamine 2M.
mg)) was heated at 45 ° C. for 12 hours and concentrated. 8 residue on silica gel
% MeOH / CH ₂ Cl ₂ to give the specified compound (120 m
g, 91%). _{MS (ESI / NH 3) m} / e: 443 (M-OH) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.53 (m, 3H), 3.67 (m, 1H), 3.87 (m,
1H), 4.50 (d, 1H, J = 11.5 Hz), 4.64 (t, 1H, J =
5.4 Hz), 4.76 (d, 1H, J = 11.5 Hz), 5.06 (m, 2H)
), 5.70 (dt, 1H, J = 10.2, 2.4 Hz), 5.86 (d, 1H)
, J = 10.2 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.40 (d
, 2H, J = 8.5 Hz), 8.10 (s, 1H), 8.11 (s, 1H), 8
. 95 (q, 1H, J = 4.8 Hz), 9.12 (s, 1H).

Example 202 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine-
Example 190B (500 mg, 1.2 mmol) in a flask purged with 2-carboxamide nitrogen
, Pd (OAc)₂(27 mg, 0.12 mmol), (Tol)₃P (110
mg, 0.36 mmol), dry degassed DMF (20 mL), tributylethoxy
Vinyltin (810 mL, 2.4 mmol) and triethylamine (835 ml)
, 6 mmol). This suspension was stirred at 80 ° C. for 14 hours. Ethyl acetate
After dilution with water, the reaction mixture is washed with 1% aqueous HCl and water and dried (MgSO 4). ₄ ) And concentrated. The residue was purified by HPLC (C-18, CH containing 0.1% TFA).₃CN
/ H₂O) to give the title compound (476 mg, 89%). MS (DCI / NH₃) M / e: 327 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆): Δ2.56 (s, 3H), 2
. 78 (d, 3H, J = 4.8 Hz), 7.15 (d, 2H, J = 8.8 Hz)
, 8.00 (d, 2H, J = 8.8 Hz), 8.03 (s, 1H), 8.36 (
s, 1H), 8.98 (q, 1H, J = 4.8 Hz), 9.28 (s, 1H).
Elemental analysis: C₁₇H₁₄N₂O₃S. 1.35CF₃CO₂Calculated value of H; C 4
9.25, H 3.45, N 5.83. Found: C, 49.31; H, 3.6.
0, N 5.93.

Example 203 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c]
A mixture of pyridine-2-carboxamide Example 203A Methyl 4- [4- (4-carboxy) phenoxy] thieno [2,3-c] pyridine-2-carboxylate THF (15 mL) and _H 2 O (15 mL), 4-bromophenoxythieno [2,3-c] pyridine-2-carboxylate (1.0 g, 2.74 m
_mol), suspension CO atmosphere (400 psi) below the _{PdCl 2 DPPFCH 2 Cl 2 (0.284g} ) and triethylamine (0.55g), 130 ℃, 1
Heat for 9 hours. EtOAc (200 ml) was added and the mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 5% CH ₃ OH / CH ₂ Cl ₂ to give the specified compound (311 mg).
, 34%). _{MS (DCI / NH 3) m} / e: 330 (M + H) +.

Example 203B Methyl 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3
Mixture of -c] pyridine-2-carboxylate DMF (5 mL) and _CH 2 _Cl 2 (15mL), Example 203A (
200 mg, 0.61 mmol) of morpholine (80 mg, 0.91 mm)
ol), PyBOP (474 mg, 0.91 mmol) and DIPEA (29
6 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 flash chromatographed on silica gel with 90% EtOAc / hexane to give the specified 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 As in example 61 but substituting example 203B for example 203A, preparing example 203C to give the title compound. Melting point:> 260 ° C. _{MS (DCI / NH 3) m} / e: 401 (M + NH 4) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.50 (m, 4H), 3
. 60 (m, 4H), 7.14 (d, 2H, J = 8.5 Hz), 7.48 (d,
2H, J = 8.5 Hz), 7.86 (s, 1H), 8.15 (s, 1H), 8.
22 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 17 N 3 O 4} S; C 59.52, H 4.47,
N 10.96. Found: C, 59.64; H, 4.52; N, 10.90.

Example 204 N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 204 was prepared as in Example 103, but substituting Example 203B for Example 61A, to give the title compound. Melting point: 173-175 [deg.] C. _{MS (DCI / NH 3) m} / e: 415 (M + NH 4) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 3.50 (m, 4H), 3.60 (m, 4H), 7.12 (d,
2H, J = 8.5 Hz), 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 (s, 1H). Elemental _{analysis: C 20 H 19 N 3 O} 4 S. Calculated 1.5CH ₃ OH; C 57.9
6, H 4.64, N 9.43. Obtained: C 57.99, H 4.86, N
9.63.

Example 206 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 206A methyl 4- [4 -({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate A solution of Example 203A (200 mg, 0.61 mmol) in DMF (11 mL) was prepared. 4- (2-aminoethyl) morpholine (158 mg, 1.21 mmol), E
DC (232 mg, 1.21 mmol), HOBt (164 mg, 1.21 mm)
ol) and triethylamine (122 mg, 1.21 mmol) at room temperature, 18
Time processed. After dilution with EtOAc, the reaction mixture was washed with brine and dried (MgSO4).
O ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 10% MeOH / EtOAc to give the specified compound (239 mg, 89%).
_{MS (DCI / NH 3) m} / e: 442 (M + H) +.

Example 206B 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Same as in Example 61, Example 206B was prepared substituting Example 206A for Example 61A to give the title compound. Melting point: 214-216 ° C. _{MS (DCI / NH 3) m} / e: 427 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.41 (t, 4H, J =
4.8 Hz), 3.37 (q, 2H, J = 6.1 Hz), 3.56 (t, 4H,
J = 4.8 Hz), 7.14 (d, 2H, J = 8.8 Hz), 7.84 (s, 1
H), 7.87 (d, 2H, J = 8.8 Hz), 8.11 (s, 1H), 8.2
2 (s, 1H), 8.39 (t, 1H, J = 6.0 Hz), 8.43 (s, 1H)
), 9.17 (s, 1H).

Example 207 N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 103 Example 207 was prepared as in Example 1, but substituting Example 206A for Example 206A, to give the title compound. Melting point: 226-228 [deg.] C. _{MS (DCI / NH 3) m} / e: 441 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.42 (m, 4H), 2
. 78 (d, 3H, J = 4.4 Hz), 3.36 (q, 2H, J = 6.1 Hz)
, 3.56 (t, 4H, J = 4.8 Hz), 7.12 (d, 2H, J = 8.5H)
z), 7.89 (d, 2H, J = 8.5 Hz), 8.03 (s, 1H), 8.2
6 (s, 1H), 8.41 (t, 1H, J = 6.0 Hz), 8.95 (q, 1H)
, J = 4.4 Hz), 9.20 (s, 1H).

Example 208 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 208A Methyl 4- {4-[(E) -3- (t-butyloxy) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxylate Performed on flasks purged with nitrogen Example 73 (50 mg, 1.37 mmol), P
_{d 2 (dba) 3 (63mg} , 0.069mmol), tri -o- tolyl phosphine (64mg, 0.21mmol), DMF ( 20mL), t- butyl acrylate (602mL, 4.11mmol) and triethylamine (575 mL,
4.11 mmol). The suspension was stirred at 100 ° C. for 12 hours under nitrogen. After dilution with ethyl acetate, the reaction mixture is washed with brine and water and dried (MgSO4).
O ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 20% EtOAc / hexane to give the title compound (323 mg, 57%). _{MS (DCI / NH 3) m} / e: 412 (M + H) +.

Example 208B Methyl 4- {4-[(E) -propenoic acid-1-yl] phenoxy} thieno [2,
3-c] pyridine-2-carboxylate Example 208A (1.76 g, 4.2 mmol) in chloroform (50 mL)
The solution was treated with trifluoroacetic acid (10 mL) at room temperature for 4 hours, followed by ice-cold aqueous
NaHCO₃Poured in. The white solid formed was collected by filtration, and water, MeOH, CH ₂ Cl₂And dried to give the specified compound (1.38 g, 100%). MS (DCI / NH₃) M / e: 356 (M + H)⁺.

Example 208C Methyl 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxylate DMF a mixture of (5 mL) and _CH 2 _Cl 2 (10mL), example 208B (
260 mg, 0.73 mmol) in morpholine (127 mg, 1.46 m).
mol), PyBOP (760 mg, 1.46 mmol) and DIPEA (3
(80 mg, 2.92 mmol) at room temperature for 12 hours. After diluted with CH ₂ Cl _2, the solution was washed with brine, dried (MgSO _4), and concentrated. The residue was flash chromatographed on silica gel with 90% EtOAc / hexane,
The specified compound was obtained. _{MS (DCI / NH 3) m} / e: 425 (M + H) +.

Example 208D 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 61 Example 208D was prepared in the same manner as in Example 1, but substituting Example 208C for Example 61A to obtain the title compound. _{MS (DCI / NH 3) m} / e: 410 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.59 (m, 6H), 3
. 70 (m, 2H), 7.13 (d, 2H, J = 8.5 Hz), 7.20 (d,
1H, J = 15.5 Hz), 7.52 (d, 1H, J = 15.5 Hz), 7.7
9 (d, 2H, J = 8.5 Hz), 7.86 (s, 1H), 8.16 (s, 1H)
), 8.18 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H).

Example 209 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide Example 209A Methyl 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine -2-Carboxylate Example 209A was prepared as in Example 208C, but substituting 4- (2-aminoethyl) morpholine for morpholine, to give the specified compound. _{MS (DCI / NH 3) m} / e: 468 (M + H) +.

Example 209B 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide As in Example 61, but Example 209B was prepared in place of Example 209A, substituting Example 209A to give the title compound. _{MS (DCI / NH 3) m} / e: 453 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.44 (m, 4H), 3
. 30 (m, 4H), 3.59 (t, 4H, J = 4.8 Hz), 6.60 (d,
1H, J = 15.8 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.42
(D, 1H, J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7
. 87 (s, 1H), 8.06 (t, 1H, J = 4.8 Hz), 8.16 (s, 1H)
1H), 8.21 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H)
.

Example 210 N-methyl-4- [4-((E) -3-{[2- (4-morpholinyl) ethyl]]
Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide As in Example 103, but Example 210 is prepared by substituting Example 209A for Example 61A. To give the title compound. _{MS (DCI / NH 3) m} / e: 467 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.38 (m, 4H), 2
. 79 (d, 3H, J = 4.4 Hz), 3.59 (m, 8H), 6.58 (d,
1H, J = 15.8 Hz), 7.11 (d, 2H, J = 8.8 Hz), 7.42
(D, 1H, J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 8
. 05 (s, 1H), 8.23 (s, 1H), 8.95 (q, 1H, J = 4.4)
Hz), 9.17 (s, 1H).

Example 211 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 211A Methyl 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino]
-3-oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-
2-Carboxylate Example 208B (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 m)
mol) and triethylamine (142 mg, 1.41 mmol) at room temperature, 1
Treated for 8 hours. After dilution with EtOAc, the reaction mixture was washed with brine and dried (Mg
SO ₄ ) and concentrated. The residue was flash chromatographed on silica gel to give the specified compound (189 mg, 63%). _{MS (DCI / NH 3) m} / e: 429 (M + H) +.

Example 211B 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-carboxamide As in Example 61, but preparing Example 211B, substituting Example 211A for Example 61A, and substituting the title compound. Obtained. Melting point: 185-187 ° C. _{MS (DCI / NH 3) m} / e: 414 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.10 (m, 1 H), 3
. 30 (m, 2H), 3.54 (m, 1H), 4.60 (t, 1H, J = 5.9)
Hz), 4.84 (d, 1H, J = 4.8 Hz), 6.66 (d, 1H, J = 1)
5.8 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.42 (d, 1H,
J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.86 (s,
1H), 8.08 (t, 1H, J = 5.5 Hz), 8.16 (s, 1H),
21 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H). Elemental _analysis: Calculated for _{C 20 H 19 N 3 O 5} S; C 58.10, H 4.63,
N 10.16. Found: C, 57.99; H, 4.54; N, 10.08.

Example 212 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide As in example 103, but example 212 was prepared by substituting example 211A for example 61A. The title compound was obtained. Melting point: 225-226 ° C. _{MS (DCI / NH 3) m} / e: 428 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.10 (m, 1H), 3.30 (m, 2H), 3.54 (m, 1H)
1H), 4.60 (t, 1H, J = 5.5 Hz), 4.84 (d, 1H, J = 4
. 8 Hz), 6.66 (d, 1H, J = 15.8 Hz), 7.11 (d, 2H,
J = 8.8 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.61 (d,
2H, J = 8.8 Hz), 8.06 (s, 1H), 8.08 (t, 1H, J = 5)
. 5Hz), 8.23 (s, 1H), 8.97 (q, 1H, J = 4.8 Hz),
9.18 (s, 1H). Elemental analysis: Calcd. For C ₂₁ H ₂₁ N ₃ O ₅ S; C 59.00, H 4.95,
N 9.83. Found: C, 58.85; H, 4.90; N, 9.58.

Example 213 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [2
, 3-c] pyridine-2-carboxamide Same as in Example 212, except that 3-amino-1,2-propanediol was converted to 2
Example 213 was prepared in place of-(1H-imidazol-5-yl) ethylamine to give the title compound. _{MS (DCI / NH 3) m} / e: 448 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.5 Hz), 2.85 (t, 2H, J = 6.6 Hz), 3.49 (q, 2H,
J = 6.0 Hz), 6.53 (d, 1H, J = 15.8 Hz), 7.11 (d,
2H, J = 8.5 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.47
(S, 1H), 7.61 (d, 2H, J = 8.5 Hz), 8.07 (s, 1H)
, 8.24 (s, 1H), 8.27 (t, 1H, J = 5.5 Hz), 8.97 (
q, 1H, J = 4.8 Hz), 9.01 (s, 1H), 9.21 (s, 1H).

Example 214 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] ethyl} amino) -3-oxo-1-propenyl] phenoxy} -N- Methylthieno [2,3-c] pyridine-2-carboxamide Same as in Example 212, except that 3-amino-1,2-propanediol was replaced with 2
Example 214 instead of-[bis (2-hydroxyethyl) amino] ethylamine
Was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 485 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.34 (m, 6H), 3.58 (q, 2H, J = 6.1 Hz)
, 3.77 (t, 4H, J = 5.1 Hz), 6.55 (d, 1H, J = 15.6)
Hz), 7.13 (d, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 1)
5.6 Hz), 7.64 (d, 2H, J = 8.5 Hz), 8.07 (s, 1H)
, 8.24 (s, 1H), 8.43 (t, 1H, J = 4.8 Hz), 8.97 (
q, 1H, J = 4.8 Hz), 9.20 (s, 1H).

Example 215 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] ethyl} amino) -3-oxo-1-propenyl] phenoxy} thieno [2 , 3-
c] Pyridine-2-carboxamide As in Example 211, but substituting 3-amino-1,2-propanediol for bis (2-hydroxyethyl) aminoethylamine, preparing Example 215, to give the title compound Was. _{MS (DCI / NH 3) m} / e: 471 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.56 (m, 4H), 3
. 21 (m, 2H), 3.41 (m, 4H), 4.37 (t, 2H, J = 5.6
Hz), 6.56 (d, 1H, J = 15.4 Hz), 7.13 (d, 2H, J =
8.8 Hz), 7.42 (d, 1H, J = 15.4 Hz), 7.61 (d, 2H)
, J = 8.8 Hz), 7.86 (s, 1H), 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: C 23 H 26 N 4 O} 5 S. CH ₃ OH calculated; C 56.36, H
5.41, N 11.15. Obtained: C 56.40, H 5.76, N 1
1.40.

Example 216 4- (4- {3-hydroxy-3- [4-({2-[(methylamino) carbonyl] 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, 0.55mm
ol) at −50 ° C. for 30 minutes and slowly warmed to room temperature in 10 minutes. Aqueous NH ₄ Cl solution was added and the mixture was extracted with ether. The combined organic phases were washed with brine and water, dried (MgSO _4), and concentrated. Residue on silica gel, 5
Flash chromatography with% MeOH / EtOAc afforded the title compound (60 mg, 40%). _{MS (ESI / NH 3) m} / e: 653 (M + H) +. _{^{1 H NMR (300MHz, DMSO-}} d 6): δ1.58 (s, 3H), 2
. 77 (d, 3H, J = 4.8 Hz), 2.80 (d, 3H, J = 4.8 Hz)
, 3.35 (d, 1H, J = 13.0 Hz), 3.49 (d, 1H, J = 13.0 Hz).
0 Hz), 5.27 (s, 1H), 7.02 (d, 2H, J = 8.8 Hz), 7
. 08 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz)
, 7.96 (d, 2H, J = 8.8 Hz), 7.99 (s, 2H), 8.13 (
s, 1H), 8.30 (s, 1H), 8.94 (m, 2H), 9.08 (s, 1)
H), 9.21 (s, 1H). Elemental _{analysis: C 34 H 28 N 4 O} 6 S 2. Calculated CH ₃ OH; 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
] Pyridin-2-carboxamide Example 217A Methyl 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,
Example 17A (0.88 g, 3-c] pyridine-2-carbosylate in THF (15 mL) and DMF (5 mL).
5 mmol) with 4- (1-imidazolyl) phenol and potassium t-butoxide (1N in THF, 5.0 mL, 5 mmol) at 70 ° C. for 4 hours, followed by 0
After cooling to ℃, methyl thioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 mmol) were added, and the mixture was refluxed for 1 hour. The reaction mixture was poured into water, diluted with brine and extracted with ethyl acetate. Then add 1N ethyl acetate solution
NaOH (2 × 20 mL) then brine (3 × 20 mL) and dry (M
gSO ₄ ) to give the title compound. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.25 (d, 2H), 9.25 (s, 1H)
1H).

Example 217B 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide Example 217A was dissolved in 2M ammonia in methanol and placed in a sealed tube at 50 ° C.
Heated for 4 hours. Then the reaction mixture was evaporated and crystallized from methanol to give the title compound. Melting point: 310-312 ° C. _{MS (DCI / NH 3) m} / e: 337 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.10 (s, 1 H), 7
. 28 (m, 2H), 7.68 (t, 1H), 7.25 (dd, 2H), 7.8
5 (br s, 1H), 8.15 (s, 1H), 8.20 (d, 2H), 8.4
5 (br s, 1H), 9.15 (s, 1H). Elemental _{analysis: C 17 H 12 N 4 O} 2 S. Calculated 0.50H ₂ O; C 59.12
, H 3.79, N 16.22. Found: C, 59.40; H, 3.63; N
16.30.

Example 218 N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 218A Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,
3-c] Pyridine-2-carboxylate Example 17A (0.8 g, 5 mmol) in THF (15 mL) was refluxed for 4 hours.
Time, 4- (1H-pyrazol-1-yl) phenol and cesium carbonate (1
. 6 g, 5 mmol) and then cooled to 0 ° C., then methyl thioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 m
mol) was added and the mixture was refluxed for 1 hour. The mixture was poured into water, diluted with brine and extracted with ethyl acetate. Then, the ethyl acetate was added to 1N NaOH
(2 × 20 mL), then with brine (3 × 20 mL) and dried (MgSO ₄ )
To give the title compound. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.50 (d,
1H), 9.22 (s, 1H).

Example 218B N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 218A was dissolved in 2M methylamine in methanol and heated in a round bottom flask at 50 ° C. for 4 hours. Then the reaction mixture was evaporated and crystallized from methanol to give the title compound. Melting point: 192-194 [deg.] C. _{MS (DCI / NH 3) m} / e: 351 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.70 (d, 3H), 6
. 55 (m, 1H), 7.25 (d, 2H), 7.75 (brs, 1H), 7
. 90 (d, 2H), 8.12 (s, 1H), 8.20 (s, 1H), 8.50
(D, 1H), 9.00 (m, 1H), 9.18 (s, 1H). Elemental _{analysis: C 18 H 14 N 4 O} 2 S. Calculated 0.25H ₂ O; C 60.15
, H 4.21, N 15.59. Found: C 60.30, H 3.93, N
15.73.

Example 219 N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Examples 17A and 4 -(1H-1,2,4-Triazol-1-yl) phenol was treated as in Example 218 to give the title compound. Melting point: 214-215 [deg.] C. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 9.00 (q, 1H), 9.30 (s, 1H)
1H).

Example 220 N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenoxy} thieno [2,3-c] pyridine- 2-carboxamide Example 220A N-methyl-4- [4- (N-hydroxyaminedino) phenoxy] thieno [2
Example 186 (50) in a mixture of DMF (10 mL) and EtOH (10 mL).
0 mg, 1.62 mmol) in 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 dried to give the specified compound (376mg, 68%). _{MS (ESI / NH 3) m} / e: 343 (M + H) +.

Example 220B N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenoxy} thieno [2,3-c] pyridine- 2-Carboxamide 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 hour. The resulting yellow solution was heated at 120 ° C. for 18 hours and then concentrated. The residue was separated by HPLC (C-18,0.1% TFA containing _{CH 3 CN / H 2 O)} ,
The title compound was obtained (169 mg, 69%). Melting point: 174-176 [deg.] C. _{MS (ESI / NH 3) m} / e: 421 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.26 (d, 2H, J = 8.8 Hz), 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: Calculated for _{C 18 H 11 N 4 O 3} SF 3; C 51.43, H 2.6
4, N 13.33. Obtained: C 51.56, H 2.76, N 13.32
.

Example 221 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy]
-N- methylthieno [2,3-c] pyridine-2-carboxamide MeOH ₍₃₀ mL), in a mixture of _{Et 2 O (20mL), CH} 2 Cl 2 (30mL), Example 186 (800 mg, 2.6 mmol) Hydrogen chloride gas was introduced into the solution at 0 ° C. for 1.5 hours, and the solution was stirred at room temperature for 24 hours and concentrated. Residue is M
Dissolved in MeOH (30 mL) and ethylenediamine (3 mL) and heated at 70 ° C. for 2 hours. After cooling the reaction mixture, the resulting white solid was collected by filtration, washed with methanol and dried to give the title compound (804 mg, 88%). Melting point:> 280 [deg.] C. _{MS (ESI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 3.32 (brs, 4H), 6.88 (brs, 1H), 7
. 11 (d, 2H, J = 8.8 Hz), 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 (s, 1H). Elemental _analysis: Calculated for _{C 18 H 16 N 4 O 2} S; C 59.36, H 4.46,
N 14.57. Found: C, 59.60; H, 4.55; N, 14.40.

Example 222 N-methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide A flask purged with nitrogen was charged to Example 190B (200 mg, 0.48 mmol).
), Pd (OAc) ₂ (11 mg, 0.048 mmol), tri-o-tolylphosphine (44 mg, 0.14 mmol), dry degassed DMF (10 mL), 2-
Filled with tributylstannylthiophene (305 mL, 0.96 mmol) and triethylamine (334 mL, 2.4 mmol). This suspension is heated at 80 ° C.
Stir for 15 hours. After dilution with ethyl acetate, the reaction mixture was washed brine, then with water, dried (MgSO _4), and concentrated. The residue was purified by HPLC (C-18, 0.1% TF
A-containing CH ₃ CN / H ₂ O) to give the title compound (212 mg, 90%).
). _{MS (ESI / NH 3) m} / e: 367 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.4 Hz), 7.13 (m, 1H), 7.17 (d, 2H, J = 8.8 Hz)
, 7.48 (d, 1H, J = 3.7 Hz), 7.54 (d, 1H, J = 5.1 H)
z), 7.71 (d, 2H, J = 8.8 Hz), 8.15 (s, 1H), 8.2
4 (s, 1H), 9.02 (q, 1H, J = 4.4 Hz), 9.22 (s, 1H)
).

Example 223 4-[(1,1′-biphenyl) -4-yloxy] -N-methylthieno [2,
3-c] pyridine-2-carboxamide Example 223 was prepared as in Example 222, except that (tributylstannyl) thiophene was replaced with tributylphenyltin, to give the title compound. _{MS (ESI / NH 3) m} / e: 361 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.5 Hz), 7.19 (d, 2H, J = 8.8 Hz), 7.36 (t, 1H,
J = 7.4 Hz), 7.47 (t, 2H, J = 7.3 Hz), 7.66 (d, 2
H, J = 7.3 Hz), 7.72 (d, 2H, J = 8.8 Hz), 8.15 (s
, 1H), 8.23 (s, 1H), 9.00 (q, 1H, J = 4.4 Hz), 9
. 19 (s, 1H).

Example 224 N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 224 is a title compound. In place of 2-tributylstannylthiophene to provide the method of literature (K. Gaare et al., ActaChem.
. 1993, 47, 57) except that 1-methyl- (5-tributylstannyl) imidazole was used. mp 256-258 ° C. _{MS (ESI / NH 3) m} / e365 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 2
. 1 Hz), 3.67 (s, 3H), 7.03 (s, 1H), 7.17 (d, 2
H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz), 7.69 (s)
, 1H), 8.12 (s, 1H), 8.22 (s, 1H), 9.00 (q, 1H)
, J = 2.1 Hz), 9.16 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 16 N 4 O 2} S: C, 62.62; H, 4.43;
N, 15.37. Theory: 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-hydroxymethylcyclo) Propyl) anisole 1- (4-methoxyphenyl) -1-cyclopropane-carboxylic acid (5.0 g)
, 26 mmol) in THF (100 mL) was added to LiAlH ₄ (0.95 g, 2
(5 mmol) at −20 ° C. for 0.5 h, then warmed to room temperature for 2 h. Excess LiAlH ₄ was consumed by slow addition of EtOH. After dilution with ether, the reaction mixture is washed with 2% HCl brine, water, dried (MgSO ₄ ) and concentrated to provide the specified compound (5.0 g, 100%). _{MS (DCI / NH 3) m} / e: 196 (M + NH 4) +.

Example 225B 4- (1-Hydroxymethylcyclopropyl) phenol NaH (60% in mineral oil, 392 mg, 9.8 mmol) in DMF (10 mL)
To the suspension was added neat ethanethiol (610 mg, 9.8 mmol) slowly at room temperature. Then Example 225A (500 mg, 2.8 mmol) was added and the mixture was heated at 145 ° C. for 4 hours. After dilution with ether, the reaction mixture is
HCl, brine, dried (MgSO ₄ ) and concentrated. Residue is 50% Et
Flash chromatography on silica gel with OAc / hexane provided the specified 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 added to triphenylmethyl chloride (1.87 g, 6.7 mmol). At room temperature for 18 hours. After dilution with ether, the reaction mixture was washed with 1% aqueous HCl, water and dried (M
gSO ₄₎ was. The residue was subjected to flash chromatography on silica gel with 12% EtOAc / hexane to provide the specified compound. _{MS (DCI / NH 3) m} / e: 407 (M + H) +.

Example 225D Methyl 4- [4- (1-triphenylmethoxymethyl) cyclopropyl] phenoxy- [2,3-c] pyridine-2-carboxylate Example 225D was used to provide the specified compound. -Prepared as in Example 61A except for using Example 225C instead of chlorophenol. _{MS (DCI / NH 3) m} / e: 598 (M + H) +.

Example 225E Methyl 4- [4- (1-hydroxymethyl) cyclopropyl] phenoxy- [2
, 3-c] pyridine-2-carboxylate Example 225D (230mg, 0.38mmol) in _CH 2 _Cl 2 (10mL
) And MeOH (5 mL) were treated with trifluoroacetic acid (1 mL) at 0 ° C. for 1 hour, allowed to warm to room temperature, stirred for 1 hour, and poured into an aqueous solution of NaHCO ₃ . This mixture was extracted with methylene chloride. Wash the combined organic layers with water and dry (
MgSO ₄ ). The residue was subjected to flash chromatography on silica gel with 65% EtOAc / hexane to provide the specified 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 Example 225F was prepared to provide the specified compound. Prepared similarly to Example 103 except that Example 225E was used instead of 61A. _{^{MS (ESI / NH 3) m}} / e: 355 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ0.72 (m, 2H), 0.
82 (m, 2H), 2.80 (d, 3H, J = 4.7 Hz), 3.51 (d, 2
H, J = 5.8 Hz), 4.66 (t, 1H, J = 5.8 Hz), 7.01 (d
, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.8 Hz), 8.06
(S, 1H), 8.13 (s, 1H), 8.96 (q, 1H, J = 4.7 Hz)
, 9.10 (s, 1H).

Example 226 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide 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 prepared.
Treat with NaH (60% in mineral oil, 312 mg, 7.8 mmol) and 15-crown-5 (1.33 mL, 6.7 mmol) at room temperature for 15 minutes to obtain the literature method (
C. 2- (2-ethoxyethoxy) ethyl tosylate (1.9) prepared according to Almansa et al., Tetrahedron 1991, 47, 5867).
(3 g, 6.7 mmol). The brown slurry was stirred at room temperature for 5 hours,
Poured into saline. The mixture was extracted with CH ₂ Cl ₂ and the combined organic layers were dried (
MgSO ₄ ) and concentrated. The residue was subjected to flash chromatography on silica gel with 25% EtOAc / hexane to give the specified 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 ° C. for 5 hours. After cooling to room temperature, methylene chloride (100 mL) was added and the mixture was
Washed with Cl saline. Dry the organic layer (MgSO ₄ ) and concentrate to 35% residue.
Silica gel flash chromatography with EtOAc / hexane provided the specified compound (1.33 g, 93%). _{MS (ESI / NH 3) m} / e: 298 (M + NH 4) +.

Example 226C Methyl 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}
Cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2
-Carboxylate Example 226C was prepared as Example 61A except that Example 226B was used in place of 4-chlorophenol to provide the designated compound. _{MS (ESI / NH 3) m} / e: 472 (M + H) +.

Example 226D 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 226D was prepared as Example 103 except that Example 226C was used in place of Example 61A to provide the title compound. _{MS (ESI / NH 3) m} / e: 471 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.84 (m, 2H), 0.
87 (m, 2H), 1.06 (t, 3H, J = 6.7 Hz), 2.82 (d, 3
H, J = 4.4 Hz), 3.37 (t, 2H, J = 6.7 Hz), 3.39-3
. 55 (m, 10H), 7.07 (d, 2H, J = 8.8 Hz), 7.36 (d
, 2H, J = 8.8 Hz), 8.13 (s, 1H), 8.26 (s, 1H), 9
. 10 (q, 1H, J = 4.4 Hz), 9.28 (s, 1H). Elemental _analysis: Calculated for _{C 25 H 30 N 4 O 5} S: C, 59.22; H, 6.16;
N, 5.52. Theory: C, 59.50; H, 6.16; N, 5.26.

Example 227 N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-
c] Pyridine-2-carboxamide Example 227 was prepared as in Example 103 except that 4-trifluorophenol was used instead of 4-chlorophenol to provide the title compound. _{mp 132~133 ℃; MS (ESI /} NH 3) m / e: 368 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 4
. 4 Hz), 7.20 (d, 2H, J = 9.2 Hz), 7.41 (d, 2H, J
= 9.2 Hz), 8.08 (s, 1H), 8.21 (s, 1H), 8.95 (q
, 1H, J = 4.4 Hz), 9.18 (s, 1H). Elemental _analysis: Calculated for _{C 16 H 11 N 2 O 3} SF 3: C, 52.17; H, 3.0
1; N, 7.61. Theory: C, 52.21; H, 3.26; N, 7.29.

Example 228 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}
Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl} -1
, 3,4-oxadiazol-2-amine Example 22 was replaced with Example 22A to provide the title compound.
Except using 6C, it prepared like Example 275 and Example 756. mp 113-114 ° C. _{MS (ESI / NH 3) m} / e: 497 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ0.82 (m, 2H), 0.
85 (m, 2H), 1.05 (t, 3H, J = 7.1 Hz), 3.40 (t, 2H)
H, J = 7.1 Hz), 3.42 to 3.54 (m, 10H), 7.00 (d, 2
H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz), 7.55 (s
, 1H), 7.58 (s, 2H), 8.18 (br s, 1H), 9.15 (b
rs, 1H).

Example 229 4- [4- (1,1-Difluoro-2-hydroxyethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229A 4- [4- ( 1,1-Difluoro-2-ethoxy-2-oxoethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide A suspension of active copper (512 mg, 8 mmol) in dry DMSO (5 mL) was prepared. The mixture was treated with ethyl iododifluoroacetate (1.0 g, 4 mmol) at room temperature for 10 minutes. Then phenol (188 mg, 2 mmol) and Example 190B were added.
The reaction mixture was stirred at room temperature for 20 hours. After dilution with 1: 1 ether / EtOAc, the mixture was washed with 1% HCl brine, water, dried (MgSO ₄ ) and concentrated. The residue was purified by a silica gel flash chromatography with 65% EtOAc / hexanes, further purified by _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA) specifying the compound (85 mg, 15%) Provided. _{MS (ESI / NH 3) m} / e: 407 (M + H) +.

Example 229B 4- [4- (1,1-Difluoro-2-hydroxyethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229A (40 mg, 0.1 mmol) ) In MeOH (5 mL)
The mixture was treated with aBH ₄ (50 mg) at room temperature for 2 hours. Brine was added and the mixture was added to EtO
Extracted with Ac. And the combined organic layers dried _(Na 2 SO ₄₎ and concentrated. The residue was purified by _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA) designated compound (44.4mg, 94%) was subjected to. _{MS (ESI / NH 3) m} / e: 365 (M + H) +. ¹ H NMR (300 MHz, CD ₃ OD) δ 2.94 (s, 3H), 3.93
(T, 2H, J = 13.5 Hz), 7.27 (d, 2H, J = 9.2 Hz), 7
. 65 (d, 2H, J = 9.2 Hz), 8.15 (s, 2H), 9.24 (s,
1H). Elemental _{analysis: C 17 H 14 N 2 O} 3 SF 2. Calculated TFA: C, 47.70; H
, 3.16; N, 5.86. Theory: C, 47.67; H, 3.10; N, 5.
76.

Example 230 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1difluoroethyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229B (40 mg, 0.11 mmol) in THF (3 mL)
NaH (60% in mineral oil, 7 mg, 0.16 mmol) and 15-crown-5
(35 mg, 0.16 mmol) at room temperature for 15 minutes. Next, literature methods (C. Almansa et al., Tetrahedron 1991, 47, 5867).
2- (2-ethoxyethoxy) ethyl tosylate (46)
mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 15 hours and then subjected the isolated title compound (46 mg, 81%) in _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA). _{MS (ESI / NH 3) m} / e: 481 (M + H) +. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.16 (t, 3 H, J = 7.1
Hz), 2.97 (s, 3H), 3.49 (q, 2H, J = 7.1 Hz), 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)
. 8Hz), 8.22 (s, 1H), 8.33 (s, 1H), 9.46 (s, 1H)
H).

Example 231 4- (4-chlorophenoxy) -6-{[(2,2-dimethylpropanoyl) oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pyridine-6-ium, was dissolved in trifluoroacetic acid salt example 103 (47.4 mg, 0.149 mmol) and 1.5mL dry acetonitrile (warmed) of _{(N 2} atmosphere), chloromethyl pivalate (
(25 mg, 0.167 mmol) at room temperature. The reaction was stirred for 16 hours, then tetraammonium iodide (1 mg) was added and warmed for 48 hours to perfuse the solution. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (C-18, 20-70).
(A gradient of 100% acetonitrile-0.1% aqueous TFA, elution 60 minutes) to give 24 mg (34%) of the title compound as a foam. MS (APCI +) m / e: 433 (M) ^<+> . HPLC: Supelco C-18 column, 0.1% TFA aqueous solution over 30 minutes: gradient elution with acetonitrile from 0:90 to 90: 0, detection at 254 nm, 0.
8 mL / min flow rate, RT 20.0 min. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.18 (s, 9H);
01 (s, 3H), 6.4 to 6.6 (brs, 2H), 7.1 to 7.3 (brs
, Aprox. 2H), 7.49 (brs, 2H), 7.74 (brs, 1H
), 8.41 (brs, 1H), 8.64 (brs, 1H), 9.3-9.9 (
vbrs, 1H). Elemental analysis: Calculated for C ₂₃ H ₂₂ F ₃ Cl ₂ O ₆ S: C, 45.43; H, 3.
51; N, 4.24. Theory: C, 45.93; H, 3.70; N, 4.34.

Example 232 4- (4-Bromophenoxy) -6-{[(2,2-dimethylpropanoyl) oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] Pyridine-6-ium Example 171 (69.4 mg, 0.191 mmol) was dissolved in 2 mL of acetonitrile, then tetraammonium iodide (1 mg) was added under N2 atmosphere, and chloromethyl pivalate (22 mg, 0.146 mmol) was added. added. The reaction solution was heated and perfused for 24 hours. Additional chloromethyl pivalate (11 mg, 0.0
73 mmol) was added and the reaction was perfused for an additional 72 hours. The reaction was concentrated under reduced pressure and the solid was partitioned between 15 mL of water and 15 mL of EtOAc. 2 x 15 mL aqueous layer
Of EtOAc and then the aqueous layer was concentrated in vacuo to a yellow material (93.5 mg).
I got HPLC purification (C-18 column, 20-75% acetonitrile-0.1
% TFA aqueous solution) provided the pure title compound (55.9 mg, 49%).
HPLC: Supelco C-18 column, 0.1% TFA aqueous solution over 30 minutes: gradient elution with acetonitrile from 0:90 to 90: 0, detection at 254 nm, 0.
8 mL / min flow rate, RT 20.3 min. MS (APCI-) m / e: 475, 477 (MH) ^- . ^{2. 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.17 (s, 9H);
02 (brm, 3H), 6.0 to 6.7 (vbrs, 2H), 7.14 (brd
, 2H), 7.64 (brd, 2H), 7.78 (s, 1H), 8.07-8.
17 (brs, 1H), 8.34 (s, 1H), 9.44 to 9.65 (vbrs
, 1H). Elemental _{analysis: 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. Theory: C, 40.94; H, 3.25
N, 3.76.

Example 233 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(isopropoxycarbonyl) oxy] methyl} thieno [2,3-c] pyridine-6-ium Nitrogen atmosphere Below, sodium tetraphenylboronate (387 mg, 1.13) was added to a solution of Example 61 (300 mg, 0.94 mmol) in acetonitrile (15 mL).
mmol), sodium iodide (169 mg, 1.13 mmol), and [isopropoxycarbonyl) oxy] methyl chloride (172 mg, 1.13 mm)
ol) was added. The reaction mixture was heated and perfused for 4 hours, cooled to room temperature, and celite (
(Celite) before diluting with acetonitrile (100 mL). The filtrate was concentrated, trityled with methanol to a foam, and provided pyridinium tetraphenylborate (550 mg) as a yellow solid. Tetraphenyl _borates, CH 3 CN: i-PrOH 1: dissolved in 1, was passed through an ion exchange column using 50-100 mesh Dowex 1X2 chloride. The eluent was concentrated and the residue was trityled with ether to give Example 233 as a white solid (210 mg, 49 mg).
%). MS (FAB) m / e: 421 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26 (d, J = 7 Hz,
6H), 4.81 (q, J = 7 Hz, 1H), 6.44 (s, 2H), 7.41
(M, 2H), 7.62 (m, 2H), 8.31 (brs, 1H), 8.59 (
s, 1H), 8.68 (s, 1H), 8.80 (brs, 1H), 9.98 (s
, 1H); Elemental _{Analysis: C 19 H 18 Cl 2 N} 2 O 5 Calculated S: C, 49.90
H, 3.96; N, 6.13. Theory: C, 49.74; H, 3.95; N,
6.14.

Example 234 4- (cyclopentyloxy) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide Example 234A Example except 5-chloro-3-cyclopentyloxypyridine uses the title compound (5.91 g, 77%) instead of benzyl alcohol with cyclopentanol (4.2 mL, 46.31 mmol). 2
Prepared as described in 36A. MS (APCI) m / e: 198 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53 to 1.76 (m, 6
H), 1.86-2.02 (m, 2H), 4.92-4.99 (m, 1H), 7
. 55 (t, J = 2.25 Hz, 1H), 8.18 (d, J = 2.25 Hz, 1
H), 8.22 (d, J = 3 Hz, 1H). Example 234B 5-Chloro-3-cyclopentyloxypyridine-4-carboxaldehyde The title compound (5.22 g, 77%) was prepared using Example 23 instead of Example 236A.
Prepared as described in Example 236B except using 4A (5.9 g, 30 mmol). MS (APCI) m / e: 226 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55 to 1.85 (m, 6
H) 1.93 to 2.04 (m, 2H), 5.14 to 5.22 (m, 1H), 8
. 36 (s, 1H), 8.63 (s, 1H), 10.31 (s, 1H). Example 234C Methyl 4- [cyclopentyloxy] thieno [2,3-c] pyridine-2-carboxylate The title compound (4.31 g, 67%) was prepared using Example 23 instead of Example 236B.
Prepared as described in Example 236C except using 4B (5.2 g, 23.11 mmol). MS (APCI) m / e: 278 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.59 to 1.69 (m, 2
H) 1.74 to 1.81 (m, 2H), 1.83 to 1.90 (m, 2H), 1
. 97 to 2.07 (m, 2H), 3.93 (s, 3H), 5.12 to 5.17 (
m, 1H), 8.05 (s, 1H), 8.24 (s, 1H), 8.94 (s, 1H)
H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 23.63 (CH ₂ ), 3
_{2.30 (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] pyridine-2-N-methylamide Example 234C (1.6 g, 61%) was replaced with Example 23A instead of Example 73A.
Prepared as described in Example 171 except using 4C (2.6 g, 9.4 mmol). mp 216-217 ° C. MS (APCI) m / e: 277 (M + H) ^<+> , 244 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.60 to 1.69 (m, 2
H) 1.73-1.90 (m, 4H), 1.97-2.08 (m, 2H), 2
. 83 (d, J = 4 Hz, 3H), 5.10 to 5.17 (m, 1H), 8.11
(S, 1H), 8.19 (s, 1H), 8.85 (s, 1H), 8.93 (d,
J = 4 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 23.60 (CH ₂ ), 2
_{6.14 (NCH 3), 32.34 (} CH 2), 80.14 (CH), 119.
68 (CH), 126.91 (CH), 135.73 (C), 137.17 (C
H), 144.2 (C), 149.02 (C), 161.18 (C).

Example 235 4- (2-cyclohexene-1-yloxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 235A Methyl 4- [2-cyclohexene-3-oxy] thieno [2,3-c] pyridine-2-carboxylate The title compound (158 mg, 57%) was substituted for 3-hydroxytetrahydrofuran Prepared as described in Example 99A, except using 2-cyclohexenol (0.113 mL, 0.115 mmol). The pure product is
Obtained by flash chromatography on silica gel using 10% acetone-hexane. MS (APCI) m / e: 290 (M + H) ^<+> , 288 (M-H) < ^{- >} , 324 (
M + Cl) ⁻ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.95 to 1.62 (m, 1
H), 1.66~2.14 (m, 5H ), 3.92 (s, 3H, OCH 3), 5
. 22-5.26 (m, 1H), 5.91-5.99 (m, 2H), 8.03 (
s, 1H, CH), 8.36 (s, 1H, CH), 8.95 (s, 1H, CH)
.

Example 235B 4- (2-cyclohexene-1-yloxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 235 (59 mg, 40%) of 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) ^<+> , 287 (M-H) < ^{- >} , 323 (
M + Cl) ⁻ . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.62 to 1.70 (m, 1
H) 1.78-1.91 (m, 2H), 1.96-2.17 (m, 3H), 2
. 82 (d, J = 5 Hz, 3H), 5.21 (brs, 1H), 5.93-5.
98 (m, 1H), 6.01 to 6.05 (m, 1H), 8.14 (s, 1H),
8.30 (s, 1H), 8.87 (s, 1H), 8.75 (d, J = 5 Hz, 1
H). ¹³ C NMR (75 MHz, 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 5-chloro-3-pyridinol at 0 ° C. under nitrogen atmosphere (10 g, 77.19 m
benzyl alcohol (9.6 mL, 92.63 mmol) and triphenylphosphine (26.mol) in a stirred solution of anhydrous tetrahydrofuran (155 mL).
32 g, 100.35 mmol) and diethyl azodicarboxylate (15
. 8 mL, 100.35 mmol) was added. The reaction mixture was stirred at room temperature overnight,
The solvent was removed under reduced pressure. The obtained residue (70 g) was treated with diethyl ether (2 × 30).
0 mL) and the solids were removed by filtration. The resulting filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 5% acetone and hexane to give the title compound in 36% (5.8 g) yield.
MS (APCI) m / e: 220 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.22 (s, 2H), 7.
33-7.49 (m, 5H), 7.77 (d, J = 5 Hz, 1H), 8.23 (
d, J = 5 Hz, 1H), 8.34 (d, J = 5 Hz, 1H).

Example 236B 5-Chloro-3-benzyloxypyridine-4-carboxaldehyde Diisopropylamine (4.5 mL, 31.78 mm) at −5 ° C. under a nitrogen atmosphere.
ol) in anhydrous tetrahydrofuran (20 mL).
N-BuLi in hexane (2.5 M solution, 12.8 mL, 31
. 78 mmol) was added dropwise. The reaction mixture was stirred at −10 ° C. for 10 minutes, then at 0 ° C. for 30 minutes. This was cooled to −78 ° C. and Example 236A (5.8 g, 26
. (5 mmol) in anhydrous tetrahydrofuran (30 mL) was added slowly. −
Stirring at 78 ° C. was continued for 1 hour. The reaction was then run in anhydrous THF (15 mL)
Quenched by dropwise addition of methyl formate (5 mL, 79.5 mmol) in
The mixture was stirred at -78 ° C for 3.5 hours. During this reaction, the internal temperature of the reaction mixture was maintained at or below -74C. After 3.5 hours, the reaction mixture was poured into ice-cold saturated aqueous NaHCO ₃ (200 mL) and stirred for 15 minutes. The mixture was treated with ethyl acetate (2
(50 mL) and the organic layer was separated and washed with brine (2 × 60 mL). The dried (MgSO ₄ ) organic layer was concentrated under reduced pressure to obtain a crude product (8.5 g). The title compound was obtained in 75% (4.2 g) yield by flash chromatography on silica gel, eluting with 6% acetone-hexane. MS (APCI) m / e: 248 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ5.42 (s, 2H), 7.
33 to 7.45 (m, 3H), 7.48 to 7.52 (m, 2H), 8.41 (s
, 1H), 8.72 (s, 1H), 10.39 (s, 1H).

Example 236C Methyl 4-benzyloxythieno [2,3-c] pyridine-2-carboxylate To a ice-cooled solution of Example 236B (4.2 g, 17 mmol) in tetrahydrofuran (42 mL) under a nitrogen atmosphere. Methyl thioglycolate (1.83 mL, 20
. 4 mmol) followed by powdered cesium carbonate (6.65 g, 20.4 mmol). The reaction mixture is then allowed to warm to room temperature while stirring under nitrogen.
After 30 minutes, the reaction is refluxed for 15 minutes and cooled to room temperature. The reaction mixture was added to ice (5
0 mL) and partitioned with ethyl acetate (250 mL). The separated organic layer was washed with an ice-cold solution of saturated NaCl (3 × 60 mL) and dried (Na ₂ SO ₄ )
After concentration under reduced pressure, the obtained crude product was recrystallized from methanol. The mother liquor was purified by flash chromatography on silica gel eluting with 7% acetone-hexane. The combined fractions gave the title compound in 55% (3.07 g) yield. MS (APCI) m / e: 300 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ3.92 (s, 3H), 5.
42 (s, 2H), 7.35 to 7.47 (m, 3H), 7.52 to 7.57 (m
, 2H, Ar-CH), 8.12 (s, 1H), 8.36 (s, 1H), 8.9
8 (s, 1H).

Example 236D Methyl 4-hydroxythieno [2,3-c] pyridine-2-carboxylate 10% by weight Pd / activated carbon (38 mg, 10% w / w) in anhydrous ethanol (3 mL) Example 236C (380 mg, 1.3 mmol) under a nitrogen atmosphere
A cold ethanol solution of (82 mL) was added. The reaction solution was then degassed and stirred at room temperature under a hydrogen atmosphere. After one night, the reaction mixture was treated with 10 wt% Pd / activated carbon (190
mg, 50% w / w), and the mixture was stirred under a hydrogen atmosphere. Additional catalyst (10
(0 mg, 26% w / w) was added to the reaction mixture after 48 hours. The reaction mixture was stirred for a further 24 hours under a hydrogen atmosphere and filtered through Celite. The filtrate was evaporated to dryness under reduced pressure to obtain a crude product (320 mg). Example 23 of the title compound
6E was obtained in 75% yield (200 mg) by flash chromatography on silica gel eluting with 5% acetone-hexane followed by 40% acetone-hexane. MS (APCI) m / e: 210 (M + H) ⁺ , 208 (M−H) ⁻ , 244 (
M + Cl) ⁻ . 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.93 (s, 3H), 8.
08 (s, 1H), 8.21 (s, 1H), 8.81 (s, 1H), 10.66
-10.90 (br, s, 1H).

Example 236E 4-benzyloxythieno [2,3-c] pyridine-2-carboxamide The title compound (50 mg, 67%) was prepared in Example 236C (75 mg, 0.25 m
mol) was prepared as described in Example 44. MS (APCI) m / e: 285 (M + H) ^<+> , 319 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.43 (s, 2H), 7.
49-7.50 (m, 3H), 7.58-7.63 (m, 2H), 7.79 (b
rs, 1H), 8.30 (s, 1H), 8.36 (s, 1H), 8.48 (br
s, 1H), 8.93 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 70.13 (CH ₂ ), 1
20.56 (CH), 126.21 (CH), 127.5 (CH), 128.1
4 (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-carboxamide Example 17A (15.00 g, 85.22 mmol) was dissolved in THF (80 mL) and cesium carbonate (27.77 g, 85 .22 mmol). THF
Methyl thioglycolate (7.62 mL, 85.2) diluted in (20 mL).
2 mmol) was added dropwise over 20 minutes. The reaction was stirred for 1.5 hours and then heated to 40 ° C. for 1 hour. The reaction mixture was poured into 850 mL of stirring water. After 10 minutes, the precipitate was collected by filtration and washed twice with water. The product was dried in a desiccator to yield the title compound (15.2 g, 78%) as a solid. _{MS (DCI / NH 3) m} / e: 228 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ3.96 (s, 3H), 8.
15 (s, 1H), 8.65 (s, 1H), 9.38 (s, 1H).

Example 237B 4-Chlorothieno [2,3-c] pyridine-2-carboxylic acid Example 237A (15.17 g, 66.63 mmol) was added in MeOH / water (50
0 mL) in a 1: 4 solution and LiOH hydrate (4.34 g, 103.50).
mmol). The reaction was stirred for 1.5 hours and concentrated (100 m
L). The aqueous layer was washed with Et ₂ O, then acidified to pH 5 with 1N HCl (aq). The precipitate was isolated by filtration and washed once with water and then twice with acetonitrile. The product was dried in a desiccator and 4-chlorothieno [2,3-
c] Pyridine-2-carboxylic acid (12.10 g, 85%) was produced. _{MS (DCI / NH 3) m} / e: 214 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H);
62 (s, 1H), 9.34 (s, 1H).

Example 237C Dimethylethyl 4-chlorothieno [2,3-c] pyridine-2-carboxylate Example 237B (12.07 g, 56.50 mmol) in THF (200 mL)
) The suspension was added at 0 ° C with t-butyl 2,2,2-trichloroacetamidodate (25
. 00 g, 114.41 mmol), followed by dropwise addition of boron trifluoride-diethyl etherate (2.14 mL, 16.95 mmol). The reaction was warmed to room temperature and stirred for 18 hours. Additional t-butyl 2,2,2-trichloroacetamidodate (12.50 g, 57.21 mmol) was added and stirred for 3 hours. The stirring reaction was treated with NaHCO ₃ (14 g) and then water (300 mL)
Diluted. The reaction was partitioned between 50% EtOAc / Et ₂ O water (300 mL). The organic layer was washed with saturated NaHCO ₃ , brine, partially dried (Na ₂ SO ₄ ), filtered and concentrated. The residue using EtOAc / hexanes as eluent was purified by silica gel flash chromatography neutralized with Et 3 _N. The compound was isolated as a solid (10.04 g, 66%). _{MS (DCI / NH 3) m} / e: 270 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.59 (s, 9H),
04 (s, 1H), 8.64 (s, 1H), 9.35 (s, 1H).

Example 237D Dimethylethyl 4- (ethoxycarbonyl) thieno [2,3-c] pyridine-2
-Carboxylate Example 237C (1.00 g, 3.71 mmol), 1,3-bis (diphenylphosphino) propane (0.46 g, 1.11 mmol), triethylamine (1.55 mL, 11.13 mmol) 2: 3 EtOH / DMF (25 mL
)) To the solution was added palladium (II) acetate (0.25 g, 1.11 mmol). The reaction was inhaled with a stream of CO (g) for 15 minutes. A balloon of CO (g) was attached and heated at 105 ° C. for 16 hours, then cooled to room temperature. This reaction is converted to water (
(400 mL). The aqueous layer was washed with brine (25 mL) and saturated NaHCO ₃ (25 mL
) And then extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with 20% saturated NaHCO ₃ (2 × 200 mL), brine (2 × 100 mL), partially dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the title compound as a solid (0.60 g, 53%). MS (APCI) m / e: 308 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.44 (t, J = 7.1 Hz)
, 3H), 1.59 (s, 9H), 4.44 (q, J = 7.1 Hz, 2H), 8
. 65 (s, 1H), 8.65 (s, 1H), 9.12 (s, 1H), 9.25
(S, 1H).

Example 237E Dimethylethyl 4-formylthieno [2,3-c] pyridine-2-carboxylate NaBH ₄ (0.18 g, 4.89 mmol) in anhydrous 50% MeOH / THF
To a stirred solution of at 0 ° C. was added powdered CaCl ₂ (0.54 g, 4.89 mmol). The suspension was stirred for 20 minutes and the solution of Example 237D (0.50 g, 1.63) was obtained.
mmol) in 50% MeOH / THF was added slowly over 10 minutes. The reaction was stirred at 0 ° C. for 1 hour, followed by stirring at room temperature for 16 hours. The reaction is diluted A
Quenched in cOH (aq) / ice slurry. After completing all the gas in occasional stirring, basified with saturated NaHCO _3. The aqueous layer was washed with methylene chloride (3 × 40
mL), and the extracts were combined. The organic layer was dried _(Na 2 SO _4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the dimethylethyl 4- (hydroxymethyl) -thieno [2,3-c] pyridine-2-carboxylate compound as a solid (0. 14 g, 32%). MS (APCI) m / e: 266 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.54 (s, 9H), 4.9
4 (s, 2H), 8.08 (s, 1H), 8.40 (s, 1H), 9.02 (s)
, 1H).

To a stirred solution of oxalyl chloride (0.10 mL. 1.17 mmol) in anhydrous methylene chloride (1 mL) at -78 ° C was added DMSO (0.19 mL, 2.65 mmol).
l) was added. After 20 minutes, dimethylethyl 4- (hydroxymethyl) -thieno [
2,3-c] pyridine-2-carboxylate (0.28 g, 1.06 mmol
)) In anhydrous methylene chloride (4 mL). The reaction was stirred at -78 <0> C for 1 hour, then treated with triethylamine (0.74 mL, 5.30 mmol). After 5 minutes, the reaction was warmed to room temperature over 30 minutes. The reaction was quenched with water (5 mL) and methylene chloride (50 mL) and 50% saturated aqueous NaHCO ₃ (50 m
L). The organic phase was washed with 50% saturated aqueous NaHCO ₃ (1 × 50 mL)
And dried (Na ₂ SO ₄ ), filtered, concentrated and dried in a desiccator to yield the title compound as a solid (0.25 g, 90%). MS (APCI) m / e: 264 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.59 (s, 9H), 8.7
4 (s, 1H), 8.91 (s, 1H), 9.31 (s, 1H), 10.24 (
s, 1H).

Example 237F Dimethylethyl 4-[(4-chlorophenyl) (hydroxy) methyl] thieno [
2,3-c] Pyridine-2-carboxylate To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) at −5 ° C. is a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether ( 2.85 mL, 2.85 mmol) was added. 10 minutes later, water (1m
L) was added dropwise to quench, methylene chloride (25 mL) and 50% saturated N
aHCO ₃ (50 mL). The aqueous phase was washed with methylene chloride (25 mL
), The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the title compound as a foam which was crushed and dried in a desiccator to yield a powder (0.36 g, 100%). MS (APCI) m / e: 376 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.52 (s, 9H), 6.1
8 (d, 1H), 7.25 to 7.34 (continuous m, 4H), 7.96 (s, 1
H), 8.47 (s, 1H), 9.03 (s, 1H).

Example 237G Methyl 4-[(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-
c] pyridine-2-carboxylate Example 237F (0.12g, 0.32mmol) and _{10% H 2} SO 4 / Me
Dissolve in OH (10 mL) solution and heat to 50 ° C. for 18 hours. The reaction was run with saturated NaH
Quenched in CO ₃ (100 mL). The aqueous phase was washed with methylene chloride (2 × 50 mL
) And the organic extracts were combined. The organic layer was washed with a saturated aqueous solution of NaHCO ₃ (1 × 10
0 mL), washed with brine (1 × 100 mL) and partially dried (Na ₂ SO ₄ )
Then, the mixture was filtered and concentrated. The product is dried in a desiccator to give the title compound as a solid (
0.10 g, 94%). MS (APCI) m / e: 334 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 3.85 (s, 3H), 6.1
7 (d, 1H), 7.23 to 7.33 (continuous m, 4H), 8.05 (s, 1
H), 8.48 (s, 1H), 9.05 (s, 1H).

Example 237H Methyl 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2-carboxylate oxalyl chloride (0.023 mL. 0.26 mmol) in anhydrous methylene chloride (1 mL) ) In DMSO (0.045 mL, 0.63 m
mol) was added. After 15 minutes, Example 237G (0.07 g, 0.21 mmol)
) In anhydrous DMSO / methylene chloride (5 mL) was added dropwise. The reaction was stirred at -78 ° C for 1 hour, then triethylamine (0.15 mL
, 1.05 mmol). After 5 minutes, the reaction was warmed to room temperature over 1 hour. The reaction was quenched with water (2 mL), EtOAc (50 mL) and sat.
Partitioned with aqueous O ₃ (50 mL). Wash the organic layer with 50% saturated aqueous NaHCO ₃ (2 × 50 mL), brine (1 × 50 mL) and dry (Na ₂ SO ₄ )
, Filtered and concentrated. Dry in a desiccator to give the title compound as a white solid (0.
(07 g, 100%). MS (APCI) m / e: 332 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) 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)) ^<+> . IR (KBr) 3208, 2959, 1719, 1657, 1585, 1567
, 1434, 1308, 1268 cm ^-1 .

Example 237I 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 237H (70 mg, 0.21 mmol) was suspended in MeOH (5 mL) and chloroform was added until the solid dissolved. Heated at 50 ° C. for 20 hours with an ammonia balloon attached. The reaction solution was concentrated, and the residue was eluted with EtOA.
Purified by flash chromatography on silica gel using c / hexane.
The resulting title compound was dried in a desiccator to yield a white solid (35 mg, 53%). mp 216-218 ° C. MS (APCI) m / e: 317 (M + H) ^<+> . _{^{1 H NMR (DMSO-d 6}} ) δ7.68 (m, 2H), 7.86 (brs,
1H), 7.88 (m, 2H), 8.38 (s, 1H), 8.53 (brs, 1H)
H), 8.67 (s, 1H), 9.55 (s, 1H). ¹³ C NMR (DMSO-d ₆ ) δ 123.4, 128.0, 129.3, 1
32.0, 135.9, 137.9, 138.9, 143.2, 145.1, 1
48.8, 148.9, 162.7, 193.6. IR (KBr) 3289, 3145, 1681, 1655, 1399, 1270
cm ^-1. Elemental _{analysis: C 15 H 9 ClN 2 O} 2 S, Calculated for _{0.1C 6 H 14: C, 57} .
59; H, 3.22; N, 8.61. Theory: 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 Example 94 was treated according to the method of Example 237D to provide the title compound.

Example 238B 4- (Carboxy) thieno [2,3-c] pyridine-2-carboxamide Example 238A was treated according to the method of Example 159A to provide the title compound.

Example 238C N-4- (4-Chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide Example 238B was treated according to the method of Example 24 to provide the title compound. . mp> 270 ° C. MS (ESI) m / e: 332 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.46 (m, 2H), 7.
84 (brs, 1H), 7.85 (m, 2H), 8.52 (m, 1H), 8.5
6 (brs, 1H), 8.90 (m, 1H), 9.47 (m, 1H), 10.7
9 (brs, 1H).

Example 239 [4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl] methanol Example 239 (900 mg, 97%) was replaced with Example 73 in place of Example 61A.
(1 g, 2.74 mmol), but prepared as described in Example 90. MS (APCI) m / e: 336; 338 (M + H) ^<+> , 370; 372 (M +
Cl) ⁻ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.78 (d, J = ₆ Hz,
2H), 5.88 (t, J = 6 Hz, 1H), 6.98 (d, J = 9 Hz, 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 Example 240 (400 mg, 80%) was replaced with Example 239 in place of Example 90.
(500 mg, 1.49 mmol), but prepared as described in Example 91A. MS (APCI) m / e: 334; 336 (M + H) ^<+> , 333; 335 (M-
H) ^- . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J = 9 Hz,
2H), 7.62 (d, J = 9 Hz, 2H), 8.26 (s, 1H), 8.40
(S, 1H), 9.27 (s, 1H), 10.21 (s, 1H).

Example 241 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime The title compound was prepared from Example 91A in a similar manner to Example 30. HPLC: Supelco C-18 column, water: acetonitrile 0: 90-
90: 0, 30 min elution, flow rate 0.8 mL / min, rt: 19.61 min and 20.
28 minutes. _{MS (DCI / NH 3) m} / e: 305 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.16 (m, 3H)
), 8.51 (s, 1H), 9.05 (s, 1H), 9.14 (s, 1H), 1
1.91 (s, 1H), 12.66 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 119.28, 119.3
3, 120.58, 122.21, 125.25, 127.51, 128.13
, 128.82, 129.99, 133.03, 133.84, 135.37,
136.10, 137.11, 139.40, 139.95, 140.83, 1
41.28, 143.24, 143.66, 146.31, 146.58, 15
5.69. Elemental _{analysis: C 14 H 9 ClN 2 O} 2 S, 0.4 Calculated toluene: C, 59.0
7; H, 3.60; N, 8.20. Theory: C, 59.15; H, 3.65; N
, 8.25.

Example 242 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde O-methyloxime Example 242 was prepared from Example 91A in a similar manner to Example 26. . E-Isomer spectral data: HPLC: Supelco C-18 column, gradient elution of water: acetonitrile 0: 90-90: 0 over 30 minutes, flow rate of 0.8 mL / min, RT 22.72 minutes and 23. 60 minutes. ^{MS (ESI) m / e:} 319 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ3.94 (s, 3H), 7.
12 (m, 2H), 7.47 (m, 2H), 7.65 (s, 1H), 8.18 (
s, 1H), 8.61 (s, 1H), 9.08 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 62.29, 119.35.
, 122.26, 124.01, 127.60, 130.01, 133.77,
136.85, 140.91, 141.38, 144.34, 146.46, 1
55.58.

Example 243A Mike Stager 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone O-methyloxime Example 159A was The treatment was performed in the same manner as in Example 22. The derived amide was treated according to the method of Example 33 to produce the corresponding methyl ketone. This ketone was treated according to the method of Example 26 to provide the title compound as a mixture of E- and Z-isomers. Both isomers were separated by column chromatography on type H (Sigma) silica gel, eluting with 25% EtOAc: hexane. Spectral data for Z-isomer: mp 126-128 ° C. MS (APCI) m / e: 333 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 1H), 9.01 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 12.18, 62.32,
118.85, 119.88, 127.77, 130.01, 132.98, 1
36.94, 136.98, 140.32, 145.60, 146.94, 15
0.84, 155.40. Elemental _{analysis: C 16 H 13 ClN 2 O} 2 Calculated S: C, 57.74; H, 3.9
4: N, 8.42. Theory: C, 58.03; H, 3.92; N, 8.14.

Example 243B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone O-methyloxime E-isomer is a preparation of Example 243A. MS (APCI) m / e: 333 (M + H) ^<+> . 3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H);
04 (s, 3H), 7.18 (m, 2H), 7.48 (m, 2H), 7.82 (
s, 1H), 8.11 (s, 1H), 9.12 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 19.25, 62.16,
119.88, 120.17, 121.60, 127.95, 130.04, 1
31.98, 134.49, 136.52, 138.85, 140.68, 14
6.21, 147.39, 155.22.

Example 244A 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime Example 244A was prepared using hydroxyl hydrochloride in place of methoxyamine hydrochloride. Prepared similarly as in Example 243A using an amine. ^{MS (APCI) m / e:} 319 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.23 (s, 3H), 7.
15 (m, 2H), 7.48 (m, 2H), 7.62 (s, 1H), 8.10 (
s, 1H), 9.02 (s, 1H), 11.89 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 11.41, 117.45
, 119.73, 124.45, 127.65, 129.97, 133.14,
136.78, 137.17, 140.28, 146.72, 147.39, 1
49.85, 155.51. Elemental _analysis: C ₁₅ H 11 ClNO ₂ Calculated S: C, 54.96; H, 3.69
N, 8.55. Theory: C, 55.37; H, 3.47; N, 8.37.

Example 244B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime Z-isomer was isolated from Example 244A. Was. MS (APCI) m / e: 319 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 7.
15 (d, J = 9 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 7.73
(S, 1H), 8.10 (s, 1H), 9.12 (s, 1H), 12.35 (s
, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 19.32. 118.36
, 119.96, 120.01, 127.81, 130.02, 132.08,
134.60, 136.99, 138.95, 140.73, 145.08, 1
47.18, 155.40.

Example 245 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-propanone The title compound was obtained using ethylmagnesium bromide instead of methylmagnesium bromide. And prepared in the same manner as in Example 33. mp 101-102 ° C. MS (APCI) m / e: 318 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.11 (t, J = 8 Hz,
3H), 3.18 (d, J = 8 Hz, 2H); 7.21 (m, 2H), 7.51
(M, 2H), 8.13 (s, 1H), 8.32 (s, 1H), 9.19 (s,
1H).

Example 246 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime The title compound was prepared using hydroxylamine hydrochloride in Example 26. Example 2 as in
Prepared from 45 and provided a mixture of E- and Z-oxime isomers. mp 195-198 ° C (decomposition). MS (APCI) m / e: 333 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.10 (m, 6H), 2.
77 (m, 4H), 7.17 (m, 4H), 7.48 (m, 4H), 7.61 (
s, 1H), 7.71 (s, 1H), 8.09 (s, 1H), 8.11 (s, 1H)
H), 9.00 (s, 1H), 9.12 (s, 1H), 11.88 (s, 1H)
, 12.42 (s, 1H). HPLC: Supelco C-18 column, water: acetonitrile 0: 90-
Elution at 90: 0 for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, RT = 20
. 20 minutes and 21.10 minutes (E- and Z-alien). Elemental _{analysis: C 16 H 13 ClN 2 O} 2 Calculated S: C, 57.74; H, 3.9
4: N, 8.42. Theory: C, 57.51; H, 4.12; N, 8.22.

Example 247 2- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide Example 88 (0. 38 mmol) is prepared as described in Example 42;
Then at -78 ° C combined with THF (1.0 mL) and LDA (0.92 mL of a freshly prepared 0.5 M solution in THF, 0.46 mmol). The clear, pale yellow solution was transferred to a solution of bis (N, O-dimethylhydroxyl) oxamide (88 mg, 0.50 mmol) in THF (1.0 mL) at −78 ° C. before being cannulated at −78 ° C. at 1.25 ° C. Stirred for hours. The solution was gradually warmed to room temperature, diluted with 2N aqueous hydrochloric acid (20 mL) and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were washed with brine (1 × 10 mL), dried (MgSO ₄ ) and concentrated to a yellow solid. Silica gel flash column chromatography (15% acetone in hexane) as a yellow solid (25 mg, 17%
Yield). mp 135.0-137.8 ° C. ^{_{MS (DCI / NH 3) m}} / e: 377 (35 Cl) / 379 (37 Cl). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.31 (s, 3H);
64 (s, 3H), 7.27 (d, J = 8.8 Hz, 2H), 7.52 (d, J
= 8.8 Hz, 2H), 8.15 (s, 1H), 8.22 (s, 1H), 9.2
6 (s, 1H).

Example 248 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile The pyridine of the compound obtained from Example 61B (500 mg, 1.64 mmol)
7 mL) solution at −78 ° C. under nitrogen under trifluoroacetic anhydride (1 mL, 6.6 mmol).
1), stirred at -78 ° C for 40 minutes, gradually warmed to room temperature and stirred for another 2 hours. The mixture was diluted with ethyl acetate, washed with saturated NaHCO _3, brine and dried (MgSO ₄₎ and concentrated. The resulting pale purple solid was dissolved in a minimum amount of ethyl acetate, filtered through a silica plug, washed with 50/50 hexane / ethyl acetate and concentrated to give 395 mg (84%) of the title compound as a white solid. Was. _{mp140~142 ℃; MS (APCI-NH} 3) m / e: 287 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.04 (d, 2H), 7.40
(D, 2H), 8.00 (s, 1H), 8.14 (s, 1H), 8.96 (s,
1H). Elemental _analysis: C ₁₄ H 7 _ClN 2 OS Calculated: C, 58.64; H, 2.46 ;
N, 9.77. Theory: C, 58.45; H, 2.62; N, 9.52.

Example 249 4- (4-Chlorophenoxy) -N′-hydroxythieno [2,3-c] pyridine-2-carboxymidamide Ethanol of the compound obtained from Example 248 (100 mg, 0.35 mmol) (2 mL) solution at room temperature under nitrogen under triethylamine (90 mL, 0.6 mmol)
), Hydroxylamine hydrochloride (40 mg, 0.53 mmol) and stirred for 18 h. The resulting white heterogeneous mixture was dissolved in ethyl acetate and saturated NaHC
Washed with O ₃ , brine, dried (MgSO ₄ ) and concentrated to give 120 mg of an off-white foam. The foam was dissolved in ethyl acetate, filtered through a plug of silica and concentrated to give the title compound as a white solid (110 mg, 98%). _{mp194~196 ℃; MS (APCI-NH} 3) m / e: 320 (M + H) +. ¹ H NMR (300 MHz, 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, 2H), 6.26 (brs, 2H). Elemental _{analysis: C 14 H 10 ClN 3 O} 2 Calculated S: C, 52.59; H, 3.1
5; N, 13.14. Theory: C, 52.72; H, 3.05; N, 12.82.
.

Example 250 4- (4-chlorophenoxy) -N′-cyanothieno [2,3-c] pyridine-
2-Carboximidamide THF (2 mg) of the compound obtained from Example 248 (100 mg, 0.35 mmol).
mL) solution at ambient temperature under nitrogen, cyanamide (74 mg, 1.75 mmol), 1,
8-diazabicyclo [5.4.0] undec-7-ene (52 mL, 0.35 m
mol) and stirred for 24 hours. The resulting yellow homogeneous solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated,
This gave a pale yellow solid which was tritylated with CH ₂ Cl ₂ to give 123 mg of a white powder. This was dissolved in ethyl acetate and THF, washed with distilled water and saline, and dried (M
gSO ₄ ) and concentrated to give 99 mg of a white powder (MgSO ₄ ), which was tritylated with CH ₂ Cl ₂ and then placed in a vacuum oven at 60 ° C. overnight to afford the title compound (78 mg, 69%). mp 265-268 ° C. _{MS (APCI-NH 3) m} / e: 329 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.58 (brs, 1H),
9.17 (s, 1H), 9.05 (brs, 1H), 8.41 (s, 1H), 8
. 19 (s, 1H), 7.48 (d, 2H), 7.15 (d, 2H). Elemental _analysis: C ₁₅ H 9 _ClN 4 OS Calculated: C, 54.80; H, 2.76 ;
N, 17.04. Theory: C, 54.50; H, 3.01; N, 17.16.

Example 251 (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone Example 251A [4- (4-Chlorophenoxy) thieno [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) was added a suspension of 1.3 M s-butyllithium in cyclohexane at −78 ° C. (3
. 52 mL, 4.58 mmol) were added dropwise over 10 minutes. After 40 minutes, the reaction was cooled at -48 ° C to 2-nitrobenzaldehyde (1.43 g, 9.55 mmol).
) Was cannulated into a stirred solution of THF (10 mL). After 20 minutes, the reaction was
OH (6 mL) was added slowly to quench. The reaction was treated with EtOAc (125 m
L) and the organic layer was washed with 1: 1 saturated aqueous NaHCO ₃ (1 × 75 mL), brine (1 × 75 mL), partially dried (Na ₂ SO ₄ ) and concentrated.

The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound as a solid (1.49 g, 95%). mp 85-90 ° C. MS (APCI) m / e: 413 (M + H) ^<+> . 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.54 (s, 1H);
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)
H), 7.98 (m, 1H), 8.12 (s, 1H), 9.02 (s, 1H).
Elemental _{analysis: C 20 H 13 ClN 2 O} 4 S, 0.3H 2 O Calculated: C, 57.4
3; H, 3.28; N, 6.70. Theory: C, 57.42; H, 3.45; N
, 6.42.

Example 251B (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol Example 251A (0.10 g, 0.24 mmol) was treated with EtOH (1.7 mL).
, And a solution of tin (II) chloride dihydrate (0.43 g, 1.92 mmol) in concentrated hydrochloric acid (0.70 mL) was gradually added. The reaction was stirred for 18 hours and then CH
Partitioned between Cl ₃ (50 mL) and saturated NaHCO ₃ (75 mL). Et water layer
Extract with OAc (1 × 50 mL), combine all organic extracts and partially dry (N
a ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound as a pale colored solid (0.08 g, 87%). mp 92-96 ° C. MS (APCI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.08 (brs, 2H),
6.10 (d, J = 4.3 Hz, 1H), 6.54 (d, J = 4.3 Hz, 1H)
), 6.55 (m, 1H), 6.61 (m, 1H), 6.98 (m, 1H), 7
. 05 (m, 2H), 7.13 (m, 1H), 7.19 (m, 1H), 7.42
(M, 2H), 8.09 (s, 1H), 8.98 (s, 1H). Elemental _{analysis: C 20 H 15 ClN 2 O} 2 Calculated S: C, 62.74; H, 3.9
5; N, 7.32. Theory: C, 63.09; H, 4.05; N, 7.06.

Example 251C (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone silica gel (0.13 g) and celite (0.13 g) in dichloromethane (
Pyridinium chlorochromate (0.13 g, 0. 6 mL) in an anhydrous stirred solution.
59 mmol) was added. A solution of Example 251B (0.15 g, 0.39 mmol) in anhydrous dichloromethane (9 mL) was slowly added dropwise. One hour later, saturated NaHCO ₃ (5 mL) was added, and the mixture was stirred for one hour. The reaction was filtered and the black solid was crushed and washed with 5% MeOH / dichloromethane (3 × 20 mL). The combined organic filtrate and washings were combined with saturated NaHCO ₃ (2 × 100 mL), brine (1 × 75 mL)
), Partially dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound (45 mg, 39%) as a light colored solid. mp 152-154 ° C. MS (APCI) m / e: 381 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ6.54 (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, 1H), 7.5
8 (m, 1H), 8.24 (s, 1H), 9.21 (s, 1H). ¹³ C NMR (300 MHz, 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
, 1552, 1483, 1409, 1267, 1245, 1219, 1155c
m- ¹ . Elemental _{analysis: C 20 H 13 ClN 2 O} 2 Calculated S: C, 63.08; H, 3.4
4: N, 7.36. Theory: C, 62.94; H, 3.51; N, 7.25.

Example 252 (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252A [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
3-Nitrophenyl) methanol Example 251A was used, substituting 3-nitrobenzaldehyde for 2-nitrobenzaldehyde. mp 79-83 ° C. MS (APCI) m / e: 413 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.33 (d, J = 4.4 H
z, 1H), 6.99 (d, J = 4.4 Hz, 1H), 7.07 (m, 2H),
7.27 (m, 1H), 7.43 (m, 2H), 7.66 (m, 1H), 7.9
2 (m, 1H), 8.13 (s, 1H), 8.15 (m, 1H), 8.34 (m
, 1H), 9.01 (s, 1H). Elemental _{analysis: C 20 H 13 ClN 2 O} 4 Calculated S: C, 58.19; H, 3.1
7; N, 6.79. Theory: C, 57.97; H, 3.23; N, 6.70.

Example 252B (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252A was treated according to the method of Example 251B to provide the title compound. mp 73-78 ° C. MS (APCI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.03 (s, 2H), 5.
88 (s, 1H), 6.45 (continuous m, 2H), 6.57 (m, 1H), 6
. 64 (m, 1H), 6.96 (m, 1H), 7.06 (m, 2H), 7.11
(M, 1H), 7.42 (m, 2H), 8.08 (s, 1H), 8.97 (s,
1H). Elemental _{analysis: C 20 H 15 ClN 2 O} 2 Calculated S: C, 62.74; H, 3.9
5; N, 7.32. Theory: C, 63.06; H, 4.22; N, 6.92.

Example 252C (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252B was treated according to the method of Example 251C to provide the title compound. mp 174-178 ° C. MS (APCI) m / e: 481 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.47 (brs, 2H),
6.86 to 6.96 (continuous m, 2H), 7.06 (m, 1H), 7.16 to
7.23 (continuous m, 3H), 7.48 (m, 2H), 7.77 (s, 1H)
, 8.20 (s, 1H), 9.22 (s, 1H).

Example 253 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine methyltriphenylphosphonium bromide (113 mg, 0.314 mmol
) Was added to a stirred solution of anhydrous tetrahydrofuran (2 mL) at -78 ° C under a nitrogen atmosphere under n-BuLi (2.5 M solution in hexane, 0.125 mL, 0.314 mmol).
l) The solution was added dropwise. The reaction mixture was then stirred for 40 minutes at 0 ° C.,
Cooled to 8 ° C. While maintaining the internal temperature at -72 ° C or lower, the solution was added to Example 24.
A solution of 0 (100 mg, 0.3 mmol) in anhydrous tetrahydrofuran (2 mL) was added. Upon completion of the addition, the reaction mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 1 hour. Next, the reaction mixture was partitioned between ethyl acetate (60 mL) and brine (20 mL). The organic layer was washed with brine (2 × 20 mL), dried (MgSO ₄ ) and evaporated to dryness under reduced pressure to give a crude (145 mg). The title compound is 26% by silica gel flash chromatography eluting with 25% acetone-hexane.
In a yield of 26 mg. MS (APCI) m / e: 332, 334 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.53 (d, J = 10 Hz)
, 1H), 5.86 (d, J = 16 Hz, 1H), 7.02 (d, J = 9 Hz,
2H), 7.06 to 7.14 (m, 1H), 7.37 (s, 1H), 7.57 (
d, J = 9 Hz, 1H), 8.17 (s, 1H), 9.04 (s, 1H).

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 254A (70 mg, 10%) was replaced with Example 91 in place of Example 240.
Prepared as in Example 253 except using A (700 mg, 2.42 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.53 (d, J = 10.5
Hz, 1H), 5.86 (d, J = 18 Hz, 1H), 7.04 to 7.14 (m
, 1H), 7.10 (d, J = 9 Hz, 2H), 7.38 (s, 1H), 7.4
5 (d, J = 9 Hz, 2H), 8.16 (s, 1H), 9.04 (s, 1H).

Example 254B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol Example 254A (22 mg, 28%) was prepared. Example 25 Instead of Example 253
Prepared as in Example 255 except using 4A (70 mg, 0.26 mmol). MS (APCI) m / e: 322 (M + H) ⁺ , 356 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.50 to 3.64 (m, 2
H), 4.86-4.91 (m, 1H), 5.0 (t, J = 6 Hz, 1H), 6
. 04 (d, J = 4 Hz, 1H), 7.07 (d, J = 9 Hz, 2H), 7.2
1 (s, 1H), 7.43 (d, J = 9 Hz, 2H), 8.14 (s, 1H),
9.04 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 66.52 (CH ₂ ), 7
0.24 (CH), 114.60 (CH), 119.06 (CH), 127.2
2 (C), 129.91 (CH), 133.36 (CH), 137.16 (C)
, 137.42 (C), 140.79 (CH), 145.79 (C), 155.
91 (C), 156.59 (C).

Example 255 1- [4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol Tetrahydrofuran of Example 253 (90 mg, 0.271 mmol) (2m
L) To the solution was added 4-methylmorpholine N-oxide (63.5 mg, 0.542 m
mol) and osmium tetroxide (14 mg, 0.054 mmol) in water (0.
(5 mL) was added at room temperature. The reaction mixture was stirred for 48 hours and the solvent was removed. The resulting residue was purified by flash chromatography on silica gel, eluting directly with 20% acetone-hexane to give the title compound (52 mg, 53%). MS (APCI) m / e: 366; 368 (M + H) ^<+> , 402 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.50 to 3.64 (m, 2
H), 4.89 (m, 1H), 5.01 (t, J = 6 Hz, 1H), 6.05 (
d, J = 4 Hz, 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
(S, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 66.52 (CH ₂ ), 7
0.25 (CH), 114.60 (CH), 115.08 (C), 119.24
(CH), 132.84 (CH), 133.49 (CH), 137.18 (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 diethyl azodicarboxylate (180 mL, 1.13 mmol) was prepared in Example 90 (
220 mg, 0.750 mmol), THF (7.5 mL), triphenylphosphine (297 mg, 1.13 mmol) and phthalimide (166 mg,
1.13 mmol). After 16 hours, the orange solution was concentrated under reduced pressure to obtain an orange solid. Silica gel flash column chromatography (20% acetone in hexane) provided one compound (100% yield) as the main product, which was combined with hydrazine hydrate (230 mL, 7.50 mmol) and ethanol (75 mL). Heated to reflux. After 4 hours, the solution was cooled to room temperature, concentrated, 5N HCl
(30 mL) and filtered through a fritted glass funnel. Filtrate is 3NN
Added to pH> 12 with aOH and extracted with EtOAc (3 × 30 mL).
The organic extracts were combined, washed once with brine (30 mL), dried (MgSO ₄ ),
Filter and concentrate under reduced pressure to give the title compound as a white solid (190 mg, 87% yield). mp 78.6-79.8 <0> C. _{MS (DCI / NH 3) m} / e: 321 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.24 (brs, 2H),
4.02 (s, 2H), 7.03 (d, J = 9.1 Hz, 2H), 7.15 (s
, 1H), 7.42 (d, J = 9.1 Hz, 2H), 8.14 (s, 1H), 9
. 01 (s, 1H). Elemental _{analysis: C 14 H 11 ClN 2 OS} , 0.25H 2 O Calculated: C, 56.9
5; H, 3.93; N, 9.49. Theory: C, 56.86; H, 3.81; N
, 9.62.

Example 257 [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methylcarbamate Example 90 (50 mg, 0.17 mmol) in CH ₂ Cl ₂ (0.5 mL) ),
Sodium cyanate (22 mg, 0.34 mmol) and trifluoroacetic acid (4
0 mL, 0.34 mmol), and gas generation was observed. After 24 hours, the mixture was partitioned distilled water (15mL) _CH 2 _Cl 2 and (50 mL). The layers were separated and the organic layer dried (MgSO _4), filtered and concentrated. Silica gel column chromatography (30% acetone in hexane) gave the title compound as a white solid (21 mg).
, 37% yield). mp 113-115 ° C. ^{_{MS (DCI / NH 3) m}} / e: 335 (35 Cl) / 337 (37 Cl). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.30 (s, 2H), 6.
80 (brs, 2H), 7.06 (d, J = 9.2 Hz, 2H), 7.37 (s
, 1H), 7.45 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H), 9
. 10 (s, 1H).

Example 258 N-{[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methyl} urea Potassium cyanate (41 mg, 0.50 mmol) was prepared according to Example 256 ( 130m
g, 0.45 mmol), distilled water (2.0 mL) and concentrated hydrochloric acid (40 mL, 0.1 mL).
45 mmol) and the solution was heated at 50 ° C. After 3 hours, the solution was cooled slowly to 0 ° C. and the resulting precipitate was isolated by filtration. Silica gel flash column chromatography (20% acetone in hexane to 1% in EtOAc)
(Change to 0% MeOH) to give the title compound as a white solid (63 mg, 42% yield).
Was provided. mp 202-204 ° C. ^{_{MS (DCI / NH 3) m}} / e: 334 (35 Cl) + / 336 (37 Cl) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.47 (d, J = 6.1 H
z, 2H), 5.68 (s, 2H), 6.68 (t, J = 6.1 Hz, 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: C 15 H 12 ClN 3 O} 2 Calculated S: C, 53.97; H, 3.6
2: N, 12.59. Theory: C, 53.80; H, 3.67; N, 12.37.
.

Example 259 (E) -3- [4- (4-Bromophenoxy) thieno [2,3-c] pyridine-
2-yl] propenamide Example 259A Methyl 3- (4- (4-bromophenoxy) thieno [2,3-c] pyridine-2
-Yl) propenoate Example 259A (590 mg, 57%) was replaced by Example 2 instead of Example 91A.
Prepared as in Example 91B except using 40 (890 mg, 2.67 mmol). MS (APCI) m / e: 390; 392 (M + H) ⁺ , 389; 391 (M-
H) ^- . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.75 (s, 3H), 6.
58 (d, J = 16 Hz, 1H), 7.07 (d, J = 9 Hz, 2H), 7.5
9 (d, J = 9 Hz, 2H), 7.89 (s, 1H), 8.02 (d, J = 16
Hz, 1H), 8.17 (s, 1H), 9.12 (s, 1H).

Example 259B 3- (4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl) propenonic acid Example To provide the title compound (270 mg, 93%). 259A and the method of Example 88 were used. MS (APCI) m / e: 376; 378 (M + H) ^<+> . _{^{1 H NMR (300MHz, DMSO-}} d 6) d: 6.45 (d, J = 16H
z, 1H), 7.07 (d, J = 9 Hz, 2H), 7.58 (d, J = 9 Hz,
2H), 7.81 (s, 1H), 7.90 (d, J = 16 Hz, 1H), 8.1
6 (s, 1H), 9.10 (s, 1H).

Example 259C 3- (4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl) propenamide Example 259B instead of Example 91c to provide the title compound. The methods of Example 259B (222 mg, 81%) and Example 92 were used except that mp 195-196 ° C. MS (APCI) m / e: 375; 377 (M + H) ⁺ , 409; 411 (M +
Cl) ^- . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.62 (d, 16 Hz, 1
H), 7.04 (d, J = 9 Hz, 2H), 7.26 (s, 1H), 7.56 (
d, J = 9 Hz, 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 (100 MHz, DMSO-d ₆ ) δ 115.55 (C), 11
9.98 (CH), 122.11 (CH), 126.68 (CH), 131.8
0 (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-2-yl] propenamide Example 260 (25 mg, 50%) was prepared as follows: Prepared from Example 259A (50 mg, 0.13 mmol) as described in 171. ^{MS (APCI) m / e:} 389 (M + H) +; 1 H NMR (400MHz, DMSO-d 6) δ2.71 (d, J = 4.5H
z, 3H), 6.62 (d, J = 16 Hz, 1H), 7.06 (d, J = 9 Hz)
, 2H), 7.58 (d, J = 9 Hz, 2H), 7.69 (s, 1H), 7.7
4 (d, J = 16 Hz, 1H), 8.15 (s, 1H), 8.27 (d, J = 4
. 5 Hz, 1H), 9.08 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 25.7 (CH ₃ ), 11
5.6 (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] pyridine-
2-yl] -2,3-dihydroxypropanamide To provide the title compound, Example 260 (90 mg, 0.2
Example 2 as described in Example 255 except that 32 mmol) was used.
60 (52 mg, 53%) was prepared. MS (APCI) m / e: 423; 425 (M + H) ^<+> , 456 (M + Cl) < ^- >. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.61 (d, J = 4.5H)
z, 3H), 4.09 (brd, J = 3 Hz, 1H), 5.27 (brd, J =
3 Hz, 1 H), 5.68 (d, J = 6 Hz, 1 H), 6.09 (d, J = 6 H)
z, 1H), 7.00 (d, J = 9 Hz, 2H), 7.23 (s, 1H), 7.
56 (d, J = 9 Hz, 2H), 7.77 (d, J = 4.5 Hz, 1H), 8.
14 (s, 1H), 9.04 (s, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 25.5 (CH ₃ ), 70.
3 (CH), 75.1 (CH), 115.0 (CH), 115.1 (C), 11
9.5 (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 Example to prepare the title compound 261 and the product from Example 259C may be used.

Example 263 4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine Example 159A (0.500 g, 1.64 mmol) and 1,8-bis (dimethylamino) naphthalene A mixture of N, N, N ′, N′-tetramethyl-1,8-naphthalenediamine (0.350 g, 1.64 mmol) in 90 mL of anhydrous THF was warmed until all solids were in solution. The solution was stirred for 15 minutes and diphenylphosphoryl azide (0.450 g, 1.64 mmol) was added. The solution was heated at 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 / hexane,
422 mg of the intermediate isocyanate were provided as a light orange solid. The resulting product was dissolved in 100 mL of toluene and heated at reflux for 6 hours. The product was evaporated to dryness. The resulting dark orange solid was dissolved in 20 mL of a 2.0 M solution of hydrogen chloride in dioxane. The solution was evaporated, leaving 313 mg (84.9%) of the title compound. MS (APCI) m / e: 277 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ6.91 (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 ° C. for 3 hours. . The solution was cooled and the amine from Example 263 (32 mg, 0.1
2 mmol) was added. The mixture was stirred for 4 days and poured into 50 mL of HCl. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated sodium carbonate, then with water, dried (MgSO ₄ ) and evaporated. Purification of the product by preparative HPLC using a gradient of 30% -70% acetonitrile / water + 0.1% TFA over 40 minutes gave 18 mg (49%) of the title compound. MS (APCI) m / e: 305 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₃ OD) δ 7.16 (s, 1H), 7.24
(D, 2H), 7.46 (d, 2H), 8.08 (s, 1H), 8.61 (s,
1H), 9.13 (s, 1H).

Example 265 N- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] urea Hydroxidation of the Isocyanate Obtained from Example 263 (110 mg, 0.364 mmol) The mixture in 10 mL of ammonium was stirred vigorously for 18 hours. The resulting red solid was collected and dried under reduced pressure to give 60.7g (52.2%) of the title compound. MS (APCI) m / e: 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (d, 2H), 7.
34 (s, 1H), 7.50 (d, 2H), 7.65 to 7.79 (m, 4H),
8.06-8.16 (m, 2H), 9.18 (s, 1H).

Example 266 N- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N′-methylthiourea Obtained from Example 263 (150 mg, 0.542 mmol). 5 mL of the pyridine solution of the prepared amine in methyl isothiocyanate (198 mg, 2.71 mmol)
Processed. The solution was heated at 100 ° C. for 5 days under a nitrogen atmosphere. All volatiles were removed under reduced pressure. The resulting product was purified by flash column chromatography on silica gel, eluting with chloroform / NH ₄ OH to give 110 mg (58.
1%) of the title compound. MS (APCI) m / e: 350 (M + H) ^<+> . ¹ H NMR (300 MHz, 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), 8.67 (s, 1H).

Example 267 Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide A solution of Example 124A (261 mg, 1 mmol) in THF (2 mL) was added with -7.
N-BuLi (2.5 M solution in hexane, 0.60 mL
, 1.5 mmol). This was stirred at −78 ° C. for 2 hours and a rapid flow of SO ₂ was introduced to the surface of the reaction mixture. After 15 minutes, the reaction mixture was warmed to 0 ° C. while continuing to introduce SO ₂ . After 10 minutes at 0 ° C., the flow of SO ₂ was stopped and the reaction mixture was
Warmed to 0 ° C. Then, the solvent and excess SO ₂ gas were removed under reduced pressure to obtain a cream-colored solid lithium sulfinate. This material was dissolved in saturated aqueous NaHCO ₃ (1 mL) and N-chlorosuccinimide (200 mg, 1.
5 mmol). The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The product formed was extracted into CH ₂ Cl ₂ (2 × 50 mL) and water (2 × 20
mL). The dried (Na ₂ SO ₄ ) organic layer was evaporated to dryness under reduced pressure to obtain a sulfonyl chloride derivative. Part of this material (143 mg, 0.398 mmol)
Was dissolved in CH ₂ Cl ₂ (1 mL) at −5 ° C. and treated with diisopropylethylamine (0.083 mL, 0.478 mmol) and a 2M solution of methylamine in methanol (0.239 mL, 1.2 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. This was purified by flash chromatography on silica gel eluting directly with 10% acetone-hexane followed by 25% acetone-hexane to give the title compound (19 mg, 13.5%). MS (APCI) m / e: 355 (M + H) ^<+> , 353 (M-H) < ^{- >} . _6. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.57 (s, 3H),
19 (d, J = 9 Hz, 2H), 7.49 (d, J = 9 Hz, 2H), 7.76
(S, 1H), 8.16 (br, d, J = 3 Hz, 1H), 8.24 (s, 1H)
), 9.24 (s, 1H).

Example 268 2,3-Dihydroxypropyl 4- (4-chlorophenoxy) thieno [2,3-
c] Pyridine-2-sulfonamide Example 268 (8.6 mg, 7.5%) except that methylamine was replaced with 3-amino-1,2-propanediol (0.086 mL, 1.12 mmol) Was prepared as described in Example 267. MS (APCI) m / e: 415 (M + H) ⁺ , 413 (MH) ⁻ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.76 (d, J = 7.5 H).
z, 1H), 2.81 (d, J = 7.5 Hz, 1H), 3.02 (d, J = 4.
5 Hz, 1H), 3.08 (d, J = 4.5 Hz, 1H), 3.44 to 3.55
(M, 1H), 4.47 to 4.64 (m, 1H), 4.80 (d, J = 6 Hz,
1H), 7.17 (d, J = 9 Hz, 2H), 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 Example 269 (25 mg, 16%) was prepared by substituting 2- Example 26 except that hydroxyethylamine (0.072 mL, 1.2 mmol) was used.
Prepared as described in 7. MS (APCI) m / e: 385 (M + H) ^<+> , 383 (M-H) < ^{- >} . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.97 (t, J = ₆ Hz,
2H), 3.38-3.45 (m, 2H), 4.69-4.78 (m, 1H),
7.18 (d, J = 9 Hz, 2H); 7.48 (d, J = 9 Hz, 2H);
78 (s, 1H), 8.23 (s, 1H), 9.21 (s, 1H). ¹³ C NMR (75 MHz, 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- (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 s-butyllithium in cyclohexane was added at -78 ° C in THF.
(10 mL). T of Example 124A (1.00 g, 3.82 mmol)
An HF (5 mL) solution was added dropwise. The reaction was stirred for 30 minutes and tributyl borate (1.55 mL, 5.73 mmol) was added slowly. The mixture was stirred for 45 minutes while removing the cooling bath and warming to room temperature. A 2N NaOH (15 mL) solution was added. After 10 minutes, the reaction was diluted with hexane (15 mL) and the aqueous layer was collected. Organic layer is 2NNa
Extracted with OH (2 × 5 mL), combined all aqueous layers with 6N HCl to pH 2 and extracted with 10% MeOH / CH ₂ Cl ₂ (4 × 25 mL). The organic extracts were combined and concentrated. The resulting solid was washed with acetonitrile (1 × 25 mL) and dried in a desiccator to yield the title compound as a tan solid (0.83 g, 71%). MS (APCI) m / e: 262 (M + H-B (OH) ₂ ) ^<+> , m / e: 340
(M + Cl ⁻ ) ⁻ . ¹ H NMR (300 MHz, 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] anisole Example 270A (0.25 g, 0.82 mmol), 4-iodoanisole (
0.19 g, 0.82 mmol), [1,1′-bis (triphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1: 1) (
0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.46 mm)
ol), triethylamine (0.11 mL, 0.82 mmol) in DME (7 m
The mixture in L) was sucked with dry nitrogen for 10 minutes. The reaction was heated at 75 ° C. for 18 hours, then partitioned between EtOAc (100 mL) and saturated NaHCO ₃ (100 mL). The organic layer was washed with saturated NaHCO ₃ (100 mL), brine (75 mL),
Partially dried (Na ₂ SO ₄ ) and concentrated to a colored, wet solid. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to produce a colored solid. The title product was crystallized from hot acetonitrile (0.11 g, 37%). mp 121-123 ° C. MS (APCI) m / e: 368 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 2H), 8.13 (s, 1H), 9.05 (s, 1H)
H). Elemental _analysis: C ₂₀ H 14 ClNO ₂ Calculated S: C, 65.30; H, 3.84
N, 3.81. Theory: C, 65.06; H, 3.69; N, 4.05.

Example 270C 4- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] phenol Anhydrous CH ₂ Cl _{2 of} Example 270B (0.09 g, 0.24 mmol) (4m
L) To the solution was added a 1 M solution of boron tribromide in CH ₂ Cl ₂ (0.96 mL, 0.9
6 mmol) was added. After 2 hours, 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) and partially dried (
Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using ETOAc / hexane as eluent to give the solid title compound (0
. 08g, 96%). mp 213-215 ° C. MS (RSI) m / e: 354 (M + H) ^<+> . _{^{1 H NMR (300MHz, DMSO-}} d 6) 6.86 (m, 2H), 7.1
1 (m, 2H), 7.45 (m, 2H), 7.56 (s, 1H), 7.68 (m
, 2H), 8.13 (s, 1H), 9.03 (s, 1H), 9.99 (s, 1H)
). Elemental _{analysis: C 19 H 12 ClNO 2 S} , 0.5H 2 O Calculated: C, 62.90
H, 3.61; N, 3.86. Theory: 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- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] nitrobenzene Example 170A (0.25 g, 0. 82 mmol), 1-iodo-4-nitrobenzene (0.20 g, 0.82 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1:
1) (0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.4
A mixture of 6 mmol) and triethylamine (0.11 mL, 0.82 mmol) was aspirated with anhydrous nitrogen in DME (8 mL) for 10 min. The reaction was heated at 70 ° C. for 18 hours, and EtOAc (100 mL) and saturated NaHCO ₃ (100 mL)
). The organic layer was saturated NaHCO ₃ (100 mL), brine (75 mL)
, Partially dried (Na ₂ SO ₄ ) and concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a colorless solid (0.15
g, 48%). Melting point 193-195 [deg.] C. MS (ESI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 2H), 9.17 (s, 1H). Elemental _{analysis: C 19 H 11 ClN 2 O} 3 Calculated S: C, 59.61; H, 2.9
0; 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 Example 272A (0.13 g, 0.34 mmol) in EtOH (3.5 mL) )
To the suspension was added tin (II) chloride dihydrate (0.31 g, 1.36 mmol) in concentrated HC.
1 (0.68 mL) solution was added slowly. 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 1N NaOH (1 × 50 mL), brine (1 × 50 mL), partially dried (Na ₂ SO ₄ ), and concentrated to give a colored solid (0.13 g). Crystallization from acetonitrile gave the desired product as colored crystals (0.08 g, 6
8%). MP 178-182 [deg.] C MS (APCI) m / e: 353 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.68 (brs, 2H),
6.62 (m, 2H), 7.09 (m, 2H), 7.39 (s, 1H), 7.4
4 (m, 2H), 7.51 (m, 2H), 8.11 (s, 1H), 8.97 (s
, 1H). Elemental _analysis: 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] -3-pyridinamine Example 273A 6- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -3-nitropyridine Example 273A (in the same manner as in Example 272A) using 2-bromo-5-nitropyridine instead of 1-iodo-4-nitrobenzene. 120 mg, 32%). Melting point 221-223 [deg.] C MS (APCI) m / e: 384 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (m, 2H), 7.
49 (m, 2H), 8.16 (s, 1H), 8.50 (s, 1H), 8.61 (
d, J = 8.8 Hz, 1H), 8.70 (dd, J = 8.8, 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] -3-pyridinamine Example 273B (0.07 g, 59) as in Example 272B. %) Was prepared.
MP 225-227 ° C MS (APCI) m / e: 354 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.82 (broads, 2
H), 6.92 (dd, J = 8.5, 2.6 Hz, 1H), 7.05 (m, 2H
), 7.39 (m, 2H), 7.60 (m, 1H), 7.79 (d, J = 8.5)
Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 8.04 (s, 1H)
, 8.39 (s, 1H). Elemental _analysis: 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 Example 270A (0.20 g, 0.65 mmol), 2-amino-5-bromo
Pyridine (0.11 g, 0.65 mmol), [1,1'-bis (diphenylphosphine)
Sufino) ferrocene] dichloropalladium (II) dichloromethane complex (1:
1) (0.11 g, 0.13 mmol), cesium fluoride (0.30 g, 1.9)
5 mmol), a mixture of triethylamine (0.09 mL, 0.65 mmol)
Was sucked with anhydrous nitrogen in DME (6 mL) for 20 minutes. Heat the reaction to reflux for 4 hours
And concentrated. 10% residueⁱPrOH / CHCl₃(100mL)
And filtered, and the organics are washed with saturated NaHCO₃(2 x 100 mL)
Partially dried (Na₂SO₄) And concentrated to give a crude colored solid (0.2
5g). 25% to 65% acetonitrile / water + 0.1% T over 40 minutes
Purification was performed by preparative HPLC using a concentration gradient of FA. The product is saturated NaHCO ₃ And the precipitate is filtered off and dried in a desiccator to give a pale colored solid.
To give the title compound (54 mg, 23%). 208-210 ° C MS (APCI) m / e: 254 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 6.50 (brs, 2H),
6.53 (dd, J = 8.9, 0.9 Hz, 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.
9Hz, 1H), 9.00 (s, 1H). Elemental analysis: C₁₈H₁₂ClN₃OS calc: 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-oxadiazol-2-amine Example 156 (0 .15 g, 0.47 mmol) in 1,4-dioxane (3 m
L) and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.5
0 mmol) was added. The reaction was stirred for 10 minutes and NaHCO ₃ (0.04 g
, 0.50 mmol) in water (1.4 mL) was added dropwise. 2 colored reactants
Stirred for hours and poured into saturated NaHCO ₃ (75 mL). 10% aqueous phase
Extracted with isopropanol / CHCl ₃ (4 × 25 mL). The organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated to give a solid (0.13 g). A portion of the crude was purified by HPLC using a gradient of 30% to 70% acetonitrile / water + 0.1% TFA over 40 minutes to give the title compound as a tan solid.
MP 262-263 [deg.] C MS (APCI) m / e: 345 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (m, 2H), 7.
47 (m, 2H), 7.52 (s, 1H), 7.60 (broads, 2H),
8.24 (s, 1H), 9.17 (s, 1H). _{^{13 C NMR (DMSO-d 6}} ) δ164.3,155.6,153.1,1
46.6, 141.2, 137.0, 136.9, 134.0, 131.4, 1
30.1 (2C), 127.7, 119.5 (2C), 117.5. IR (KBr) 3325, 3234, 3080, 1665, 1578, 1547
, 1486, 1411, 1287, 1257, 1229, 1203 cm ^-1 . Elemental _{analysis: C 15 H 9 ClN 4 O} 2 Calculated S: 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-2-ylamine Example 157 (0 .15 g, 0.41 mmol) in 1,4-dioxane (4 m
L), and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.1 mL).
50 mmol) was added. The reaction was stirred for 10 minutes and NaHCO ₃ (0.04
g, 0.50 mmol) in water (1.4 mL) was added dropwise. The color reaction was stirred for 3 hours and poured into saturated NaHCO ₃ (75 mL). 10 aqueous phases
Extracted with% IPA / CHCl ₃ (4 × 25 mL). The organic extracts were combined, partially dried (Na ₂ SO ₄ ), and concentrated to give a solid. 40 parts of crude
Purification by HPLC using a gradient of 30% to 70% acetonitrile / water + 0.1% TFA over a minute to afford the title compound as a tan solid. 270-273 ° C MS (APCI) m / e: 389 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.08 (m, 2H), 7.
52 (s, 1H), 7.56 (brs, 2H), 7.59 (m, 2H), 8.2
7 (s, 1H), 9.19 (s, 1H). Elemental _{analysis: C 15 H 9 BrN 4 O} 2 Calculated S: C, 46.29; H, 2.33
N, 14.39. Found: C, 46.08; H, 2.59; N, 14.12.

Example 277 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -4H-1,2,4-triazol-3-amine 61A (0.33 g) , 1.03 mmol) and aminoguanidine hydrochloride (3
. 45 g, 31.20 mmol) in a dry flask containing 25 wt.
A Me / MeOH (7.13 mL, 34.32 mmol) solution was added slowly. The reaction was stirred at ambient temperature for 1 hour and at 50 ° C. for 20 hours, then at 70 ° C. for 2 hours.
Heat for 4 hours. The reaction was poured into water (200 mL) and 3N HCl (
10 mL). The precipitate was collected by filtration, washed with water (2 × 20 mL) and dried in a desiccator. Crude the crude for 40 minutes from 25% to 65% acetonitrile /
Purified by preparative HPLC using a concentration gradient of water + 0.1% TFA. The product is neutralized with saturated NaHCO ₃ , the precipitate is filtered off and dried in a desiccator,
The title compound was obtained as a white solid (0.16 g, 45%). Melting point> 270 ° C MS (APCI) m / e: 344 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.46 (brs, 2H),
7.27 (m, 2H), 7.58 (m, 2H), 7.67 (s, 1H), 8.3
1 (s, 1H), 9.21 (s, 1H). Elemental _analysis: 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-Thiadiazol-2-amine Example 88 (0.36 g, 1.18 mmol) was suspended in thionyl chloride (4 mL).
It became cloudy and the suspension was heated at 45 ° C. for 2 hours. The reaction was concentrated and the residue was₂Cl ₂ (2 × 5 mL) and concentrated to give a colored solid. DM the crude solid
F (5 mL) and thiosemicarbazide (2.69 g, 29.50 mmol)
) Was added and the reaction was stirred for 24 hours. Pour the reaction into water (250 mL)
And the aqueous suspension was washed with saturated NaHCO₃PH> 7 with aqueous solution (10 mL)
Processed. Collect the precipitate, wash with water (2 × 20 mL) and desiccator
Dried in to give the corresponding acyl semicarbazate as a solid (0.30 g
) [MS (APCI) m / e: 377 (M + H)⁺]. Crude (0.20 g)
Suspended in toluene (2 mL), methanesulfonic acid (0.10 mL, 1.60 mm
ol) was added. The reaction was heated at reflux for 4 hours and cooled to room temperature. Uneven
Dilute one mixture with hexane (5 mL) and remove solvent by decantation
Thus, a colored residue was obtained. Triturate the residue with hexane (2 × 10 mL) and dry under vacuum
did. The solid is suspended in water (15 mL) and NH 9 until pH 9₄Treated with OH
. The precipitate was collected and washed with water (2 × 5 mL). Use acetone as eluent
Crude was partially purified on silica gel by flash chromatography
. 25% -65% acetonitrile / water + 0.1% TF over 40 minutes
Further purification by preparative HPLC using a concentration gradient of A. The product is saturated NaHC
O₃Neutralize with aqueous solution, filter precipitate and dry in desiccator, tan
The title compound was obtained as a solid (0.04 mg, overall yield 14%). Melting point> 270 ° C MS (APCI) m / e: 361 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆6.) δ 7.15 (m, 2H);
46 (m, 2H), 7.68 (s, 1H), 7.75 (brs, 2H), 8.1
1 (s, 1H), 9.06 (s, 1H). Elemental analysis: C_FifteenH₉ClN₄OS₂Calculated: C, 49.93; H, 2.51
N, 15.53. Found: C, 49.82; H, 2.64; N, 15.58.

Example 279 4- (4-Chlorophenoxy) -2- (5-methyl-1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Obtained from Example 249 Pyridine (2.0 mL) solution of the obtained compound (160 mg, 0.5 mmol) in acetyl chloride (50 mL, 0.55 mm) in nitrogen at ambient temperature
ol) and heated to reflux for 15 hours. The resulting dark yellow homogeneous solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered through silica and concentrated to give 169 mg of an off-white powder Was.
This solid was flash chromatographed on silica gel using 30-50% ethyl acetate / hexane to give the title compound (150 mg, 87%). _{Mp: 120~121 ℃ MS (APCI-NH} 3) m / e: 344 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (s, 1 H), 8.
27 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.16 (
d, 2H), 2.69 (s, 3H). Elemental _{analysis: C 16 H 10 ClN 3 O} 2 Calculated S: C, 55.90; H, 2.9
3; N, 12.22. Found: C, 56.10; H, 3.16; N, 12.01.
.

Example 280 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-2-amine Example 158 was treated according to the method of Example 275 to give the title compound. MS (APCI) m / e: 358.9 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ7.22 (d, 2H), 7.
51 (s, 1H), 7.60 (s, 2H), 7.79 (d, 2H), 8.40 (
s, 1H), 9.25 (s, 1H).

Example 281 4- (4-Chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
4-oxadiazol-2-yl] thieno [2,3-c] pyridine Example 281A 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1, 3,4-oxadiazole-2-thiol The compound from Example 156 (100 mg, 0.31 mmol) was treated with ethanol (
2 mL) and cooled to 0 ° C. Carbon disulfide (0.04 mL, 0.71 m
mol), followed by potassium hydroxide (20 mg, 0.31 mmol).
The reaction was stirred for 1 hour and the cold bath was removed. After 1 hour at ambient temperature, the reaction was refluxed for 3 hours and concentrated to a solid. The crude solid was added to chloroform (1 × 5 m
Triturated in l) and concentrated. The residue was dissolved in water (15ml) and acidified with formic acid.
The resulting precipitate was filtered off, washed with water (2 × 15 ml) and dried in a desiccator to give the title compound (106 mg, 94%). Melting point: 236-240 ° C MS (ESI) m / e: 362 (M + H) ⁺ . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 7.15 (m, 2H), 7.4
6 (m, 2H), 7.65 (m, 1H), 8.24 (s, 1H), 9.18 (s
, 1H). Elemental _{analysis: C 15 H 8 ClN 3 O} 2 S 2 Calculated: C, 47.89; H, 2.5
7; N, 11.17. Found: C, 47.89; H, 2.49; N, 10.97.
.

Example 281B 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
To a suspension of 4-oxadiazol-2-yl] thieno [2,3-c] pyridine 281A (100 mg, 0.28 mmol) in THF (1 ml) at 0 ° C. with stirring, was added a 1M aqueous sodium hydroxide solution (0%). .28ml, 0.28mmo
l) was added. After 30 minutes all solids dissolved and iodomethane (0.02 ml,
0.31 mmol) was slowly added dropwise. The reaction was stirred for 30 minutes and water (8
ml) was added. The solid was collected by filtration, washed with water (2 × 15 ml) and dried in a desiccator to give 80 mg of a pale 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 (41mg, 39%). Melting point: 158-160 <0> C MS (ESI) m / e: 376 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 2.75 (s, 3H), 7.0
1 (m, 2H), 7.33 (m, 2H), 7.91 (s, 1H), 8.12 (s
, 1H), 8.93 (s, 1H). Elemental _{analysis: 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, 10.8.
9.

Example 282 4- (4-Chlorophenoxy) -2- (2-methyl-1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Example 282A 4- (4-Chlorophenoxy) -2- (1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Toluene of the compound (90 mg, 0.314 mmol) obtained in Example 248 (1.5 mL) solution at room temperature under nitrogen under nitrogen dibutyltin oxide (8 mg, 0.1 mg).
031 mmol), trimethylsilyl azide (125 mL, 0.942 mmol)
), Heated to reflux for 24 hours and stirred at room temperature for another 2.5 days. The resulting yellow heterogeneous mixture was concentrated and flash chromatographed with 20% methanol / dichloromethane to give 105 mg of a pale yellow powder. This powder was dissolved in ethyl acetate and extracted with 10% NaHCO ₃ (twice), the aqueous extracts were combined,
Acidify to pH 2 with N HCl, extract with ethyl acetate, dry (Na ₂ SO ₄ ) and concentrate to give the title compound as a white powder (63 mg, 61%).
. ^{_{Mp: 250~254 ℃ MS (APCI-NH}} 3) m / e: 330 (M + H) + 1 H NMR (300MHz, DMSO-d 6) δ9.26 (s, 1H), 8.
27 (s, 1H), 8.01 (s, 1H), 7.48 (d, 2H), 7.19 (
d, 2H). Elemental _{analysis: 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 4- (4-Chlorophenoxy) -2- (2-methyl-1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Obtained by Example 282A A solution of the compound obtained (100 mg, 0.3 mmol) in methanol (4 mL) was treated with diazomethane (
Treatment with diethyl ether and N-methyl-N'-nitro-N-nitrosoguanidine in 40% KOH) until the yellow color persists for more than 5 minutes, stir for an additional 15 minutes, until the yellow color disappears (gassing vigorously). Glacial acetic acid (as evolved) was quenched by slow dropwise addition and concentrated. Reverse phase silica gel pale yellow solid thus obtained was with 5% methanol / dichloromethane and filtered through silica gel and using a 25 to 65% _CH 3 CN in 0.1% TFA / water with 0.1% TFA (Dy
Flash chromatography was performed on a C.I. namax 21.4 mm C-18 column) to give the title compound as a white powder (40 mg, 39%). ^{_{Mp: 131~133 ℃ MS (APCI-NH}} 3) m / e: 344 (M + H) + 1 H NMR (300MHz, DMSO-d 6) δ9.25 (s, 1H), 8.
28 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.18 (
d, 2H), 4.47 (s, 3H). Elemental _{analysis: C 15 H 10 ClN 5 OS} 0.25H 2 O Calculated: C, 51.7
H; 3.04; N, 20.11. Found: C, 51.74; H, 2.93;
N, 19.93.

Example 283 5- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazol-3-amine water Sodium oxide (60% in oil, 0.02 g, 0.42 mmol) at 0 ° C
Was suspended in DMF (1 mL). Example 277 (0.11 g, 0.32 mm
ol) 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 minutes the reaction was quenched with water (
75 mL). The resulting precipitate was collected by filtration and washed with water (1 × 20 mL) and 50% EtOAc / hexane (2 × 25 mL). The crude solid was dried to give a colored solid (0.11 g). The title compound was isolated by preparative HPLC using a gradient of 25% to 65% acetonitrile / water + 0.1% TFA over 40 minutes. The product was neutralized with saturated aqueous NaHCO ₃ and the precipitate was collected by filtration and dried in a desiccator (31 mg, 27%). ^{Mp: 233~235 ℃ MS (APCI) m} / e: 358 (M + H) + 1 H NMR (300MHz, DMF-d 7) δ3.75 (s, 3H), 6.5
8 (brs, 2H), 7.23 (m, 2H), 7.54 (m, 2H), 7.61
(S, 1H), 8.27 (s, 1H) 9.18 (s, 1H). Elemental _analysis: 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 4- (4-Chlorophenoxy) -2- [5- (trifluoromethyl) -1,2,2
4-oxadiazol-3-yl] thieno [2,3-c] pyridine Pyridi of the compound obtained from Example 249 (100 mg, 0.31 mmol)
Trifluoroacetic anhydride (50 mL, 0.1 mL) in nitrogen at room temperature.
31 mmol), stirred for 20.5 hours and heated to reflux for 3 hours.
Dilute the brown solution with ethyl acetate and add saturated NaHCO 3₃, Washed with saline and dried (
MgSO₄), Concentrate and concentrate with 50/50 hexane / ethyl acetate.
Filter through Kagel and concentrate to give 120 mg of a yellow residue. This residue
20-33% ethyl acetate / hexane and 0-1% methanol / CH₂Cl₂To
Chromatography on silica gel twice using as a white solid
The title compound was obtained (67 mg, 54%). Melting point: 52-54 ° C MS (APCI-NH₃) M / e: 398 (M + H)⁺, 416 (M + NH₄) ⁺ .¹ 1 H NMR (300 MHz, DMSO-d₆7.) δ 9.30 (s, 1H);
29 (s, 1H), 8.10 (s, 1H), 7.48 (d, 2H), 7.20 (
d, 2H). Elemental analysis: C₁₆H₇ClF₃N₃O₂S 0.25 H₂Calculated value of O: C, 4
7.77; 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-Oxadiazol-3-amine Methanol of the compound (100 mg, 0.3 mmol) obtained from Example 250
(1.5 mL) solution in hydroxylamine hydrochloride (40 m
g, 0.45 mmol) and triethylamine (70 mL, 0.5 mmol).
And stirred for 18 hours, added 4 mL of THF and stirred for 2 days,
Conversion to 0/50 dichloromethane / methanol, followed by hydroxylamine hydrochloride
(100 mg, 1.4 mmol) and triethylamine (200 mL, 2.7
mmol) was added, stirred at ambient temperature for 24 hours and refluxed for 8 hours. Anti
The reaction mixture was diluted with ethyl acetate and diluted with NaHCO₃, Washed with saline and dried (M
gSO₄) And concentrated to give 105 mg of an off-white solid. Get
0.1% TFA / H containing 0.1% TFA₂25-65% CH in O ₃ CN followed by 0.1% TFA / H with 0.1% TFA₂20-80% in O
CH₃Reversed phase silica gel using CN (Dynamax 21.4 mm C-18)
Column) twice to give the title compound as a white powder.
(26 mg, 25%). Melting point: 217-219 ° C MS (APCI-NH₃) M / e: 345 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆7.) δ 9.26 (s, 1H);
25 (s, 1H), 8.02 (s, 1H), 7.49 (d, 2H), 7.14 (
d, 2H), 6.62 (brs, 2H). Elemental analysis: C_FifteenH₉ClN₄O₂Calculated value of S: C, 52.25; H, 2.63
N, 16.25. Found: C, 51.94; H, 2.88; N, 15.98.

Example 286 of 5- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazol-2-amine thiosemicarbazide The title compound (4% overall yield) was prepared in the same manner as in Example 278 using 4-methylthiosemicarbazide instead. Melting point: 226-229 [deg.] C MS (APCI) m / e: 375 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.95 (d, J = 1.7 H
z, 3H), 7.14 (m, 2H), 7.45 (m, 2H), 7.69 (s, 1
H), 8.17 (s, 1H), 8.19 (brm, 1H), 9.07 (s, 1H)
). Elemental _{analysis: C 16 H 11 ClN 4 OS} 2 Calculated: C, 51.27; H, 2.9
6; N, 14.95. Found: C, 51.24; H, 3.03; N, 14.85.
.

Example 287 4- (4-Chlorophenoxy) -2- (1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Example 287A 4- (4-chloro) Phenoxy) -N ′-(diethoxymethoxy) thieno [2,3
-C] Pyridine-2-carboximimidamide A solution of the compound obtained in Example 249 (100 mg, 0.31 mmol) in triethyl orthoformate (1.3 mL) was placed in nitrogen at 140 ° C. for 5 hours and 160 ° C. for 2 hours.
And stirred at room temperature for 14 hours. The obtained pale yellow oil (110 mg) was added to 2
Flash chromatography on silica gel using 0-70% ethyl acetate / hexane provided 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) δ9.05 (s, 1H), 8.
15 (s, 1H), 7.97 (s, 1H), 7.46 (d, 2H), 7.10 (
d, 2H), 6.65 (brs, 2H), 5.66 (s, 1H), 3.62-3
. 71 (m, 4H) 1.15 (t, 6H).

Example 287B 4- (4-Chlorophenoxy) -2- (1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Compound obtained from Example 287A ( A solution of 50 mg (0.119 mmol) in toluene (6 mL) was heated at reflux in nitrogen for 20 hours, and cooled and concentrated. The yellow residue (46 mg) was flash chromatographed on silica gel using 25-50% ethyl acetate / hexane to give the title compound as a white solid (
39 mg, 100%). Analytical HPLC: 4.6 x 250 mm C-18 column, 0.8 mL / min, 254
nm, _CH containing _{0.1% TFA 3 CN: H 2} O, 0: 100 (0~3 minutes), 9
Slope to 0:10 (3-30 minutes), 90:10 (30-35 minutes), 0:10
Slope to 0 (35-40 minutes), Rt = 22.47 minutes (100% peak area)
_{Mp: 151~152 ℃ MS (APCI-NH} 3) m / e: 330 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.86 (s, 1 H), 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 Example 183 (100 mg) , 0.283 mmol) of triethyl orthoformate (
15 mL) solution was heated to reflux under a nitrogen atmosphere for 28 hours. All volatiles were removed under reduced pressure. The resulting oil was purified by flash column chromatography using hexane / ethyl acetate (2: 1) as eluent to give the title compound as a colorless oil (65 mg, 63%). This oil solidified on standing. MS (ESI) m / e: 364 (M + H) ^<+> . ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.14 (d, 2H), 7.66
(D, 2H), 8.05 (s, 1H), 8.24 (s, 1H), 8.50 (s, 1H)
1H), 9.07 (s, 1H). Elemental _analysis: Calculated for _{C 16 H 8 N 3 F 3} O 2 S: C, 52.89; H, 2.22
N, 11.57. Found: C, 53.03; H, 2.25; N, 11.48.

Example 289 3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine Example 289A 3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -5- (trichloromethyl-1,2,4-oxadiazole The compound obtained from Example 249 (50 mg, 0.156 mmol) in trichloroacetyl chloride (20 mL) in nitrogen at ambient temperature.
, 0.17 mmol), heated to reflux for 1.5 hours, cooled to room temperature, stirred overnight, further treated with trichloroacetyl chloride (100 mL, 0.86 mmol) and stirred for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated. The resulting brown residue was flash chromatographed on silica gel using 25-50% ethyl acetate / hexane to give the title compound as a clear residue (37m
g, 53%). _{MS (APCI-NH 3) m} / e: 448 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1 H),
24 (s, 1H), 8.09 (s, 1H), 7.46 (d, 2H), 7.18 (
d, 2H).

Example 289B 3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine Obtained from Example 289A Of the obtained compound (30 mg, 0.067 mmol).
A 0 M ammonia solution in methanol (6 mL) was heated to 60 ° C. under a pressure tube for 15 hours and cooled to ambient temperature, washing the flask with methanol and distilled water. Most of the methanol was removed under vacuum, the cloudy mixture was filtered and washed with distilled water. The resulting 25 to 65% and reverse phase silica gel using 20 to 80% _CH 3 CN in a yellow brown solid in 0.1% TFA / water containing 0.1% TFA (Dyn
flash chromatography twice on an Amax C-18 21.4 mm column) to give the title compound as a white solid (4 mg, 17%). Analytical HPLC: 4.6 x 250 mm C-18 column, 0.8 mL / min, 254
nm, _CH containing _{0.1% TFA 3 CN: H 2} O, 0: 100 (0~3 minutes), 9
Slope to 0:10 (3-30 minutes), 90:10 (30-35 minutes), 0:10
Slope to 0 (35-40 minutes), Rt = 19.44 minutes (100% peak area)
_{Mp: 268~270 ℃ MS (APCI-NH} 3) m / e: 345 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (s, 1 H),
27 (s, 1H), 8.22 (brs, 2H), 7.67 (s, 1H), 7.4
7 (d, 2H), 7.15 (d, 2H).

Example 290 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4- (
The title compound was prepared as described in Example 288 using triethyl orthoacetate as the solvent. Reflux was maintained for 5 days, giving a 29% yield. MS (APCI) m / e: 377 (M + H) ^<+> . ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.65 (s, 3H), 7.13
(D, 2H), 7.65 (d, 2H), 7.94 (s, 1H), 8.27 (s,
1H), 9.06 (s, 1H).

Example 291 4- (4-Chlorophenoxy) -2- (2-furyl) thieno [2,3-c] pyridine Example 270A (0.30 g, 0.98 mmol), 2,5-dibromofuran (0.66 g, 2.94 mmol), cesium fluoride (0.45 g, 2.94 m)
mol), triethylamine (0.14 mL, 0.98 mmol)
In ME (9 mL), the mixture was sucked with anhydrous nitrogen for 25 minutes, and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1
: 1) (0.16 g, 0.20 mmol) was added. The reaction was heated at reflux for 4 hours and stirred at ambient temperature overnight. The reaction was diluted with EtOAc (100 mL) and filtered. The organic layer was washed with saturated NaHCO ₃ (3 × 50 mL), brine (75 mL)
Washed with), partially dried _(Na 2 SO _4), and concentrated to give a colorless 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 is called EtO
H (10 mL) and 5% Pd / C (3 mg, 0.02 mmol) was added. A balloon of hydrogen gas was attached and the reaction 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 combined filtrate and washings were concentrated to give a colored wet foam. Run the crude for 40 minutes 30% -70% acetonitrile / water + 0
. Purified by preparative HPLC using a concentration gradient of 1% TFA. The product is saturated with N
Neutralized with aHCO ₃ , the precipitate was collected by filtration and dried in a desiccator to give the title compound as a pale colored solid (15 mg, 5% overall yield). Melting point: 75-77 [deg.] C MS (APCI) m / e: 328 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.70 (dd, J = 3.4)
, 1.7 Hz, 1H), 7.12 (m, 2H), 7.24 (d, J = 3.4 Hz)
, 1H), 7.46 (m, 2H), 7.59 (s, 1H), 7.88 (d, J =
1.7 Hz, 1H), 8.16 (s, 1H) 9.08 (s, 1H).

Example 292 4- (4-chlorophenoxy) -2- (2-thienyl) thieno [2,3-c] pyridine Example using 2-iodothiophene instead of 1-iodo-4-nitrobenzene. Example 292 (50 mg, 22%) was prepared as for 272A. Melting point: 101-103C MS (APCI) m / e: 344 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (m, 2H), 7.
19 (dd, J = 5.0, 3.4 Hz, 1H), 7.46 (m, 2H), 7.5
4 (d, J = 0.9 Hz, 1H), 7.67 (dd, J = 3.4, 1.3 Hz,
1H), 7.73 (dd, J = 5.0, 1.3 Hz, 1H) 8.14 (s, 1H)
) 9.05 (s, 1H). Elemental _{analysis: 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-4-carboxamide Example 293A 2- [4- ( Ethyl 4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-4-carboxylate Ethyl bromopyruvate (390 mL, 2.30 mmol) was prepared in Example 146 (
672 mg, 2.09 mmol) and absolute ethanol (100 mL) and the orange homogeneous solution was heated to 60 ° C. After 48 hours, the mixture was cooled to ambient temperature and concentrated in vacuo. Purification was done by flash silica gel chromatography (15% acetone in hexane) to give the title compound as a white solid (297 mg, 34% yield). ^{_{MS (DCI / NH 3) m}} / e: 417 (35 Cl) / 419 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.94 (s, 1 H), 8.24
(S, 1H) 8.12 (s, 1H) 7.88 (s, 1H) 7.36 (d, J = 8
. 8 Hz, 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-4-carboxamide Example 293A (32 mg, 77 mmol) Methanol (2.0M solution 4m
L) Combined with the ammonia in and the solution was heated to 40 ° C. in a sealed tube. After 16 hours, the homogeneous solution was cooled to room temperature and concentrated to give a brown solid which was dry-packed on flash silica gel eluting with 20% acetone in hexane followed by 40% acetone in hexane to afford the title compound. Was recovered (8 mg, 27% yield). Mp _{215~218 ℃ MS (DCI / NH 3} ) m / e: 388 (M + H) / 405 (M + NH 3), 4
_{^{07 (37 Cl + NH 3)}} . ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.67 (brs, 2H), 7.
06 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H),
8.09 (s, 1H), 8.25 (s, 1H), 8.94 (s, 1H).

Example 294 tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazol-4-ylcarbamate Example 293 was prepared. Conversion to the corresponding carboxylic acid was performed in a similar manner as described in Example 18. To a mixture of carboxylic acid (40 mg, 0.10 mmol), tert-butanol (10 mL) and triethylamine (20 μL, 0.10 mmol) was added diphenylphosphoryl azide (25 μL, 0.10 mmol),
The solution was heated to 80C. After 18 hours, the solution was cooled and concentrated. The yellow residue was dissolved in CH ₂ Cl ₂ (30 mL), 0.5N aqueous HCl (40 mL), saturated Na
Washed sequentially with an aqueous HCO ₃ solution (25 mL) and brine (25 mL). The combined aqueous washes were back-extracted with CH ₂ Cl ₂ (2 × 25 mL). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated to give a yellow residue. Flash silica gel flash column chromatography (15% acetone in hexane)
Gave the title compound as a lighter yellow solid (13 mg, 28% yield). ^{MS (APCI) m / e:} 460 (35 Cl) / 462 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.91 (s, 1 H), 8.11
(S, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.9 Hz, 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-4-amine trifluoroacetic acid (0.5 mL) Example 294 (9.0 mg, 20 μmol) was added at 0 ° C. in CH ₂ Cl ₂ (1.5 mL). After 1 hour, remove volatiles,
The organic residue was dissolved in 0.5N aqueous HCl (35 mL). The aqueous phase was extracted with Et ₂ O (
10 mL) and the ether washes were extracted with 1N HCl (2 × 20 mL). The acidic layers are combined, and a saturated aqueous solution of potassium carbonate is made basic (pH> 12).
). The basic phase was extracted with EtOAc (3 × 40 mL), the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give a dark brown solid (9 mg). Purification by flash silica gel column chromatography (20% acetone in hexane) provided the title compound as a bright yellow solid (
6.8 mg, 97% yield). Mp 168-170 ° C. ^{(decomposition) MS (APCI) m / e} : 360 (35 Cl) / 362 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.90 (s, 1 H), 8.11
(S, 1H), 7.68 (s, 1H), 7.35 (d, J = 9.2 Hz, 2H)
, 7.02 (d, J = 8.9 Hz, 2H), 6.07 (s, 1H), 3.89 (
brs, 2H).

Example 296 4- (4-Chlorophenoxy) -2- (4,5-dihydro-1,3-oxazoline
Ru-2-yl) thieno [2,3-c] pyridine Example 150 (0.14 g, 0.38 mmol) in anhydrous dichloromethane (4 m
L) In the solution, 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU
) (0.09 mL, 0.57 mmol) was added. The reaction was stirred for 24 hours,
An excess of morpholine (0.2 mL) was added to react with the remaining starting material.
The reaction was stirred for 4 hours and EtOAc (100 mL) and H₂O (100 mL
) And liquid separation. The organic layer is diluted with NaH₂PO₄(100 mL), saturated NaHCO ₃ (100 mL), washed with brine (100 mL) and partially dried (Na₂SO ₄ ) And concentrated to give a solid. EtOAc / hexane as eluent of crude product
Purification by flash chromatography using the title compound as a solid
(0.07 g, 55%). 158-160 ° C (decomposition) MS (APCI) m / e: 331 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 4.01 (t, J = 9.6H)
z, 2H), 4.48 (t, J = 9.6 Hz, 2H), 7.14 (m, 2H),
7.47 (m, 2H), 7.62 (s, 1H), 8.24 (s, 1H), 9.1
9 (s, 1H). Elemental analysis: C₁₆H₁₁ClN₂O₂Calculated S: C, 58.09; H, 3.3
5; N, 8.47. Found: C, 58.16; H, 3.31; N, 8.27.

Example 297 4- (4-Chlorophenoxy) -2- (1,3-oxazol-2-yl) thieno [2,3-c] pyridine The method of Ishibashi et al. (Tetrahedron Lett. 1996, 3
7 (17), pp. 2997-3000) to give the title compound from Example 296.

Example 298 4- (4-Chlorophenoxy) -2- (4,5-dihydro-1H-imidazol-2-yl) thieno [2,3-c] pyridine Example 154 (0.15 g, 0 .43 mmol) and calcium oxide (0.4%).
12 g, 2.15 mmol) of a phenyl ether (10 mL) suspension
Heated to 250 ° C. The reaction was stirred for 45 minutes, during which time the reaction volume decreased due to evaporation of the solvent. The reaction was cooled to room temperature and 10% MeOH / dichloromethane (2
5 mL) and filtered. Concentrate the filtrate and concentrate the residue in 40 minutes for 30%
Preparative HPLC using a concentration gradient of ９０90% acetonitrile / water + 0.1% TFA
And purified. The fractions containing the product were combined, neutralized with saturated NaHCO _3. The product crystallized on standing for 3 days, was filtered off and dried in a desiccator,
The title compound was obtained as tan needles (23 mg, 16%). Melting point: 154-155 [deg.] C MS (APCI) m / e: 330 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.46 (td, J = 9.9)
, 1.7 Hz, 2H), 3.83 (t, J = 9.9 Hz, H), 7.12 (m,
2H), 7.34 (brs, 1H), 7.46 (m, 2H), 7.81 (s, 1
H), 8.17 (s, 1H), 9.11 (s, 1H). Elemental _analysis: 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 4- (4-Chlorophenoxy) -2- (1H-imidazol-2-yl) thieno [2,3-c] pyridine Zimmerman, S.A. C. The title compound can be synthesized from Example 298 according to the method of J. Org. Chem. 1989, 54 (6), 1256-1264.

Example 300 4-Chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide Method of Example 125 from the corresponding 4-chloromethyl ester isolated as a by-product of Example 125A To prepare Example 300. _{MS (DCI / NH 3) m} / e: 227 (M + H) +. 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H),
95 (d, 2H), 7.57 (d, 2H), 7.90 (b, 1H), 8.00 (
b, 1H), 8.27 (s, 1H), 9.15 (s, 1H).

Example 301 3-Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide From the crude mixture of Example 131B, 3-amino-4-chlorothieno [2,3-c
] Methyl pyridine-2-carboxylate was isolated. The mixture was hydrolyzed as described in Example 18 and the resulting acid was reacted with ammonium chloride using the method in Example 92. After the reaction mixture was poured into 5% aqueous sodium bicarbonate and precipitated, 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 ) δ 7.01 (brs, 2H),
7.49 (brs, 2H), 8.42 (s, 1H), 9.11 (s, 1H).

Example 302 9- (4-Chlorophenoxy) pyrido [4 ′, 3 ′: 4,5] thieno [3,2-
d] Pyrimidine-2,4 (1H, 3H) -dione Example 131D (70 mg, 0.22 mmol) in anhydrous tetrahydrofuran (
5 mL) was added to a suspension of 1,1-carbonyldiimidazole (71
mg, 0.44 mmol) and triethylamine (60 μL, 0.44 mmol)
l) was added. The reaction mixture was stirred at reflux for 48 hours and at ambient temperature for a further 24 hours. The reaction mixture was poured into a 1: 1 solution of water: sat. NH ₄ Cl and the resulting solid was collected by filtration. This material was purified by flash chromatography on silica gel eluting with 20% acetone-hexane. The desired fractions were combined, evaporated and suspended in hot EtOAC to give the title compound (39m
g) was obtained in 51% yield. MS (APCI) m / e: (M-H) - 344. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.32 (m, 2H), 7.
55 (m, 2H), 7.92 (s, 1H), 9.09 (s, 1H), 11.22
(Brs, 1H), 11.72 (brs, 1H). HPLC: Supelco C-18 column, water: acetonitrile 0: 90-9
0: 0, 30 minutes elution, flow rate 0.8 mL / min, room temperature 20.33 minutes.

Example 303 4- (4-Chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine-2-carboxamide Example 125A was prepared in the same manner as in Example 218 to obtain the title compound. Was. _{MS (DCI / NH 3) m} / e: 333 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 9.18 (s, 1H).

Example 304 4- (4-Bromophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 17A and 4-bromophenol were treated as in Example 125,
The title compound was obtained. Mp _{177~178 ℃ MS (DCI / NH 3} ) m / e: 364 (M + H) +. 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H),
95 (d, 2H), 7.57 (d, 2H), 7.90 (m, 1H), 8.00 (
m, 1H), 8.27 (s, 1H), 9.15 (s, 1H). Elemental _{analysis: C 15 H 11 BrN 2 O} 2 Calculated S: C, 49.60; H, 3.0
5; N, 7.71. Found: C, 49.36; H, 3.24; N, 7.61.

Example 305 7-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 305A 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Methyl carboxylate, N-oxide Example 125A was prepared according to the method of Example 123A to give the title compound.
_{MS (DCI / NH 3) m} / e: 350 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.78 (s, 3H), 3.
88 (s, 3H), 7.28 (m, 2H), 7.51 (m, 2H), 7.68 (
brs, 1H), 8.92 (brs, 1H).

Example 305B 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Example 305A was prepared according to the method of Example 1C to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 31.64 minutes. _{MS (DCI / NH 3) m} / e: 368 (M + H) +. ¹ H NMR (300 MHz, 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-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Example 305B was prepared according to the method of Example 18 using tetrahydrofuran instead of isopropanol pyridine-2-carboxylate to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 27.25 min. MS (APCI) m / e: 354 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.72 (s, 3H), 7.
16 (m, 2H), 7.49 (m, 2H), 8.01 (s, 1H).

Example 305D 7-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 305C was prepared according to Example 92 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 24.75 min. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. _6. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.58 (s, 3H),
10 (m, 2H), 7.47 (m, 2H), 8.0 (brs, 1H), 8.02
(S, 1H), 8.03 (brs, 1H).

Example 306 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Tert-Butyl pyridine-3-carboxylate Example 306A tert-butyl 3,5-dichloropyridine-4-oxalate Example 17A except for using t-butyl chlorooxalate instead of methyl formate.
To give the title compound. _{MS (DCI / NH 3) m} / e: 241 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.5 (s, 9H), 8.8
5 (s, 2H).

Example 306B 2- (methoxycarbonyl) -4- (4-chlorophenoxy) thieno [2,3-
c] tert-Butyl pyridine-3-carboxylate treating Example 306A and 4-chlorophenol analogously to Example 61,
The title compound was obtained. _{MS (DCI / NH 3) m} / e: 420 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42 (s, 9H);
95 (s, 3H), 7.18 (d, 2H), 7.50 (d, 2H), 8.05 (
s, 1H), 9.20 (s, 1H).

Example 306C 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Tert-Butyl pyridine-3-carboxylate Example 306B was prepared in the same manner as in Example 217 to obtain the title compound. _{MS (DCI / NH 3) m} / e: 405 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (s, 9H), 7.
10 (d, 2H), 7.45 (d, 2H), 7.95 (m, 1H), 8.08 (
s, 1H), 8.14 (m, 1H), 9.18 (s, 1H).

Example 306D 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridine-3-carboxylic acid Example 306C (0.08 g, 0.2 mmol) was treated with trifluoroacetic acid (0.5
mL) and a cold solution of methylene chloride (0.5 mL) and stirred for 1 hour.
The solution was concentrated, treated slowly with a cold solution of sodium bicarbonate (20 mL), and the mixture was extracted with ethyl acetate (3 × 20 mL). The ethyl acetate extract was dried and concentrated to give the title compound. _{MS (DCI / NH 3) m} / e: 349 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 4- (4-Toluidino) thieno [2,3-c] pyridine-3-carboxamidomethyl Example 93C (271 mg, 1 mmol), 4-methylaniline (150 mg)
, 1.4 mmol), sodium t-butoxide (134.5 mg, 1.4 mm)
ol), 18-crown _{-6 (370mg, 1.4mmol), Pd} 2 (dba
) ₃ (46mg, 5mol%) and BINAP (31 mg, a mixture of 5 mol%), a reflux condenser was adjusted to 3 neck round bottom flask equipped with an internal temperature probe and _{N 2} inlet. This was evacuated under nitrogen and anhydrous tetrahydrofuran (5 mL) was added. The reaction mixture was warmed at 45 ° C. for 3 days, and the solid was filtered through celite and washed with a mixture of ethyl acetate and acetone. The filtrate was washed with ethyl acetate (100 m
L), washed with brine (2 × 50 mL), dried (MgSO ₄ ), concentrated and dried under reduced pressure. Flash chromatography on silica gel eluting with 30% acetone-hexane gave the title compound in 29% yield (86 mg).
I got it. _{MS (DCI / NH 3) m} / e: 298 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), 2.
80 (d, J = 6 Hz, 3H), 7.02 (d, J = 9 Hz, 2H), 7.10
(D, J = 9 Hz, 2H), 8.13 (s, 1H), 8.26 (s, 1H), 8
. 36 (m, 1H), 8.76 (brs, 1H). ¹³ C NMR (75 MHz, 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 4-chloroaniline instead of 4-methylaniline (510 mg, 4 mmol
), And the title compound (500 mg, 84%) was prepared in the same manner as in Example 307 except that the reaction was heated to 60 ° C for 20 hours. MS (APCI) m / e: 318 (M + H) ^<+> , 352 (M + Cl) < ^- >. _{^{1 H NMR (400MHz, DMSO-}} d 6) d: 2.83 (d, J = 4Hz
, 3H), 7.07 (d, J = 9 Hz, 2H), 7.32 (d, J = 9 Hz, 2H)
H), 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 (100 MHz, DMSO-d ₆ ) δ 26.3 (CH ₃ ), 11
8.1 (2 × CH), 121.7 (CH), 123.6 (C), 129.1 (2
× CH), 133.0 (CH), 134.4 (C), 137.1 (C), 137
. 2 (C), 138.2 (CH), 142.6 (C), 143.2 (C), 16
1.4 (C).

Example 309 Example 308 except for using morpholine (0.175 mL, 2 mmol) instead of 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamidomethyl 4-chloroaniline The title compound (105 mg, 38%) was prepared in the same manner as described above. MS (APCI) m / e: 278 (M + H) ^<+> , 312 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.91 (d, J = 4 Hz,
3H), 3.23 (m, 4H), 3.91 (m, 4H), 8.14 (s, 1H)
, 8.18 (s, 1H), 8.96 (s, 1H), 8.99 (d, J = 4 Hz,
1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 26.1 (CH ₃ ), 51
. 6 (2 × CH 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 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 311A 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Methyl carboxylate Example 61A was prepared as in Example 1C to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 30.35 min. _{MS (DCI / NH 3) m} / e: 354 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
14 (m, 2H), 7.45 (m, 2H), 7.91 (s, 1H), 8.24 (
s, 1H), 9.21 (s, 1H).

Example 311B 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 311A was prepared according to the method of Example 44 to give the title compound. _{MS (DCI / NH 3) m} / e: 339 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (m, 2H), 74
8 (m, 2H), 7.94 (brs, 1H), 8.04 (s, 1H), 8.22
(S, 1H), 8.49 (brs, 1H). Elemental _{analysis: C 14 H 8 Cl 2 N} 2 O 2 Calculated S: C, 56.42; H, 3.2
8; 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 prepared as described in Example 171 to give the title compound. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3H), 7.
16 (m, 2H), 7.49 (m, 2H), 8.05 (s, 1H), 8.17 (
s, 1H), 9.04 (brs, 2H).

Example 313 7-Chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2-carboxamide Example 311A was prepared according to the method of Example 114. Prepared to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 23.49 minutes. Mp _{129~132 ℃ MS (DCI / NH 3} ) m / e: 382 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.33 (m, 2H);
51 (m, 2H), 4.82 (t, 1H), 7.19 (m, 2H), 7.48 (
m, 2H), 8.08 (s, 1H), 8.27 (s, 1H), 9.12 (brt
, 1H), 9.18 (s, 1H), 12.81 (brs, 1H).

Example 314 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 314A 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Methyl carboxylate Example 123A was prepared in a similar manner to Example 1C using phosphorus oxybromide instead of phosphorus oxychloride to give the title compound. MS (ESI) m / e: 400 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
22 (m, 2H), 7.48 (m, 2H), 8.19 (s, 1H), 8.20 (
s, 1H).

Example 314B 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 314A was prepared according to Example 44 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 24.95 minutes. _{MS (DCI / NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.22 (m, 2H), 7.
44 (m, 2H), 7.95 (s, 1H), 8.02 (s, 1H), 8.29 (
s, 1H), 8.51 (brs, 1H).

Example 315 7-bromo-4- (4-chlorophenoxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 314A was prepared according to the method of Example 171 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 25.40 min. _{MS (DCI / NH 3) m} / e: 397 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.81 (d, 3H);
97 (s, 3H), 7.19 (m, 2H), 7.48 (m, 2H), 8.04 (
s, 1H), 8.21 (s, 1H), 9.05 (brs, 1H).

Example 316 4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2
-Carboxamide Example 316 was prepared in the same manner as in Example 311, except that 4-bromophenol was used instead of 4-chlorophenol, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 383,385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (d, 2H, J = 8)
. 9 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.98 (brs, 1H)
), 8.05 (s, 1H), 8.22 (s, 1H), 8.52 (brs, 1H).
. Elemental _{analysis: 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]
Example 317 was prepared in the same manner as in Example 312 except that 4-bromophenol was used instead of pyridine-2-carboxamide 4-chlorophenol to obtain the title compound. _{MS (DCI / NH 3) m} / e: 397,399 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 4
. 7 Hz), 7.13 (d, 2H, J = 9.2 Hz), 7.60 (d, 2H, J
= 9.2 Hz), 8.07 (s, 1H), 8.13 (s, 1H), 9.03 (q
, 1H, J = 4.7 Hz). Elemental _{analysis: 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 Example 17A and 4-trifluoromethylphenol were treated in the same manner as in Example 311 to obtain the title compound. Mp _{^{175~176 ℃ MS (DCI / NH 3}} ) m / e: 373 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ7.30 (d, 2H), 7.
80 (d, 2H), 8.00 (s, 1H), 8.20 (s, 1H), 8.25 (
s, 1H), 8.55 (s, 1H). Elemental _{analysis: C 16 H 10 ClF 3 N} 2 O 2 Calculated S: 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-2-carboxamide Example 17A and Example 17A Treatment of 4-trifluoromethylphenol gave the title compound. Mp _{178~179 ℃ MS (DCI / NH 3} ) m / e: 387 (M + H) +. ¹ H NMR (300 MHz, 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: C 16 H 10 ClF 3 N} 2 O 2 Calculated S: 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 amino in place of methylamine Example 320 was prepared according to the method of Example 319 using ethanol. Mp _{96~97 ℃ MS (ESI / NH 3} ) m / e: 415 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.66 (t, 2H, J = 4.8)
Hz), 3.87 (t, 2H, J = 4.8 Hz), 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 4- (4-chlorophenoxy) -N, 7-dimethyl Methyl thieno [2,3-c] pyridine-2-carboxylate Methyl boric acid instead of 4- (trifluoromethyl) phenyl boric acid, dichlorobis (tricyclohexylphosphine) palladium instead of tetrakis (triphenylphosphine) palladium, Then, Example 311A was prepared in the same manner as in Example 95A, except that NMP was used instead of DME, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 334 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ2.74 (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 Example 321A is prepared according to the method of Example 171 to give the title compound. Was. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 20.70 min. _{MS (DCI / NH 3) m} / e: 334 (M + H) +. ¹ H NMR (300 MHz, 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 (brs, 1H).

Example 322 4- (4-Chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxamide Example 322A 4- (4-Chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxylic acid Example 311A (100 mg, 0.28 mmol) was dissolved in a 25% solution of sodium methoxide in methanol (10 mL) and heated to 60 ° C. in a pressure tube for 3 days. The solvent was removed under reduced pressure, the residue was redissolved in methylene chloride and acidified with formic acid. The organic layer was washed with _{H 2} O and brine, dried _(Na 2 SO _4), and the solvent was removed under reduced pressure to give the title compound as an off-white solid (50mg, 54%). MS (DCI) m / e: 336 (M + H) ^<+> . ¹ H NMR (300 MHz, 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 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxamide Example 322A (40 mg, 0.12 mmol) was treated according to the method of Example 92 to give the title compound (23 mg, 0.58 mmol) as a white solid. _{Mp> 250 ℃ MS (DCI / NH} 3) m / e: 335 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.08 (s, 3H), 7.
01 (m, 2H), 7.38 (m, 2H), 7.82 (brs, 1H), 7.9
0 (s, 1H), 8.04 (s, 1H), 8.43 (s, 1H).

Example 323 4- (4-Chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] pyridine-2-carboxamide Example 323A 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] Methyl pyridine-2-carboxylate Example 311A (200 mg, 0.597 mmol) in acetic anhydride (20 mL)
The solution was heated at reflux for 18 hours. The reaction was cooled and poured on ice. Mix 1
Time stirring _was added CH ₂ Cl ₂ (100mL). The organic extract was washed with 1N Na
Washed with OH (100 mL), H ₂ O (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and rotary evaporated to give a crude brown residue. The residue was dissolved directly in DMF (20 mL) and H ₂ O (3 mL), treated with K ₂ CO ₃ and warmed at 60 ° C. for 2 hours. The reaction was cooled to room temperature and rotoevaporated. The crude residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate / hexane gradient to 50% ethyl acetate / hexane to give the title compound. _{MS (DCI / NH 3) m} / e: 336 (M + H) +. ¹ H NMR (300 MHz, 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 (brs, 1H).

Example 323B 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] Pyridine-2-carboxamide Example 323A was prepared according to Example 44 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 18.61 minutes. M.p.> 250 [deg.] C MS (APCI) m / e: 321 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.04 (m, 2H), 7.
38 (m, 2H), 7.40 (s, 1H), 7.75 (s, 1H), 8.32 (
brs, 1H).

Example 324 4- (4-Chlorophenoxy) -N-methyl-7- (methylamino) thieno [2
, 3-c] pyridine-2-carboxamide Barraclough et al. (J. Med. Chem. 1990, 33
Example 311A (27 mg, 76 mmol) was treated according to the procedure described in Example 1 (27 mg, 76 mmol) to give the title compound (12 mg, 45% yield). ^{_{MS (DCI / NH 3) m}} / e: 348 (35 Cl) / 350 (37 Cl). ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 7.86 (s, 1H)
.

Example 325 N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4-c]
Pyridine-2-carboxamide Example 142D (10 mg, 33 mmol) was treated according to the method of Example 96 to give the title compound as a white solid (1.5 mg, 75%). ^{_{MS (DCI / NH 3) m}} / e: 300 (M + H) +, 317 (M + NH 3) +. ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.39 (s, 3H), 3.07
(D, J = 5.1 Hz, 3H), 7.06 (d, J = 8.8 Hz, 2H), 7.
23 (d, J = 8.5 Hz, 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-carboxami
Example 327A 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxylic acid
Cyl 4-chlorophenol (1.08 g, 8.7 mmol) in anhydrous tetrahydroph
A potassium t-butoxide solution (T) was added to a run (25 mL) solution at 0 ° C. under a nitrogen atmosphere.
A 1.0 M solution in HF, 8.7 mL, 8.7 mmol) was added dropwise. And anti
The reaction mixture was heated and stirred at 65 ° C for 2 hours, cooled to 0 ° C, and
Treated with Example 17A (1.0 g, 5.7 mmol) in furan (10 mL), 6
Heated to 5 ° C. for 2 hours. The reaction was cooled to 0 ° C. and ethyl glycolate (1.07
mL, 11.4 mmol) and cesium carbonate (3.0 g, 9.2 mmol).
Was added and the mixture was heated at 65 ° C. for 3 hours. Cool and concentrate the reaction,
The residue was diluted with ethyl acetate (50 mL) and washed with brine (3 × 50 mL).
And dried (MgSO 4)₄)did. Then, ethyl acetate was concentrated to obtain an oil.
Flash chromatography on silica gel with 10% ethyl acetate-hexane as eluent
Purification by chromatography gave 0.110 g of the title compound as a glassy residue (6.
1%). MS (DCI / NH₃) M / e: 318 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 1.35 (t, 2H, CH₂ ), 4.4 (q, 3H, CH₃), 7.2, (d, J = 9 Hz, 2H), 7.5
(D, J = 9 Hz, 2H), 8.09 (s, 1H), 8.23 (s, 1H), 9
. 25 (s, 1H) Example 327B 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carboxylic acid tetrahydrate of lithium hydroxide monohydrate (0.0113 g, 0.5 mmol)
To a solution of furan (5 mL) and water (1 mL) was added Example 327A (0.1 g, 0.1 g).
3 mmol) was added and the mixture was heated at 50 ° C. for 2 hours. Allow the mixture to cool and
Formic acid until acidic (pH?). The mixture is then added to ethyl acetate (5
0 mL), the extract is washed with brine (2 × 20 mL) and dried (MgSO 4). ₄ ) And concentrated. On silica gel with 20% acetone-hexane as eluent
Purification by flash chromatography gave the title compound 0 as a glassy residue.
. 710 g (81.6%) were obtained. MS (DCI / NH₃) M / e: 290 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 3.4 (brs, 1H), 7
. 2 (d, J = 9 Hz, 2H), 7.5 (d, J = 9 Hz, 2H), 8.09 (
s, 1H), 8.23 (s, 1H), 9.25 (s, 1H).

Example 327C 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide A solution of Example 327B (0.15 g, 0.5 mmol) in DMF (10 mL) was added to 1-hydroxy Benzotriazole hydrate (0.104 g, 0.66 mmol
_), And treated with NH 4 Cl (0.0948g, 0.017mmol) and 4-methylmorpholine (0.141 g, 0.14 mmol). Cool the solution to 0 ° C., treat with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.115 g, 0.6 mmol), warm to room temperature, stir overnight, Pour into saturated NaHCO ₃ , filter, wash with brine (3 × 20 mL) and dry (M
gSO ₄ ) and concentrated. 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 NMR (300 MHz, DMSO-d ₆ ) δ 7.18 (d, 2H), 7.
29 (s, 1H), 7.5 (d, 2H), 7.82 (brs, 1H), 8.25
(S, 1H), 8.35 (brs, 1H), 8.95 (s, 1H).

Example 328 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide A solution of Example 327 (0.06 g, 0.2 mmol) in toluene (5 mL) was treated with Lawesson's reagent ( (0.1 g, 0.2 mmol). The reaction was then refluxed for 1 hour, cooled, concentrated, and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (3 × 15 mL), dried (MgSO ₄ ) and concentrated. Purification by flash chromatography on silica gel eluting with 20% acetone-hexane gave 0.022 g (37%) of the title compound as a pale yellow solid. _{MS (DCI / NH 3) m} / e: 305 (M + H) +. ¹ H NMR (300 MHz, 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 E- and Z-4- (2-phenylethenyl) thieno [2,3 -C] pyridine-
To a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene (0.2 mL) was added a solution of diethyl tert-butyl 2-carboxylate (0.08 mL, 0.38 mmol) in dichloromethane (2 mL) at −78 ° C. while stirring. 84 mL, 0.42 mmol) was added dropwise. After 45 minutes, a solution of Example 237E (0.10 g, 0.38 mmol) in dichloromethane (3 mL) was slowly added dropwise, and the reaction was stirred for 1 hour. The cooling bath was removed and the reaction was stirred for 20 minutes. The reaction was quenched by pouring into dilute aqueous NaHCO ₃ . The aqueous solution was extracted with dichloromethane (2 × 25 mL) and ethyl acetate (2 × 25 mL). Combine all organic phases and dry (Na ₂ SO ₄ )
And concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent. The mixture of stereoisomers was dried in a desiccator to give a solid (0.07 g, 55%). MS (APCI) m / e: 338 (M + H) ^<+> .

Example 329B E-4- (2-phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide Example 329A (0.07 g, 0.21 mmol) was added to 10% H ₂ SO ₄ / Me
Dissolved in OH (10 mL) solution. The solution was heated at reflux for 6 hours and stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and saturated NaHCO ₃ (50 mL)
Basified with. The aqueous phase was extracted with dichloromethane (2 × 50 mL) and the organic extracts were combined. The organic layer was washed with dilute brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a colored residue. The residue was treated with methanol (8 mL
)) And chloroform (1 mL). A balloon of ammonia gas was attached and the reaction was heated at 35 ° C. for 24 hours. The reaction was concentrated and the residue was purified by HPLC using 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 further the corresponding Z-isomer (14 mg, 24%).
I got Mp _{257~258 ℃ MS (DCI / NH 3} ) m / e: 281 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.34 (dd, J = 7.6)
, 7.2 Hz, 1H), 7.46 (dd, J = 7.6, 7.2 Hz, 2H), 7
. 55 (d, J = 16.5 Hz, 1H), 7.64 (d, J = 16.5 Hz, 1
H), 7.73 (d, J = 7.2 Hz, 2H), 7.88 (brs, 1H), 8
. 37 (brs, 1H), 8.62 (s, 1H), 8.85 (brs, 1H),
9.18 (s, 1H). Elemental _{analysis: C 16 H 12 N 2 OS} 0.2H 2 O Calculated: C, 67.68; H
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-carboxamide Rate The title compound was prepared in the same manner as in Example 95A except that 4-chlorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (160 mg,
53%). MS (APCI) m / e: 304 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
69 (m, 4H), 8.30 (s, 1H), 8.60 (s, 1H), 9.42 (
s, 1H).

Example 330B 4- (4-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 330A was prepared in a similar manner to Example 44 to give the title compound (60 mg).
, 60%). MS (APCI) m / e: 289 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8 Hz,
2H), 7.69 (d, J = 8 Hz, 2H), 7.77 (s, 1H), 8.19
(S, 1H), 8.41 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H)
1H).

Example 331 4- [3- (Trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxalamide Example 331A 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxylate The title compound was prepared in the same manner as in Example 95A, except that 4- (trifluoromethyl) phenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (100 mg, 30%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
81-7.93 (m, 4H), 8.01 (s, 1H), 8.67 (s, 1H),
9.46 (s, 1H).

Example 331B 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxalamide Example 331A was prepared in a similar manner to Example 44 to give the title compound (90 mg).
, 94%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (s, 1 H), 7.
90-7.97 (m, 4H), 8.25 (s, 1H), 8.46 (s, 1H),
8.69 (s, 1H), 9.38 (s, 1H).

Example 332 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 332A 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxa The title compound was prepared in the same manner as in Example 95A, except that 3-chlorophenylboric acid was used instead of 4-chlorophenylboric acid (130 mg, 43%). MS (APCI) m / e: 304 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 1H).

Example 332B 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 332A was prepared in a similar manner to Example 44 to give the title compound (82 mg).
, 86%). MS (APCI) m / e: 288 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.58-7.62 (m, 3
H), 7.62 (s, 1H), 7.69 (s, 1H), 8.19 (s, 1H),
8.49 (s, 1H), 8.51 (s, 1H), 9.31 (s, 1H).

Example 333 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 333A 4- (4-bromophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 4-bromophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (148 mg,
42%). MS (APCI) m / e: 305 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
61 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 7.5 Hz, 2H),
8.02 (s, 1H), 8.57 (s, 1H), 9.40 (s, 1H).

Example 333B 4- (4-Bromophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 333A was prepared in a similar manner to Example 44 to give the title compound (118m).
g, 88%). MS (APCI) m / e: 333, 335 (1: 1) (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 7.5 H
z, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.84 (s, 1H),
8.22 (s, 1H), 8.46 (s, 1H) 9.33 (s, 1H).

Example 334 4- (3-Aminophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 334A 4- (3-aminophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 3-aminophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (90 mg, 3 mg).
2%). MS (APCI) m / e: 285 (M + H) ^<+> . ¹ H NMR (300 MHz, 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 = 7.5 Hz, 1H), 8.07 (s, 1H), 8.53 (s
, 1H), 9.36 (s, 1H).

Example 334B 4- (3-Aminophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 334A was prepared in a similar manner to Example 44 to give the title compound (83 mg).
, 98%). MS (APCI) m / e: 270 (M + H) ^<+> . 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.30 (s, 2H),
67-6.82 (m, 3H), 7.22 (t, J = 7.5 Hz, 1H), 7.7
9 (s, 1H), 8.23 (s, 1H), 8.43 (s, 1H), 8.51 (s
, 1H), 9.25 (s, 1H).

Example 335 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 335A 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine- The title compound was prepared in the same manner as in Example 95A, except that 3,5-dichlorophenylboric acid was used instead of 2-carboxalate 4- (trifluoromethyl) phenylboric acid (90 m
g, 27%). MS (APCI) m / e: 338 (M + H) ^<+> .

Example 335B 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 335A was prepared in the same manner as in Example 44 to obtain the title compound (21 mg).
, 24%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (d, J = 2.25)
Hz, 2H), 7.80 (m, 1H), 7.88 (s, 1H), 8.20 (s,
1H), 8.53 (s, 1H), 8.56 (s, 1H), 9.36 (s, 1H)
.

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-carboxalate The title compound was prepared in the same manner as in Example 95A, except that 2,4-dichlorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid.
mg, 30%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.38 (s, 3H), 7.
59 (s, 1H), 7.61 (d, J = 2.25 Hz, 1H), 7.70 (s, 1H)
1H), 7.86 (d, J = 2.25 Hz, 1H), 8.49 (s, 1H), 9
. 45 (s, 1H).

Example 336B 4- (2,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 336A was prepared in the same manner as in Example 44 to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.60 (s, 1 H), 7.
64 (m, 1H), 7.81 (brs, 1H), 7.87 (s, 1H), 7.9
1 (m, 1H), 8.37 (brs, 1H), 8.45 (s, 1H), 9.37
(S, 1H).

Example 337 4- (3,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 337A 4- (3,4-Dichlorophenyl) thieno [2,3-c] pyridine- The title compound was prepared in the same manner as in Example 95A, except that 3,4-dichlorophenylboric acid was used instead of 2-carboxalate 4- (trifluoromethyl) phenylboric acid (130
mg, 39%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.94 (s, 3H), 7.
67-7.76 (m, 1H), 7.85 (m, 1H), 7.79 (d, J = 2.
25 Hz, 1H), 8.06 (s, 1H), 8.63 (s, 1H), 9.44 (
s, 1H).

Example 337B 4- (3,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 337A was prepared in the same manner as in Example 44 to obtain the title compound (44 mg).
, 46%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65-7.68 (m, 1
H), 7.84-7.87 (m, 2H), 8.96 (d, J = 2.25 Hz, 1
H), 8.21 (s, 1H), 8.47 (s, 1H), 8.56 (s, 1H),
9.35 (s, 1H).

Example 338 4- (2,4-Difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 338A 4- (2,4-Difluorophenyl) thieno [2,3-c] The title compound was prepared in the same manner as in Example 95A, except that 2,4-difluorophenylboric acid was used in place of pyridine-2-carboxalate 4- (trifluoromethyl) phenylboric acid (13
0 mg, 42%). MS (APCI) m / e: 306 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.90 (s, 3H), 7.
26 (m, 1H), 7.45 (m, 1H), 7.63 (m, 1H), 7.81 (
d, J = 3 Hz, 1H), 8.55 (s, 1H), 9.44 (s, 1H).

Example 338B 4- (2,4-Difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 338A was prepared in the same manner as in Example 44 to obtain the title compound. MS (APCI) m / e: 291 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.30 (m, 1 H), 7.
49 (m, 1H), 7.66 (m, 1H), 7.77 (s, 1H), 7.99 (
s, 1H), 8.39 (s, 1H), 8.47 (s, 1H), 9.34 (s, 1)
H).

Example 339 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 339A 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 4-fluorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (100 mg).
, 35%). MS (APCI) m / e: 288 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 7.
38-7.48 (m, 2H), 7.55-7.64 (m, 1H), 7.78 (d
, J = 3 Hz, 1H), 8.57 (s, 1H), 9.44 (s, 1H).

Example 339B 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 339A was prepared in a similar manner to Example 44 to give the title compound. MS (APCI) m / e: 273 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.40-7.50 (m, 2
H), 7.57-7.65 (m, 2H), 7.81 (s, 1H), 8.01 (s
, 1H), 8.47 (s, 1H), 8.51 (s, 1H), 9.36 (s, 1H)
).

Example 340 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 340A Lithium 2,3,5-trichloro-4-formylpyridine diisopropylamine (7.3 mL, 1.5 M in cyclohexane,
1 mmol) in dry THF (10 mL) at −78 ° C. under nitrogen for 30 minutes
Solution of 2,3,5-trichloropyridine (2 g, 11 mmol) in THF (20 mL)
The solution was stirred for a further 30 minutes, and methyl formate (1.
4 mL, 1.3 g, 22 mmol) was slowly added to the brown solution over 15 minutes.
Slowly warmed to room temperature and stirred overnight. The resulting dark brown solution is washed with ice and
And saturated NaHCO₃, Extracted with ethyl acetate, washed with brine and dried (
Na₂SO₄) And concentrated. 20-33% ethyl acetate / hexa brown oil
Flash chromatography on silica gel using the title compound afforded the title compound.
(1.7 g, 74%). MS (APCI-NH₃) M / e: 211 (M + H)⁺, 229 (M + NH₄) ⁺ .¹ 1 H NMR (300 MHz, DMSO-d₆) 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 added through a syringe to potassium tert-butoxide ( (4 mL, 1 M in THF, 4 mmol), warmed to room temperature, stirred for 1 hour, and cooled to 0 ° C. Example 340A (390 mg, 2 mmol) in 2 mL THF was added, the reaction was heated at 60 ° C. for 2 hours and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and 1N NaOH
Washed with brine, dried (Na ₂ SO ₄ ) and concentrated. 1-2% of brown residue
Flash chromatography on silica gel twice with methanol / dichloromethane and 5-20% ethyl acetate / hexane gave the title compound (235).
mg, 24%). _{MS (APCI-NH 3) m} / e: 483 (M-H) -, 517 (M + Cl) -. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.20 (s, 1 H), 8
. 24 (s, 1H) 7.63 (m, 2H), 7.53 (m, 2H), 7.24 (
m, 2H), 6.99 (m, 2H).

Example 340C 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-A 2 mL THF solution of methyl carboxylate 340B (227 mg, 0.47 mmol) was added to methyl thioglycolate (50 μL, 0.52 mmol) followed by Cs ₂ CO ₃ powder (17
9 mg, 0.55 mmol), stirred at room temperature for 21 hours, heated at 60 ° C. for 15 minutes, and cooled to room temperature. Dilute the reaction with ethyl acetate and distilled water,
Washed with 1M K ₂ CO ₃ , brine, dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel using 5-20% ethyl acetate / hexanes, followed by HPLC purification _{30~90% CH 3 CN / H 2} O with 0.1% TFA as gradient eluent ( C-18) to give the title compound (6
mg, 3%). _{MS (APCI-NH 3) m} / e: 400 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.20 (s, 1 H), 7.
78 (s, 1H) 7.51 (d, 2H), 6.93 (d, 2H), 3.90 (s
, 3H).

Example 340D 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide 340C (5 mg, 0.013 mmol) in 1 mL methanol and 1 mL dichloromethane was added to a 2M ammonia / methanol solution (3 mL, 6 mL) in a pressure tube.
mmol), heated at 60 ° C. for 4 hours, cooled to room temperature and concentrated. 95
/ 5 dichloromethane / methanol and filtered and the residue through silica with, concentrated, and purified by reverse-phase H using _{20~75% CH 3 CN / H 2} O containing 0.1% TFA
Purification by PLC (C-18) provided the title compound (4.2 mg, 84%).
. HPLC (C-18, 4.6 × 250 mm), 0.8 mL / min, λ = 254 nm
, _CH 3 containing _{0.1% TFA CN: H 2 O} 0~90%, rt 23.3 min (9
8.52% area). _{MS (APCI-NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.98 (s, 1 H), 7.
9 (s, 1H), 7.49 (d, 2H), 6.83 (d, 2H).

The above are merely specific examples, and the present invention is not limited to the compounds described. Variations and modifications which are obvious to one skilled in the art are included within the scope and nature of the invention as defined in the appended claims.

[Procedure amendment]

[Submission date] March 27, 2001 (2001. 3.27)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Detailed description of the invention

[Correction method] Change

[Correction contents]

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to compounds useful for treating inflammatory diseases, drug compositions containing the compounds and methods of inhibiting inflammation in mammals.

BACKGROUND OF THE INVENTION Inflammation results from a multi-step event involving vasodilation with increased vascular permeability and exudation of body fluids and plasma proteins. This destruction of the vascular prototype proceeds with or occurs simultaneously with the infiltration of inflammatory cells. Inflammatory mediators that occur at the site of the initial lesion function to recruit inflammatory cells to the site of injury. These mediators (IL
-8, MCP-1, MIP-1 and RANTES, chemokinesis such as complement fragments and lipid mediators) have leukocyte chemotactic activity and attract inflammatory cells towards inflamed lesions . These chemotactic mediators that localize circulating leukocytes to sites of inflammation require cells to cross the vascular endothelium at precise locations. This leukocyte recruitment involves a process called cell adhesion.

[0003] Cell adhesion is achieved by a series of coordinately regulated steps that cause leukocytes to first adhere to specific areas of the vascular endothelium and then travel across the endothelial barrier toward inflamed tissue. Occur (Springer, TA, 1994, "Communications Signals for Lymphocyte Recirculation and Leukocyte Migration: A Multistep Paradigm (Traff
ic Signals for Lymphocyte Recirculator
ion and Leukocyte Emigration: The Mu
ltest Step Paradigm) ", Cell, Vol. 76, No. 301-30.
Page 4; Lawrence, M .; B. And Springer, T .; A. , 1991
"Rotation of leukocytes to selectin at physiological flow rates: discrimination from adhesion by integrins and prerequisites therefor (Leukocytes' Roll on
a Selectin at Physiological Flow Rates
: Distraction from and Prerequisite
for Adhesion Through Integrins) ", Cel
1, 65, 859-873; von Adrian, U.S.A. , Chamb
ers, J. et al. D. McEnvoy, L .; M. Bargatze, R .; F. ,
Arfos, K .; E. FIG. And Butcher, E .; C. 1991, "Two-Step Model of Leukocyte-Endothelial Cell Interaction in Inflammation.
of Leukocyte-Endothelial Cell Intera
actions in Inflammation) ", Proc. Natl. A
cad. Sci. USA, 88, 7538-7542; and Ley,
K. Gaehgens, P .; Fennie, C .; Singer, M .; S
. Lasky, L .; H. And Rosen, S.M. D. 1991, "Lectin-like cell adhesion molecule 1 mediates rotation in mesenteric venules in vivo (Le
ctin-like Cell Adhesion Molecule 1 M
edites Rolling in Mesentelic Venule
s in vivo) ", Blood, 77, 2555-2555).
These steps are mediated by a family of adhesion molecules, such as integrins, members of the Ig supergene family and selectins, which are expressed on the surface of circulating leukocytes and on vascular endothelial cells. The first step consists of leukocyte rolling along the vascular endothelial cell lining in the area of inflammation. This rolling step is performed using leukocyte surface oligosaccharides such as sialylated Lewis-X antigen (Slex
)) And the selectin molecule expressed on the surface of endothelial cells in the area of inflammation. Selectin molecules are not normally expressed on the surface of endothelial cells, but rather are induced by the action of inflammatory mediators such as TNF-α and interleukin-1. Rolling reduces the speed of circulating leukocytes in the area of inflammation, causing the cells to adhere more tightly to endothelial cells. This tight adhesion involves the interaction of integrin molecules present on the surface of rolling leukocytes with their opposing receptor-Ig superfamily molecules on the surface of endothelial cells. Ig superfamily molecules or CAMs (cell adhesion molecules) are not expressed or are expressed at low levels on normal vascular endothelial cells. CAM, like selectin, has TNF-α
And induced by the action of inflammatory mediators such as IL-1. The final event in the adhesion process is the migration of leukocytes along the chemotactic gradient of leukocytes through the endothelial cell barrier to sites of extravasation and inflammation. This transfer is mediated by the conversion of leukocyte integrins from a low avidity state to a high avidity state. The adhesion process relies on the inducible expression of selectins and CAMs on the surface of vascular endothelial cells to mediate leukocyte rotation and tight adhesion to vascular endothelium.

[0004] Inducible expression of selectins and CAMs is mediated by the transcription factor NFkB.
NFkB is a family of dimeric transcription factors made from monomers containing a 300 amino acid Rel domain. These factors can bind to DNA, interact with each other, and bind to inhibitor molecules at the IkB terminus (Verma).
a, I. M. Stevenson, J .; K. Schwarz, E .; M. , A
ntwerp, D .; V. And Miyamoto, S .; , 1995, "Rel /
NFIB / IkB family: a detailed story of association and dissociation (Rel / NFIB / I
KB Family: Initiate Tales of Associate
and Dissociation) ", Genes Dev. 9, pp. 2723-2735 and Baldwin, A .; S. , 1996, "
NFkB and IkB proteins: new discoveries and insights (The NFkB an
d IkB proteins: New Discoveries and
Insights) ", Annu. Rev .. Immunol. , Volume 14, Volume 6
49-681). NFkB has been found in the cytoplasm complexed with IkB.
Activation of NFkB occurs in response to inflammatory mediators such as TNF-α, IL-1 and lipopolysaccharide. Activation of NFkB requires phosphorylation of IkB, followed by ubiquitinylation of the IkB molecule and subsequent degradation by the proteosomes. N from meeting with IkB
The release of FkB results in a translocation of the dimer to the nucleus, where it contains specific DNA
May be associated with the sequence. The e-selectin gene and CAM contain an NFkB recognition sequence upstream from their coding region. DNA-binding NFkB, which works with other proteins in the transcription complex, is directed, inter alia, to the expression of e-selectin and CAM genes controlled by this transcription factor.

[0005] The present invention discloses compounds that inhibit the expression of e-selectin and ICAM-1 on VCAM-1. These compounds are useful for treating or preventing a disease caused by expression of an adhesion molecule. These diseases include those in which leukocyte migration plays a role, markedly acute and chronic inflammatory diseases, autoimmune diseases, tumor metastases,
Allograft rejection as well as reperfusion injury are included.

SUMMARY OF THE INVENTION In one embodiment of the present invention, structural formula I:

[0007]

Embedded imageOr a pharmaceutically acceptable salt or prodrug thereof
Is disclosed. In the structural formula I,-----Is a single bond or a double bond;
However, when one bond is a double bond, the adjacent bond is a single bond, and E, F, and G are (1) carbon, (2) nitrogen, and (3) N⁺-O⁻Independently selected from, wherein at least one of E, F or G is nitrogen or N⁺-O⁻And more
Wherein at least one of E, F or G is carbon, and Y and Z are (1) carbon, (2) nitrogen, (3) oxygen, and (4) S (O)_t(T is an integer from 0 to 2), independently selected from the group consisting of: wherein at least one of Y or Z is other than carbon;_AIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆− (R₆Is optionally substituted with one or two substituents independently selected from: (a) hydrogen, (b) (i) aryl and (ii) cycloalkyl of 3 to 10 carbons. (C) alkanoyl wherein the alkyl moiety is 1 to 10 carbons, and (d) cycloalkyl of 3 to 10 carbons), (5) -C (W X) is selected from: (a) O and (b) S, and (6) alkenylene;_A(1) halo, (2) (a) oxo, (b) cycloalkyl of 3 to 10 carbons, (c) -CO₂R₇(R₇Is selected from: (i) hydrogen and (ii) aryl and cycloalkyl of 3 to 10 carbons, 1 to 10 carbons optionally substituted with one or two substituents independently selected from And (d) -NR₈R₉(R₈And R₉Is selected from: (i) hydrogen, (ii) -OH, aryl, heterocycle, cycloalkyl of 3 to 10 carbons, and -NR_AR_B(R_AAnd R_BIs independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted with one or two substituents selected from hydrogen and -OH), independently selected from 1-6 alkyl optionally substituted with one or two substituents, (iii) alkanoyl wherein the alkyl moiety is 1-10 carbon atoms, (iv) cycloalkyl of 3-10 carbons. Alkyl, (v) alkoxy, (vi) heterocycle, and (vii) aryl, wherein (vi) and (vii) are alkyl of 1 to 6 carbon atoms And halo, substituted with one or two substitutions independently selected from:), (e) -C (W) R₁₀(W is as defined above, and R₁₀Represents 1 to 10 carbon atoms optionally substituted with one or two substituents independently selected from: (i) hydrogen, (ii) aryl and cycloalkyl of 3 to 10 carbons Alkyl of (iii) -NR₈R₉And (iv) -OR₇(F) —OH, (g) aryl, and (h) heterocycle, 1 to 10 optionally substituted with 1, 2 or 3 substituents independently selected from Wherein (g) and (h) are: (i) alkyl of 1 to 20 carbons, (ii) -NR₈R₉(Iii) alkoxy of 1 to 10 carbons, (iv) thioalkoxy of 1 to 10 carbons, (v) halo, (vi) perfluoroalkyl of 1 to 3 carbons, (vii) 2 to 10 Alkenyl of 1 carbon, (viii) alkoxy of 1 to 10 carbons and alkyl of 1 to 10 carbons optionally substituted with 1 or 2 substituents independently selected from -OH, (Ix) -CO₂R₇, (X) aryl, and (xi) -CHO, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: (10) cycloalkyl of 10 carbons, (4) aryl, (5) heterocycle, wherein (4) and (5) are (a) alkyl of 1 to 20 carbons, (b) (i) -OR₁₁(R₁₁Is hydrogen, -C (W) R₁₂(R₁₂Is selected from alkyl of 1 to 10 carbons, cycloalkyl of 3 to 10 carbons, aryl, and heterocycle), and 1 or 2 substituents selected from -OH and -OH Selected from alkyl of 1 to 6 carbons, optionally substituted with; heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from: ii) alkoxy and alkoxyalkoxy, 1 to 10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (iii) 3 to 10 carbon spiroalkyl, And (iv) alkyl of 1 to 10 carbons, optionally substituted with 1, 2, or 3 substituents independently selected from halo, (c) (i) alkoxy and (ii) alkyl Xyalkoxy, 1-10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (d) 1-10 carbon thioalkoxy, (e) halo, (F) perfluoroalkyl of 1 to 3 carbons, (g) (i) -C (W) R₁₀And (ii) -C (W) R₁₂Alkenyl of 2 to 10 carbons optionally substituted with one or two substituents independently selected from: (h) -CO₂R₇, (I) -NR₈R₉, (J) aryl, (k) -C (W) R₁₂, (L) -CHO, (m) -C (O) NR₈R₉(N) -CN, (o) (i) alkyl of 1 to 10 carbons and (ii) perfluoroalkyl of 1 to 3 carbons, with one or two substituents independently selected from Optionally substituted heterocycle, (p) -C (W) R₁₀, (Q) ethylenedioxy, and (r) -OCF₃, Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from), (6) -OR₇, (7) hydrogen, and (8) -NR₈R₉L is selected from_BIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆-, (5) C (W)-, and (6) -C (= NR₁₃)-(R₁₃Are (a) hydrogen, (b) -NO₂, (C) -CN, and (d) -OR₁₄(R₁₄Is selected from: (i) hydrogen, (ii) aryl, and (iii) aryl and -C (O) R_Fifteen(R_FifteenIs hydrogen, -OH, alkoxy, and NR_AR_BX selected from 1 to 10 alkyls optionally substituted with 1 to 2 substituents, independently selected from_BAre (1) hydrogen, (2) (a) -CO₂R₇, (B) -NR₈R₉, (C) -C (W) NR₈R₉(D) heterocycle, (e) (i) alkyl of 1 to 10 carbons, (ii) -NO₂And (iii) -NR_AR_BAryl optionally substituted with one or two substituents independently selected from:, (f) -OR₁₆(R₁₆Is (i) hydrogen and (ii) -C (W) NR_AR_BAnd (g) -NR_AC (W) NR₈R₉1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (3) (a) -C (W) NR_AR_B, (B) -CO₂R₇And (c) a heterocycle, an alkenyl of 2 to 6 carbons optionally substituted with one or two substituents independently selected from: (4) -NR₁₇R₁₈(R₁₇And R₁₈(A) hydrogen, (b) (i) -OH, (ii) -C (W) R₁₀, (Iii) -NR_AC (= NR₁₃) NR_BR₁₉(R_A, R_B  And R₁₃Is already defined and R₁₉Is hydrogen, alkyl of 1 to 10 carbons, and -NO₂  (Iv) heterocycle, (v) aryl, (vi) halo, and (vii) -NR_AR_B(C) alkoxy; (d) (i) halo; (ii) 1-alkyl of 1 to 10 carbons optionally substituted with 1, 2 or 3 substituents independently selected from (Iii) 1 to 10 carbon alkoxy, and (iv) 1 to 3 carbon perfluoroalkyl, 1, 2, or 3 substitutions independently selected from: Aryl optionally substituted with a group, (e) heterocycle, (f) -NR_AR_B, (G) -C (O) R₂₀(R₂₀Is (i) hydrogen, (ii) alkyl of 1 to 10 carbons, (iii) -OR₁₂And (iv) -NR_AR_B(H) cycloalkyl of 3 to 10 carbons, and (i) independently selected from -OH), (5) alkoxy, (6) -OH, (7) -NR_AC (= NR₁₃) NR_BR₁₉, (8) -C (W) NR₈R₉(9) aryl, (10) heterocycle, wherein (9) and (10) are (a) halo, (b) (i) halo, (ii) alkoxy of 1 to 10 carbons, iii) -NR_AR_B, (Iv) -OH, (v) -CO₂R₇, (Vi) -C (W) NR_AR_BAnd (vii) aryl, 1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (c) -NR_AR_B(D) alkoxy of 1 to 10 carbons, (e) thioalkoxy of 1 to 10 carbons, (f) perfluoroalkyl of 1 to 3 carbons, (g) -OH, (h) -C (W) NR₈R₉, (I) -CO₂R₇, (J) -NR_AC (W) OR₂₁(R_AIs already defined and R₂₁Is (i) aryl and 1-10 carbon alkyl optionally substituted with one or two substituents selected from 3-10 carbon cycloalkyl, (ii) aryl, and (iii) (K) cycloalkyl of 3 to 10 carbons, (k) alkenyl of 1 to 10 carbons, (l) heterocycle, (m) aryl, and (n) -NO₂Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(11) -CN, (12) -CHO, (13) halo, and (14) -B (OR_A) (OR_B), Where R₁, R₂, R₃, R₄, And R₅Is hydrogen or lacking
, -L_A-Is a covalent bond, -L_B-Is a covalent bond, X_AOr X_BOne of them is
Other than hydrogen, R₁, R₂, R₃, R₄, And R₅Is missing or (1) hydrogen, (2) (a) -OC (O) R₂₂(R₂₂Is (i) alkyl, (ii) alkoxy, and (iii) NR_AR_B(B) alkoxy, (c) -OH, (d) -NR_AR_B(E) a heterocycle, and (f) aryl, alkyl of 1 to 6 carbons optionally substituted with one or two substituents independently selected from: (3) -CO₂R₇, (4) -C (O) NR_AR_B, (5) -SR₂₃(R₂₃Is one or two substituents selected from: (a) hydrogen, (b) alkyl of 1 to 6 carbons, (c) (i) alkyl of 1 to 6 carbons, and (ii) halo. Selected from aryl optionally substituted with), (6) -NR_AR_B(7) halo, (8) alkoxy, (9) perfluoroalkyl of 1 to 3 carbons, (10) -OH and (11) heterocyclic ring, with the proviso that E, F, and When Y is carbon, G is nitrogen and Z is sulfur
, -L_A-Is a covalent bond, X_AIs halo and R₁Is -CO₂R₇Other than
].

In another aspect of the present invention, a method for treating a disease comprising administering an effective amount of a compound having formula I is disclosed.

In yet another aspect of the present invention, there is disclosed a pharmaceutical composition comprising a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms As used herein, the term “alkanoyl” refers to an alkyl group attached to the parent molecular group through a carbonyl group.

As used herein, the term “alkenyl” refers to a group of 2 to 12 carbon atoms containing at least one carbon-carbon double bond derived from an alkene by removal of one hydrogen atom. Refers to a monovalent linear or branched group of carbon atoms.

As used herein, the term “alkenylene” refers to a 2-10 carbon atom containing a carbon-carbon double bond derived from an alkene by removal of two hydrogen atoms. Refers to a divalent linear or branched group.

As used herein, the term “alkoxy” refers to an alkyl group attached to the parent molecular group through an oxygen atom.

As used herein, the term “alkoxyalkoxy” refers to an alkoxy group attached to the parent molecular group through another alkoxy group.

As used herein, the term “alkoxycarbonyloxy” is defined herein as attached to the parent molecular moiety through a carbonyloxy group, as defined herein. Refers to such an alkoxy group.

As used herein, the term “alkoxycarbonyloxymethylene” is defined herein as attached to the parent molecular moiety through a methylene group as defined herein. Refers to such an alkoxycarbonyloxy group.

As used herein, the term “alkyl” refers to a saturated linear or branched group of 1 to 20 carbon atoms derived from an alkane by removal of one hydrogen atom. Point.

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

As used herein, the term “alkylcarbonyloxy” is as defined herein appended to the parent molecular moiety through a carbonyloxy group as defined herein. Refers to such an alkyl group.

As used herein, the term “alkylcarbonyloxymethylene”
Refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.

The term “alkylene” refers to a divalent group derived from a straight or branched chain hydrocarbon group of 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited _{to, -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 C
_{H 2 CH 2 CH 2 -,} - CH 2 CH (CH 3) CH 2 - and the like are included.

As used herein, the term “amino” refers to —NR₈₀R₈₁Group (wherein R ₈₀ And R₈₁Independently selected from hydrogen and alkyl).

As used herein, the term “aminocarbonyl” as defined herein, appended to the parent molecular moiety through a carbonyl group as defined herein Refers to an amino group.

As used herein, the term “aminocarbonyloxy” is as defined herein, appended to the parent molecular moiety through an oxy group as defined herein. An aminocarbonyl group.

As used herein, the term “aminocarbonyloxymethylene” is defined herein as attached to the parent molecular moiety through a methylene group as defined herein. Refers to such an aminocarbonyloxy group.

As used herein, the term “aryl” refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings. This aryl group may be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of the present invention may be optionally substituted.

The term “carbonyl,” as used herein, refers to a —C (O) — group.

As used herein, the term “carbonyloxy” as defined herein attached to the parent molecular moiety through an oxy group as defined herein Refers to a carbonyl group.

As used herein, the term “cycloalkyl” refers to a monovalent saturated cyclic hydrocarbon group of 3 to 12 carbons derived from cycloalkane by removal of one hydrogen atom. Point to.

As used herein, the term “ethylenedioxy” refers to a —O (CH ₂ ) ₂ O— group. Here, the oxygen atom of the ethylenedioxy group is bonded to the parent molecular moiety through one carbon atom to form a five-membered ring, or the oxygen atom of the ethylenedioxy group is two adjacent carbon atoms. It bonds to the parent molecular moiety through an atom to form a 6-membered ring.

As used herein, the term “halo” or “halogen” refers to F, Cl, B
Refers to r or I.

The term “heterocycle” refers to 4-, 5-, 6- or 7- containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Represents a member ring. The 4- and 5-membered rings have zero to two double bonds, and the 6- and 7-membered rings are
It has zero to three double bonds. The term “heterocycle” includes bicyclic, tricyclic and tetracyclic groups (provided that all of the above heterocyclic rings are aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene rings) Or fused to one or two rings independently selected from other monocyclic heterocyclic rings).
Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolinyl, imidazolinyl , Isoquinolyl, isothiazolidinyl, isothiazolyl,
Isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxadiazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, quinolinyl, quinolinyl Includes tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl and the like.

Further, the heterocyclic ring includes

[0034]

Embedded image Also included are bridged bicyclic groups, wherein a monocyclic heterocyclic group is bridged by an alkylene.

Further, the heterocyclic ring has the formula

[0036]

Embedded image (Wherein X ^* is selected from —CH ₂ —, —CH ₂ O— and —O—, and Y ^* is
—C (O) — and — (C (R ″) ₂ ) _v —, wherein R ″ is hydrogen or a group having 1 to 1 carbon atoms.
And v is 1 to 3). These heterocycles include 1,3-benzodioxolyl,
4-benzodioxanyl and the like. The heterocyclic groups of the present invention may be optionally substituted.

As used herein, the term “oxo” refers to ＝ O.

As used herein, the term “oxy” refers to —O—.

As used herein, the term “methylene” refers to a —CH ₂ — group.

As used herein, the term “perfluoroalkyl” refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms.

As used herein, the term “phenyl” refers to a monocyclic carbocyclic ring system having one aromatic ring. Further, the aryl group may be fused to a cyclohexane ring or a cyclopentane ring. The phenyl groups of the present invention may be optionally substituted.

As used herein, the term “pharmaceutically acceptable prodrug” refers to human and lower animals that have adverse toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment. These prodrugs of the compounds of the invention and, where possible, the invention are suitable for use in contact with tissue, which correspond to a reasonable effect / risk ratio and are effective for their intended use. Represents the zwitterionic form of the compound

As used herein, the term “prodrug” refers to a compound that is rapidly transformed in vivo, for example, by hydrolysis in blood, to a parent compound of the above formula. A thorough study is provided by T.W. Higuchi and V.M. Stella, "Prodrugs as Novell Deliv as a Novel Delivery System
ery Systems) ", A.I. C. S. Volume 14 of the symposium series and Edward B. Roche, “Bioreversible Carriers in Drug Design (B
ioreversable Carriers in Drug Design
) ", American Pharmaceutical Association
locations and Pergamon Press
1987), both of which are incorporated herein by reference.

As used herein, the term “spiroalkyl” means that two carbon atoms of the alkylene group are bonded to one carbon atom of the parent molecular group, thereby forming 3-11 carbon atoms. Refers to an alkylene group that forms a carbocyclic ring of atoms.

As used herein, “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule, in which case two or more structures Different compounds are in equilibrium with each other.

As used herein, the term “thioalkoxy” refers to an alkyl group attached to the parent molecular group through a sulfur atom.

The compounds of the present invention may exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers, (±)
Is specified. The individual stereoisomers of the compounds of the invention can be synthesized from commercially available starting materials containing an asymmetric or chiral center or can be prepared by preparing a racemic mixture followed by resolution known to those skilled in the art. it can. These resolution methods include (1) coupling of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and isolation of an optically pure product from the auxiliary. Or (2) exemplified by the direct separation of a mixture of optical enantiomers on a chiral chromatography column.

[0048] Geometric isomers may be present in the compounds of the present invention. The present invention relates to carbon-
Various geometric isomers and mixtures thereof resulting from the configuration of substituents around a carbon double bond or the configuration of substituents around a carbocyclic ring are contemplated. Substituents around a carbon-carbon double bond are designated as being in a Z or E configuration. in this case,
The term "Z" refers to a substituent on the same side of the carbon-carbon double bond and the term "E"
Represents a substituent on the opposite side of the carbon-carbon double bond. The configuration of the substituents around the carbocyclic ring is designated as cis or trans. In this case, the term "cis" refers to a substituent on the same side of the plane of the ring, and the term "trans" refers to a substituent on the opposite side of the plane of the ring. Mixtures of compounds in which the substituents are located both on the same side and on the opposite side of the plane of the ring are designated cis / trans.

Also, tautomers may be present in the compounds of the present invention. The present invention provides for a proton shift from one atom to another atom of the same molecule, which is in equilibrium with each other.
Tautomers are contemplated that result in giving rise to a variety of different compounds.

Compounds of the present invention include, but are not limited to:

Methyl 2-[(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio
Acetate, 6-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-d] pyri
Midine, 6-ethyl-4- (2-pyridinylthio) thieno [2,3-d] pyrimidine, 6-ethyl-4-[(2-methylethyl) thio] thieno [2,3-d] pyrimidin
Gin, 6-ethyl-4-[(phenylmethyl) thio] thieno [2,3-d] pyrimidi
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-carboxylate, 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidine-4-
Amine, 6-ethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) thio
Eno [2,3-d] pyrimidin-4-amine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6
Ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine
Midine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-
Ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyrimidine
Midine, 7-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)
Thio] thieno [3,2-d] pyrimidine, 7-methyl-4-[[5- (methylthio) -1,3,4-thiadiazole-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] pyrimidine
Limidin-7-amine, 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyri
Midine-6-carboxamide, methyl 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-carboxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubonic acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2-carboxa
Imide, 4-[(4-chlorophenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxamide, N-methoxy-N-methyl-4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, N-methoxy-4-[(4-methylphenyl) thio] thieno [2,3-c] pi
Lysine-2-carboxamide, N- (4-chlorophenyl) -4-[(4-methylphenyl) thio] thieno [
2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-methyloxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O- (phenylmethyl) oxime, 2-[[[4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
4-N-ylmethylene] amino] oxy] acetic acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-phenyl oxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, oxime, 2-[[[4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
2-Ethylmethylene] amino] oxy] acetamide, (E) -3-[(4-methylphenyl) thio] thieno [2,3-c] pyridine
-2-yl] -2-propenamide, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, 2-benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c]
Pyridine, 2-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pyri
Gin, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, oxime, N- (2,3-dihydroxypropyl) -4-[(4-methylphenyl) thio
Thieno [2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubonic acid, hydrazide, N ² -4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] carbonyl] -N ⁶ -[(Nitroamino) iminomethyl] -L-lysi
, Methyl ester, N- (aminoiminomethyl) -4-[(4-methylphenyl) thio] thieno [
2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubothioamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine, methyl 4-[(2-methoxy-2-oxoethyl) thio] thieno [2,3-c
] Pyridine-2-carboxylate, 4-[(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridi
2-carboxamide, 4-[(4-bromophenyl) thio] thieno [2,3-c] pyridine-2-ca
Luboxamide, 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-ca
Ruboxamide, 4-[(3-methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxamide, 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] pyridi
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-carboxa
Mido, 4-[(4-methylphenyl) thio] -N- [3- (4-morpholinyl) pro
Pyl] thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl
Luacetate salt, 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine
-2-carboxamide, methyl 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pi
Lysine-2-carboxylate, 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 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-carboxy
Samide, 4- (4-ethenylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, 4- [2- (2,3-dihydroxypropyl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, 1-oxide, 4- [3- (pentadecyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-
4-yl] oxy] benzoate, 4-phenoxythieno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2-carbox
Samide, 4- (4- (methoxymethyl) phenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic
Acid, N- (4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
) -O- (3-tetrahydrofuranyl) carbamate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-methanol
(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenoic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Aldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenamide, 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] pi
Lysine-2-carboxylate, N-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] pyri
Gin-2-carboxamide, 4- (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2-ca
Ruboxamide, ethyl 4-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-
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-carboxy
Samide, methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-ca
Ruboxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-meth
Tanol, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N, N-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -N, N-diethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pi
Lysine-2-carboxamide, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] pyrrolidine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] piperidine, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] morpholine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4-methylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4-phenylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4- (phenylmethyl) piperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -4- (2-pyridinyl) piperazine, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-carboxamide, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide
, Trifluoroacetate salt, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thio
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1,1-bis (hydroxymethyl) e
Tyl] thieno [2,3-c] pyridine-2-carboxamide, (D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl
) Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thi
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfone
Amide, 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine-2-
Carboxamide, methyl 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine
-2-carboxylate, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, N-oxide, methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbo
Acid, N-oxide, 4- (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] pyri
Gin-2-carboxylate, 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c] pyridi
2-Carboxamide, methyl 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c]
Pyridine-2-carboxylate, 4- (4-chlorophenoxy) -3- (1-methylethoxy) thieno [2,3
-C] pyridine-2-carboxamide, 3-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3 -Carbon
Acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-3-carboxy
Samide, 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-carboxamide, methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyri
Gin-2-carboxylate, 3-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-ca
Ruboxamide, 4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5
-Carboxamide, ethyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio
Thieno [2,3-b] pyridine-5-carboxylate, 7-[(4-methylphenyl) thio] thieno [3,2-b] pyridine-2-ca
Ruboxamide, methyl 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-
2-carboxylate, methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxy
Silate, 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-2-ca
Ruboxamide, 2-bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyri
Gin, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-ca
Ruboxamide, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-ca
Rubonitrile, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboxy
Samide, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboni
Tolyl, 7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2-cal
Boxamide, Methyl 7- (4-methylphenoxy) oxazolo [5,4-c] pyridine-2
-Carboxylate, 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-
2-carboxamide, methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyri
Gin-2-carboxylate, 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2
-Carboxamide, methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridi
2-carboxylate, 4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carbo
Oxamide, 4- (4-chlorophenoxy) thieno [2,3-d] pyridazine-2-carbo
Acid, 7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carbamic acid
7- (4-chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid
Acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Oamide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3-dihydroxypropyl) thiye
[2,3-c] pyridine-2-carboxamide, N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-carboxamide, 4- (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide, N- (2-hydroxyethyl) -4- [4- (trifluoromethyl) phenoxy
[Thi] thieno [2,3-c] pyridine-2-carboxamide, N- (2-aminoethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxyl
Drazide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohi
Drazide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carbohydrazide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridi
2-Carboxamide, 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl @ amino) acetic acid, N- (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thiye
No [2,3-c] pyridine-2-carboxamide, N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thiye
No [2,3-c] pyridine-2-carboxamide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl @ amino) -3-hydroxypropanoic acid, N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl
] -4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) -3-hydroxypropanoic acid, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methyl
Amino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxa
Amide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1S) -1-methyl-2- (methyl
Amino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)
-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)
-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-
c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-
Carboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pi
Lysine-2-carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine
-2-carboxamide, N-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, N-methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3
-C] pyridine-2-carboxamide, 4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridi
2-Carboxamide, N, N-dimethyl-4- (4-vinylphenoxy) thieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2-carbox
Samide, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine
-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] -N-methylthieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (methoxymethyl) phenoxy] -N-methylthieno [2,3-c
Pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} thieno [2,3
-C] pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} -N-methylthio
Eno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy
) Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy
) -N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] fe
Nonoxydithieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy)
Methyl] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4-{[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl
] Oxy} benzyl-2-furoate, 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6-
(Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl
) Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxami
, 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine
-2-carboxamide, 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide, N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno
[2,3-c] pyridine-2-carboxamide, 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) f
Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} ca
Rubonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propeni
L] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino}-
3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- [4-((E) -3-{[2- (4-morpholinyl) ethyl]
] Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c]
Pyridine-2-carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3
-Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3
-Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pi
Lysine-2-carboxamide, 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
] Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [
2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] "
Ethyl {amino) -3-oxo-1-propenyl] phenoxy} -N-methylthio
Eno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-(} 2- [bis (2-hydroxyethyl) amino]
Ethyl {amino) -3-oxo-1-propenyl] phenoxy} thieno [2,3
-C] pyridine-2-carboxamide, 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-
c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno
[2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) phene
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxa
Diazol-3-yl] phenoxydithieno [2,3-c] pyridin-2-cal
Boxamide, 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy
] -N-methylthieno [2,3-c] pyridine-2-carboxamide, N-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, N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) phene
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] phenoxy} -N-
Methylthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclic
L-propyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-ca
Ruboxamide, N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,
3-c] pyridine-2-carboxamide, 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl]
{Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl}-
1,3,4-oxadiazol-2-amine, 4- [4- (1,1-difluoro-2-hydroxyethyl) phenoxy] -N
-Methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1-diif
Fluoroethyl {phenoxy) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-chlorophenoxy) -6-{[(2,2-dimethylpropanoyl)
Oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c]
Pyridine-6-ium, 4- (4-bromophenoxy) -6-{[(2,2-dimethylpropanoyl)
Oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c]
Pyridine-6-ium, 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(iso
Propoxycarbonyl) oxy] methyldithieno [2,3-c] pyridine-6-
Iium, 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-carboxy
Samide, [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl]
Methanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde oxime, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Aldehyde O-methyl oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone O-methyloxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone O-methyloxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1] -propanone, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -1-propanone oxime, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboni
Tolyl, 4- (4-chlorophenoxy) -N′-hydroxythieno [2,3-c] pyri
Gin-2-carboximidamide, 4- (4-chlorophenoxy) -N'-cyanothieno [2,3-c] pyridine
-2-carboximidamide, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(2-nitrophenyl) methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
(3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanone, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] methanol, 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine -2-b
L] -1,2-ethanediol, 1- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-i
] -1,2-ethanediol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
Methanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl]
Methyl carbamate, N-{[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] methyldiurea, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine
-2-yl] -2-propenamide, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine
-2-yl] -N-methyl-2-propenamide, 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
] -2,3-dihydroxy-N-methylpropanamide, 3- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
L] -2,3-Dihydroxypropanamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylamido
4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-ylform
Muamide, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Ru] urea, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-sulfonamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thiye
No [2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,
3-c] pyridine-2-sulfonamide, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Phenol], 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] aniline, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
Ru] aniline, 4- (4-chlorophenoxy) -2- (5-nitro-2-pyridinyl) thieno
[2,3-c] pyridine, 6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -3-pyridineamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -2-pyridineamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
1,3,4-oxadiazol-2-amine, 5- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-i
1,3,4-oxadiazol-2-ylamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
] -4H-1,2,4-triazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (5-methyl-1,2,4-oxadia
Zol-3-yl) thieno [2,3-c] pyridine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c]
Pyridin-2-yl {-1,3,4-oxadiazol-2-amine, 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3
, 4-oxadiazol-2-yl) thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (2-methyl-2H-1,2,3,4-
Tetraazol-5-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
4-Methyl-4H-1,2,4-triazol-3-amine, 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) -1,2
, 4-oxadiazol-3-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,2,4-oxadiazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] -N-methyl-1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (1,2,4-oxadiazole-3-
Yl) thieno [2,3-c] pyridine, 2- (1,3,4-oxadiazol-2-yl) -4- [4- (trifluoro
L-methyl) phenoxy] thieno [2,3-c] pyridine, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
] -1,2,4-oxadiazol-5-amine, 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4-
(Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -1,3-thiazole-4-carboxylate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
1,3-thiazole-4-carboxamide, tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c
] Pyridin-2-yl] -1,3-thiazol-4-ylcarbamate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] -1,3-thiazol-4-amine, 4- (4-chlorophenoxy) -2- (1,3-oxazol-3-yl) thio
Eno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (1H-imidazol-3-yl) thiye
No [2,3-c] pyridine, 4-chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide
3-amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide
4- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-
2-carboxamide, 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c
Pyridine-2-carboxamide, tert-butyl 2- (aminocarbonyl) -4- (4-chlorophenoxy)
) Thieno [2,3-c] pyridine-2-carboxylate, N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- (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-chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide, 7-bromo-4- (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, 7-chloro-N-methyl-4- [4- (trifluoromethyl) phenoxy] thio
Eno [2,3-c] pyridine-2-carboxamide, 7-chloro-N- (2-hydroxyethyl) -4- [4- (trifluoromethyl
Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,
3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [
2,3-c] pyridine-2-carboxamide, 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-
2-carboxamide, N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4-c
] Pyridine-2-carboxamide, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide
Mido, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothio
Amide, 4-[(E) -2-phenylethenyl] thieno [2,3-c] pyridine-2-
Carboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine
-2-carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxy
Samide, and 4- (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-
2-carboxamide.

Determination of Biological Activity Pooled first human umbilical vein endothelial cells (HUVEC) (Clonetics) between passages 3 and 7 were placed in a 96-well plate with hydrocortisone non- In the presence, Clonetics EBM / 2% FBS /
In EGF / bovine brain extract / gentamicin were placed in 100 [mu] L / well, 5 × 10 ⁴ cells / mL. The next day, the compound of the present invention was added to 10 μL / well medium,
Incubated at 37 ° C. for 24 hours after compound addition. TNF (Gibco / BRL) in 10 μL / well medium was added to a final concentration of 5 ng / mL and the cells were incubated for an additional 6 hours at 37 ° C. The medium was then removed and the plate was washed once with D-PBS (Gibco / BRL),
-First antibody (Becton Dickinson, City, Becton Dickinson, PBS / 2% BSA (Sigma) /0.01% azide)
(City)), 100 μL / well. An initial concentration of 1 mg / mL primary antibody was used at the following dilutions. Anti-ELAM-1, 1: 2000, anti-ICAM-
1, 1: 2000 and anti-VCAM, 1: 3000. The plates were stored overnight at 4 ° C., washed three times with D-PBS, and the second antibody (Jackson Labs)
on Labs)), 100 μL / well, 1: 8000 dilution, D-PBS / 2
Treated with HRP-conjugated donkey anti-mouse IgG (H + L) in% BSA. Plates were incubated for a minimum of 1 hour at room temperature, washed three times with D-PBS, and treated with 100 μL per well of ortho-phenylenediamine.2HCl reagent. The plate was allowed to develop for about 15 minutes and neutralized with 100 μL / well of 1N sulfuric acid. The absorbance was read at 490 nm. Inhibitory titers for representative compounds of the present invention are shown in Table 1.

[0053]

[Table 1] Thus, the compounds of the present invention act as anti-inflammatory agents at a titer of less than 1 μM and are therefore useful for treating inflammatory diseases.

Pharmaceutical Compositions and Methods of Treatment The present invention also provides pharmaceutical compositions comprising a compound of the present invention formulated with one or more non-toxic pharmaceutically acceptable carriers. The drug compositions may be particularly formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The drug formulations of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally (as by powder, ointment or drop). B) topically, orally, or as an oral or nasal spray. The term “parenteral” administration as used herein refers to intravenous, intramuscular,
Refers to modes of administration including intraperitoneal, intrasternal, subcutaneous and intraarterial injection and infusion.

The parenterally-injected pharmaceutical compositions of the present invention include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions immediately before use. Sterile powder to be reconstituted into a neat solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and olein. Injectable organic esters such as ethyl acid are included. The appropriate liquidity is, for example,
It can be maintained by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersion, and by using a surfactant.

[0057] Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microbial activity can be reliably prevented by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay the absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material that has poor water solubility. In that case, the absorption rate of the drug depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0060] Injectable formulations can be prepared, for example, by filtration through a bacteria-retaining filter.
Alternatively, sterilization can be accomplished by incorporating the bactericide in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0061] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound comprises at least one
Two inert pharmaceutically acceptable excipients or carriers (such as citric acid or dicalcium phosphate) and / or a) fillers or bulking agents (starch, lactose, sucrose, glucose, mannitol and silicic acid) B) binder (
For example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), c) humectants (such as glycerol), d) disintegrants (agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicas) Acid salts and sodium carbonate), e) dissolution retarders (such as paraffin), f) absorption enhancers (such as quaternary ammonium compounds)
G) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl. Sodium sulfate, and mixtures thereof). In the case of capsules, tablets and pills, the dosage form also contains buffering agents.

[0062] Solid compositions of a similar type may also include excipients such as lactose or lactose,
It can be used as a filler in soft-filled gelatin capsules or hard-filled gelatin capsules using high molecular weight polyethylene glycol or the like.

Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Such dosage forms may optionally contain an opacifying agent, and may contain only the active ingredient (s) or preferentially the active ingredient (s) to identify the intestinal tract. Can be made from compositions that release in a delayed manner, if desired. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0065] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions,
Suspensions, syrups and elixirs are included. In addition to the active compound, liquid dosage forms can contain inert diluents, solubilizing agents and emulsifying agents that are widely used in the art, such as, for example, water or other solvents. Such solubilizers and emulsifiers include, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, Peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

In addition to the inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum aluminum hydroxide, bentonite, agar. And gum tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories. Such suppositories may render the compound of the present invention solid at room temperature, liquid at body temperature, and therefore suitable nonirritating excipients or carriers that melt in the rectal or vaginal cavity to release the active compound. body(
Cocoa butter, polyethylene glycol or suppository wax).

[0069] The compounds of the present invention can also be administered in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-lamellar or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins).

[0070] Methods for forming liposomes are well known in the art. For example, Prescott
Hen, Methods in Cell Biology, Volume XIV, Acad
emic Press, New York, N.M. 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. "Pharmaceutically acceptable salts" are intended for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment. Appropriate and reasonable effect /
A salt corresponding to the risk ratio is meant. Pharmaceutically acceptable salts are well-known in the art. For example, M. Berge et al. Disclose pharmaceutically acceptable salts. P
The details are described in Pharmaceutical Sciences, 1977, 66: 1 et seq. Such salts can be prepared during the final isolation and purification of the compounds of the present invention or separately by reacting the free base function with a suitable acid. Typical acid addition salts include acetate, adipate, alginate, citric acid, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate , Digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate Salt), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate,
Persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,
Includes but is not limited to bicarbonate, p-toluenesulfonate and undecanoate. In addition, basic nitrogen-containing groups include lower alkyl halides (methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl and butyl bromide, methyl iodide, ethyl iodide, Propyl iodide and butyl iodide, etc.); dialkyl sulfates (dimethyl sulfate, diethyl sulfate,
Long chain halides (decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, decyl iodide, lauryl iodide, iodide) It can be quaternized with agents such as myristyl and stearyl iodide, etc .; arylalkyl halides such as benzyl bromide and phenethyl bromide. A water-soluble or oil-soluble or dispersible product is thereby obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and oxalic, maleic, succinic and Organic acids such as citric acid are included.

The base addition salt may be prepared by subjecting the carboxylic acid-containing moiety to a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation during the final isolation and purification of the compound of the invention. It can be prepared by reacting with a suitable base such as bicarbonate, or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include lithium, sodium, potassium,
Cations based on alkali or alkaline earth metals such as calcium, magnesium and aluminum salts, and non-toxic compounds including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like Includes, but is not limited to, quaternary ammonia and amine cations. Other representative organic amines useful for forming base addition salts include ethylenediamine,
Ethanolamine, diethanolamine, piperidine, piperazine and the like are included. Preferred salts of the compounds of the present invention include phosphate, Tris and acetate.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
Ophthalmic formulations, eye ointments, powders and solutions are also included as being within the scope of this invention.

The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention will depend on the particular patient,
The composition and mode of administration can be varied to provide an effective amount of active compound (s) to achieve the desired therapeutic response. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and previous medical history of the patient being treated. However, it is within the skill of the art to start doses of the compounds at lower levels than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. is there.

Generally, dosage levels of about 1 mg to about 50 mg, more preferably about 5 mg to about 20 mg, of active compound per kg of body weight per day are orally administered to a mammalian patient. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, for example, two to four separate doses per day.

Preparation of Compounds of the Invention Abbreviations The abbreviations used in the following schemes and in the description of the examples are shown below. BH ₃ : borane, BH ₃ .DMS: borane dimethylsulfide complex, BINA
P: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, BF ₃ OEt ₂ : boron trifluoride diethyl ether complex, n-BuLi: n-butyl lithium, 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: dimethylsulfoxide, DIPEA : Diisopropylethylamine, DPPA: diphenylphosphoryl azide, EDCl or EDC: 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, Et ₃ N: triethylamine, E
t ₂ O: diethyl ether, EtOAc: ethyl acetate, EtOH: ethanol,
K ₂ CO ₃ : potassium carbonate, LiAlH ₄ : lithium aluminum hydride, LD
A: lithium diisopropylamide, MeOH: methanol, NaOMe: sodium methoxide, NaOH: sodium hydroxide, HCl: hydrochloric acid, NMP: 1-
_{Methyl-2-pyrrolidinone,} H 2 / Pd: hydrogen and a palladium catalyst, iPrO
H: isopropyl alcohol, PPh ₃ : triphenylphosphine, THF: tetrahydrofuran, THP: tetrahydropyran, TFA: trifluoroacetic acid,
pyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium =
Hexafluorophosphate.

Synthetic Methods The compounds and processes of the present invention are better understood with the following synthetic schemes that illustrate how the compounds of the present invention may be prepared. Moreover, all references in this case are incorporated by reference.

[0078]

Embedded image Scheme 1 describes a thieno [2,2 from an ester of general formula 1 according to a published procedure.
3 shows the preparation of 3-d] pyrimidines. 4-chlorothieno [2,3-d of the general formula 3
The pyrimidines were substituted with thiols to obtain the 4-thioethers of general formula 4 or with amines to obtain the 4-aminothieno [2,3-d] pyrimidines of general formula 5.

[0079]

Embedded image Scheme 2 shows the preparation of 2-carboxy-substituted thieno [2,3-d] pyrimidines. The pyrimidinones of the general formula 1 are reacted with phosphoryl chloride to form the general formula 6
Which was then substituted with a thiol to give the thioether of general formula 7.

[0080]

Embedded image Scheme 3 shows the thieno [3,2 derived from chloropyrimidines of general formula 8
-D] shows the preparation of pyrimidines. The thioether of general formula 9 was obtained by substituting this chloride with thiol. By substituting the chloride with an amine, aminopyrimidines of the general formula 10 were obtained.

[0081]

Embedded image Analogs having a 2-carboxamide group in thieno [3,2-d] pyrimidine were prepared as shown in Scheme 4. The 2-position of thiophene was deprotonated with a strong base such as lithium diisopropylamide, and the corresponding carbanion was treated with carbon dioxide to give the acid of general formula 11. This acid was converted to the corresponding amide of general formula 12 via the intermediate acid chloride.

[0082]

Embedded image Scheme 5 shows a 6-alkyl-substituted thieno with an alkylthio group at the 4-position [2,
3 shows the preparation of 3-d] pyrimidines. Using known procedures, 2-aminothiophene 13 is acylated to amide 14, which is cyclized to thienopyrimidinone 1
It was set to 5. This pyrimidinone was converted to chloride 16 and further converted to thioether 17 by standard procedures.

[0083]

Embedded image A general process for preparing 2,4-disubstituted thieno [2,3-c] pyridines is shown in Scheme 6. Commercially available 3,5-dichloropyridine was added in an anhydrous solvent,
Treatment with a strong base such as lithium diisopropylamide at low temperature followed by reaction with methyl formate (or dimethylformamide) gave the known pyridine-4-carboxaldehyde 18. The aldehyde 18 is then substituted with one equivalent of a thiol (R ¹ = substituted or unsubstituted aryl, alkyl or heterocycle) to give a compound of general formula 1
9 chloroaldehydes were obtained. 19 is treated with methyl thioglycolate and a base (such as cesium carbonate or potassium carbonate) to give a 4-thioether of general formula 20 [
2,3-c] thienopyridine ester was obtained. This ester was converted to the corresponding acid of general formula 21 by, for example, base hydrolysis using lithium, sodium or potassium hydroxide in a mixture of water and alcohol or tetrahydrofuran. The acid of general formula 21 can also be treated first with oxalyl chloride or thionyl chloride, and then with a selected amine (R ² , R ³ can be substituted or unsubstituted alkyl, aryl, heterocycle). Can be converted to an amide of the general formula 22 or 23 via an intermediate acid chloride. Alternatively, the acid 21 can be a carbodiimide (eg, N-ethyl-N ′-(3-dimethylamino) propylcarbodiimide hydrochloride (EDC)), a mixed anhydride (derived from treatment of pivaloyl chloride or isobutyl chloroformate), And active ester (
The amides 22 or 23 can be converted by other coupling methods such as, for example, N-hydroxysuccinimide, derived from p-nitrophenol).

[0084]

Embedded image Scheme 7 illustrates a similar preparation of 4-ether substituted thienopyridines of general formula 30. Substitution of aldehyde 18 with an alcohol (R ¹ = substituted or unsubstituted aryl, heterocycle) under basic conditions (eg, anhydrous tetrahydrofuran or dimethylformamide containing potassium tert-butoxide or cesium carbonate) yields a compound of general formula The pyridine-ethers of 24 were then reacted further with methyl thioglycolate to give thieno [2,3-c] pyridine esters of general formula 25. This ester can be converted to the corresponding primary amide of general formula 26 by heating in a methanolic ammonia solution. Alternatively, general formula 2
The ester of 5 can be reacted with a mono- or disubstituted amine in a polar solvent such as dimethylformamide or methanol. The ester of general formula 25 was hydrolyzed to the carboxylic acid of general formula 28 by base hydrolysis using sodium hydroxide or lithium hydroxide in aqueous methanol or aqueous tetrahydrofuran. The acid was then converted to an amide of general formula 30 by reacting the corresponding acid chloride of general formula 29 with an amine. Alternatively, acid 30 was coupled to the amine by standard peptide coupling conditions as described in Scheme 6 for amide 22 or 23.

[0085]

Embedded image A similar method is shown in Scheme 8, as shown in 4-bromothieno [2,
3-c] pyridine 32 can be used. 3,5-Dibromopyridine was converted to aldehyde 31 by the procedure described in Scheme 6 for the preparation of compound 18. The reaction of 31 with methyl thioglycolate was performed, for example, in DMF in the presence of cesium carbonate to give 4-bromothieno [2,3-c] pyridine ester 32. The bromide 32 is a starting material for preparing 4-aryl, 4-heterocyclic, 4-alkyl or 4-alkenyl derivatives of general formula 33 using Suzuki coupling methodology as shown. Used as a substance. Bromide 32 also contains Sanogash
ira method (Sanogashira, K .; Tohda, Y .; Hagihar)
a, N .; Tetrahedron Lett. 1975, 4467-70) can be coupled with a terminal alkyne to obtain an alkynyl derivative (R ¹ = alkynyl). The ester of general formula 33 is converted to 26 in scheme 7,
Conversion to the amide of general formula 34 by the procedure described for 27 or 30.

[0086]

Embedded image Scheme 9 illustrates the conversion of an acid of general formula 21 to an aldehyde or ketone derived compound. For example, an aldehyde of general formula 36 was obtained by reducing N-methyl-N-methoxylamides of general formula 35. The amide of general formula 35 also reacted with the Grignard reagent to give an asymmetric ketone of general formula 39.
Aldehydes of general formula 36 and ketones of general formula 39 were utilized to obtain oximes of general formula 37 or 40 by reaction with hydroxylamine derivatives. The aldehyde of general formula 36 was reacted with a phosphorane (or phosphonoacetate salt) to give a 2-alkenyl substituted derivative of general formula 38. The ketone of general formula 39 was reduced to the corresponding alkane of general formula 41 by treatment with hydrazine and a strong base such as potassium hydroxide. The 2-position analog derivative of the thienopyridine ether of general formula 28 in Scheme 7 follows a similar synthetic route as described in Scheme 9. Thus, acid 28 can be converted to an aldehyde, ketone, oxime, alkene or alkane substituent at the 2-position.

[0087]

Embedded image An amide of general formula 34 (or 26, 27 or 30) can be converted to the corresponding thionoamide of general formula 42 by treatment with a Lawesson reagent, as shown in Scheme 10.

[0088]

Embedded image As shown in Scheme 11, 4-sulfoxide of general formula 43 is obtained by reacting a thioether of general formula 20 with an oxidizing agent such as m-chloroperoxybenzoic acid under controlled conditions. Was done.

[0089]

Embedded image Another functional group was introduced at the 2-position of the thienopyridines of general formula 44 by metallization at the 2-position followed by reaction with a suitable electrophile, as shown in Scheme 12. Formula 21 acid (L A _X A ₌ thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) (optionally in the presence of copper powder) to a high temperature by decarboxylation, of the general formula 44 The 2-unsubstituted derivative was obtained. The compound of general formula 44 is deprotonated with a strong organic base such as n-butyllithium and then subjected to standard procedures (Ma
Sakatsu, N .; Kazuhiro, N .; Ichiro, M .; ; Iwa
o, W. Chem. Lett. 1983, 6, 905-908) with an electrophile such as borate, cyanoformate, aldehyde or trialkyltin chloride.

[0090]

Embedded image Scheme 13 illustrates another method for preparing 2-carboxaldehydes of general formula 36 or 47. Esters of general formula 20 or 25 (R ¹ = thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocycle) were reduced to the corresponding alcohols of general formula 46 using calcium borohydride. The alcohol was then oxidized to aldehyde using Swern conditions. The aldehyde was then reacted with the Wittig reagent. For example, reaction with phosphoranes gave acrylate derivatives of general formula 48 (Jung, ME and Ki).
ankarami, M .; J. Org. Chem. 1998, 63, 2968-2
974).

[0091]

Embedded image As shown in Scheme 14, thienopyridines of general formula 27 or 30 are converted to alkyl iodides (or alkyl bromides or alkyl triflates).
Alkylation at the pyridine nitrogen using afforded the pyridinium salt of general formula 49. For example, R can be alkylcarbonyloxymethylene, aminocarbonyloxymethylene, alkoxycarbonyloxymethylene, or alkyl. Such derivatives can be used as prodrug forms of thienopyridine amide 27 or 30.

[0092]

Embedded image Various 2-aminothienyl [2,3-c] pyridine derivatives can be obtained starting from a 2-carboxylic acid of general formula 21 or 28, as shown in Scheme 15, where R ¹ can be thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocycle. According to Curtius rearrangement, general formula 5
An isocyanate of 0 was obtained, which was reacted with an alcohol (alkyl, aryl, heterocycle or dialkylaminoalkyl) to give a carbamate of the general formula 51. Isocyanate 50 can be reacted with an amine (ammonia, primary alkyl or secondary alkyl) to form a urea of general formula 52. Further, 50 can be reacted with an alkyl magnesium halide, an aryl magnesium halide or an alkyl lithium salt to give an amide of the general formula 53. The isocyanate 50 was hydrolyzed under aqueous conditions to give the 2-amino derivative of general formula 54.

[0093]

Embedded image This position was further derivatized by reacting the amine of general formula 54 with a suitable electrophile. Thus, by reacting 54 with an arylsulfonyl chloride or an alkylsulfonyl chloride (R ² = alkyl, aryl, heterocycle) or by reacting with a sulfamoyl chloride (R ² = NH ₂ , monoalkylamino or dialkylamino) The sulfonamide of the general formula 55 was obtained. Amino derivative 54 also reacted with an acyl chloride (R ² = alkyl, heterocycle or aryl) to give the amide of general formula 53, as shown in Scheme 16.

[0094]

Embedded image The functional groups present on the aryl ring bonded to the 4-position of the thieno [2,3-c] pyridines can be further reacted effectively, as illustrated in Scheme 17. For example, 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 displaced by an arylboronic acid under palladium catalyst under Suzuki conditions to yield the biaryl derivative of general formula 59. Alternatively, the alkoxycarbonylation with palladium catalysis efficiently yielded the ester of general formula 61.

[0095]

Embedded image Scheme 19 shows that a boric acid derivative is used to functionalize the 4-position of thieno [2,3-c] pyridines. The chemistry shown is bromostyrene 6
It can be applied to a wide range of aryl olefins similar to 2. Where indicated, bromostyrene 62 is converted to boric acid 63 under standard conditions,
Then, the boronic acid was converted to 4-bromothienopyridine 32 under Suzuki conditions.
To give styryl analog 64. Esters 64 can be prepared as previously described (Miyara, N and Suzuki, A. Chem. Rev.
1995, 95, 2457-2463). The olefin group can then be converted to an epoxide 66. This can undergo a reaction with a nucleophile at the less sterically hindered position of the epoxide to give an analog of general formula 67. Alternatively, styryl derivative 65 can be converted to diol 68 by standard methods.

[0096]

Embedded image Another method for introducing a substituent at the 4-position of thieno [2,3-c] pyridines is shown in Scheme 20. Bromide 32 can be converted to the corresponding cuprate by an intermediate zinc bromide reagent, which is then reacted with a suitable electrophile (acid chloride, alkyl halide, aldehyde, ketone). To give a substituted compound of the general formula 69 (Zhu.L .; Wehmeyer, RM; Rieke, RD).
. J. Org. Chem. 1991, 56, 1445-1453).

[0097]

Embedded image Scheme 21 illustrates the preparation of a 5-halothienopyridine derivative, as exemplified by the preparation of the 5-chloro analog 75. 2,3,5 lithiated
Aldehyde 72 was obtained by formylation of trichloropyridine with methyl formate. Replacement of 3 and 5 chlorine by excess 4-bromophenol,
And by reaction with methyl thioglycolate, 5-chlorothienopyridine 74 was obtained in low yield together with the main product 73. The 5-chloro isomer was treated with ammonia in methanol in a pressure tube to give amide 75. It should be noted that this chemistry can be applied using various phenols or hydroxy heterocycles instead of 4-bromophenol.

[0098]

Embedded image The 2-position of the thienopyridines was substituted with an aryl, vinyl, acetylenic or alkyl group using the procedure shown in Scheme 22. Scheme 1
The boronic acid of general formula 79 prepared according to 2 was coupled with an aryl halide under a palladium catalyst to give the 2-aryl derivative of general formula 80.

[0099]

Embedded image Scheme 23 illustrates the preparation of 4-acyl derivatives of thieno [2,3-c] pyridines. Carboxylic acid 85 was converted to amide 86 by acid chloride. The hydroxyamide 86 is then cyclized via thionyl chloride-mediated oxazoline 87
(Meyers, AI; Stoianova, DJ Org. Ch.
em. 1997, 62, 5219-5221). Ester 88 was obtained by palladium mediated alkoxycarbonylation of 87 (Heck, RF et al., J. Am.
Org. Chem. 1974, 39, 3318). Ester 88 can be converted to Weinreb amide 89 by standard methods. Amide 89 was reacted with a suitable Grignard reagent to give the desired 4-acyl product of general formula 90. The desired product of general formula 91 was obtained by hydrolyzing oxazoline and converting the resulting carboxylic acid to an amide.

[0100]

Embedded image Scheme 24 shows a proposed method for obtaining 4-hydroxy-substituted thieno [2,3-c] pyridines. Reaction of phenol 92 with dihydropyran under acidic conditions gives tetrahydropyranyl ether 93 (Gr.
ant, H .; N. Et al., Helv. Chim. Acta. 1963, 46, 41)
. The aldehyde 9 can be prepared by lithiation of 93 followed by treatment with methyl formate.
4 is obtained. Displacement of this chloride with methyl thioglycolate followed by cyclization with cesium carbonate gives ester 95. Removal of the tetrahydropyranyl ether with aqueous HCl gives hydroxypyridine 96. This can be converted to an amide as described previously.

[0101]

Embedded image Scheme 25 proposes that a 4-hydroxy group be used to introduce a functional group at the 4-position of the thieno [2,3-c] pyridines. The 2-carboxylic acid group is first protected as oxazoline 99 (via the intermediate amide 98) and then the hydroxy group is converted to the aryl triflate 100 by standard conditions. Triflate 100 can then be converted to N-methyl-N-methoxyamide 89 under conditions similar to those for bromide 87. It should be noted that 4-triflate 100 can be used as a coupling partner in various transition metal-mediated couplings with suitable nucleophile partners (e.g., boronic acids, boranes, alkyl zinc reagents or aryl zinc reagents). No.

[0102]

Embedded image Compounds with amino substitution at the 3-position of thieno [2,3-c] pyridines were prepared according to the procedure outlined in Scheme 26. Aldehyde 18 was converted to cyanopyridine 107 by treatment with hydroxylamine under dehydrating conditions.
Cyanopyridine 107 was sequentially substituted with phenols and methyl thioglycolate in a manner similar to the reaction involving aldehyde 18 to give 3-aminothieno [2,3-c] pyridines of general formula 108. The ester of general formula 108 was then converted to the amide of general formula 109 by standard procedures.

[0103]

Embedded image Scheme 27 illustrates additional derivatives that can be derived from amino esters of general formula 108 or aminoamides of general formula 109. For example, an aminoamide of general formula 109 can be treated with 1,1'-carbonyldiimidazole to form a cyclic imide of general formula 110. A 3-amino group can be added (e.g., with acid chlorides and weak bases or by coupling with acids using carbodiimides).
Acylation afforded the diamide of general formula 111. The 3-amino group can be alkylated to an alkylated amine of general formula 112 under reducing conditions using an aldehyde and a reducing agent (such as triacetoxyborohydride).

[0104]

Embedded image Scheme 28 illustrates the preparation of compounds having an alkyl substituent at the 3-position of thieno [2,3-c] pyridines. Using similar chemistry as described for compound 30, 3,5-dichloropyridine is deprotonated with a strong base (eg, lithium diisopropylamide) and then acylating agent (ester, N-methyl-N
-Methoxyamide, acylpyrazole, etc.) to give ketone 113.
Alternatively, reacting the anion with an aldehyde (eg, acetaldehyde)
The product can then be oxidized (eg, with tetrapropylammonium perruthenate) to ketone 113. The dichloroketone was reacted sequentially with phenols and then with methyl thioglycolate according to the protocol outlined for Example 30 to give the cyclic product of general formula 114. The ester of general formula 114 can be converted to various derivatives as outlined previously.

[0105]

Embedded image Scheme 29 describes a similar method used to obtain derivatives with an alkoxy group at the 3-position of thieno [2,3-c] pyridines. Substitution and cyclization of ester 116 provided the 3-hydroxy analog of general formula 117. The hydroxy group can be left unsubstituted to form an amide of general formula 118 (or other derivative). Alternatively, the hydroxy ester of general formula 117 can be alkylated by standard procedures to a 3-alkoxy derivative of general formula 119, which can then be amide to a compound of general formula 120.

[0106]

Embedded image Scheme 30 shows the procedure used to convert commercially available furo [2,3-b] pyridine 121 to amide 122.

[0107]

Embedded image Scheme 31 proposes the preparation of a thienopyridine derivative containing an amide group at the 3-position. The thienopyridines of the general formula 44 are converted to an electrophilic halide source (eg, N
- bromosuccinimide, and halogenated using I _2), 3 of the general formula 123
-Halothienopyridines were obtained. Metal-halogen exchange followed by capture with carbon dioxide gives the acid of general formula 124. The acid can be converted to the amide of general formula 125 by standard procedures, or (e.g., Arndt-Eis
(by the procedure of ert). The ester of general formula 126 can then be converted to an amide or other functional group in the manner described above.

[0108]

Embedded image Scheme 32 describes the method used to prepare various thieno [2,3-b] pyridines starting from the known 4-chloro-5-ester 127. The substitution of chlorine at 127 proceeds with a thiol in the presence of potassium carbonate to give a compound of the general formula 12
This resulted in the 4-thioether of 8. Ester 127 was also hydrolyzed to acid 129, which was subsequently converted to the amide of general formula 130 by standard coupling conditions.

[0109]

Embedded image Scheme 33 illustrates the conversion of a thioether of general formula 128 to a 2,4-disubstituted analog. The corresponding acid of general formula 131 is thermally decarboxylated to give 5 of general formula 132
-Unsubstituted analogs can be obtained. The compound of the general formula 132 is treated with a strong base (for example, n-butyllithium), reacted with carbon dioxide,
A carboxylic acid was obtained. This acid was then converted to the amide of general formula 134 by procedures previously described.

[0110]

Embedded image Scheme 34 illustrates the preparation of thieno [3,2-b] pyridines. The chloride 135 was converted by a group of conditions similar to those described in Scheme 33 to give the acid of general formula 139 and the amide of general formula 140.

[0111]

Embedded image Scheme 35 illustrates the preparation of thieno [3,2-c] pyridines. Starting from thienopyridone 141, 4-oxo-4,5-dihydrothieno [3,2-c]
Pyridine-2-nitrile 144 was prepared according to literature methods (Eloy, F. et al.
Deryckere, A .; Bull. Soc. Chim. Belg. 1970,
79, 301; Troxler, F .; Wiscott, E .; US Patent No. 3,9
98,835). Treatment of thienopyridone 144 with phosphoryl chloride at 130 ° C. afforded chloride 145, which when exposed to thiols under basic conditions, provided the thioether of general formula 146. Hydrolysis of the nitrile group with polyphosphoric acid gave the corresponding amide of general formula 147.

[0112]

Embedded image Scheme 36 shows that the ether of general formula 149 was prepared in a similar manner as described previously in Scheme 35.

[0113]

Embedded image Scheme 37 illustrates the preparation of an intermediate of general formula 151 useful for preparing another 2-derivative. Treatment of a known 2-bromo-4-chlorothieno [3,2-c] pyridine 150 with one equivalent of thiol gives 2-bromothieno [
[3,2-c] pyridines were obtained.

[0114]

Embedded image Scheme 38 shows an example of the preparation of a related class of inhibitors based on the oxazolopyridine structure. Commercially available 3-chloropyridine is oxidized to N-oxide 152 with peracetic acid, which is then nitrated in a mixture of concentrated nitric acid, sulfuric acid and fuming sulfuric acid to give the 4-nitro derivative 153. The chlorine of 153 is then replaced with the sodium salt of p-cresol and the resulting biaryl ether 154 is hydrogenated (Raney nickel catalyzed) to reduce both the nitro function and the N-oxide to give 155. The amino group of 155 was protected with an N-trimethylacetyl group, and the 5-hydroxyl group was treated with the procedure of Chu-Moyer and Berger (J. Org. Che.
m. 1995, 60, 5721), by introduction of the dianion of 156, treatment with trimethylborate and oxidation of the intermediate boronate ester, followed by hydrolysis with basic hydrogen peroxide to give the hydroxypyridine 157. The amide is hydrolyzed with hydrochloric acid to 158, which is condensed with methyl oxalyl chloride to give oxazolopyridine 158. The methyl ester at 159 is then converted to a primary amide by treatment with ammonia in methanol to give the desired compound 160.

[0115]

Embedded image Scheme 39 shows an example of the preparation of a similar thiazolopyridine-based inhibitor. Although the scheme shows the use of paracresol-substituted pyridine as a starting material, the synthesis can be generalized to other aryl, heterocyclic, or alkyl esters. The dianion of 4- (N-trimethylacetyl) -amino-3- (4-methylphenoxy) -pyridine is quenched with tetramethylthiuram disulfide to introduce a 5-mercapto group into the substituted pyridine ring as dithiocarbamate 161. The amine is subsequently deprotected under acidic conditions and the free aniline 162 is acylated with methyl oxalyl chloride to give oxalamide 163. The thiazolopyridine bicyclic nucleus 164 is then prepared by treatment with a mild acid (eg, formic acid at reflux). The ester functionality was converted to the corresponding amide 165 by the amine solution in methanol with warming.

[0116]

Embedded image Related compounds, the imidazopyridines, can be prepared from the intermediates shown in Scheme 40. 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. C).
hem. 1960, 25, 214). After removing the pivaloyl group of 166 with hydrochloric acid, the obtained diaminopyridine 167 can be condensed with methyl oxalyl chloride to give imidazopyridine 168. The ester functionality can then be converted to the amide 169 by treatment with ammonia in methanol as described above.

[0117]

Embedded image Scheme 41 is a diagram of the preparation of thienopyridazine-containing inhibitors. Deprotonating protected thiophenic acid 170 with a strong base (eg, n-butyllithium);
It was reacted with a formylating reagent. The obtained oxazoline aldehyde 171 was hydrolyzed and cyclized with hydrazine to obtain hydroxythienopyridazine 172. The hydroxyl group was converted to chloride 173 by the action of phosphorus oxychloride, followed by substitution with alkoxide to give ether 174. The amide group was introduced into the thienopyridine in a manner similar to that described above to give the amide 176.

[0118]

Embedded image The synthesis of the water-soluble glycosylamide derivative of the general formula 178 is shown in Scheme 42.
With the aid of PyBOP, a thienopyridinecarboxylic acid of general formula 21 or 28 and 2
Tributylphosphine-mediated coupling with 3,3,4,6-tetra-acetyl-D-glucopyranosyl azide afforded a protected glycosylamide of general formula 177. No other isomer was detected in the reaction. Cleavage of the acetyl group with methylamine provided the compound of general formula 178.

[0119]

Embedded image Scheme 43 illustrates the preparation of 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxamide using a modification of the pathway described in Scheme 7. A two-step series was employed to build the thienopyridine nucleus in the synthesis of 182. Treatment of dichloropyridine aldehyde with one equivalent of N-BOC-protected 4-hydroxyaniline provided compound 179, which was cyclized to give ester 180. Conversion to the amide 181 was carried out as described above, and the Boc-group was removed by treatment with trifluoroacetic acid. Aniline 182 acts as a starting material for a Sandmeyer reaction via a diazonium salt, whose amino groups can be converted to various functional groups, including the halogen, hydroxy, cyano groups of other standard sandmeier products. Note what you can do.

[0120]

Embedded image Scheme 44 is based on the methodology described by Buchwald et al. (Wolfe
Buchwald, Stephen L., J .; J. Org. Chem
. 1997, 62, 6066) using 4-substituted aminophenoxythieno [2
1 illustrates a general method for preparing [3-c] pyridine. The iodide 183 prepared by the method described above can be used in the presence of bis (dibenzylideneacetone) dipalladium and BINAP in the presence of a disubstituted amine (such as morpholine described in the above example).
And substituted aniline 184 was obtained.

[0121]

Embedded image Scheme 45 describes the preparation of 4- (4-hydroxymethylphenyl) thieno [2,3-c] pyridine 188 using a modification of the pathway shown in Formula 7. Starting with mono-tritylated 4-hydroxybenzyl alcohol, condensed with dichloroaldehyde 18 and cyclized with methylthioglycolate to give protected benzyl alcohol 188.

[0122]

Embedded image Scheme 46 describes the preparation of protected benzyl alcohol 190, starting from mono-tetrahydropyran-protected hydroxybenzyl alcohol 189. Also, benzyl alcohol analog 188 can be obtained by standard acid-catalyzed hydrolysis of THP groups.

[0123]

Embedded image Also, as shown in Scheme 47, benzyl alcohol 188 can be derivatized to an ester using, for example, the carbodiimide conditions described above, or standard coupling procedures using acid chlorides. Further, the alcohol can be converted to a carbamate (R = N by treatment with isocyanate or carbamoyl chloride).
H ₂ , monosubstituted amino or disubstituted amino).

[0124]

Embedded image The glycoside of benzyl alcohol 187 can be produced using the procedure described in Scheme 48. Alcohol 187 and tri-O-acetyl-D
-Treatment of glucar with stoichiometric scandium triflate gave stereospecific protected glycoside 192, which was deprotected with methylamine to give free glycoside 193.

[0125]

Embedded image Stille coupling of the iodophenyl derivative 194 (or its corresponding bromophenyl analog) with tributylethoxyvinyltin allows the introduction of an acetyl group on the phenyl ether at the 4-position, as shown in Scheme 49. The acetophenone derivative 195 is obtained by hydrolyzing the intermediate vinyl ether during the reaction conditions. Addition of methylmagnesium bromide to ketone 195 at -50 ° C did not give the desired adduct, but conversely isolated aldol adduct 196 in 40% yield. Palladium-catalyzed carbonylation of bromophenoxymethyl ester 197 in an aqueous medium affords acid 198 in moderate yields.
was gotten. PyBOP or EDC mediated coupling with an amine (exemplified above with morpholine) followed by amination of the 2-methyl ester provided the diamide 199.

[0126]

Embedded image Scheme 50 describes the preparation of a cinamide ether. Bromophenoxymethyl ester 197 using tolylphosphine as ligand
Cinnamate 200 in good yield by Heck reaction of
was gotten. Hydrolysis of the t-butyl ester with trifluoroacetic acid followed by PyBOP, or EDC-mediated coupling with an amine followed by amination of the methyl ester gave diamide 201.

[0127]

Embedded image Scheme 51 illustrates the preparation of a 4-heterocyclic phenoxythienopyridine. When the para-cyanophenyl derivative 202 is treated with hydroxyamine in a mixture of DMF and ethanol, hydroxyimidamide 203 is obtained smoothly and oxadiazole 204 is obtained by heating with trifluoroacetic anhydride in pyridine. Was. The cyano derivative 202 was converted to imidazoline 205 under the conditions described above. Still of iodine compound 194 and tributylstannylthiophene
Attachment of other heterocycles using known Stille, Suzuki or Heck conditions as exemplified by e-coupling provided compound 205A. The aryl coupling reactions described above can be applied to compounds using various substituents at C-2 of thienopyridine in addition to the methyl amide illustrated in Scheme 51.

[0128]

Embedded image By the methods described in Scheme 52 and Scheme 53, cyclopropylcarbinyl alcohol derivatives of 4-phenyl ether can be prepared. Commercial phenylcyclopropanecarboxylic acid is converted to the corresponding alcohol 206 by LAH reduction, followed by demethylation of the hydroxymethyl group and selective protection to give phenol 207. Using the procedure of Scheme 7, phenol 2
07 was condensed with dichloroaldehyde 18 and then with methylthioglycolate to give thienopyridine 208. Conversion of the standard yielded the desired compounds 209 and 21
0 was obtained.

[0129]

Embedded image Alcohol 206 was alkylated to give polyether phenol 211 and converted to cyclopropylcarbinyl polyether 212 using a similar procedure described in Scheme 52, as shown in Scheme 53. Such alkylation chemistry is:
It can be done widely by substituting the diether tosylate shown by other alkyl halide or sulfonate esters.

[0130]

Embedded image In Scheme 54, the difluoroacetic acid derivative 213 was synthesized by copper-mediated coupling of iodide 194 and ethyl iododifluoroacetate in the presence of phenol, which was found to significantly inhibit side effects. Ester 21
The reduction of 3 gave difluoroethyl alcohol 214. Alkylation of alcohol 214 with ethoxyethyl tosylate in the presence of sodium hydride and 15-crown-5 provided polyether 215.

[0131]

Embedded image Scheme 55 shows a 4-alkoxythieno [2, via phenolic alkylation
3-c] describes an alternative synthesis of pyridine. Mitsunobu alkylation of 5-chloro-3-hydroxypyridine provided benzyl ether 216, which was deprotonated with an alkyl lithium base and the resulting anion was treated with methyl formate to give pyridinecarboxaldehyde 217. The thienopyridine nucleus was constructed by condensation with methyl thioglycolate under the conditions described above to give ester 218. The method can be applied to other alkyl ethers similar to 216 to obtain various 4-alkoxyl derivatives related to 218. The ester 218 was then converted to another active derivative, such as an amide, using the methods described above. Benzyl ether 218 was hydrocracked to phenol 219 and converted to the corresponding amide 220 by standard procedures. Phenol 219 also acts as a partner in the Mitsunobu reaction with various primary or secondary alcohols to give alkyl ethers of general formula 221 (Huang, F. et al.
J. Med. Chem. 1998, 41, 4216-4223). General formula 221
Was converted to the amide of general formula 222 by treatment with a methanolic amine solution under standard conditions of reflux.

[0132]

Embedded image Thienopyridine analogs having one 4-carbonyl group can be prepared by the procedure described in Scheme 56. Under the conditions described above, dichloropyridine aldehyde 18 was treated with methyl thioglycolate to give 4-chlorothienopyridine ester 223. Transesterification to the acid 224 by base catalyzed hydrolysis and tertiary butyl esterification to 225 was carried out under O-
Performed using t-butyl trichloroacetimidate. Palladium catalyzed carboethoxylation was performed under the conditions described above to give diester 226. Aldehyde 227 was obtained by reduction / oxidation reaction and then condensed with an arylmagnesium halide reagent (exemplified above with 4-chlorophenyl magnesium chloride) to give alcohol 228. Ester 228 can be directly converted to various 2-substituted thienopyridine analogs or can be oxidized to the corresponding 4-keto derivative 230. The synthesis is complete by standard conversion of ester 230 to amide 231. Ester 226 is the first alkaline hydrolysis of the ethyl ester,
It should be noted that coupling to an amine, acidic hydrolysis of a tertiary butyl ester, final coupling to another amine, can be selectively converted to the amide derivative to give 308.

[0133]

Embedded image Various 2-substituted thieno [2,3-c] pyridines have the general formula 20 and 25-2
-Available from esters. Scheme 57 illustrates the products obtainable from the hydroxymethyl derivative of general formula 232. General formula 20 or 25
Reduction of the ester of the formula to calcium borohydride provided the alcohol of general formula 232. Aldehydes of general formula 233 were obtained neatly by Swern oxidation. As exemplified by the preparation of 2-vinylthienopyridine of general formula 234, this versatile intermediate can be converted to an olefin by standard Wittig conditions (Hibino, SJ Org. Chem. 1984, 49, 50).
06-5008). ) Additional modifications to the dihydroxyethyl compound 235 were made by using osmium tetroxide catalyzed with 4-methylmorpholine N-oxide as the stoichiometric oxidant.

[0134]

Embedded image Scheme 58 illustrates the conversion of aldehyde 233 to acrylate 236, which is a Horner-Emmo using trimethylphosphonoacetate.
ns condensation (Jung, ME and Kiankarami,
M. J. Org. Chem. 1998, 63, 2968-2974). The described method can be extended to analogs with various C-4 substituents, including aryloxy, alkoxy, arylamino, aryl, alkyl. Next, the derivative ester 236 was hydrolyzed to obtain an acid 237. Carboxylic acid 237 was subjected to standard coupling conditions to give amide 238. The derivative acrylate of general formula 239 can be oxidized to the corresponding diol of general formula 240 using osmium tetroxide in the presence of 4-methylmorpholine-N-oxide.

[0135]

Embedded image Scheme 59 uses starting materials in the preparation of oxime derivatives of general formula 241
And L_AX_A= Using aldehyde 233 with aryloxy
Explain. The outlined method generally involves various L_AX_AAnalogs with substituents
Applicable to In addition, the aldehyde of the general formula 233 is converted to an organic magnesium
Or an organolithium) reagent to give a secondary alcohol, which is represented by the general formula 2
Oxidized to the corresponding ketone of 42. Oxidation was performed under standard Swern conditions (low temperature CH ₂ C1₂DMSO and oxalyl chloride, and
Treatment with a tertiary amine such as amine).
(Tetra-n-propyltetraoxolthenium (VII) salt, man dioxide
Gun). Thereafter, the ketone is converted to the general formula 243 by the method described above.
Oxime.

[0136]

Embedded image The preparation of the 2-heterocyclic thienopyridine of general formula 249 is illustrated in Scheme 60. Treatment of a primary amide of general formula 26 with an excess of trifluoroacetic anhydride in pyridine affords a smooth nitrile of general formula 244, which acts as a useful intermediate in the preparation of amidine and azole derivatives. Therefore, the general formula 244
Was converted to the amidoxime of general formula 245 by treatment with hydroxylamine hydrochloride and triethylamine. Reaction of the amidoxime of general formula 245 with acetyl chloride, trifluoroacetic anhydride, triethyl orthoformate or trichloroacetyl chloride in pyridine, general formula having a variable site of X determined by the choice of acylating or dehydrating reagent 246 oxadiazoles were obtained. The trichloromethyloxadiazole of the general formula 246 (X = CCl ₃ ) is heated together with ammonia in a sealed tube to give 5-amino-1,4 of the general formula 247.
Converted to 2,4-oxadiazole. When DBU is used as a base and reacted with an excess of cyanamide in THF, the nitrile of the general formula 244 is converted to a compound of the general formula 248
Was converted to cyanoamidine. Thereafter, the cyanoamidine of the general formula 248 is treated with hydroxylamine hydrochloride and triethylamine in methanol to obtain a compound of the general formula 2
49 3-amino-1,2,4-oxadiazole was obtained.

[0137]

Embedded image Scheme 61 illustrates the preparation of a 2-arylcarbonylthienopyridine. The thienopyridine of general formula 44 was deprotonated with an alkyl lithium base and condensed with nitrobenzaldehyde to give benzyl alcohol of general formula 250. General formula 25
Tin (II) -induced reduction of nitrophenyl to the aniline 1 was performed by selective alcohol oxidation using pyridinium chlorochromate. Further, the nitrobenzyl alcohol of general formula 250 was converted to the corresponding ketone of general formula 253 under Swern conditions (eg, treatment with low temperature oxalyl chloride / DMSO / CH ₂ Cl ₂ , and further with an amine base).

[0138]

Embedded image Scheme 62 describes the preparation of 2-carbamate thienopyridine and 2-urea thienopyridine. The alcohol of general formula 232 was converted to amines of general formula 254 by Mitsunobu reaction with phthalimide and further deprotection with hydrazine. The amine of general formula 254 was converted to the corresponding urea derivative of general formula 255 by reaction with potassium isocyanate under acidic conditions. Similarly, the alcohol of general formula 232 was converted to the corresponding carbamate of general formula 256. This chemistry is generally applicable to the use of substituted isocyanates or carbamoyl chlorides, resulting in mono- or disubstituted carbamate or urea derivatives.

[0139]

Embedded image Scheme 63 shows the 2-aminothienopyridine of general formula 54,
2 illustrates the preparation of thiourea thienopyridine. Reaction of 54 with the substituted isothiocyanate in pyridine at reflux provided the thiourea of general formula 257.

[0140]

Embedded image Scheme 64 illustrates the synthesis of a sulfonamide at the 2-position of a thienopyridine. 4 shows an improved method for the decarboxylation of thienopyridine-2-carboxylic acid, wherein a thienopyridine of general formula 44 is obtained in high yield by heating an acid of general formula 21 at 210 ° C. in diphenyl ether. Compound 44 was deprotonated with a strong base and then treated with sulfur dioxide to give the intermediate sulfinic acid. Addition of N-chlorosuccinimide affords the sulfonyl chloride of general formula 258, which is then reacted with ammonia, primary or secondary amine in the presence of diisopropylethylamine in a protic solvent such as methanol, and then reacted with general formula 25
Nine different sulfonamides were prepared (Prough, JD et al., J. Med.
Chem. 1991, 34, 1805-1818; Davidsen, S .; K
. Et al. Med. Chem. 1998, 41, 74-95).

[0141]

Embedded image Scheme 65 provides an overview on the synthesis of new 2-arylthienopyridines having an amino or hydroxyl group on the aryl ring. Suzuki of nitro-substituted aryl iodides with boronic acids of general formula 79 using the method of Scheme 24
Coupling provided the biaryl of general formula 260. The biaryl of general formula 260 was reduced with tin (II) chloride to the aminophenyl derivative of general formula 261. The methyl ether of general formula 262 is prepared from boronic acid 79 by coupling with methoxyiodobenzene and converted to the hydroxy derivative of general formula 263 by using boron tribromide to demethylate the methyl ether. did.

[0142]

Embedded image Schemes 66-71 illustrate the synthesis for an additional 5-membered heterocycle at the 2-position of the thienopyridine. Scheme 66 outlines a method for producing 1,3,4-oxadiazole. The hydrazide of general formula 264 was prepared by treating an ester of general formula 20 or 25 with hydrazine in methylene chloride. The hydrazide is reacted with cyanogen bromide to give 5-amino-1 of the general formula 265.
, 3,4-oxadiazole. The hydrazide of the general formula 264 can be converted to the 5-unsubstituted-1,1 of the general formula 266 by condensation with an orthoester under reflux conditions.
It can be converted to 3,4-oxadiazole or 5-alkyl-substituted-1,3,4-oxadiazole.

[0143]

Embedded image Scheme 67 illustrates a method for preparing a 1,3,4-triazole from a methyl ester of general formula 20 or 25. By condensation with aminoguanidine under basic conditions (eg sodium methoxide in methanol),
67 2-amino-1,3,4-triazoles were obtained. Non-specific methylation is carried out using sodium hydride and methyl iodide using 1,3,4 of the general formula 267.
Carried out with a triazole, a monomethyltriazole of the general formula 268, a general formula 26
9 and trimethyltriazole of the general formula 270 were obtained, which were separable by chromatography.

[0144]

Embedded image Scheme 68 illustrates a method for preparing a 1,3,4-thiadiazole of general formula 272. Reaction of an acid chloride derived from an acid of general formula 21 or 28 with thiosemicarbazide or a substituted thiosemicarbazide provides an intermediate acylated thiosemicarbazide of general formula 271 and acid catalysis (eg, methanesulfone at toluene reflux). Cyclization under acid) gave the thiadiazole of general formula 272.

[0145]

Embedded image Scheme 69 comprises 1,3,4-oxadiazole-2-thione and general formula 2
Methods are provided for the preparation of 74 derived alkylthio substituted oxadiazoles. General formula 2
Treatment of 64 hydrazides with potassium disulfide in potassium hydroxide dissolved in an aqueous ethanol solution gave the cyclic thiocarbamates of general formula 273. The thiocarbonyl group was alkylated with an alkyl halide in low yield to obtain alkylthio 1,3,4-oxadiazole of the general formula 274.

[0146]

Embedded image Scheme 70 illustrates the preparation of tetrazole at the 2-position of thienopyridine.
The 2-cyano derivative of general formula 244 was converted to a tetrazole of general formula 275 using trimethylsilyl azide in the presence of dibutyltin oxide as a catalyst. Tetrazole was converted to the N-methyl derivative of general formula 276 using a diazomethane solution in methanol.

[0147]

Embedded image Scheme 71 illustrates the synthesis of 2-oxazole and 2-imidazole thienopyridine. The chloroethylamide of general formula 277 was prepared by chlorination of the corresponding hydroxyethylamide and then cyclized to an oxazoline of general formula 278 under a base catalyst (eg, diazabicycloundecane in dichloromethane). Oxazolines of general formula 278 can be converted to oxazoles of general formula 278 by dehydrogenation according to the method of Meyer et al. (Meyers,
A. I. J. et al. Amer. Chem. Soc. 1975, 97, 7383).
The aminoethylamide of general formula 280 was cyclized to imidazoline of general formula 281 by treatment with calcium oxide in diphenyl ether at elevated temperature. Imidazolines of general formula 281 can be converted to imidazoles of general formula 282 by literature methods (Hughey, JL et al., Synthesi).
s [SYNTBF] 1980, (6), 489).

[0148]

Embedded image Scheme 72 illustrates an improved method for preparing 3-alkyl-substituted thienopyridines of general formula 115. Aldehyde 18 was condensed with preformed potassium phenoxide to give a mixture of mono- and disubstituted aryloxyaldehydes. Next, this mixture was reacted with a desired Grignard reagent, and then the obtained mixture of secondary alcohols was subjected to a Swern oxidation treatment to obtain a desired aryloxy ketone compound. Further, the mixture of aryloxy ketones is reacted with methylthioglycolate in the presence of cesium carbonate to form 2,3,3 of the general formula 114
The 4-trisubstituted thieno [2,3-c] pyridine ester was obtained. These esters were converted to the corresponding acids by hydrolysis with lithium hydroxide and then coupled with various amines, for example, with carbodiimide, to give the desired amide of general formula 115.

[0149]

Embedded image Scheme 73 provides for the synthesis of 3-carboxythienopyridine. Using a methodology similar to that described for the preparation of 20 or 25, 3,5-dichloropyridine is treated at low temperature with a strong base such as lithium diisopropylamide in anhydrous ethereal solvent, followed by t-butylchlorooxoacetate. Was added to give the 4-tert-butyl-2-ketoester of 3,5-dichloropyridine 283. The ester 283 was then reacted at room temperature with 1.25 equivalents of preformed potassium phenoxide to give the monoaryloxy derivative as the major product.
Without purification, the monoaryloxy ester is treated with methyl thioglycolate and a base such as potassium t-butoxide or cesium carbonate to give the desired compound of general formula 2
84 thienopyridine diester was obtained. Thereafter, the diester of general formula 284 was treated with a methanolic amine to give the corresponding 3-t-butyl ester amide of general formula 285. The t-butyl ester amide of general formula 285 was converted to the corresponding acid amide of general formula 287 by solvolysis using trifluoroacetic acid. further,
The diester of general formula 284 can be converted to the acid of general formula 286 by a similar solvolysis reaction.

[0150]

Embedded image Scheme 74 shows a scheme for preparing 4-amino-substituted thienopyridine derivatives.
It describes the use of bromothienopyridine 32. Ester 32 is converted to the amide of general formula 288 by standard methods and then variously catalyzed using palladium (0) catalysis as described by Buchwald (J. Org. Chem. 1997, 62, 6066-6068). Coupling to various amines, general formula 2
The 4-amino derivative of 89 was obtained.

[0151]

Embedded image Scheme 75 outlines the preparation and reaction of 7-chlorothienopyridine and 7-bromothienopyridine derivatives. Analogs serve as synthetic intermediates for various 7-substituted thienopyridines and are useful for preparing active derivatives. The ester of the general formula 25 is metachloroperbenzoic acid and is represented by the general formula 29
Oxidized to 0 pyridine-N-oxide. The N-oxide was rearranged to a 7-halogen derivative of the general formula 291 by heating in phosphorus oxychloride or phosphorus oxybromide. The resulting 7-halide can be converted to the amide derivative of general formula 292 by standard methods without reaction of the 7-chloro or 7-bromo component. However, under further forcing conditions, replacement of the chloro or bromo group with an amine or alcohol provides a 7-amino derivative of general formula 293,
And a 7-alkoxy derivative of the general formula 294 can be obtained. The ester of general formula 294 was converted to the amide of general formula 295 using standard methods. The 7-hydroxy analog of general formula 296 was prepared from the derivative of 291 using acetic anhydride, followed by hydrolysis with water. Further, the 7-halogen derivative 2
91, especially the 7-Moromo derivative, was an effective educt in the Suzuki reaction with arylboronic acids, as described in Scheme 19 and Scheme 65.

[0152]

Embedded image Scheme 76 describes the preparation of a furopyridine analog such as 299 (Example 327). By a procedure analogous to that of the preparation of 20 or 25, low yields of furopyridine esters are obtained by successively reacting dichloropyridinecarboxaldehyde 18 with potassium phenoxide and then with ethyl glycolate and further cyclizing under basic conditions. 298 were obtained. Amide 299 was obtained by standard hydrolysis and coupling conditions. The amide was converted to thioamide 300 by treatment with Lawesson's reagent in heated toluene.

[0153]

Embedded image Scheme 77 illustrates the preparation of N-alkyl 5-amino-1,3,4, -oxadiazole. Treatment of 265 with refluxing trimethyl orthoformate and further reduction of the eneamine intermediate with sodium borohydride in refluxing ethanol provides N-alkylated 5-amino-1,3,4, -oxadiamides of general formula 301. An azole is obtained.

[0154]

Embedded image Scheme 78 illustrates the synthesis of a substituted vinyl moiety at the 4-position of a thienopyridine. Aldehyde 2 in the presence of potassium bis (trimethylsilyl) amide
Treatment of 27 with the appropriate diethylphosphonate provided 302.
Thereafter, treatment of compound 302 with sulfuric acid in methanol provided methyl ester 303, followed by standard amide formation using ammonia and methanol to give 4-vinyl-substituted thienopyridine of general formula 304. The introduction of substituted vinyls can also be achieved by using Wittig phosphorane chemistry.

[0155]

Embedded image Scheme 79 illustrates the preparation of a 4-substituted alkyl thienopyridine. The alcohol 228 was subjected to palladium on carbon in acetic acid to produce the methylene derivative 305. Treatment of 305 with sulfuric acid in methanol gave 306. Amide formation was performed by treating 306 with ammonia in methanol to give 307.

[0156]

Embedded image Scheme 80 illustrates the preparation of a thiazole derivative at the 2-position of a thienopyridine. The thioamide of general formula 309 was alkylated and cyclized with ethyl bromopyruvate to give the thiazole ester of general formula 310. Standard amide formation provided the amide of general formula 311. Other amines can be used to obtain various substituted amides. Further, the ester of general formula 310 is an intermediate acid Cu
It can be converted to a carbamate of the general formula 312 via the rtius rearrangement. The t-butyl carbamate of the general formula 312 was converted to a primary amine of the general formula 313 by the action of trifluoroacetic acid.

[0157]

Embedded image Scheme 81 outlines an alternative method of preparing 3-substituted thienopyridines, where Ar is unsubstituted aryl or substituted aryl, or heterocycle, and R is alkyl, alkoxy, substituted alkyl, aryl, arylalkyl It is. Reaction of aldehyde 18 with the appropriate organomagnesium halide provided the intermediate secondary alcohol, which was oxidized to the corresponding ketone 314. The method of oxidation was the Swern method, but other standard oxidation methods of this type can also be used (eg, PCC, TPAP). The above method was then performed on the 3-unsubstituted analog to give ester 315. The ester 315 then served as the starting material in the preparation of amide or other heterocyclic derivatives at the 2-position of thienopyridine.

[0158]

Embedded image Scheme 82 describes a method for producing a cyclic derivative between the 2- and 3-positions of thienopyridine. The 3-methyl derivative 115 was treated with N-bromosuccinimide (or N-chlorosuccinimide) in carbon tetrachloride to obtain a bromomethyl (or chloromethyl) compound 316 (X = Br, Cl). Then
Compound 316 can be reacted with a primary amine via alkylation and acylation to give tricyclic lactam 317. Further treatment of compound 316 with sodium alkoxide or sodium aryl oxide (R ² = alkyl, aryl or heterocycle) provided the 3-position extended alkoxymethyl derivative 318. These esters can be reacted sequentially with a substituted amine to give the corresponding amide 319.

The compounds and processes of the present invention may be better understood with reference to the following examples. However, the examples are intended to illustrate the scope of the present invention,
It does not limit the scope of the invention.

Example 1 Methyl 2-[(6-ethylthieno [2,3-d] pyrimidin-4-yl) thio] acetate Example 1A 6-ethyl-3,4-dihydro-4-oxothieno [2,3 -D] Methyl pyrimidine-2-carboxylate The desired compound is described in Heterocyclic Chem. 1987, 24,
Prepared as described in 581-587.

Example 1B 6-Ethylthieno [2,3-d] pyrimidin-4 (3H) -one Example 1A (35 g, 140 m) in DMSO (80 mL) and water (8 mL)
mol) and LiCl (6.5 g, 153 mmol) were heated to 150 ° C. for 18 hours, cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated to give the specified compound.

Example 1C Example 1B (3.97 g, 22.0 mmol) in 4-chloro-6-ethylthieno [2,3-d] pyrimidine POCl ₃ (22 mL) was heated to reflux for 2 hours and cooled Then, poured on ice, diluted with water, made alkaline with concentrated ammonium hydroxide and extracted with ethyl acetate. The extract is dried (Mg
SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate-hexane to give the specified 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 treated sequentially 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 hours.
Cooled, poured into water, diluted with brine and extracted with dichloromethane. The extract was washed with water and brine, dried (MgSO _4), filtered, and concentrated.
The residue was triturated and washed with 10% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 269 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33 (t, 3H);
99 (q, 2H), 3.75 (s, 2H), 4.26 (s, 3H), 7.23 (
s, 1H), 8.76 (s, 1H).

Example 2 Example 1D except that thiocresol was used in place of methyl 6-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-d] pyrimidine thioglycolate
Treated Example 1C as described in the title compound to afford the title compound.

MS (DCI / NH ₃ ) m / z 286 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.32 (t, 3H);
38 (s, 3H), 2.99 (q, 2H), 7.20 (s, 1H), 7.33 (
m, 2H), 7.52 (m , 2H), 8.63 (s, 1H); Calcd for analysis _{C 15 H 14 N 2 S 2} : 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 Performed as in Example 1D, except that 2-mercaptopyridine was used instead of methyl thioglycolate. Treatment of Example 1C provided the title compound.

MS (DCI / NH ₃ ) m / z 274 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (t, 3H);
99 (q, 2H), 7.18 (s, 1H), 7.46 (dt, 1H), 7.81
(D, 1H) 7.90 (dt, 1H) 8.60 (m, 1H), 8.74 (s, 1
H).

Example 4 6-Ethyl-4-[(2-methylethyl) thio] thieno [2,3-d] pyrimidine As in Example 1D, except that isobutylmercaptan was used instead of methyl thioglycolate. To Example 1C to give the title compound.

MS (DCI / NH ₃ ) m / z 253 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.08 (d, 6H);
39 (t, 3H), 2.03 (hep, 1H), 2.95 (q, 2H), 3.2
8 (d, 2H), 7.01 (s, 1H), 8.71 (s, 1H); Calcd for analysis _{C 12 H 16 N 2 S 2} : 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 Performed as in Example 1D, except that benzyl mercaptan was used instead of methyl thioglycolate. Treatment of Example 1C provided the title compound.

MS (DCI / NH ₃ ) m / z 287 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
96 (q, 2H), 4.65 (s, 2H), 7.16 (s, 1H), 7.21 to 21
7.36 (m, 3H), 7.46 (m, 2H), 8.83 (s, 1H); Calcd for analysis _{C 15 H 14 N 2 S 2} : 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)
Example 1C was treated as in Example 1D, except that 5-methyl-1,3,4-thiadiazole-2-thiol was used instead of methyl thio] thieno [2,3-d] pyrimidine thioglycolate. do it,
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 295 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (t, 3H);
82 (s, 3H), 3.05 (q, 2H), 7.42 (s, 1H), 8.88 (
s, 1H); Calculated for C ₁₁ H ₁₀ N ₄ S ₃ : 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-6-carboxylate Example 1A was treated as in Examples 1C and 2. To give the title compound.

MS (DCI / NH ₃ ) m / z 359 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26 (t, 3H);
31 (t, 3H), 2.39 (s, 3H), 3.02 (q, 2H), 4.27 (
q, 2H), 7.17 (s, 1H), 7.33 (m, 2H), 7.57 (m, 2
H); Calcd for analysis _{C 18 H 18 N 2 O 2} S 2: C, 60.31, H, 5.0
6, N, 7.81. Found: C, 60.44; H, 4.88; N, 7.65.

Example 8 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidine-4-
Example 1C (0.27 g, 1.37 mm) in amine isopropanol (1.5 mL)
ol) was treated with benzylamine (0.19 mL, 1.71 mmol) and sodium carbonate (0.24 g, 2.3 mmol), stirred at room temperature overnight, filtered and concentrated. The residue was purified by flash chromatography on silica gel using 25% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 270 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
88 (q, 2H), 4.72 (d, 2H), 7.20 to 7.40 (m, 6H),
8.26 (s, 1H), 8.34 (t, 2H); Calcd for analysis _{C 15 H 15 N 3 S 2} : C, 66.89, H, 5.61,
N, 15.60. Found: C, 66.66, H, 5.43, N, 15.43.

Example 9 Example in 6-ethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) thieno [2,3-d] pyrimidin-4-amine isopropanol (2 mL) 1C (0.20 g, 1.01 mmol
) Was dissolved in 2-amino-5-methyl-1,3,4-thiadiazole (0.15 g).
, 1.26 mmol) and sodium carbonate (0.18 g, 1.7 mmol) and stirred at room temperature for 48 hours, cesium carbonate (0.55 g, 1.7 mmol)
) And stirred under reflux for 24 hours, concentrated, treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was recrystallized using ethanol / water to give the title compound.

MS (DCI / NH ₃ ) m / z 278 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33 (t, 3H);
63 (s, 3H), 2.96 (q, 1H), 7.81 (br s, 1H), 8.
65 (s, 1H); Calcd for analysis _{C 11 H 11 N 5 S 2} : 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-ethylthiophen-3-carboxamide Heterocyclic Chem. 1987, 24,
Prepared as described in pp. 581-587.

Example 10B 5-Ethyl-2-[(phenylacetyl) amino] -3-thiophenecarboxamide Example 10A was prepared according to Bull. Soc. Chim. France 1975, p8
Treatment as described in 15 provided the specified compound.

Example 10C 6-Ethyl-2-phenylmethylthieno [2,3-d] pyrimidine-4 (3H
) - On dioxane / water, Example 10B was stirred in the presence of 10% _Na 2 CO _3,
The specified compound was obtained.

Example 10D 4-Chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine Example 10C was treated as in Example 1C to give the specified 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-1,3,4-thiadiazole-2-thiol were treated as in Example 1D to give the title compound. I got

MS (DCI / NH ₃ ) m / z 386 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (t, 3H);
97 (q, 2H), 4.17 (s, 2H), 7.17 to 7.30 (m, 6H),
7.70 (br s, 2H); Calcd for analysis _{C 17 H 15 N 5 S 3} : C, 52.96, H, 3.92,
N, 18.17. Found: C, 53.10, H, 3.74, N, 18.03.

Example 11 Example 1D except that p-thiocresol was used in place of methyl 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyrimidine glycolate
Treatment of 3-methyl-7-chlorothieno [3,2-d] pyrimidine as in afforded the title compound.

MS (DCI / NH ₃ ) m / z 273 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.40 (s, 6H), 7.
36 (m, 2H), 7.57 (m, 2H), 8.04 (s, 1H), 8.88 (
s, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : C, 61.73, H, 4.44
, N, 10.28. Found: C, 61.73; H, 4.50; N, 10.21.

Example 12 7-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-
Treatment of 1,3,4-thiadiazole-2-thiol as in Example 1D provided the title compound.

[0190] mp _{^{144~147 ℃; MS (DCI / NH}} 3) m / z281 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.44 (s, 3H), 2.
83 (s, 3H), 8.20 (s, 1H), 9.08 (s, 1H); Calcd for analysis _{C 10 H 8 N 4 S 3} : C, 42.84, H, 2.88, N
, 19.98. Found: C, 42.72; H, 2.83; N, 19.64.

Example 13 7-Methyl-4-[[5- (methylthio) -1,3,4-thiadiazole-2
-Yl] thio] thieno [3,2-d] pyrimidine Examples of 3-methyl-7-chlorothieno [3,2-d] pyrimidine and 5- (methylthio) -1,3,4-thiadiazole-2-thiol Treatment as in ID gave the title compound.

MS (DCI / NH ₃ ) m / z 313 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.45 (s, 3H);
83 (s, 3H), 8.22 (s, 1H), 9.11 (s, 1H); Calcd for analysis _{C 10 H 8 N 4 S 4} : 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-
Treatment of 1,3,4-thiadiazole-2-thiol as in Example 1D provided the title compound.

MS (DCI / NH ₃ ) m / z 282 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.43 (s, 3H), 7.
80 (br s, 2H), 8.15 (s, 1H), 9.02 (s, 1H); Calculated for C ₉ H ₇ N ₅ S ₃ : 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-4-amine of 3-methyl-7-chlorothieno [3,2-d] pyrimidine The ethanol solution was treated with 4- (methylmercapto) aniline, stirred under reflux for 45 minutes, cooled to room temperature and filtered, and the precipitate was recrystallized from ethanol / water to give the title compound.

MS (DCI / NH ₃ ) m / z 288 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (s, 3H);
48 (s, 3H), 7.29 (m, 2H), 7.76 (m, 2H), 7.87 (
br s, 1H), 8.60 (s, 1H), 9.63 (br s, 1H); Analysis Calculated for C ₁₄ H ₁₃ N ₃ S ₂ : 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- (methyl Phenyl) thio] thieno [3,2-d] pyrimidine-2-carboxylic acid A solution of LDA at −78 ° C. (0.1 M in THF, 9.6 mL) was prepared in Example 11 (0
. 26 g, 0.96 mmol), warm to 0 ° C. over 1 hour, pour constantly swirl onto dry ice, quench with saturated NH ₄ Cl, 3:
Extracted with 1 chloroform / isopropanol. Concentrate the extract and reduce the residue to 7%
Purification by flash chromatography on silica gel with methanol / dichloromethane provided the specified compound.

Example 16B 7-Methyl-4-[(4- (methylphenyl) thio] thieno [3,2-d] pyrimidine-2-carboxamide Suspension of Example 16A in dichloromethane (3.3 mL) To oxalyl chloride (
(0.03 mL, 0.33 mmol) and DMF (1 drop) and concentrated after acid chloride formation. The residue was suspended in THF (10 mL), transferred to a vigorously stirred 1: 1 ammonium hydroxide / water solution (10 mL) and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was recrystallized from ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.40 (s, 3H);
58 (s, 3H), 7.35 (m, 2H), 7.57 (m, 2H), 8.01 (
br s, 2H), 8.93 ( s, 1H); Calcd for analysis _{C 15 H 13 N 3 OS 2} : C, 57.12, H, 4.15
, N, 13.32. Found: C, 56.81, H, 4.06, N, 13.25.

Example 17 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-
Methyl carboxylate Example 17A 3,5-dichloropyridine-4-carboxaldehyde Diisopropylamine (15.6 mL, 0 mL in 0 ° C. dry THF (25 mL))
. 111 mol) with n-butyllithium (44.6 mL, 2.5 M in hexane, 0.111 mol) for 35 minutes, stir for 30 minutes, cool to -78 ° C., and dilute with THF (100 mL). 3,5- in THF (175 mL)
Dichloropyridine (15.0 g, 0.101 mol) was added slowly over 3.5 hours to keep the internal temperature below -74 ° C. The solution was stirred at −78 ° C. for 30 minutes, and methyl formate (12.5 mL, 0.20 mL) in THF (50 mL) was added.
(3 mmol) was added dropwise over 35 minutes while maintaining the internal temperature below -74 ° C, stirred at -78 ° C for 1.4 hours and quickly added to an ice-cold solution of saturated NaHCO ₃ with vigorous stirring. Cannulated, partitioned with ethyl acetate (500 mL), extracted sequentially with saturated NaHCO ₃ (2 × 100 mL) and brine ( ₃ × 150 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using 10% acetone / hexane.

MS (DCI / NH ₃ ) m / z 176, 178, 180 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 added to p.
-Thiocresol (3.56 g, 28.7 mmol) and potassium carbonate (4.5.
36 g, 31.6 mmol) and stirred at 0 ° C. for 0.5 h, then at room temperature for 1 h, poured into water, 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 designated compound.

Example 17C Methyl 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxylic acid The solution of Example 17B was treated as in Example 1D The title compound was obtained.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
91 (s, 3H), 7.20 (m, 2H), 7.29 (m, 2H), 8.00 (
s, 1H), 8.44 (s, 1H), 9.36 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ N ₂ S ₂ .0.25H ₂ O: C, 60.07
, H, 4.25, N, 4.37. Obtained values: C, 60.04, H, 4.08, N,
4.27.

Example 18 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-
Example 17C (2.C) in carboxylic acid isopropanol (25 mL) and water (15 mL).
(G, 635 mmol) and a suspension of LiOH.H ₂ O (1.4 g, 32 mmol) were heated to 75 ° C. for 1 hour, cooled, 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.

MS (DCI / NH ₃ ) m / z 302 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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 Example 18 (0.535 g, 1.78) in dichloromethane (25 mL) at 0 ° C.
mmol) was treated sequentially with oxalyl chloride (0.34 g, 2.67 mmol) and DMF (1 drop), stirred at room temperature for 0.5 h, and concentrated. Residue T
Suspended in HF solution, THF (60 mL), water (30 mL) and concentrated NH ₄ O
Treated with H (30 mL) and stirred for 0.5 h. The THF layer was separated, washed with brine, partially dried (MgSO ₄ ), filtered and concentrated. 5% residue
Purification by flash chromatography on silica gel with methanol / dichloromethane and recrystallization from 95% ethanol gave the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H), 7.
20 (m, 2H), 7.30 (m, 2H), 7.89 (brs, 1H), 8.
26 (s, 1H), 8.35 (s, 1H), 8.54 (brs, 1H), 9.
16 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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 Example 17B, except that 2-mercaptopyridine was used in place of p-thiocresol in Example 17B. Example 17 as in 17C, 18 and 19
Treatment of A gave the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + NH ₄ ) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.99 (d, 1 H), 7.
17 (dd, 1H), 7.65 (dt, 1H), 7.85 (brs, 1H),
8.18 (s, 1H), 8.36 (m, 1H), 8.49 (br s, 1H),
8.69 (s, 1H), 9.23 (s, 1H); Calcd for analysis _{C 13 H 9 N 3 OS 2} : 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 Performed as in Example 17B, except that 4-chlorothiophenol was used instead of p-thiocresol. Example 17 as in Examples 17B, 17C, 18 and 19
Treatment of A gave the title compound.

MS (DCI / NH ₃ ) m / z 321 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.38 (s, 1H); Calcd for analysis _{C 14 H 9 ClN 2 OS 2} : C, 52.42, H, 2.8
3, N, 8.73. Found: C, 52.33, H, 2.80, N, 8.63.

Example 22 N-methoxy-N-methyl-4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide Example 18 (0.66 g, 2.2 mmol) in dichloromethane was treated sequentially with oxalyl chloride (0.29 mL, 3.3 mmol) and DMF (1 drop) to give 30 Stirred for minutes and concentrated. The residue was suspended in THF and transferred to a solution of N, O-dimethylhydroxylamine hydrochloride (0.32 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) in 1: 1 THF / water. Stir for 5 minutes. Separating the THF layer, dried (MgSO _4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 345 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
34 (s, 3H), 3.74 (s, 3H), 7.19 (m, 2H), 7.27 (
m, 2H), 8.02 (s , 1H), 8.46 (s, 1H); Calcd for analysis _{C 17 H 16 N 2 O 2} S 2: C, 59.28, H, 4.6
8, N, 8.13. Found: C, 58.76, H, 4.58, N, 8.06.

Example 23 N-Methoxy-4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxamide O-methylhydroxyl hydrochloride in place of N, O-dimethylhydroxylamine hydrochloride Example 18 was treated as in Example 22 except using an amine to give the title compound.

MS (DCI / NH ₃ ) m / z 331 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
76 (s, 3H), 7.20 (m, 2H), 7.30 (m, 2H), 7.89 (
br s, 1H), 8.15 (s, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
1H); Analysis _{C 16 H 14 N 2 O 2} S 2 · 0.25H Calcd for ₂ O: C, 58.
16, H, 4.27, N, 8.48. Obtained: 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) and refluxed. For 20 minutes and concentrated. The residue was suspended in (3: 1) benzene / dichloromethane (4 mL), treated with trimethylamine (0.5 mL) and 4-chloroaniline (46 mg, 0.36 mmol), stirred under reflux overnight, and concentrated did. The residue was treated with water and extracted with dichloromethane. The extract is dried (Mg
SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 411 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.31 (s, 1H)
H), 10.90 (br s, 1H); Calcd for analysis _{C 12 H 15 ClN 2 OS 2} : C, 61.38, H, 3.
68, N, 6.2. Found: C, 61.22, H, 3.67, N, 6.79.

Example 25 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxaldehyde THF of Example 22 (3.33 g, 9.6 mmol) at -5 ° C. The solution was treated dropwise with 1M DIBAl-H in THF (14.5 mL, 14.5 mmol),
Stir for 45 minutes, pour into ice / HCL with constant stirring and extract 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 (300 MHz, 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 , 1H), 10.23 (s, 1H); Calcd for analysis _{C 15 H 11 NOS 2: 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-methyl oxime 1: 1 in pyridine: ethanol (8 mL) Example 25 (0.22 g, 0.7
Methoxylamine hydrochloride (0.51 mL, 1.52 mmol)
), Stirred at room temperature for 3 hours, concentrated, treated with water, and extracted with dichloromethane. The extract was washed with 1N HCl, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
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 (s, 0.6H), 8.38 (s, 0.4H)
H), 8.68 (s, 0.6H), 9.20 (s, 0.6H), 9.30 (s, 0.6H).
0.4 H); Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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 The stirring time was changed from 3 hours to 18 hours Treated Example 25 and O-benzylhydroxylamine hydrochloride as in Example 26 to give the title compound.

MS (DCI / NH ₃ ) m / z 391 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
22 (s, 1.2H), 5.38 (s, 0.8H), 7.15 to 7.26 (m,
4H), 7.31 to 7.47 (m, 5H), 7.78 (s, 0.6H), 7.9
6 (s, 0.4H), 8.31 (s, 0.4H), 8.36 (s, 0.6H),
8.39 (s, 0.4H), 8.74 (s, 0.6H), 9.20 (s, 0.6H)
H), 9.30 (s, 0.4H ); Calcd for analysis _{C 22 H 18 N 2 OS 2} : C, 67.66, H, 4.65
, N, 7.17. Found: C, 67.45, H, 4.80, N, 7.13.

Example 28 2-[[[4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-ylmethylene] amino] oxy] acetic acid carboxy hemihydrochloride instead of methoxylamine hydrochloride Example 25 was treated as in Example 26 except using methoxylamine to give the title compound.

MS (DCI / NH ₃ ) m / z 359 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
71 (s, 2H), 7.19 (m, 2H), 7.25 (m, 2H), 7.84 (
s, 1H), 8.36 (s, 1H), 8.79 (s, 1H), 9.20 (s, 1)
H); Calcd for analysis _{C 17 H 14 N 2 O 3} S 2: C, 56.97, H, 3.9
4, 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-phenyloxime O-phenylhydroxylamine hydrochloride is used instead of methoxylamine hydrochloride. Example 25 was treated as in Example 26 except used to afford the title compound.

MS (DCI / NH ₃ ) m / z 337 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 7.
09 to 7.50 (m, 9H), 7.98 (s, 0.5H), 8.16 (s, 0.
5H), 8.39 (s, 0.5H), 8.42 (s, 0.5H), 8.71 (s
, 0.5H), 9.16 (s, 0.5H), 9.27 (s, 0.5H), 9.3
7 (s, 0.5H); Calcd for analysis _{C 21 H 16 N 2 OS 2} : 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 Except that hydroxylamine hydrochloride was used instead of methoxylamine hydrochloride. Example 25 was treated as in 26 to give the title compound.

[0230] mp _{^{209~210 ℃; MS (DCI / NH}} 3) m / z301 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.28 (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); Calcd for analysis _{C 15 H 12 N 2 OS 2} : C, 59.98, H, 4.03
, N, 9.33. Found: C, 59.80, H, 4.08, N, 9.30.

Example 31 2-[[[4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-ylmethylene] amino] oxy] acetamide Example 28 is in Example 19. To give the title compound.

MS (DCI / NH ₃ ) m / z 358 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H);
52 (s, 0.6H), 4.66 (s, 0.4H), 7.19 (m, 2H), 7
. 25 (m, 2H), 7.32 (brs, 1H), 7.40 (brs, 1H)
), 7.84 (s, 0.6H), 7.97 (s, 0.4H), 8.32 (s, 0H).
. 4H), 8.37 (s, 0.6H), 8.40 (s, 0.4H), 8.75 (
s, 0.6H), 9.21 (s , 0.6H), 9.32 (s, 0.4H); Analysis _{C 17 H 15 N 3 O 2} S calculated for ₂ · (1.25H ₂ O) Value: C, 5
7.12, H, 4.23, N, 11.76. Obtained: C, 56.19, H, 4.
48, N, 10.94.

Example 32 (E) -3-[(4-Methylphenyl) thio] thieno [2,3-c] pyridin-2-yl] -2-propenamide Example 25 (10 mL) in chloroform (10 mL) 0.23 g, 1.27 mmol)
To carbamoylmethylenetriphenylphosphorane (0.41 g, 1.27 mmol
Treated with 1), heated to reflux for 30 hours, cooled and concentrated. The residue was purified by flash chromatography on silica gel using 2% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 327 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H), 6.
64 (d, 1H), 7.19 (m, 2H), 7.25 to 7.37 (m, 3H),
7.68 to 7.82 (m, 3H), 8.35 (s, 1H), 9.19 (s, 1H)
); Analysis _{C 17 H 14 N 2 OS 2} · H 2 Calculated for O: C, 62.55, H,
4.32, N, 8.58. Obtained: C, 59.78, H, 4.50, N, 8.2
0.

Example 33 1- [4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone A solution of Example 22 in THF (25 mL) at 0 ° C. was treated with methyl magnesium bromide (
Treat with 1.4 M in toluene / THF, 1.85 mL, 2.6 mmol), warm to room temperature, stir overnight, and add methylmagnesium bromide (1.4 in toluene / THF).
M, 0.7 mL, 1.3 mmol), stir for 1 h, and add ice / NH ₄ Cl
Poured in a continuous swirl over top and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.33 (s, 3H);
71 (s, 3H), 7.24 (m, 2H), 7.38 (m, 2H), 8.28 (
s, 1H), 8.31 (s, 1H), 9.29 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ NOS ₂ : C, 64.19, H, 4.38,
N, 4.68. Found: C, 64.11; H, 4.41; N, 4.61.

Example 34 2-Benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c]
Treatment of pyridine Example 22 and phenyllithium as in Example 33 provided the title compound.

MS (DCI / NH ₃ ) m / z 362 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Analysis C ₂₁ H ₁₅ NOS ₂ · 1.25H Calcd for ₂ O: C, 65.68
, H, 4.59, N, 3.64. Obtained: 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 in ethylene glycol (10 mL) was treated with hydrazine hydrate (
0.18 mL, 5.8 mmol), stir at 160 ° C. for 30 minutes, cool to room temperature, treat with potassium hydroxide, stir at 150 ° C. for 45 minutes, cool to room temperature, and add water Work up and extract with ethyl acetate. The extract is washed with water and 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 (300 MHz, DMSO-d ₆ ) δ 1.28 (t, 3H);
26 (s, 3H), 2.99 (q, 2H), 7.14 to 7.27 (m, 5H),
8.34 (s, 1H), 9.11 (s, 1H); Analysis C ₁₆ H ₁₅ NS ₂ · 0.25H Calcd for ₂ O: C, 67.33,
H, 5.30, N, 4.91. Obtained: C, 66.63, H, 5.38, N, 4
. 72.

Example 36 1- [4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] ethanone, oxime Example 33 and hydroxylamine hydrochloride were treated as in Example 26 to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.22 (s, 1.5 H);
2.28 (s, 3H), 2.32 (s, 1.5H), 7.20 (m, 2H), 7
. 30 (m, 2H), 7.62 (s, 0.5), 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) ; Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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-2-carboxamide 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 methylene chloride. Treated with DCC (1.882 g, 9.13 mmol) in (15 mL), stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO _4), filtered, and concentrated. The residue was treated with 3-amino-1,2-propanediol (0.1%) in 3: 1 dioxane / methanol (20 mL).
(44 g, 1.6 mmol), stirred at room temperature for 18 hours, concentrated, dissolved in ethyl acetate, washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 6% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 375 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
19 (m, 1H), 3.4 (m, 1H), 3.65 (m, 1H), 4.62 (t
, 1H), 4.88 (d, 1H), 7.20 (m, 2H), 7.30 (m, 2H)
), 8.38 (s, 1H) , 9.1 (s, 1H), 9.28 (s, 1H); Analysis _{C 18 H 18 N 2 O 3} S 2 · 0.75H 2 Calculated for O: C, 57.
73, H, 4.84, N, 7.48. Obtained: C, 55.54, H, 5.23,
N, 6.7.

Example 38 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-2-carboxylic acid, hydrazide Hydrazine was used in place of 3-amino-1,2-propanediol Example 18 was otherwise processed as in Example 37 to give the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H);
86 (br s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 8.
2 (s, 1H), 8.4 (s, 1H), 9.28 (s, 1H), 10.4 (br s, 1H); Analysis _{C 15 H 13 N 3 OS 2} · 0.25H 2 O For C: 57.1
2, H, 4.15, N, 13.32. Obtained: C, 56.49, H, 4.19,
N, 12.29.

Example 39 N ^2-4 -[(4-Methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] carbonyl] -N ⁶ -[(nitroamino) iminomethyl] -L-lysine, methyl ester N-ω-nitroarginine methyl ester hydrochloride and NaHCO ₃ in Example 3
Processed as in 7. The residue was purified by flash chromatography on silica gel with 5% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 517 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.60 (m, 2H);
85 (m, 2H), 2.29 (s, 3H), 3.20 (m, 2H), 3.68 (
s, 3H), 4.35 (t, 1H), 4.48 (m, 1H), 7.20 (m, 2
H), 7.30 (m, 2H), 8.32 (s, 1H), 8.48 (s, 1H),
8.52 (br s, 1H), 9.30 (s, 1H), 9.42 (d, 1H);
Analysis _{C 22 H 24 N 6 O 5} S 2 · 0.25H Calcd for ₂ O: 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 methanol solution of guanidine hydrochloride (0.095 g, 1 mmol) was treated with potassium t
Treated with butoxide (0.112 g, 1 mmol) and stirred at room temperature for 30 minutes, treated with Example 17 (0.1 g, 0.3 mmol) and warmed to room temperature for 16 hours,
Concentrated. The concentrate was dissolved in ethyl acetate (100 mL), washed with water, dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 6% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 343 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.40 (s, 1H), 9.
24 (s, 1H).

Example 41 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-carbothioamide Example 19 (190 mg, 0.63 mmol) and Rosesson (15 mL) in toluene (15 mL) Lawsesson) reagent (383 mg, 9.48 mmol)
Was heated to room temperature for 5 hours and concentrated. The residue was purified by flash chromatography on silica gel with 4% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H), 7.
20 (m, 2H), 7.30 (m, 2H), 8.18 (brs, 1H), 8.
32 (s, 1H), 9.2 (s, 1H), 10.1 (br s, 1H), 10.
2 (br s, 1H); Analysis _{C 15 H 12 N 2 S 3} · 0.25H Calcd for ₂ O: C, 56.93
, H, 3.82, N, 8.85. Obtained: C, 55.89, H, 3.83, N,
8.48.

Example 42 4-[(4-Methylphenyl) thio] thieno [2,3-c] pyridine Boiling Dowtherm A (2 mL) was treated with Example 18 (0.6 g, 1 g).
. 99 mmol) and copper powder (0.3 g), stirred for 5 minutes, cooled, diluted with hexane, and purified by flash chromatography on silica gel using 15% ethyl acetate / hexane. Thereafter, the product was recrystallized from hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 258 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 , 1H), 9.27 (s, 1H); Calcd for analysis _{C 14 H 11 NS 3: 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-2-carboxylate Methyl thioglycolate in place of p-thiocresol in Example 17B Example 93A was treated as in Examples 17B and 17C but using the title compound to provide the title compound.

MS (DCI / NH ₃ ) m / z 298 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.59 (s, 3H);
94 (s, 3H), 4.04 (s, 2H), 8.14 (s, 1H), 8.55 (
s, 1H), 9.27 (s, 1H).

Example 44 4-[(2-Amino-2-oxoethyl) thio] thieno [2,3-c] pyridine-2-carboxamide Example 43 was dissolved in 2M methanolic ammonia and placed in a sealed tube. At 45 ° C. for 18 hours. The precipitate was filtered, and methanol-diethyl ether (1: 1) was added.
) And dried under vacuum to give the title compound.

MS (APCI) m / z 268 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (s, 2H), 7.
17 (br s, 1H), 7.59 (br s, 1H), 7.82 (br s, 1H)
1H), 8.29 (brs, 1H), 8.46 (s, 1H), 8.52 (brs, 1H), 9.14 (s, 1H).

Example 45 4-[(4-Bromophenyl) thio] thieno [2,3-c] pyridine-2-carboxamide Except for using 4-bromothiophenol in place of p-thiocresol in Example 17B Example 1 as in Examples 17B and 17C and 44
Treatment of 7A provided the title compound.

MS (DCI / NH ₃ ) m / z 365 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.36 (s, 1H);
Calculated for analysis _{C 14 H 9 BrN 2 OS 2} : C, 46.04, H, 2.4
8, N, 7.67. Found: C, 45.86, H, 2.30, N, 7.51.

Example 46 4- (Phenylthio) thieno [2,3-c] pyridine-2-carboxamide Same as Example 17B, 17C and 44 except that thiophenol was used in place of p-thiocresol in Example 17B. Processing Example 17A as in
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 287 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.29 to 7.40 (m, 5)
H), 7.86 (br s, 1H), 8.25 (s, 1H), 8.46 (s, 1)
H), 8.52 (br s, 1H), 9.31 (s, 1H); Calcd for analysis _{C 14 H 10 N 2 OS 2} : 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 α, α, α- in place of p-thiocresol in Example 17B Treatment of Example 17A as in Examples 17B, 17C and 44 except using trifluorothiocresol provided the title compound.

MS (DCI / NH ₃ ) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.31 (d, 2H), 7.
65 (d, 2H), 7.85 (brs, 1H), 8.19 (s, 1H), 8.
50 (br s, 1H), 8.68 (s, 1H), 9.44 (s, 1H); Calcd for analysis _{C 15 H 9 F 3 N 2} OS 2: C, 50.84, H, 2 .5
6, 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 Except for using 2-methylthiophenol in place of p-thiocresol in Example 17B. Example 1 as in Examples 17B and 17C and 44
7A was processed. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 7.
04 (dd, 1H), 7.15 (dt, 1H), 7.27 (dt, 1H), 7.
38 (br d, 1H), 7.86 (br s, 1H), 8.20 (s, 1H)
, 8.23 (s, 1H), 8.53 (br s, 1H), 9.28 (s, 1H)
; Calculated for analysis _{C 15 H 12 N 2 OS 2} : 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 Except for using 3-methylthiophenol in place of p-thiocresol in Example 17B Example 1 as in Examples 17B and 17C and 44
7A was processed. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H), 7.
06 to 7.13 (m, 2H), 7.21 to 7.27 (m, 2H), 7.89 (b
rs, 1H), 8.26 (s, 1H), 8.42 (s, 1H), 8.55 (b
r s, 1H), 9.30 ( s, 1H); Analysis _{C 15 H 12 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 59.0
8, H, 4.13, N, 9.19. Obtained: C, 59.10, H, 4.16, N
, 9.11.

Example 50 4-[(3,4-dimethylphenyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 3,4-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.09 (s, 3H);
11 (s, 3H), 7.05 (m, 2H), 7.19 (s, 1H), 7.81 (
br s, 1H), 8.12 (d, 2H), 8.49 (br s, 1H), 9.
15 (s, 1H); Analysis _{C 16 H 14 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 60.2
5, H, 4.58, N, 8.78. Obtained: C, 60.34, H, 4.52, N
, 8.75.

Example 51 4-[(3,5-dimethylphenyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 3,5-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.13 (s, 6H), 6.
83 (s, 1H), 6.92 (s, 1H), 7.81 (brs, 1H), 8.
21 (s, 1H), 8.30 (s, 1H), 8.50 (brs, 1H), 9.
19 (s, 1H); Calcd for analysis _{C 16 H 14 N 2 OS 2} : 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 Example 17A was treated as in Examples 17B and 17C and 44 except that 2,4-dimethylthiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H);
38 (s, 3H), 7.02 (d, 1H), 7.13 (d, 1H), 7.20 (
s, 1H), 7.91 (br s, 1H), 8.05 (s, 1H), 8.58 (
br s, 1H), 9.22 ( s, 1H); Analysis _{C 16 H 14 N 2 OS 2} · 0.25H Calcd for ₂ O: C, 60.2
5, H, 4.58, N, 8.78. Obtained: C, 60.40, H, 4.52, N
, 8.72.

Example 53 4-[(2-Methyl-3-furanyl) thio] thieno [2,3-c] pyridine-
2-Carboxamide Example 17A was treated as in Examples 17B and 17C and 44 except that 2-methyl-3-furanthiol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 291 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 6.
68 (d, 1H), 7.74 (d, 1H), 7.93 (brs, 1H), 8.
19. (s, 1H), 8.38 (s, 1H), 8.60 (brs, 1H), 9.
15 (s, 1H); Analysis _{C 13 H 10 N 2 O 2} S 2 · 0.25H Calcd for ₂ O: C, 52.
95, H, 3.59, N, 9.50. Obtained values: C, 52.57, H, 3.41,
N, 9.30.

Example 54 4-[[(4-Chlorophenyl) methyl] thio] thieno [2,3-c] pyridine-2-carboxamide Using 4-chlorobenzylmercaptan in place of p-thiocresol in Example 17B Example 17A was treated as in Examples 17B and 17C and 44 except where noted. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (APCI) m / z 335 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 9.15 (s, 1H); Calcd for analysis _{C 15 H 11 ClN 2 OS 2} : 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 treated as in Examples 17B and 17C and 44 except that 3,4-dichlorothiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.10 (dd, 1 H), 7
. 55 (d, 1H), 7.59 (d, 1H), 7.91 (brs, 1H), 8
. 21 (s, 1H), 8.53 (br s, 1H), 8.62 (s, 1H), 9
. 41 (s, 1H); Calcd for analysis _{C 14 H 8 Cl 2 N 2} OS 2: 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 Example 17A was treated as in Examples 17B and 17C and 44 except that 4-methoxythiophenol was used in place of p-thiocresol in Example 17B. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 317 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.76 (s, 3H), 6.
7. 99 (d, 2H), 7.46 (d, 2H), 7.89 (brs, 1H),
8. 17 (s, 1H), 8.30 (s, 1H), 8.54 (brs, 1H), 9.
18 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S 2: C, 56.94, H, 3.8
2, N, 8.85. Found: C, 56.80, H, 3.78, N, 8.79.

Example 57 4- (Cyclohexylthio) thieno [2,3-c] pyridine-2-carboxamide Examples 17B and 17C and 44 except that cyclohexylmercaptan was used in place of p-thiocresol in Example 17B. Example 17A was processed as described above. The residue was purified by flash chromatography using 5% methanol / dichloromethane to give the title compound.

MS (ESI) m / z 293 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.14-1.43 (br
m, 6H), 1.51 to 1.61 (br m, 1H), 1.66 to 1.78 (b
rm, 2H), 1.83 to 1.98 (br m, 2H), 7.90 (br s
, 1H), 8.33 (s, 1H), 8.52 (s, 1H), 8.57 (br s
, 1H), 9.22 (s, 1H); Calcd for analysis _{C 14 H 16 N 2 OS 2} : C, 57.50, H, 5.51
, N, 9.58. Found: C, 57.53, H, 5.39, N, 9.51.

Example 58 4-[(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 warmed at 70 ° C. for 4 hours, diluted with acetonitrile (6 mL), and treated with purification by C-18 reverse phase HPLC using a gradient of acetonitrile / water to 100% _CH 3 CN containing 0.1% trifluoroacetic acid to give the title compound.

MS (APCI) m / z 428 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.95 (m, 2H);
08 (m, 2H), 3.18 (m, 2H), 3.36 (m, 2H), 3.43 (
m, 2H), 3.68 (m, 4H), 7.20 (d, 2H), 7.28 (d, 2
H), 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-2-carboxylic acid Example 17C (144 mg, 0.46 in dichloromethane (10 mL) at 0 ° C.
mmol) of 3-chloroperoxybenzoic acid (57-86%, 82 mg).
And warmed to room temperature for 4 hours, treated with dichloromethane (50 mL), washed sequentially with 1 N NaOH, water, and brine, dried (MgSO ₄ )
, Filtered and concentrated. The residue was purified by flash chromatography on silica gel using 50% ethyl acetate / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 332 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
84 (s, 3H), 7.38 (d, 2H), 7.65 (d, 2H), 8.41 (
s, 1H), 9.0 (s, 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 (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 7.
38 (d, 2H), 7.79 (d, 2H), 7.94 (brs, 1H), 8.
43 (s, 1H), 8.62 (br s, 1H), 8.85 (s, 1H), 9.
43 (s, 1H).

Example 60 4- (4-Methylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 60A Methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2 -Carboxylic acid Treatment of Example 17A as in Examples 17B and 17C, except that p-thiocresol was used instead of p-thiocresol in Example 17B, gave the title compound.

[0292] mp _{96~98 ℃; MS (DCI / NH} 3) m / z317 (M + NH 4) +, 300 (M + H) +;
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.32 (s, 3H);
91 (s, 3H), 7.05 (m, 2H), 7.24 (m, 2H), 7.95 (
s, 1H), 8.12 (s, 1H), 9.17 (s, 1H); Analysis Calculated for C ₁₆ H ₁₃ NO ₃ S: 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.

MS (DCI / NH ₃ ) m / z 285 (M + H) ⁺ , 302 (M + NH ₄ ) ⁺ ;
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.31 (s, 3H), 7.
7. 04 (m, 2H), 7.25 (m, 2H), 7.82 (brs, 1H),
00 (s, 1H), 8.21 (s, 1H), 8.42 (brs, 1H), 9.
07 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S: 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 -Carboxylic acid 4-chlorophenol (2.63 g, 20.5 g) in THF (20 mL) at 0 ° C.
mmol) in a solution of potassium t-butoxide (1.0 M solution in THF, 20.
4 mL, 20.5 mmol) was added dropwise, stirred at 25 ° C. for 1 hour, and cooled to 0 ° C.
And cooled Example 17A (3.54 g, 20.23 mm) in THF (40 mL).
ol), warmed at 60 ° C. for 0.5 h, cooled to 0 ° C., and treated with methyl thioglycolate (1.989 mL, 22.25 mmol) and Cs ₂ CO ₃ (
6.59 g, 20.23 mmol), warmed at 60 ° C. for 0.25 hours, cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate, washed sequentially with water and brine, dried (MgSO _4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 4% acetone / hexane provided the title compound.

MS (APCI) m / z 320 (M + H)⁺;¹ 1 H NMR (300 MHz, DMSO-d₆) 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, 1H);¹³ C NMR (100 MHz, DMSO-d₆) Δ 56.45 (OCH₃),
120.19 (CH), 123.06 (Ar-CH), 128.04 (Ar-C
H), 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); Analysis C_FifteenH₁₀ClNO₃Calculated value for S: C, 56.34, H, 3.1
5, 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 treated as in Example 44 to give the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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); Analysis _{C 14 H 9 ClN 2 O 2} S · 0.25H Calcd for ₂ O: C, 54.
37, H, 3.10, N, 9.06. Obtained: C, 54.44, H, 2.74,
N, 9.06.

Example 62 4- [4- (Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Other than using 4- (trifluoromethyl) phenol instead of 4-chlorophenol Treated Example 17A as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 339 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.24 (d, 2H), 7.
77 (d, 2H), 7.88 (br s, 1H), 8.10 (s, 1H), 8.
33 (s, 1H), 8.45 (br s, 1H), 9.24 (s, 1H); Analysis _{C 15 H 9 F 3 N 2} O 2 Calculated for S: C, 53.26, H, 2.6
8, 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 are treated as in Example 61 to give the title compound. Was.

MS (DCI / NH ₃ ) m / z 383 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.07 (br s, 1H), 8.92 (br s, 1H)
); Analysis C ₂₂ H ₂₆ N ₂ O ₂ Calculated for S: 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 in Example 61 Workup as in to give the title compound.

MS (DCI / NH ₃ ) m / z 313 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21 (d, 6H);
92 (septet, 1H), 7.05 (d, 2H), 7.30 (d, 2H),
7.82 (br s, 1H), 8.03 (s, 1H), 8.21 (s, 1H),
8.44 (br s, 1H), 9.09 (s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.18 (d, 1 H), 7.
49 (dd, 1H), 7.90 (brs, 1H), 7.98 (s, 2H), 8
. 23 (s, 1H), 8.49 (br s, 1H), 9.14 (s, 1H); Analysis C ₁₄ H ₈ BrClN ₂ O ₂ Calculated for S: C, 43.83, H, 2
. 10, N, 7.30. Obtained: 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. Obtained.

MS (DCI / NH ₃ ) m / z 299 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, 3H);
62 (q, 2H), 7.05 (dt, 2H), 7.26 (dt, 2H), 7.8
1 (br s, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.4
3 (br s, 1H), 9.08 (s, 1H); Analysis Calculated for C ₁₆ H ₁₄ N ₂ O ₂ S.CH ₃ OH: C, 63.71.
H, 4.69, N, 9.14. Obtained: C, 63.34, H, 4.51, N, 9
. 51.

Example 67 4- (4-Ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 67A 4-Vinylphenol A solution of 4-vinylphenol in propylene glycol is treated with water and treated with diethyl ether Extraction with ether removed the propylene glycol to give the specified compound in diethyl ether.

Example 67B 4- (4-Ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and Example 67A were treated as in Example 61 to give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 297 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.24 (d, 1 H);
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 (br s, 1H), 9.13 (s, 1H); Analysis Calculated for C ₁₆ H ₁₂ N ₂ O ₂ S.0.25 CH ₃ OH: C, 64
. 13, H, 4.06, N, 9.20. Obtained: C, 64.40, H, 4.12
, N, 9.27.

Example 68 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c
Example 67B (35 mg, 0.118 mmol) in pyridine-2-carboxamide pyridine (5 mL) solution was treated with _OsO 4 (90mg, _0.354mmol) of was stirred for 5 hours, 1
Treated with 0% NaHSO ₃ aqueous solution, stirred for 5 h, treated with brine, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 1:10 methanol / dichloromethane to give the title compound.

MS (DCI / NH ₃ ) m / z 331 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.44 (t, 2H);
55 (q, 1H), 4.73 (t, 1H), 5.27 (d, 1H), 7.08 (
d, 2H), 7.39 (d, 2H), 7.85 (brs, 1H), 8.03 (
s, 1H), 8.21 (s, 1H), 8.47 (br s, 1H), 9.10 (
s, 1H); Analysis Calculated for C ₁₆ H ₁₄ N ₂ O ₄ S.0.25 CH ₃ OH: C, 57
. 68, H, 4.24, N, 8.28. Obtained: C, 57.92, H, 4.34
, 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 (300 MHz, DMSO-d ₆ ) δ 3.43 (d, 2H);
01 (m, 1H), 5.05 (m, 1H), 5.98 (m, 1H), 7.00 (
dd, 1H), 7.27 (m, 2H), 7.39 (dd, 1H), 7.82 (s
, 1H), 7.88 (br s, 1H), 8.27 (s, 1H), 8.49 (b
r s, 1H), 9.05 ( s, 1H); Analysis C ₁₇ H ₁₄ N ₂ O ₂ Calculated for S: 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 (300 MHz, DMSO-d ₆ ) δ 2.60 (dd, 1 H), 2
. 88 (dd, 1H), 3.29 (t, 2H), 3.76 (m, 1H), 4.5
5 (t, 1H), 4.63 (d, 1H), 6.94 (dd, 1H), 7.22 (
m, 2H), 7.45 (dd, 1H), 7.84 (s, 1H), 7.88 (br
s, 1H), 8.26 (s, 1H), 8.46 (br s, 1H), 9.04
(S, 1H); Analysis C ₁₇ H ₁₆ N ₂ O ₄ Calculated for S: C, 59.29, H, 4.68
, N, 8.13. Found: C, 59.16, H, 4.51, N, 8.06.

Example 71 Example 62 (26 mg) in 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 1-oxide (1 mL) and dichloromethane (5 mL) , 0.
077 mmol) in m-CPBA (80-85%, 30 mg, 0.14 m
mol), stirred at 0 ° C. for 1 hour and at room temperature for 10 hours. The precipitate formed was collected by filtration and washed with dichloromethane. HPLC analysis of the material (C-18, reverse phase) showed a mixture of the desired sulfoxide and starting tiefen in a ratio of 8: 1. The mixture was recrystallized from DMF / methanol / dichloromethane to give the title compound (97.5% pure by HPLC analysis).

MS (HPCI / NH ₃ ) m / z 355 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.39 (d, 2H), 7.
79 (br s, 1H), 7.18 (d, 2H), 8.02 (s, 1H), 8.
05 (d, 1 H), 8.36 (br s, 1 H), 9.02 (s, 1 H); Analysis Calculated for C ₁₅ H ₉ F ₃ NO ₃ S.0.25 CH ₃ OH: C, 50
. 55, H, 2.57, N, 7.73. Obtained values: 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 (300 MHz, DMSO-d ₆ ) δ 0.84 (t, 3H);
20 to 1.28 (m, 24H), 1.54 (m, 2H), 2.57 (t, 2H)
, 6.92 (m, 1H), 6.97 (t, 1H), 7.03 (d, 1H), 7.
7. 33 (t, 1H), 7.85 (br s, 1H), 8.03 (s, 1H),
23 (s, 1H), 8.44 (br s, 1H), 9.09 (s, 1H); Analysis Calculated for C ₂₉ H ₄₀ N ₂ O ₂ S: 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 potassium t-butoxide solution (1 M solution in THF, 28.6 mL, 28.
6 mmol) was added dropwise under a nitrogen atmosphere to a solution of 4-bromophenol (4.94 g, 28.55 mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes, after which anhydrous tetrahydrofuran (20 mL
) Was added and refluxed for 8 hours. The reaction mixture was cooled to 25 ° C. and methyl thioglycolate (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 and extracted with an ice-cold solution of 1 N NaOH (3 ×
75 mL). The organic layer was washed with brine (3 x 100 mL), dried (MgS
O ₄ ) and the solvent were removed under reduced pressure to give a crude product (4.2 g). 10% of this
Purification by flash chromatography on silica gel, eluting with acetone-hexane, gave the title compound (1.81 g) in 44% yield.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7
. 10 (d, J = 9 Hz, 2H), 7.59 (d, J = 9 Hz, 2H), 7.9
4 (s, 1H), 8.25 (s, 1H), 9.24 (s, 1H); MS (APCI) m / e 364, 366 (M + H) ^<+> .

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. Obtained.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.10 (m, 1 H), 7.
30 (m, 2H), 7.45 (b, 1H), 7.95 (b, 1H), 8.20 (
d, 1H), 8.30 (s, 1H), 8.6 (b, 1H), 9.30 (s, 1H)
).

Example 75 4- (4-t-Butylphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 4-t-butylphenol were treated as in Example 61. The title compound was obtained.

MS (DCI / NH ₃ ) m / z 327 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.3 (s, 9 H), 7.1
0 (d, 2H), 7.45 (d, 2H), 7.85 (brs, 1H), 8.0
5 (s, 1H), 8.20 (s, 1H), 8.45 (brs, 1H), 9.1
(S, 1H).

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 (300 MHz, 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, 1H), 8.19 (s, 1H), 8.45
(Br s, 1H), 9.15 (s, 1H).

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 (300 MHz, 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, 1H), 8.25 (s, 1H), 8.45
(Br s, 1H), 9.15 (s, 1H).

Example 78 4- (4-Methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 4-methoxyphenol were treated as in Example 61 to give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.05 (s, 1H)
1H).

Example 79 Ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-4
-Yl] oxy] benzoic acid Example 17A and ethyl 3-hydroxybenzoate were treated as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 343 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (t, 3H);
30 (s, 3H), 7.40 (dd, 1H), 7.60 (m, 2H), 7.80
(Dd, 1H), 7.85 (b, 1H), 8.15 (s, 1H), 8.20 (s)
, 1H), 8.42 (b, 1H), 9.17 (s, 1H).

Example 80 4-phenoxythieno [2,3-c] pyridine-2-carboxamide Example 17A and phenol were treated as in Example 61 to give the title compound.

MS (DCI / NH ₃ ) m / z 271 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.15 (s, 1H)
1H).

Example 81 4- (3-Flomophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 17A and 3-bromophenol were treated as in Example 61 to give the title compound. I got

MS (DCI / NH ₃ ) m / z 349, 351 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.07 (dt, 2 Hz, 1
H), 7.36-7.39 (m, 3H), 7.87 (brs, 1H), 8.1
5 (s, 1H), 8.20 (s, 1H), 8.45 (brs, 1H), 9.1
7 (s, 1H); Analysis C ₁₄ H ₉ N ₂ O ₂ Calculated for _{S · CH 3 OH: C,} 47.26, H
, 2.64, N, 7.35. Obtained: 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 give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 289 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 give the title compound.

MS (DCI / NH ₃ ) m / z 299 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.45 (b, 1H), 9.10 (s, 1)
H).

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 (300 MHz, DMSO-d ₆ ) δ 2.35 (s, 3H), 7.
00 (dd, 1H), 7.25 (d, 1H), 7.45 (d, 1H), 7.85
(B, 1H), 8.15 (s, 1H), 8.20 (s, 1H), 8.45 (b, 1H)
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 give the title compound. Obtained.

MS (DCI / NH ₃ ) m / z 397 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.94 (d, 2H), 7.
7. 74 (d, 2H), 7.86 (brs, 1H), 8.13 (s, 1H),
17 (s, 1H), 8.44 (br s, 1H), 9.16 (s, 1H); Analysis C ₁₄ H ₉ IN ₂ O ₂ Calculated for S: 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.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.30 (s, 3H);
41 (s, 2H), 7.10 (d, 2H), 7.37 (d, 2H), 7.86 (
s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), 8.45 (br
s, 1H), 9.12 (s, 1H).

Example 87 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridinium, iodide Example 61 (0.11 g, 0.0033 mol) was treated with methyl iodide (0.2 mL, 0.0033 mmol) under reflux for 2 hours and filtered. The precipitate was washed with ether, dried and recrystallized from acetonitrile to give the title compound.

MS (DCI / NH ₃ ) m / z 305 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 1H), 8.70 (br s, 1H),
9.70 (s, 1H).

Example 88 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid Example 61A (354 mg, 1.11 in 3: 1 methanol / water (4 mL).
mmol), lithium hydroxide monohydrate (98 mg, 2.33 mmol) was stirred at room temperature for 20 hours, acidified with 90% formic acid (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 ) δ 7.26 (m, 2H), 7.
47 (m, 2H), 7.83 (s, 1H), 8.23 (s, 1H), 9.21 (
s, 1H); Calculated for C ₁₄ H ₈ ClNO ₃ S: C, 55.00, H, 2.64.
, N, 4.58. Found: C, 54.77, H, 2.60, N, 4.44.

Example 89 N- (4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl) -O- (3-tetrahydrofuranyl) carbamate Example 88 in toluene (2 mL) (100 mg, 0.327 mmol) was treated with ethyldiisopropylamine (63 mg, 0.49 mmol) and diphenylphosphoryl azide (109 mg, 0.394 mmol) at 63 ° C., stirred for 1 hour, and stirred at 110 ° C. ) -3-Hydroxytellorahydrofuran (130
mg, 1.47 mmol), stirred for 18 h, and concentrated. 30 residue
Purification by flash chromatography on silica gel using% ethyl acetate / hexane and recrystallization from ethyl acetate gave the title compound.

MS (APCI) m / z 391 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.93 to 2.04 (m, 1)
H), 2.13 to 2.28 (m, 1H), 3.29 to 3.34 (m, 1H plus HOD), 3.70 to 3.86 (m, 4H), 5.33 (m, 1H). 1H), 6.5
6 (s, 1H), 7.02 (dt, 2H), 7.43 (dt, 2H), 8.14
(S, 1H), 8.91 ( s, 1H); Analysis C ₁₈ H ₁₅ ClN ₂ O ₄ Calculated for S: 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 Example 61A (254 mg, 0.793 mmol) in absolute ethanol (4 mL)
l) was treated with anhydrous CaCl ₂ (177 mg, 1.59 mmol) to give 1
Stir for hours, cool to 0 ° C., treat with NaBH ₄ (123 mg, 3,25 mmol), stir at 0 ° C. for 4 hours, stir at room temperature for 18 hours, treat with water, and extract with dichloromethane . The extract was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by silica gel using 30% ethyl acetate / hexane to give the title compound.

MS (APCI) m / z 292, 294 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ -d ₆ ) 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, 1H), 8.89 (s, 1
H); Analysis C ₁₄ H ₁₀ ClNO ₂ Calculated for S: C, 57.64, H, 3.4
5, N, 4.80. Found: C, 57.50, H, 3.58, N, 4.66.

Example 91 (E) -3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenoic acid Example 91A 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxaldehyde -DMSO (77 mg, 0.99m
oxalyl chloride (109 mg, 0.86 mmol) was added dropwise to the solution, stirred for 5 minutes, and stirred for 2 minutes with Example 90 (123 mg) in 2 mL of dichloromethane.
, 0.420 mmol) was added dropwise, stirred at -78 ° C for 1 hour, treated with ethyldiisopropylamine (326 mg, 2.53 mmol), warmed to -20 ° C, stirred for 1.5 hours, Partitioned and extracted between 10 mL of dichloromethane and 5 mL of water. Wash the extract with water (5 mL) and brine (5 mL),
Dry (MgSO ₄ ) and filter. The residue was rotary evaporated and dried under high vacuum to give the title compound.

MS (APCI) m / z 290, 292 (M + H) ^<+> .

Example 91B Methyl 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenoic acid (E) Example 91A (138 mg, 0.42 mmol) in dichloroethane (2 mL)
) And methyltriphenylphosphoranylidene acetate (210 mg, 0.628 m
mol) was stirred at 65 ° C. for 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 25% ethyl acetate / hexane to give the title compound.

MS (APCI) m / z 346, 348 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.83 (s, 3H), 6.
43 (d, 1H), 7.00 (dt, 2H), 7.35 (dt, 2H), 7.4
8 (s, 1H), 7.84 (d, 1H), 8.11 (s, 1H), 8.88 (s
, 1H); Analysis C ₁₇ H ₁₇ ClNO ₃ Calculated for S: C, 59.05, H, 3.5
0, 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-2-yl] -2-propenoic acid Example 91B was as in Example 88. To give the title compound.

MS (ESI-) m / z 330, 332 (M-H) ^- ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.46 (d, 1 H), 7.
14 (dt, 2H), 7.46 (dt, 2H), 7.83 (s, 1H), 7.9
2 (d, 1 H), 8.15 (s, 1 H), 9.10 (s, 1 H); Analysis Calculated for C ₁₇ H ₁₇ ClNO ₃ S: C, 59.05, H, 3.5.
0, 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 Performed in DMF (1 mL) at 0 ° C. Example 91C (51.5 mg, 0.155 mmol
1), N-hydroxybenzotriazole monohydrate (34.5 mg, 0.225
mmol), 4-methylmorpholine (47 mg, 0.464 mmol) and N
A solution of H ₄ Cl (31.6 mg, 0.591 mmol) was added to EDC (45.0 mg).
, 0.235 mmol), stirred at 0 ° C. for 4 hours, stirred at room temperature for 10 hours, treated with chloroform (5 mL), washed successively with 1 M NaHCO ₃ and brine, and dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 5% methanol / dichloromethane to give the title compound.

[0365] mp ^{176~178 ℃; MS (ESI) m} / z331,333 (M + H) +; 1 H NMR (300MHz, CDCDl 3 -d 6) δ5.60 (br s, 2
H), 6.46 (d, 1H), 7.01 (m, 2H), 7.35 (m, 2H),
7.46 (s, 1H), 7.84 (d, 1H), 8.11 (s, 1H), 8.8
8 (s, 1H); Calculated for C ₁₆ H ₁₁ ClN ₂ O ₂ S: 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 Diisopropylamine (6. 6 mL, 46.4
3 mmol) in n-butyllithium (2.
. 50M solution, 18.6 mL, 46.43 mmol), stir at 0 ° C. for 30 min, dilute with THF (200 mL), cool to −78 ° C. and 95 min in THF (110 mL). 3,5-dibromopyridine (10 g, 42.
21 mmol) and stirred at -78 ° C for 30 minutes to give methyl formate (5.2).
mL, 84.42 mmol) was added dropwise, stirred at -78 ° C for 2 hours, transferred into an ice-cold saturated NaHCO ₃ solution, stirred for 15 minutes and extracted with diethyl ether. The extract was washed with brine, dried (MgSO _4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 10% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 266 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.91 (s, 2H), 10
. 09 (s, 1H).

Example 93B Methyl 4-bromothieno [2,3-c] pyridine-2-carboxylic acid Treatment of Example 93A as in Example 17C except running at 0-25 ° C. to give the title compound Obtained.

MS (DCI / NH ₃ ) m / z 274 (M + H) ⁺ ; ¹ H NMR (500 MHz, 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 ) δ 7.97 (br s, 1H)
, 8.11 (s, 1H), 8.33 (brs, 1H), 8.43 (s, 1H)
, 9.24 (s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.93 (br s, 1H,
NH), 8.28 (s, 1H), 8.55 (brs, 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 Example 93B (272 mg, 1 mmol), 4- (trifluoromethyl) phenylboronic acid (209 mg, 1.1 mmol) and cesium fluoride (347 mg, 2.1 mmol) was degassed for 15 minutes and tetrakis (triphenylphosphine) palladium (0) (35 mg, 0.03 m
mol), warmed at 80 ° C. for 6 hours, stirred at room temperature for 12 hours, and celite (
(Trademark) and concentrated. The residue was purified by flash chromatography on silica gel using 5% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 338 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
94 (m, 4H), 8.06 (s, 1H), 8.66 (s, 1H), 9.47 (
s, 1H).

Example 95B 4- [4- (Trifluoromethyl) phenyl] thieno [2,3-c] pyridine-2-carboxamide Example 95A is treated as in Example 44 to give the title compound. Was.

MS (APCI) m / z 323 (M + H) ⁺ , 321 (M−H) ⁻ , and 3
57 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (brs, 1H).
, 7.93 (m, 4H), 8.24 (s, 3H), 8.45 (br s, 1H)
, 8.59 (br s, 1H), 9.37 (br s, 1H).

Example 96 N-methyl-4- [4- (trifluoromethyl) phenyl] thieno [2,3-
c] Pyridine-2-carboxamide Example 95A was treated as in Example 44 except that methylamine (2.0 M in methanol) was used instead of methanolic ammonia to give the title compound.

MS (APCI) m / z 337 (M + H)⁺, 335 (MH)⁻, And 3
71 (M + Cl)⁻;¹ 1 H NMR (400 MHz, DMSO-d₆6.) δ 2.82 (d, 3H);
90 (d, 2H), 7.94 (d, 2H), 8.17 (s, 1H), 8.58 (
s, 1H), 8.93 (br d, 1H), 9.36 (s, 1H);¹³ C NMR (100 MHz, DMSO-d₆) Δ26.1 (CH₃), 12
1.6 (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-carboxylic acid Example 93B and phenylboronic acid Was treated as in Example 95 to give the specified compound.

MS (DCI / NH ₃ ) m / z 338 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
94 (m, 4H), 8.06 (s, 1H), 8.66 (s, 1H), 9.47 (
s, 1H).

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 (300 MHz, DMSO-d ₆ ) δ 7.52 to 7.69 (m, 5)
H), 7.78 (br s, 1H), 8.23 (s, 1H), 8.44 (br
s, 1H), 8.52 (s , 1H), 9.30 (s, 1H); Calcd for analysis _{C 14 H 10 N 2 OS:} 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 as in Example 95 After workup and purification, repurification by HPLC (C18 reverse phase, 0-90% acetonitrile gradient in water containing 0.1% TFA) provided the title compound.

MS (DCI / NH ₃ ) m / z 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.36 to 7.48 (m, 5)
H), 7.63-7.68 (m, 4H), 7.91 (brs, 1H), 8.3
0 (s, 1H), 8.54 (s, 1H), 8.57 (brs, 1H), 9.3
6 (s, 1H).

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-2-carboxylic acid 3- Hydroxytetrahydrofuran (0.043 mL, 0.53 mmol),
Triphenylphosphene (138 mg, 0.53 mmol) and diethyl azodicarboxylate (0.083 mL, 0.53 mmol) at room temperature and under an atmosphere of nitrogen in Example 236E (110 mg, 0
. 53 mmol). After 22 hours, the reaction mixture was stirred in ethyl acetate
00 mL), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40S) eluting with 10% acetone-hexane to give the title compound in 22% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.05 to 2.18 (m,
1H), 2.26 to 2.49 (m, 1H), 3.61 to 3.77 (m, 2H),
3.93 (s, 2H), 4.25 to 4.31 (m, 2H), 5.32 to 5.39
(M, 1H), 8.10 (s, 1H), 8.26 (s, 1H), 8.99 (s, 1H)
1H); MS (APCI) m / e 280 (M + H) ^<+> .

Example 99B Methyl 4- [3- (2,3,4,5-tetrahydrofuranyl) oxy] thieno [2,3-c] pyridine-2-carboxamide The title compound (5.7 mg, 19%) , Example 99A (30 mg, 0.108
mmol) was prepared as described in Example 171. By C-18 reverse-phase HPLC, eluting with a gradient of _{20% CH 3 CN-H 2} O containing 0.1% trifluoroacetic acid, the product was isolated.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.05 to 22.13 (m
, 1H), 2.30 to 2.40 (m, 1H), 2.81 (d, J = 5 Hz, 3H)
), 3.78-3.84 (m, 1H), 3.90-4.01 (m, 3H), 5.
32 to 5.37 (m, 1H), 8.13 (s, 1H), 8.21 (s, 1H),
8.90 (s, 1 H), 8.55 (d, J = 5 Hz, 1 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 26.2 (CH ₃ );
_{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] pyridine-4-
Il] oxy] benzoic acid Example 73 (120 mg in DMF (6 mL) and ethanol (3 mL)
0.33 mmol), palladium (II) acetate (11 mg, 0.05 mmol)
, 1,3-bis (diphenylphosphino) propane (20.6 mg, 0.05 m
mol), and a solution of triethylamine (100 mg, 0.99 mmol) was purged with carbon monoxide, heated at 105 ° C. under a carbon monoxide atmosphere (balloon) for 12 h, treated with ether, and brine and water. Wash sequentially and dry (N
a ₂ SO ₄ ), filtered and concentrated. The residue was subjected to flash chromatography (20
(% Ethyl acetate / hexane) 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 Example 100 (50 mg) in DMF (5 mL) and ethanol (10 mL)
) Was treated with a solution of NaOH (200 mg) in water (0.5 mL) to give 1
Stir for 3 hours, treat sequentially with acetic acid (500 mg) and water, and filter. The residue was recrystallized from DMF / water to give the title compound.

MS (DCI / NH ₃ ) m / z 315 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.13 (dt, 1.8 Hz)
, 2H), 7.86 (brs, 1H), 7.98 (dt, 2H), 8.09 (
s, 1H), 8.31 (s, 1H), 8.44 (br s, 1H), 9.22 (
s, 1H); Analysis C ₁₅ H ₁₀ N ₂ O ₄ Calculated for S: 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-α-boronic acid -α- in diethyl ether (30 mL) at −78 ° C. Bromostyrene (5.5 g
, 30 mmol) with a solution of t-butyllithium (1.7 M solution, 21.2).
mL, 36 mmol), stirred at -78 ° C for 0.5 h, treated with triisopropyl borate (8.31 mL, 36 mmol) for 48 min, stirred for 1 h, and allowed to reach room temperature over 18 h. Warm, dilute with diethyl ether (100 mL), treat with 1M HCl (100 mL), stir at room temperature for 5 h, concentrate and add T
The HF was removed, brought to pH 14 with 1N NaOH, washed with hexane and 1M H
The mixture was adjusted to pH 1 with Cl 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) δ5.75 (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-carboxylic acid Example 93B and styrene-α-boronic acid were treated as in Example 95. To give the title compound.

MS (APCI) m / z 296 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.84 (s, 3H);
56 (s, 1H), 5.95 (s, 1H), 7.31 (m, 2H), 7.36 (
m, 3H), 7.47 (s, 1H), 8.5 (s, 1H), 9.40 (s, 1H)
); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 53.03 (OCH ₃ ),
118.37 _(CH 2 vinyl), 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), 13
9.59 (C), 141.88 (C), 142.97 (3-CH), 144.0
3 (C), 145.39 (CH), 161.69 (CO).

Example 102C 4- (1-Phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide Example 102B was treated as in Example 44 to give the title compound.

MS (DCI) m / z 281 (M + H) ⁺ ; ¹ H NMR (400 MHz, 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, 1H), 8.33 (s, 1H), 8.37 (
br s, 1H), 9.29 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 118.0 (CH ₂ ), 1
23.10 (CH), 126.73 (Ar-CH), 128.22 (CH), 1
28.60 (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-2-methanol NaBH ₄ (28 mg, 0.74) in 2: 3 THF / ethanol (2 mL)
3 mmol) was stirred at 0 ° C. for 10 minutes, and CaCl ₂ (41.2 mg, 0
. 37 mmol), stir for 15 minutes, and add 2: 3 THF / ethanol (
Treat with a solution of Example 17C (117 mg, 0.37 mmol) in 3 mL), stir at 0 ° C. for 4 h, treat with 20% aqueous acetic acid (5 mL), and concentrate to remove low boiling solvents. . The resulting mixture was brought 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 column chromatography on silica gel eluting with 15% acetone / hexane to give the title compound.

MS (DCI / NH ₃ ) m / z 288 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
80 (s, 2H), 5.90 (br s, 1H), 7.14 (d, 2H), 7.
18 (d, 2H), 7.32 (s, 1H), 8.36 (s, 1H), 9.15 (
s, 1H).

Example 103A 4- (4-Chlorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-Carboxamide Example 61A (100 mg, 0.3135 mmol in THF (2 mL) at 0 ° C.
l) and methylamine (2M solution in THF, 0.467 mL, 0.941 m
mol) was treated with NaH (12 mg, 0.47 mmol) at room temperature.
Stirred for hours, treated with water (0.1 mL) and concentrated. 20% acetone /
Purification by flash chromatography on silica gel with hexane provided the title compound.

MS (APCI) m / z 319 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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, 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. ,
The title compound was obtained.

MS (APCI) m / z 333 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.03 (br s, 3H)
3.12 (brs, 3H), 7.17 (d, 2H), 7.46 (d, 2H)
, 7.62 (s, 1H), 8.18 (s, 1H), 9.15 (s, 1H).

Example 105 4- (4-Chlorophenoxy) -N, N-diethylthieno [2,3-c] pyridine-2-carboxamide Example 61A and diethylamine were treated as in Example 103A.
The title compound was obtained.

MS (APCI) m / z 361 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (m, 6H);
42 (m, 4H), 7.15 (d, 2H), 7.45 (d, 2H), 7.49 (
s, 1H), 8.74 (s, 1H), 9.17 (s, 1H).

Example 106 4- (4-Chlorophenoxy) -N-sillopropylthieno [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) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.85 (m, 1 H), 7.
12 (d, 2H), 7.46 (d, 2H), 8.11 (s, 1H), 8.13 (
s, 1H), 8.93 (d, 1H), 9.12 (s, 1H).

Example 107 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] pyrrolidine Example 61A and pyrrolidine are treated as in Example 103A. To give the title compound.

MS (APCI) m / z 359 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.83 to 1.93 (m, 4)
H), 3.53 (t, 2H), 3.71 (t, 2H), 7.17 (d, 2H),
7.47 (d, 2H), 7.70 (s, 1H), 8.16 (s, 1H), 9.1
2 (s, 1H).

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) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.52 (m, 3H);
62 (m, 2H), 3.53 (m, 5H), 7.14 (d, 2H), 7.46 (
d, 2H), 7.47 (s, 1H), 8.20 (s, 1H), 9.14 (s, 1)
H).

Example 109 4-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
[Ill] carbonyl] morpholine Example 61A and morpholine were treated as in Example 103A to give the title compound.

MS (APCI) m / z 375 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.6 (m, 8H), 7.1
4 (d, 2H), 7.45 (d, 2H), 7.55 (s, 1H), 8.17 (s
, 1H), 9.14 (s, 1H).

Example 110 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -4-methylpiperazine Example 61A and methylpiperazine were added to Example 103A. Workup as in to give the title compound.

MS (APCI) m / z 388 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 3H), 2.3
2 (br s, 4H), 8.58 (br s, 4H), 7.15 (dd, 1 H)
, 7.47 (dd, 1H), 7.49 (s, 1H), 8.2 (d, 1H), 9.
15 (s, 1H).

Example 111 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl] -4-phenylpiperazine Example 61A and phenylpiperazine in Example 103A Workup as in to give the title compound.

MS (APCI) m / z 450 (M + H) ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.18 (br s, 4H).
3.73 (brs, 4H), 6.81 (t, 1H), 6.95 (d, 2H)
, 7.15 (d, 2H), 7.24 (d, 2H), 7.46 (d, 2H), 7.
57 (s, 1H), 8.20 (s, 1H), 9.17 (s, 1H).

Example 112 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-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) ⁺ ; ¹ H NMR (500 MHz, 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, 1H), 8.
91 (s, 1H), 9.13 (s, 1H).

Example 113 1-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
Il] 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) ⁺ ; ¹ H NMR (500 MHz, CDCl ₃ -d) δ 3.65 (br s, 4H).
3.85 (brs, 4H), 6.70 (m, 2H), 7.07 (d, 2H)
, 7.34 (d, 2H), 7.50 (s, 1H), 7.54 (m, 1H), 8.
15 (s, 1H), 8.29 (m, 1H), 8.96 (s, 1H).

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 (400 MHz, DMSO-d ₆ ) δ 3.33 (m, 2H);
51 (m, 2H), 5.76 (t, 1H), 7.12 (d, 2H), 7.26 (
d, 2H), 8.17 (s, 2H), 8.98 (br.t, 1H), 9.14 (
s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ42.3 (N-CH ₂ );
_{59.4 (O-CH 2),} 119.2 (CH), 119.3 (Ar-CH), 1
27.6 (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-[[4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide, trifluoroacetic acid (salt) Example 61A and N-isopropylpiperazineacetamide were prepared in Example 103.
Treatment as in A provided the title compound. 20% CH ₃ CN / water and 0.1%
The residue was purified by C-18 reverse phase HPLC using a gradient of 100% _CH 3 CN containing trifluoroacetic acid to yield the title compound.

MS (APCI) m / z 473 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.09 (m, 6H);
05 (br s, 4H), 3.43 (s, 2H), 3.87 (br s, 4H)
, 7.16 (d, 2H), 7.67 (d, 2H), 7.68 (s, 1H), 8.
20 (s, 1H), 9.18 (s, 1H).

Example 116 4- (4-Chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and DL-2-amino-1 -Propanol was treated as in Example 103A to give the title compound.

MS (APCI) m / z 363 (M + H) ⁺ , 361 (M−H) ⁻ , 397 (
M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.14 (d, 3H);
36 to 3.40 (m, 1H), 3.43 to 3.5 (m, 1H), 3.97 to 4.
04 (m, 1H), 4.77 (t, 1H), 7.15 (d, 2H), 7.48 (
d, 2H), 8.14 (s, 1H), 8.26 (s, 1H), 8.67 (d, 1)
H), 9.14 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 16.87 (CH ₃ ), 4
_{7.74 (CH), 64.06 (CH} 2 OH), 119.16 (3-CH), 1
19.46 (2xAr-CH), 127.72 (C), 130.08 (2xAr
-CH), 132.84 (5-CH), 137.51 (C), 137.91 (C
), 141.20 (7-CH), 146.62 (C), 147.28 (C), 1
55.53 (C), 160.01 (CO).

Example 117 4- (4-chlorophenoxy) -N- [1,1-bis (hydroxymethyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and 2-amino- Treatment of 2-methyl-1,3-propanediol as in Example 103A provided the title compound.

MS (APCI) m / z 393 (M + H) ⁺ , 391 (M−H) ⁻ , 393 (
M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (s, 3H);
56 to 3.66 (m, 4H), 4.71 (t, 2H), 7.16 (d, 2H),
7.48 (d, 2H), 7.92 (s, 1H), 8.11 (s, 1H), 8.3
1 (s, 1H), 9.12 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 18.45 (CH ₃ ), 5
9.80 (C), 63.08 (CH ₂ ), 119.46 (CH), 119.74
(2xAr-CH), 127.83 (C), 130.09 (2xAr-CH),
132.53 (CH), 137.43 (C), 137.84 (C), 140.9
9 (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-2-carboxamide Examples 61A and DL-1- Treatment of amino-2-propanol as in Example 103A provided the title compound.

MS (APCI) m / z 363 (M + H) ⁺ , and 397 (M + Cl) ⁻ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.08 (d, 3H);
21 (m, 2H), 3.75 to 3.84 (m, 1H), 4.8 (br s, 1H)
), 7.14 (d, 2H), 7.48 (d, 2H), 8.17 (s, 1H), 8
. 22 (s, 1H), 8.98 (br s, 1H), 9.15 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 21.13 (CH ₃ ), 4
_{7.24 (CH 2), 64.84 (} CH), 119.30 (3-CH), 119
. 42 (2xAr-CH), 127.66 (C), 130.04 (2xAr-C
H) 133.05 (CH), 137.48 (C), 137.92 (C), 14
1.30 (CH), 146.37 (C), 147.16 (C), 155.58 (
C), 160.59 (CO).

Example 119 4- (4-Chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thieno [2,3-c] pyridine-2-carboxamide Example 61A and 4- (2-amino Ethyl) monophorine was treated as in Example 103A to give the title compound.

MS (APCI) m / z 418 (M + H) ⁺ , 452 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.41 (t, 4H);
48 (m, 2H), 3.40 (m, 2H), 3.56 (t, 4H), 7.15 (
d, 2H), 7.47 (d, 2H), 8.13 (s, 1H), 8.17 (s, 1H)
H), 8.94 (t, 1H), 9.04 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 36.73 (N-CH ₃ )
, 53.21 (morpholine ring _{2xN-CH 2), 57.07 (} N-CH 2),
66.12 (morpholine ring _{2x-OCH 2), 119.14 (} 3-CH), 1
19.50 (2xAr-CH), 127.73 (C), 130.06 (2xAr
-CH), 132.96 (pyridyl ring CH), 137.35 (C), 137.
91 (C), 141.29 (pyridyl ring 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 t-butyllithium (1.7 M solution in hexane, 0.647 under nitrogen atmosphere)
mL, 1.1 mmol) of Example 124A in anhydrous THF (5 mL) at -78 ° C.
(261 mg, 1 mmol). The reaction mixture was stirred at −78 ° C. for 15 minutes and SO ₂ gas was bubbled through the solution for 15 minutes. Then, change this to -7
The mixture was stirred at 2 ° C for 2.5 hours and then at 0 ° C for 4 hours. The reaction mixture was diluted with hexane (10 mL), evaporated and the resulting residue was suspended in _CH 2 _Cl 2 (5mL), at 0 ° C. N-chlorosuccinimide (214 mg, 1.6 mmol)
Processed. After 2 hours, at ambient temperature, dilute the reaction mixture with CH ₂ Cl ₂ and add
NaHSO ₃ aqueous solution (3 × 25 mL) followed by brine (
3x25mL). The dried (MgSO ₄ ) organic layer was evaporated under reduced pressure to dryness to give the crude sulfonyl chloride as an oil. This was dissolved in acetone (5 mL) and treated at 0 ° C. with an ice-cold solution of NH ₄ OH (5 mL). After 2 hours, the reaction mixture was evaporated from toluene at 0 ° C. to give the crude product as an oil. Flash chromatography on silica gel, eluting with 20% acetone-hexane, followed by 40% acetone-hexane, gave the title compound (57 g, 16%).
I got

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.21 (d, J = 9 Hz)
, 2H), 7.51 (d, J = 9 Hz, 2H), 7.79 (s, 1H), 8.1
4 (br.s, 2H), 8.30 (s, 1H), 9.27 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 119.65 (CH), 1
20.88 (CH), 127.94 (C), 130.12 (CH), 133.6
7 (CH), 135.61 (C), 141.65 (CH), 152.11 (C)
MS (APCI) m / z 341 (M + H) ⁺ , 339 (M−H) ⁻ , 375 (M
+ Cl) ^- .

Example 121 4-[(4-Methylphenyl) methyl] thieno [2,3-c] pyridine-2-
Carboxamide Example 121A Methyl 4-[(4-methylphenyl) methyl] thieno [2,3-c] pyridine-2-carboxylic acid Example 121A is described in J. Am. Org. Chem, 1988, 53, pp. 2392
Processed as described in ~ 2394. For example, 1,2-dibromoethane (0
. Zn powder (5 mL, 0.054 mmol) in THF (2 mL) containing
(92 mg, 1.4 mM) was heated at 65 ° C for 2 minutes, cooled to 25 ° C,
Treat with trimethylsilyl chloride (0.009 mL, 0.043 mM), stir at room temperature for 25 minutes, cool to 0 ° C., and add 4-methylbenzyl bromide (0.248 mL, 1.0 mmol) in THF (5 mL) And slowly treated with a solution of
Warm to 0 ° C., cool to −10 ° C., and add CuCN (106 ml) in THF (10 mL)
g, 1.18 mM) and LiCl (100 mg, 2.35 mM)
Stir at 0 ° C. for 30 minutes and prepare Example 93B (272 mg, 1 m) in THF (5 mL).
mol), stirred at 0 ° C. for 3 hours, and
Warm to 5 ° C., treat with ethyl acetate, wash sequentially with saturated NH ₄ Cl and brine, dry (MgSO ₄ ), filter and concentrate. The residue was purified by flash chromatography on silica gel 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- (morpholino) thieno [2,3-c] pyridine-2-carboxamide 1,4-dioxo-8-azaspiro [4,5] instead of 4-methylaniline
Example 122 (241 mg, 72%) was prepared as described in Example 308 using decane (0.256 mL, 2 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.91 (m, 4H), 2
. 85 (d, J = 4 Hz, 3H), 3.25 (m, 4H), 3.96 (s, 4H)
), 8.10 (s, 1H), 8.12 (s, 1H), 8.87 (s, 1H), 8
. 96 (d, J = 4 Hz, 1 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 26.1 (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 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, N-oxide Example 123A Methyl (4-chlorophenoxy) thieno [2,3-c] pyridine -2-Carboxylic acid, N-oxide A solution of methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylate (319 mg, 1 mmol) in dichloromethane (15 mL) at 0 ° C. Treated with chloroperoxybenzoic acid (302 mg, 1.75 mmol), stirred at 0 ° C. for 0.5 h, stirred at room temperature for 4 h, washed successively with water, saturated sodium bicarbonate, water, and brine , dried _(Na 2 _SO 4), filtered, and concentrated to give the title compound.

MS (DCI / NH ₃ ) m / z 336 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (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- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide, N-oxide Example 123A is treated as in Example 44 to give the title compound. Was.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.30 (m, 2H), 7
. 52 (m, 2H), 7.74 (d, 1H), 7.81 (brs, 1H), 8
. 10 (s, 1H), 8.34 (br s, 1H), 8.93 (s, 1H).

Example 124 4- (4-chlorophenoxy) -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) is added at 210 ° C. to a solution of diphenyl ether (55 mL). At this temperature for 10 hours. The cooled reaction mixture was purified directly by flash chromatography on silica gel, eluting with hexane, followed by 10% acetone-hexane to give the title compound (3.83 g, 99.5%).

Mp 87-89 ° C. MS (DCI / NH ₃ ) m / e 262 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.09 (d, J = 9 Hz,
2H), 7.35 (d, J = 6 Hz, 1H), 7.45 (d, J = 9 Hz, 2H)
), 8.13 (d, J = 6 Hz, 1H), 8.18 (s, 1H), 9.15 (s
, 1H); Analysis _{C 13 H 8 Cl 1 N 1} O 1 calculated for _{S 1: C, 59.66, H} , 3
. 08, N, 5.35. Obtained: C, 59.52, H, 3.08, N, 5.15
.

Example 124B 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-boronic acid-To a solution of s-butyllithium (0.92 mmol) in THF (2 mL) at 78 ° C. Treat Example 124A dropwise in THF (1 mL) and treat at −78 ° C. for 30 minutes.
Stir for 5 min, treat dropwise with tributyl borate, stir at −78 ° C. for 5 min, stir at room temperature for 45 min, treat with 2M NaOH (3 mL), stir for 5 min, and hexane Washed and acidified to pH 2 with 6M HCl. The precipitate formed was collected and dried under vacuum 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) δ 7.29 (d, 2H), 7.53
(D, 2H), 8.08 (s, 1H), 8.11 (s, 1H), 9.40 (s, 1H)
1H).

Example 124C 4- (4-Chlorophenoxy) -2- (2-methoxyphenyl) thieno [2,
3-c] pyridine Example 124B was prepared as in Example 95 except that 2-iodoanisole was used instead of Example 93B and Example 124B was used instead of 4- (trifluoromethyl) phenylboronic acid. Work-up provided the title compound.

Example 125 4- (4-Chlorophenoxy) -3-methylthienol [2,3-c] pyridine-2-carboxamide Example 125A Methyl 4- (4-chlorophenoxy) -3-methylthienol [2,3-c]
Pyridine-2-carboxylic acid 4-chlorophenol was dissolved in THF (20 mL), treated with 1 M 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 ° C. for 4 hours and cooled to room temperature. It was poured into water, diluted with brine and extracted with ethyl acetate. Thereafter, the ethyl acetate was washed (3 ×
20 mL), dried and evaporated. The residue was dissolved in THF (20 mL), cooled in an ice bath, and to this was added 3M methylmagnesium bromide in ethyl ether (4 mL, 12 mmol). The reaction was stirred overnight at room temperature. Excess Grignard reagent was decomposed with a saturated ammonium chloride solution (25 mL) and then extracted with ethyl acetate (3 × 25 mL). Wash the ethyl acetate with brine (3 × 25 mL
), Dried and evaporated to give the desired phenoxy alcohol. Thereafter, the alcohol was Swern oxidized using the following conditions. Oxalyl chloride (1.1 mL, 12 mL) in anhydrous methylene chloride (20 mL) cooled to -78 ° C.
dimethylsulfoxide (1.85 mL, 24 mmol) in a solution of
Added over 0 minutes. Thereafter, a solution of the above phenoxy alcohol in methylene chloride (20 mL) was added over 15 minutes. Triethylamine (7.5 mL)
Was added and the reaction was allowed to come to room temperature over 2 hours. Thereafter, ice water was added and the mixture was extracted with ethyl acetate. Wash the ethyl acetate with brine (3x
20 mL), dried and evaporated. To a 0 ° C. solution of this residue in THF (20 mL) was added methyl thioglycolate (0.88 mL, 10 mmol) and cesium carbonate (3.2 g, 10 mmol). Thereafter, the reaction was heated at 70 ° C. for 1 hour.
Heated for hours, cooled, poured into water, diluted with brine and extracted with ethyl acetate. Thereafter, the ethyl acetate was washed with 1N NaOH (2 × 20 mL), washed with brine (3 × 20 mL), dried and evaporated to give an oil. This oil was triturated with methanol to give the desired compound.

MS (DCI / NH ₃ ) m / e 334 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (s, 3H);
90 (s, 3H), 7.22 (d, 2H), 7.45 (d, 2H), 8.12 (
s, 1H), 9.15 (s , 1H); Analysis _{C 16 H 12 ClNO 3 S ·} 0.5H Calcd for ₂ O: C, 56.0
6, H, 3.82, N, 4.09. Obtained: C, 56.03, H, 3.43, N
, 3.71.

Example 125B 4- (4-Chlorophenoxy) -3-methylthienol [2,3-c] pyridine-2-carboxylic acid Example 125A in THF (20 mL) and H ₂ O (10 mL) 1.1g
, 3.3 mmol) and a solution of LiOH.H ₂ O (0.30 g, 6.9 mmol) were heated at 50 ° C. for 1 hour, then cooled, acidified with formic acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3 × 15 mL) and then dried,
Evaporation gave the desired product as a white solid.

MS (DCI / NH ₃ ) m / e 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.76 (s, 3H);
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-methylthienol [2,3-c] pyridine-2-carboxamide Example 125B was treated as in Example 92 to afford the title compound. Obtained.

Mp 174-175 ° C. MS (DCI / NH ₃ ) m / e 319 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H), 7.
05 (d, 2H), 7.45 (d, 2H), 7.90 (m, 1H), 7.95 (
m, 1H), 8.15 (s , 1H), 9.12 (s, 1H); Analysis C ₁₅ H ₁₁ ClN ₂ O ₂ Calculated for S: 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-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 126A Ethyl 3,5-dichloropyridine-4-carboxylic acid at -78 ° C Lithium diisopropylamide in 150 mL of THF (45 mL,
A stirred solution of 1.5M in THF, 67.6 mmol) was added to 3,5 in 40 mL of THF.
-Dichloropyridine (10 g, 67.6 mmol) was added and treated over 1.5 hours, stirred at -78 ° C for 1 hour, and ethyl chloroformate (9.5 mL, 100 ml) was added.
mol), stirred for 2 hours, and saturated sodium bicarbonate (200 mL) at 0 ° C.
) And treated with diethyl ether (200 mL) and extracted with ethyl ether (2 x 100 mL). The extract was washed with saturated sodium bicarbonate solution (2 × 100 mL
), Washed sequentially with brine (2 × 100 mL), dried (MgSO _4), and concentrated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate to give the title compound.

Example 126B Methyl 4- (4-chlorophenoxy) -3-hydroxythieno [2,3-c] pyridine-2-carboxylate Example 126A was treated as in Example 61A to give the title compound. I got

Example 126C 4- (4-Chlorophenoxy) -3-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 126B was treated as in Example 61B to give the title compound. Was.

Example 127 4- (4-Chlorophenoxy) -3- (1-methylethoxy) thieno [2,3
-C] pyridine-2-carboxamide Example 127 is described in J. Am. Medicinal. Chem. 1992, 35, p.
Treated as described in 958. Example 126C (0 in 50 mL THF)
. 10 g, 0.3 mmol) and cesium carbonate (1.0 g, 0.1 mmol)
Was treated with 2-bromopropane (0.37 g, 0.3 mmol), heated for 2 hours, poured onto ice, extracted with ethyl ether, washed successively with 1N aqueous sodium hydroxide and brine, and concentrated. . The residue was purified by flash chromatography on silica gel with hexane-acetone (7: 3) to give the title compound.

Example 128 3-Bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine Archiv For Kemi (1970-74), 32, p. 249 can be applied. Example 124A in thionyl chloride at 90 ° C
For 4 hours with bromine to give the title compound.

Example 129 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-3-carboxylic acid Arkiv For Kemi (1970-74), 32, p. 249 can be applied. Example 128, cooled to -78 ° C, was treated with ethyllithium followed by reaction with carbon dioxide to give the title compound.

Example 130 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-3-carboxamide Example 129 can be treated as in Example 19 to give the title compound.

Example 131 3-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 added to hydroxylamine hydrochloride (1.04 g, 11.4 mmol) and concentrated. Sulfuric acid (0.05m
L), stirred under reflux for 18 hours and concentrated. The residue 1: 1 ethyl acetate - was partitioned extracted between water, saturated sodium bicarbonate, washed successively with water, brine, dried (Na 2 _{SO 4),} and concentrated. The residue was recrystallized from hexane to give the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s); IR (KBr, νcm ⁻¹ ) 1710, 1525, 1400, 1250, 119
0, 1100, 920, 820, 800, 750.

Example 131B Methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid 4-chlorophenol (1.12 g) in THF (20 mL) at 0 ° C. , 8.72
mmol) in a solution of potassium t-butoxide (8.72 mL, 8.72 m2).
mol, 1M in THF), stir at 0 ° C. for 1 hour, and add THF (10
Treated with Example 131A (1.5 g, 8.72 mmol) in acetic acid (mL), warmed to room temperature, stirred overnight, concentrated, and extracted by partitioning between 1: 1 ethyl acetate-water. . The extract was washed with brine, dried _(Na 2 _SO 4), and concentrated. D at 0 ° C
A solution of the concentrate in MF (50 mL) was treated with potassium carbonate (2.42 g, 17.51 m).
mol) and methyl thioglycolate (778 μL, 8.72 mmol), warmed to room temperature, stirred overnight, and poured into ether (400 mL). The organic layer was washed with brine, dried _(Na 2 _SO 4), and concentrated. 0-5% residue
Purification by flash chromatography on silica gel with acetone-hexane of the title compound afforded the title compound.

MS (APCI) m / z 335 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.81 (s, 3H), 6.
86 (br s, 2H), 7.22 to 7.32 (m, 2H), 7.45 to 7.5
6 (m, 2H), 7.88 (s, 1H), 8.89 (s, 1H); Analysis C ₁₅ H ₁₁ ClN ₂ O ₂ Calculated for S: C, 53.81, H, 3.
31, N, 8.36. Found: C, 53.80, H, 3.27, N, 8.27.

Example 131C 3-Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-Carboxylic acid The title compound was prepared from Example 131B using the procedure of Example 18.

Mp 173-176 ° C (decomposition); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.29 (m, 2H), 7.
52 (m, 2H), 7.88 (s, 1H), 8.89 (s, 1H); MS (ESI) m / e321 (M + H) +; Analysis _{C 14 H 9 ClN 2 O 3} 0.25H 2 Calculated value for O: C, 51.7
0; H, 2.94; N, 8.61. Actual value? ? .

Example 131D 3-Amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-Carboxamide Example 131C (96 mg, 0.3 mmol) in DMF (2 mL) was added to 1
-Hydroxybenzotriazole hydrate (67 mg, 0.44 mmol), NH ₄ Cl (61 mg, 1.14 mmol) and 4-methylmorpholine (100 μμ
L, 0.9 mmol), cooled to 0 ° C., and treated with 1- [3- (dimethylamino)
Propyl] -3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol)
, Warm to room temperature, stir overnight, and add saturated NaHCO₃Pour into, collect, with water
Washed and dried. Recrystallization of the residue from methanol / toluene / hexane
The title compound is obtained.

MS (APCI) m / z 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.84 (br s, 2H).
, 7.21-7.30 (m, 2H), 7.39 (brs, 2H), 7.47-
7.56 (m, 2H), 7.88 (s, 1H), 8.90 (s, 1H); Analysis C ₁₄ H ₁₀ ClN ₃ O ₂ Calculated for S: C, 52.58; H, 3 .
15; N, 13.14. Found: C, 52.63; H, 3.18; N, 13.1.
2.

Example 132A Ethyl 4-chlorothieno [2,3-b] pyridine-5-carboxylate Heterocyclic Chem. 1977, 1
4, p. Treatment as in 807-812 afforded the title compound.

MS (DCI / NH ₃ ) m / z 259 (M + H) ⁺ ; 242 (M + NH ₄ ) ⁺ ;
3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37 (t, 3H);
41 (q, 2H), 7.64 (d, 1H), 8.17 (d, 1H), 8.95 (
s, 1H); Analysis C ₁₀ H ₈ ClNO ₂ Calculated for S: C, 49.69; H, 3.33
N, 5.79; S, 13.26. Found: C, 49.46; H, 3.13; N
5.52; S, 13.42.

Example 132B Ethyl 4-[(4-methylphenyl) -thio] thieno [2,3-b] pyridine-5-carboxylate Example 132A and thiocresol were treated as in Example 2. To give the title compound.

MS (DCI / NH)₃) M / z 347 (M + NH₄)⁺And 330 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆1.) δ 1.30 (t, 3H);
28 (s, 3H), 4.26 (q, 2H), 7.00 (d, 1H), 7.17 (
m, 2H), 7.24 (m, 2H), 7.91 (d, 1H), 8.81 (s, 1
H); Analysis C₁₇H_FifteenNO₂S₂For 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.

MS (DCI / NH)₃) M / z 275 (M + NH₄)⁺And 258 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆5.) δ 2.39 (s, 3H);
66 (d, 1H), 7.38 (m, 2H), 7.46 (d, 1H), 7.53 (
m, 2H), 7.46 (d, 1H), 7.53 (m, 2H), 7.95 (d, 1H)
H); 8.12 (d, 1H); analysis C₁₄H₁₁NS₂For 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 diisopropylamine (0.056 g, 0.56 mmol) in THF (10 m
L) The solution was added at −78 ° C. with n-butyllithium (0.22 mL, 0.56 mmol).
l, 2.5M in hexane), stirred for 15 minutes, and treated with Example 132C (0.1
(3 g, 0.51 mmol) in THF (5 mL), stir for 0.5 h, warm to 0 ° C. in 1 min, re-cool to −78 ° C., pour onto solid CO ₂ , add 0.
Stir for 5 h, dilute with saturated NH ₄ Cl, and extract with ethyl acetate. The extract was washed with brine, dried (MgSO _4), and concentrated to give the title compound.

280-282 ° C .; MS (DCI / NH₃) M / z 318 (M + NH₄)⁺And 301 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆5.) δ 2.41 (s, 3H);
62 (d, 1H), 7.40 (m, 2H), 7.57 (m, 2H), 7.77 (
br s, 1H), 8.26 (s, 1H), 8.36 (d, 1H), 8.43 (
brs, 1H); Analysis C_FifteenH₁₂N₂OS₂For C: 59.97; H, 4.02.
N, 9.32. Found: C, 59.83; H, 4.03; N, 9.11.

Example 133 4-Chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5
- carboxamide Example 132A, as in Examples 18 and 19, however, is treated by replacing the 4-chloroaniline with concentrated _NH 4 OH in Example 19, the title compound was obtained.

199-202 ° C .; MS (DCI / NH₃) M / z 340 (M + NH₄)⁺, 342 (M + NH₄) ⁺ , 323 (M + H)⁺, 325 (M + H)⁺;¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 7.6 (m, 2H), 7.6
2 (d, 1H), 7.77 (m, 2H), 8.19 (d, 1H), 8.79 (s
, 1H); Analysis C₁₄H₈Cl₂N₂OS₂For 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-carboxylate Example 132A and 5-methyl-1,3,4-thiadiazole-2-thiol were treated as in Example 17B to give the title compound.

MS (DCI / NH)₃) M / z 355 (M + NH₄)⁺And 238 (M + H) ⁺ ;¹ 1 H NMR (300 MHz, DMSO-d₆1.) δ 1.32 (t, 3H);
66 (s, 3H), 4.36 (q, 2H), 7.34 (d, 1H), 8.13 (
d, 1H), 9.00 (s, 1H); Analysis C₁₃H₁₁N₃O₂S₂For C: 46.27; H, 3.2.
8; 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
Treatment as in Examples 17B, 18 and 19 provided the title compound.

MS (DCI / NH ₃ ) m / z 301 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 6.
83 (d, 1H), 7.37 (m, 2H), 7.56 (m, 2H), 7.83 (
br s, 1H), 8.25 (s, 1H), 8.41 (br s, 1H),
53 (d, 1H); Calcd for analysis _{C 15 H 12 N 2 OS 2} : 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-
2-Carboxylate Example 136A 2,6, Dichloro-3-pyridinecarbonitrile Example 136B Methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate Example 136A and methylthioglycolate Treatment as in Example 1D afforded the specified compound.

Example 136C Methyl 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-
2-carboxylate 75% H of Example 136B (32 g, 1.34 mmol)₂SO₄(7.4m
L) The solution was added at 0 ° C with NaNO₂Water (0.24 g / 1.5 mL, 3.5 mmol
), Stirred for 30 minutes, cold 50% H₂PO₃(11.8 mL)
, Stirred for 30 minutes, stored at 0 ° C. for 60 hours, warmed to room temperature, NaHCO 3 ₃ And extracted with ether. Dry the extract (MgSO 4₄) Then filter and concentrate
Shrank. Dissolve the residue in methanol (7 mL), heat to 50 ° C., ₃ (0.08 g, 1.45 mmol) and p-thiocresol (0.18 g,
(1.45 mmol), stirred at room temperature for 18 hours and concentrated. Residue
Was treated with 10% citric acid and extracted with dichloromethane. Dry the extract (MgS
O₄), Filtered and concentrated. The residue is purified using 25% ethyl acetate / hexane
Purification by silica gel flash chromatography provided the title compound.

MS (DCI / NH ₃ ) m / z 316 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) 2.39 (s, 3H), 3.8
9 (s, 3H), 7.02 (d, 7.36 (m, 2H), 7.57 (m, 2H)
, 8.13 (s, 1H), 8.23 (d, 1H); Calcd for analysis _{C 16 H 13 NO 2 S 2} : 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 Example 136C using the procedure of Example 44. .

Example 138 2-Bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyri
Gin para-thiocresol (500 mg, 4 mmol) in DMF (10 mL)
At room temperature with potassium t-butoxide (451 mg, 4 mmol),
After 5 minutes, the mixture was cooled to 0 ° C., and 2-bromo-4-chlorothieno [3,2-c] pyridyl was added.
(F. Eloy and A. Deryckere (Bull. Soc. Chim)
. Belg. 1970, 79, 301) (prepared in 6 steps) (1.0
g, 4.0 mmol) and stirred at 0 ° C. for 2 hours and at room temperature for 12 hours,
And extracted with diethyl ether. The extract is washed with water and dried (Na₂SO ₄ ) And dried under vacuum. The residue was washed with 1:20 ethyl acetate-hexane.
Purification by Ricagel flash chromatography provided the title compound.

MS (DCI / NH ₃ ) m / z 336, 338 (M + H) ⁺ ; ¹ H NMR (300 Hz, CDCl ₃ ) δ 2.36 (s, 3H), 7.18 (
d, 2H), 7.40 (d, 2H), 7.48 (brs, 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 F . Eloy and A.J. Deryckere, Bull. Soc. Chim.
Belg. 4-oxo-4,5-dihydrothieno [3,2-c] pyridine-2-nitrile prepared as in 1970, 79, 301 (500 mg, 2.84 mm
ol) and phosphoryl chloride (5 mL) were heated at reflux for 1 hour. The red solution formed was poured on ice and extracted with methylene chloride (2 × 150 mL). The dichloromethane solution was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Residue 1: 1
Purification by flash chromatography using 0 EtOAc / hexane gave the title compound.

MS (DCI / NH ₃ ) m / z 195 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, 1 H), 8.10
(S, 1H), 8.41 (d, 1H).

Example 139B 4-[(4-Methylphenyl) thio] thieno [3,2-c] pyridine-2-carbonitrile para-thiocresol (192 mg, 1.54 mmol) in DMF (5 mL)
The solution was added at room temperature with potassium tert-butoxide (173 mg, 1.54 mmol).
), Stirred for 15 minutes, cooled to 0 ° C., and treated with Example 139A (200 mg,
1.03 mmol), stirred initially at 0 ° C. and then at room temperature for 48 hours, treated with water and extracted with dichloromethane. The extract is dried (MgSO ₄ ), filtered,
Concentrated. The residue was purified by silica gel flash chromatography using 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 / z 283 (M + H) ⁺ ; ¹ H NMR (300 MHz, 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 ); Calcd for analysis _{C 15 H 10 N 2 S 2} : 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 prepared. Heated at 3O 0 C for 3 hours, cooled, treated with water and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel flash chromatography using 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 (brs, 1H), 7.
84 (d, 1H), 8.19 (d, 1H), 8.34 (s, 1H), 8.46 (
br s, 1H); Calcd for analyzing _{C 15 H 12 N 2 OS 2} : 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); Calcd for analysis _{C 15 H 10 N 2 OS:} C, 67.65; H, 3.78;
N, 10.52. 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, 1H), 8.38 (br s, 1H), 8.
41 (s, 1H); Calcd for analysis _{C 15 H 12 N 2 O 2} S: 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 prepared using Caldwell and Martin (J. Hetero).
cyclic Chem. , 1980, 17, 989). 3-Chloropyridine (15.0) with cooling to maintain the internal temperature below 30 ° C.
g, 132 mmol) in acetic anhydride (75 mL) was treated with hydrogen peroxide (75 mL of a 30% aqueous solution), stirred at room temperature for 3 hours, heated at 60 ° C. for 18 hours, and treated with water (
(200 mL), concentrated, solid sodium bisulfite was added portionwise until peroxide was no longer detectable (by the enzymatic peroxide test) and the remaining solvent was removed under reduced pressure. The residue was triturated with ethyl acetate. The wash was filtered and concentrated to give the specified compound.

Example 141B 4-Nitro-3-chloropyridine-N-oxide Example 141B was prepared as described in Caldwell and Martin (J. Hetero).
cyclic Chem. , 1980, 17, 989). Example 141A (16.8 g, 130 mmol) sulfuric acid (25 mL, 98%) of fuming sulfuric acid _{(30% SO 3, 10mL)} , and nitric acid (60 mL, 90%) solution, 1
Heat at 20 ° C. for 2 hours, cool to room temperature, pour into ice water (200 mL), add solid ammonium carbonate to bring the solution to pH = 9, and extract with methylene chloride (4 × 100 mL). The extracts were dried _(Na 2 SO _4), and concentrated. The residue was treated with ethyl acetate-
Recrystallization from hexane gave a clean first group of the title compound. A second group of recrystallizations provided a mixture of the title compound and by-products.

MS (DCI / NH ₃ ) m / z 194 ( ³⁷ Cl) / 192 ( ³⁵ Cl), (
M + NH ₄ ) ⁺ ; 177 ( ³⁷ Cl) / 175 ( ³⁵ Cl), (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (d, 1H), 8.14
(Dd, 1H), 8.32 (d, 1H).

Example 141C 4-Nitro-3- (4-methylphenoxy) pyridine-N-oxide A solution of NaH (834 mg, 34.8 mmol) in DMF (20 mL) was added at room temperature to p-cresol (3.57 g, 33). 1.0 mmol) Example 141B (5.75)
g, 32.9 mmol), stirred at room temperature for 10 minutes, and 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 ₂ SO ₄ ) and concentrated. Recrystallization from diethyl ether gave the title compound.

MS (DCI / NH ₃ ) m / z 264 (M + NH ₄ ) ⁺ , 247 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.39 (s, 3H), 7.02
(D, 2H), 7.26 (d, 2H), 7.78 (d, 1H), 7.89 (dd
, 1H), 7.98 (d, 1H).

Example 141D 3- (4-Methylphenoxy) -4-pyridinamine Example 141C (3.65 g, 14.8 mmol) in methanol (100 mL)
), Treated with Raney nickel (1.00 g), flushed with hydrogen, pressurized to 4 atm at 37 ° C. for 2.5 hours, and filtered. The filtrate was concentrated to give the title compound.

MS (DCI / NH ₃ ) m / z 201 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.32 (s, 3H), 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 treated with methylene chloride (50 m
L), cooled to 0 ° C., and triethylamine (1.78 g, 17.6 mm
ol) and trimethylacetyl chloride (1.86 g, 15.4 mmol), stir at room temperature for 15 hours, and add a little sodium chloride in water (100 ml).
L). The organic layer was separated, treated with activated carbon, filtered through Celite®, washed with saturated sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated,
The title compound was obtained.

MS (DCI / NH ₃ ) m / z 285 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 8.42 (d,
1H).

Example 141F 5-Hydroxy-4- (N-trimethylacetyl) amino-3- (4-methylphenoxy) pyridine Chu-Moyer and Berger (J. Org. Chem. 1995;
60, 5721). Example 141E (5.50 g, 19.3 m
mol) was dissolved in diethyl ether and cooled to -78 ° C. Tert-butyllithium (24.0 mL of a 1.7 M solution in 1.7 M pentane, 40.8 mmol) was added dropwise and stirring was continued at -78 ° C for 2 hours. Trimethyl borate (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 30% aqueous hydrogen peroxide (5.8 m).
L) was added. The reaction was stirred at room temperature for 2 hours, then poured into 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 is washed once with water, once with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a mixture of the two compounds, where a higher R _f is desired. The mixture is applied to a 40M Biotage cartridge (Biotage ca
rtridge), purified by flash silica chromatography using a 1.5% methanol in CH ₂ Cl ₂ eluent to give 0.15 mmol (15% yield) of the desired product and 0.73 mmol (73%) The title compound was obtained.

MS (DCI / NH ₃ ) m / e 301 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 10.2
6 (br s, 1H).

Example 141G 5-Hydroxy-4-amino-3- (4-methoxyphenoxy) pyridine Example 141F (850 mg, 2.83 mmol) was suspended in 3N aqueous HCl and stirred at 90 ° C. for 18 hours. The reaction was then cooled to 0 ° C. and 6N NaO
Neutralized with H water 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 (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H);
16 (s, 2H), 6.81 (d, 2H), 7.12 (d, 2H), 7.50 (
s, 1H), 7.71 (s, 1H), 8.14 (s, 1H), 9.55 (br
s, 1H).

Example 141H Methyloxazolo [5,4-c] -4- (4-methylphenoxy) pyridine-
2-Carboxylate To a DMF solution of Example 141G (1.00 mmol) was added pyridine (1.10 m).
mol) and methyl oxalyl chloride (1.10 mmol) are added and the resulting solution is stirred overnight at room temperature. The reaction is then partitioned between methylene chloride and 1N aqueous HCl, the organic layer is 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) pyridine Example 141E (284 mg, 1.00 mmol) in diethyl ether (12
The solution was treated dropwise at −78 ° C. with tert-butyllithium (1.3 mL of a 1.7 M solution in pentane, 2.21 mmol, Aldrich), followed by 3 mL.
Stirred at -78 ° C for hours. Tetramethylthiuram disulfide (529 mg, 2
. 20 mmol) was added to the resulting dianion and stirring and temperature increase were continued for 18 hours. The reaction was quenched with water and extracted with _CH 2 Cl _2. Dry the organic phase (N
a ₂ SO ₄ ) and concentrated under reduced pressure. The title compound (50 mg, 12% yield) was obtained
Isolated by flash silica gel column chromatography.

MS (DCI / NH ₃ ) m / e 404 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.32 (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, 1H), 8.45 (s, 1H)
.

Example 142B 5- (N, N-dimethylthiuram) sulfide-4-amino-3- (4-methylphenoxy) pyridine Example 142A (270 mg, 0.67 mmol) was prepared using formic acid (20 mL of 96%).
, Aldrich) and stirred at 90 ° C for 72 hours. The reaction was then cooled to room temperature and the formic acid was removed under reduced pressure. The resulting residue is purified by flash silica gel chromatography (70% EtOAc in hexane) to give the title compound (96 mg, 45% yield).

MS (DCI / NH ₃ ) m / e 320 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.33 (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, 1H), 8.12 (s,
1H).

Example 142C 5- (N, N-dimethylthiuram) sulfide-4-methyloxamate-3
- (4-methylphenoxy) pyridine Example 142B (90 mg, 0.28 mmol) _to, CH ₂ Cl ₂ (7.0m
L). Triethylamine (0.39 mL, 2.2 mmol) was added,
Then, methyl oxalyl chloride (120 mL, 1.30 mmol, Aldrich) was added. After 6 hours, the mixture was combined with saturated aqueous sodium bicarbonate 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 , 300 MHz) δ 2.33 (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, 1H), 8.41 (s, 1H)
, 9.20 (br s, 1H).

Example 142D Methyl 4- (4-methylphenoxy) thiazolo [5,4-c] -pyridine-2
-Carboxylate Example 142C (50 mg, 0.12 mmol) was added to formic acid (14 mL, 96%,
Aldrich) and heated to reflux. After 4 hours, the reaction was cooled and volatiles were removed. Flash silica gel column chromatography (6 in hexane)
(0% EtOAc) provided 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 , 300 MHz) δ 2.39 (s, 3H), 4.10
(S, 3H), 7.08 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8
. 5 Hz, 2H), 8.14 (s, 1H), 9.00 (s, 1H).

Example 142E 4- (4-Methylphenoxy) thiazolo [5,4-c] -pyridine-2-carboxamide Example 142D (2.0 mg, 6.7 mmol) was treated according to the procedure of Example 44. This afforded 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 , 300 MHz) δ 2.39 (s, 3H), 5.66
(Br s, 1H), 7.06 (d, J = 8.2 Hz, 2H), 7.22 (d,
J = 7.8 Hz, 2H), 7.32 (brs, 1H), 8.20 (s, 1H)
, 9.04 (s, 1H).

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) is suspended in ammonium hydroxide (28%), saturated with sulfur dioxide, heated to 150 ° C in a pressure vessel for 27 hours, cooled and treated with ethyl acetate. Extracted. Concentrate the extract to give the title compound.

Example 143B 5- (4-Methylphenoxy) -3,4-pyridinediamine Example 143A (1.00 mmol) is suspended in HCl (3N aqueous) and 90 ° C.
For 18 hours, cooled to 0 ° C., neutralized with 6N aqueous NaOH, and water was removed.
The residue obtained is triturated with methanol. Concentrate the wash to give the title compound.

Example 143C Methyl 7- (4-methylphenoxy) -3H-imidazo [4,5-c] pyridine-2-carboxylate A DMF solution of Example 143B (1.00 mmol) was added to pyridine (1.10 m
mol) and methyl oxalyl chloride (1.10 mmol), stir at room temperature overnight, and partition 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 can be 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 is described in Prugh et al. (J. Med. Chem.
1805). Dibromothiophene (14 g, 58 mmol)
In THF (100 mL) at −78 ° C. in n-butyllithium (24 mL, 5 mL).
9 mmol), stir for 15 minutes, dry DMF (6.8 mL, 87 mmol)
1), stirred at -78 ° C for 10 minutes, slowly warmed to 0 ° C over 15 minutes, poured into cold 1N aqueous HCl and extracted with diethyl ether. Extract 1N
Washed with aqueous HCl, water and saturated sodium bicarbonate. The washing 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 on silica gel with 5% ethyl acetate / hexane to give the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.16 (d, 1H), 7.7
4 (d, 1H), 10.0 (s, 1H).

Example 144B 3-Bromo-2- (2-dioxolanyl) thiophene Example 144B is described in Prugh et al. (J. Med. Chem. 1991, 34;
1805). In a three-necked flask equipped with a Dean-Stark trap, Example 144A (5.24 g, 27.4 mmol), ethylene glycol (6.2 mL, 110 mmol), pyridinium tosylate (276 mg)
, 1.10 mmol) and toluene (30 mL), heat to reflux for 14 hours, cool to room temperature, pour into water and extract with diethyl ether. The organic layer was washed with water and saturated sodium bicarbonate, dried (MgSO _4), filtered, and concentrated.
The residue is purified by flash chromatography on silica gel with 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 , 300 MHz) δ 4.11-4.02 (m, 4H)
, 6.14 (s, 1H), 6.97 (d, 1H), 7.30 (d, 2H).

Example 144C Ethyl-2- (2-dioxiranyl) thiophene-3-carboxylate Example 144C was prepared according to Prugh et al. (J. Med. Chem. 1991, 34,
1805). Example 144B (1.00 g, 4.25 mmol
l) in THF (12 mL) was treated with n-butyllithium (1.7 mL, 4.25 mmol) while maintaining the temperature between -105 and -95 ° C, and diethyl carbonate (0.57 mL, 4 mL). .68 mmol) and warm to room temperature. The solution is poured into water and extracted with diethyl ether. The extract was washed with brine and dried (M
gSO ₄ ), filter and concentrate under reduced pressure. The residue is purified by flash chromatography on silica gel using 5% ethyl acetate / hexane to give the title compound.

Example 144D 2-Formylthiophen-3-carboxylic acid Example 144C (1.0 mmol) and ethanol (1.0 mL) were combined with 1N
Treat with aqueous sodium hydroxide solution (100 mmol), stir for 1 h, bring to pH = 5 by adding glacial acetic acid, stir for 1 h, dilute with water and extract with ethyl acetate.
The combined extracts were washed with brine, washed with saturated sodium bicarbonate and dried (Mg
SO ₄ ), filter and concentrate. The specified compounds are used without further purification.

Example 144E 4-Oxothieno [2,3-d] pyridazine Example 144D is described in Bull. Soc. Chim. Fr. 1967, 2495
Process as follows.

Example 144F 4-Chlorothieno [2,3-d] pyridazine Example 144E is described in Bull. Soc. Chim. Fr. 1967, 2495
Process as follows.

Example 144G 4- (4-Chlorophenoxy) thieno [2,3-d] pyridazine Robba and others (Bull. Soc. Chim. Fr., 1967, 42).
Example 144F (100 mg, 0.59 mmol) was obtained by employing the method of 20).
Combined with 4-chlorophenol (1.0 mL, 10.0 mmol) and sodium metal (21 mg, 0.90 mmol). The mixture was heated at 100 ° C. for 14 hours. After cooling to room temperature, the residue was diluted with chloroform and washed once with 2N aqueous sodium hydroxide and once with brine. The organic layer was dried (MgSO ₄ ), filtered,
Concentrated under reduced pressure. Recrystallization from diethyl ether gave the title compound (124 mg
, 85%) as a white solid.

MS (DCI / NH ₃ ) m / e: 363 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.27 (d, J = 8.9 Hz,
2H), 7.42 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 5.5H)
z, 1H), 7.88 (d, J = 5.2 Hz, 1H), 9.41 (s, 1H).

Example 144H 4- (4-Chlorophenoxy) thieno [2,3-d] pyridazine-2-carboxylic acid A solution of Example 144G (1.0 mmol) in THF (1.0 mL) at -78 ° C. Treat with n-butyllithium (1.0 mmol), stir for 15 min, saturate with CO ₂ , slowly warm to room temperature, partition between 1N aqueous sodium hydroxide and diethyl ether, separate, ice Acetic acid is added to the aqueous layer until pH = 5. The acidic solution is extracted three times with methylene chloride. The extracts are combined, 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 is described in Desai and Stramiello (Tetrahee).
(Dron Lett, 1993, 34, 7665). Example 144H (1.0 mmol), 1-hydroxybenzotriazole (1.4 mm
ol), N-methylmorpholine (12 mmol), and DMF (1.0 mL)
And cooled to 0 ° C., treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.4 mmol), stirred at 0 ° C. for 1 hour, and treated with methylene chloride and saturated sodium bicarbonate. Distribute between and separate. Dry the extract (Mg
SO ₄ ), filter and concentrate. Recrystallization from hot methanol gives the title compound.

Example 145 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carbamide Example 145A 2,5-Dibromo-3-thiophenecarboxaldehyde A 3-thiophenecarboxaldehyde solution was added to a Bull solution. . Soc. Chem.
Fr. , 1974, 3040 to give the title compound.

Example 145B Dimethylacetyl- (2,5-dibromo-3-thienyl) carboxyiminoethane Example 145A was prepared according to Bull. Soc. Chem. Fr. , 1974, 304
Treat as 0 to give the title compound.

Example 145C 6,7-Dihydro-7-oxothieno [3,2-c] pyridine Example 145B was prepared according to Bull. Soc. Chem. Fr. , 1974, 304
Treat as 0 to give the title compound.

Example 145D 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine Example 145D was prepared from Lindley (Tetrahedron, 1983, 1).
433). Example 145C (1.0 mmol) and DMF
(2.0 mL) at 0 ° C. was treated with sodium hydride (1.0 mmol), slowly warmed to room temperature, and treated with 1-chloro-4-iodobenzene (1.0 mm).
ol) and copper iodide (0.1 mmol), heat at 80 ° C. overnight and cool. The solution is poured into water and extracted with diethyl ether. Combine the extracts and dry (
MgSO ₄ ), filter and concentrate. Recrystallization from ethyl acetate / hexane gives the title compound.

Example 145E 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carboxylic acid The specified compound is treated as described in Example 144H.

Example 145F 7- (4-Chlorophenoxy) thieno [3,2-c] pyridine-2-carboxamide The specified compound is treated as described in Example 144I.

Example 146 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbothioamide Example 61 (50 mg, 0.16 mmol) and Lawesson (Lawess)
on) Reagent (73 mg, (0.18 mmol)) in toluene (2 mL)
Heat to reflux for 4 hours. Removal of the solvent under reduced pressure gives the crude product (150 mg) as a yellow residue. Purified title compound (24 mg, 47%) was obtained by flash chromatography on silica gel, eluting with 10% methanol in dichloromethane.

MS (DCI / NH ₃ ) m / e: 321 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (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 Example 61A (200 mg, 0.627 mmol) was added to ethylamine (1 ml).
, 17.65 mmol) was replaced with methylamine to give the title compound (209 mg, 100%).

MS (DCI / NH ₃ ) m / e 333 (M + H) ⁺ , 303; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.14 (t, J = 8 Hz,
3H), 3.30 (m, 2H), 7.14 (d, J = 9 Hz, 2H), 7.47
(D, J = 9 Hz, 2H), 8.13 (s, 1H), 8.17 (s, 1H), 8
. 91 (t, J = 6 Hz, 1H), 9.15 (s, 1H).

Example 148 4- (4-Chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno [2,3-c] pyridine-2-carboxamide Example 148 comprises 3-amino-1,2 -Propanediol (60 mL, 0.7
82 mmol) and Example 61A (250 mg, 0.782 mmol) were prepared in an analogous manner to Example 103A to give the title compound (133 mg).
, 45% yield) as a white solid.

MS (DCI / NH ₃ ) m / e: 379 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.16 (m, 2H);
38 (m, 2H), 3.63 (m, 1H), 4.56 (t, J = 5.7 Hz, 1
H), 4.81 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 9.2, 2
H), 7.47 (d, J = 9.2 Hz, 2H), 8.18 (s, 1H), 8.2
1 (s, 1H), 8.95 (t, J = 5.7 Hz, 1H), 9.16 (s, 1H)
); Analysis _{C 17 H 15 ClN 2 O 4} S 2 0.25H 2 O Calculated: C, 53.27;
H, 4.08; N, 7.31. Found: C, 53.19; H, 4.22; N, 6
. 22.

Example 149 4- (4-Bromophenoxy) -N- (2,3-dihydroxypropyl) thieno [2,3-c] pyridine-2-carboxamide Example 149 is methyl 4- (4-bromo Phenoxy) -thieno [2,3-c
Prepared following the procedure for Example 114, substituting Example 61A for pyridine-2-carboxylate.

MS (DCI / NH ₃ ) m / e: 423, 425 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.12 (m, 2H);
41 (m, 3H), 3.63 (m, 2H), 7.06 (d, 2H, J = 8.8H)
z), 7.59 (d, 2H, J = 8.8 Hz), 8.20 (s, 1H), 8.2
2 (s, 1H), 8.99 (t, 1H, J = 5.5 Hz), 9.18 (s, 1H)
).

Example 150 N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-
c] Pyridine-2-carboxamide To a solution of Example 114 (0.32 g, 0.92 mol) in anhydrous THF (5 mL)
Slowly, thionyl chloride (0.34 mL, 4.60 mmol) was added. reaction
Heat the material to 50 ° C. for 18 hours, cool to room temperature, and add saturated NaHCO 3₃And neutralized.
The aqueous suspension was extracted with dichloromethane (100 mL) and the organic layer was diluted with dilute NaHCO₃ (2 × 100 mL), diluted with brine (50 mL) and partially dried (Na₂SO ₄ ) And concentrated to a solid. The crude product was eluted with EtOAc / hexane.
Purified by flash chromatography on silica gel using the title compound
Was obtained as a solid (0.27 g, 80%).

MS (DCI-NH ₃ ) m / e: 367 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.60 (m, 2H), 3 .
75 (t, J = 6.1 Hz, 2H), 7.15 (m, 2H), 7.48 (m, 2H)
H), 8.18 (s, 1H), 8.18 (s, 1H), 9.17 (s, 1H),
9.26 (m, 1H); Analysis _{C 16 H 12 Cl 2 N 2} O 2 Calculated for S: 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 Example 151 was prepared according to the procedure of Example 114 using methyl 4- (4-bromophenoxy) -thieno [2,3-c] pyridine-2-carboxylate as Example 61.
Prepared in place of A.

MS (DCI / NH ₃ ) m / e: 393, 395 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.32 (m, 2H);
51 (m, 3H), 4.79 (t, 1H, J = 5.9 Hz), 7.06 (d, 2
H, J = 8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 8.17 (s)
, 1H), 8.20 (s, 1H), 9.02 (t, 1H, J = 5.5), 9.1
7 (s, 1H).

Example 152 4- (2-Bromo-4-chlorophenoxy) -N- (2-hydroxyethyl)
Thieno [2,3-c] pyridine-2-carboxamide Example 152 was prepared according to the procedure of Example 114, substituting 4-chlorophenol for 2-bromo-4-chlorophenol.

MS (DCI / NH ₃ ) m / e: 428 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.86 (q, 1 H, J = 5)
. 4 Hz), 3.34 (m, 2H), 3.55 (m, 2H), 7.15 (d, 1
H, J = 8.8 Hz), 7.48 (dd, 1H, J = 2.4, 8.8 Hz), 7
. 97 (d, 1H, J = 2.7 Hz), 8.02 (s, 1H), 8.25 (s,
1H), 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 Example 62A (322 mg, 0.912 mmol) Was treated with 226 mg (3.65 mmol) of ethanolamine. The solution was heated at reflux for 4 hours. Crystals formed upon cooling. Recrystallization from ethyl acetate gave 170 mg (48.8%) of white crystals.

MS (DCI / NH ₃ ) m / e: 383 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3-3.4 (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); Analysis _{C 17 H 13 F 3 N 2} O 3 Calculated for S: 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 Example 88 (0.50 g, 1.64 mmol) in anhydrous methylene chloride (15 mL)
) The suspension was added with N, N-diisopropylethylamine (0.57 mL, 3.28 m
mol) was added. The reaction was cooled in an ice bath and pivaloyl chloride (0.24 mL, 1
. 97 mmol) was added slowly. After 10 minutes, the ice bath was removed and the reaction was stirred at ambient temperature for 1.5 hours. The reaction contents were slowly transferred via cannula to a solution of anhydrous ethylenediamine (0.33 mL, 4.92 mmol) in methylene chloride (5 mL) at 0 ° C. over 5 minutes. The reaction was stirred for 15 minutes and the cold bath was removed. The reaction was stirred for 1 hour and then partitioned between CHCl ₃ / sat. NaHCO ₃ . The organic layer was washed with dilute aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated to give a light yellow foam. The crude product was reduced to 25% over 40 minutes.
Purified by preparative HPLC using a gradient of -65% acetonitrile / water + 0.1% TFA. The product was neutralized with saturated aqueous NaHCO ₃ and the precipitate was collected by filtration and dried in a desiccator to give the title compound as a white solid (0.45 g,
79%).

MS (ACPI) m / e: 348 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.69 (t, J = 6.4 H).
z, 2H), 3.25 (t, J = 6.4 Hz, 2H), 7.14 (m, 2H),
7.47 (m, 2H), 8.16 (s, 1H), 8.18 (s, 1H), 9.1
5 (s, 1H).

Example 155 4- (4-Chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine-2-carboxamide Example 155 comprises Example 88 (161 mg, 0.527 mmol) and hydroxylamine hydrochloride. Prepared as in Example 92 by combining the salts (37.0 mg, 0.527 mmol) to give the title product (40 mg, 24% yield) as a white solid.

[0567] mp 145 ° 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 = 9.2 Hz, 2H), 7.90 (s, 1H), 8.
05 (s, 1H), 9.01 (s, 1H); IR (KBr) 3200-2800 (m), 1660 (s), 1640 (s),
1560 (m), 1485 (s ), 1420 (s) cm -1; Analysis _{C 14 H 9 ClN 2 O 3} S + 0.25H calcd for ₂ O: 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-carboxyhydrazide Example 61A (0.50 g, 1.56 mmol) was treated with dichloromethane (10 mL).
) And anhydrous hydrazine (1 mL) was added. After 24 hours, the precipitate was collected by filtration and washed with dichloromethane (2 × 25 mL) and water (2 × 50 mL). The product was dried in a desiccator to give the title compound as a white solid (0.
35 g, 70%).

MS (APCI) m / e: 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.62 (broad s, 2H
), 7.12 (m, 2H), 7.46 (m, 2H), 8.03 (s, 1H), 8
. 19 (s, 1H), 9.15 (s, 1H), 10.24 (br s, 1H);
Analysis Calculated for C ₁₄ H ₁₀ ClN ₃ O ₂ S: C, 52.59; H, 3.
15; N, 13.14. Found: C, 52.59; H, 3.12; N, 13.1.
8.

Example 157 4- (4-Bromophenoxy) thieno [2,3-c] pyridine-2-carbohydrazide Example 73A (0.21 g, 0.58 mmol) in dichloromethane (2 mL)
And anhydrous hydrazine (1 mL) was added. After 18 hours, the precipitate was collected by filtration, dichloromethane (2 × 5 mL), water (2 × 5 mL), acetonitrile (
(2 x 5 mL) to give a white solid. The washes were combined, diluted with saturated NaHCO ₃ (100 mL) and extracted with dichloromethane (4 × 25 mL). The organic extracts were combined, partially dried (Na ₂ SO ₄ ) and concentrated to give a white solid, which was combined with the collected precipitate and dried in a desiccator (0.21 g, 99%).

MS (APCI) m / e: 364 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.62 (br s, 2H).
, 7.06 (m, 2H), 7.58 (m, 2H), 8.02 (s, 1H),
21 (s, 1H), 9.16 (s, 1H), 10.24 (br s, 1H); Analysis C ₁₄ H ₁₀ BrN ₃ O ₂ Calculated for S: C, 46.17; H, 2.
77; N, 11.54. Found: C, 46.08; H, 2.90; N, 11.4.
One.

Example 158 4- [4- (Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carbohydrazide Example 62A is treated according to the procedure of Example 157 to give the title compound. Obtained.

MS (ESI) m / e: 353.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.18 (d, 2H);
11 (t, 1H), 7.19 (d, 2H), 7.77 (d, 2H), 7.78 (
s, 1H), 8.36 (s, 1H), 9.21 (s, 1H).

Example 159 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl @ amino) acetic acid Example 159A 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid Example 61A (354 mg, 1.11 mmol) in 3 mL methanol and 1
The suspension mL water, lithium hydroxide monohydrate (98 mg, 2.33 mmol) was treated with the resulting mixture at room temperature _{(N 2} under) was stirred for 20 h. The reaction was treated with 0.
Acidified with 13 mL of 90% formic acid, the white suspension was stirred for 5 minutes, then the solid was isolated by suction filtration. The solid was washed successively with 15 mL of water and 5 mL of diethyl ether, then dried under vacuum to give 302 mg (89%) of the title compound.

[0575] _{^{MS (DCI-NH 3) m}} / e: 306,308 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ7.15 (m, 2H), 7.
47 (m, 2H), 7.82 (s, 1H), 8.23 (s, 1H), 9.21 (
s, 1H), 13-15 (vbr s, 1H); Analysis C ₁₇ H ₈ ClNO ₃ Calculated for S: C, 55.00; H, 2.64
N, 4.58. Found: C, 54.77; H, 2.60; N, 4.44.

Example 159B Methyl 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) acetate The title compound was prepared from Example 159A in Example Prepared as in 92, but replacing glycine methyl ester hydrochloride with ammonium chloride.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 1 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (APCI) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.68 (s, 3H);
05 (d, J = 6 Hz, 2H), 7.13 (m, 2H), 7.49 (m, 2H)
, 8.19 (s, 1H), 8.21 (s, 1H), 9.19 (s, 1H), 9.
50 (brt, J = 6 Hz, 1H); Calculated for C ₁₇ H ₁₃ ClN ₂ O ₄ S: C, 54.19; H, 3.
48; N, 7.43. Found: C, 53.92; H, 3.61; N, 7.52.

Example 159C 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl {amino) acetic acid The title compound was prepared from Example 159B using the procedure of Example 18.
The title compound was obtained.

MS (APCI) m / e: 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.95 (d, J = ₆ Hz,
2H), 7.13 (m, 2H), 7.48 (m, 2H), 8.19 (s, 1H)
, 8.21 (s, 1H), 9.19 (s, 1H), 9.41 (brt, J = 6)
Hz, 1H), 12.77 (br s, 1H); Analysis _{C 16 H 11 ClN 2 O 4} S · 1H 2 O Calcd for: 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-2-carboxamide The title compound was obtained from Example 159C to Example 92. Prepared as in

MS (APCI) m / e: 363 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.82 (br s, 2H).
, 7.12 (m, 2H), 7.49 (m, 2H), 8.19 (s, 1H),
21 (s, 1H), 9.20 (s, 1H), 9.29 (br s, 1H); Analysis Calculated for C ₁₆ H ₁₂ ClN ₃ O ₃ S.1.35H ₂ O: C, 49
. 77; H, 3.84; N, 10.88. Found: C, 49.86; H, 3.7.
9; N, 10.59.

Example 161 N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 161A Methyl N- (2-amino- 2-oxoethyl) -4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxylate Example 73A was hydrolyzed according to the procedure of Example 18. The derived carboxylic acid was coupled to glycine methyl ester hydrochloride as in Example 92.

MS (DCI / NH ₃ ) m / e: 421 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 370 (s, 3H), 4.1
1 (br d, 2H), 7.11 (br d, 2H), 7.61 (br d, 2H)
H), 8.22 (br d, 2H), 9.19 (s, 1H), 9.51 (br
t, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 41.15, 51.84,
104.95, 115.57, 119.74, 119.97, 132.93, 1
33.32, 137.36, 138.04, 141.45, 145.06, 14
7.03,156.10,161.09,169.80; Analysis C ₁₇ H ₁₃ BrN ₂ O ₄ Calculated for S: C, 48.47; H, 3.
11; N, 6.65. Found: C, 48.16; H, 3.27; N, 6.65.

Example 161B 2-({[4- (4-bromophenoxy) thieno [2,3-c] pyridine-2
-Yl] carbonyl {amino) acetic acid The title compound was prepared from Example 161A using the procedure of Example 18.
The title compound was obtained.

MS (DCI / NH ₃ ) m / e: 407 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.11 (br d, 2H)
, 7.10 (br d, 2H), 7.60 (br d, 2H), 8.21 (br
d, 2H), 9.19 (s, 1H), 9.40 (brt, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 41.50, 115.85.
, 120.00, 120.09, 133.25, 133.67, 137.76,
138.34, 141.79, 145.74, 147.29, 156.46, 1
61.28,171.05; Analysis _{C 16 H 11 BrN 2 O 4} S · H 2 O Calculated for: 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-2-carboxamide The title compound was obtained from Example 161B to Example 92. Prepared as in

MS (APCI) m / e: 406 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.81 (br d, J = 6).
Hz, 2H), 7.08 (m, 2H), 7.10 (brs, 1H), 7.60
(M, 2H), 8.19 (s, 1H), 8.22 (s, 1H), 9.20 (s,
1H), 9.28 (br t, J = 6Hz, 1H); Analysis _{C 16 H 12 BrN 3 O 3} S · 0.3H Calcd for ₂ O: C, 46.
68; H, 3.09; N, 10.21. Found: C, 46.68; H, 3.30.
N, 10.16.

Example 162 N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl] -4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 162A (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid Prepared as in Example 92, replacing L-serine ethyl ester hydrochloride with ammonium chloride. Then, the intermediate ester was prepared in Example 1.
Hydrolysis according to the procedure of 8 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, APCI m / e: 392 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.70 (m, 2H);
43 (brt, 2H), 5.04 (brs, 1H), 7.13 (m, 3H)
, 7.49 (m, 3H), 8.18 (s, 1H), 8.37 (s, 1H),
98 (br s, 1H), 9.18 (s, 1H).

Example 162B N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl] -4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 162B was prepared from Example 162A in the same manner as Example 92.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, APCI m / e: 392 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.70 (m, 2H);
43 (brt, 2H), 5.04 (brs, 1H), 7.13 (m, 3H)
, 7.49 (m, 3H), 8.18 (s, 1H), 8.37 (s, 1H),
98 (br s, 1H), 9.18 (s, 1H).

Example 163 (2R) -2-({[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) -3-hydroxypropanoic acid Example 163 Was prepared as in 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, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS, (ESI) m / e: 393 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.78 (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 4- (4-Chlorophenoxy) -N-[(1R) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 164A (2R) -2-({[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid Example 164A is the same as Example 92. Thus, D-alanine methyl ester hydrochloride was prepared using ammonium chloride instead. The derived ester is
Hydrolysis according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (DCI / NH ₃ ) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (d, J = 7 Hz;
3H), 4.41 (q, J = 7 Hz, 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 (brs, 1H).

Example 164B 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 164 was prepared as in Example 92, using D-alanine methyl ester hydrochloride instead of ammonium chloride. The derived ester was treated according to the procedure of Example 171 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
Min, RT17.46 _{^{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 (br d, 1H), 8.19 (s, 1H), 8.38 (
s, 1H), 9.13 (br d, 1H), 9.19 (s, 1H).

Example 165 4- (4-Chlorophenoxy) -N-[(1S) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 165A (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] carbonyl} amino) propanoic acid Example 165A is the same as Example 92. As such, L-alanine methyl ester hydrochloride was prepared using ammonium chloride instead. The derived ester was hydrolyzed according to the procedure of Example 18 to give the title compound.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
MS (DCI / NH ₃ ) m / e: 377 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40 (d, J = 7 Hz,
3H), 4.41 (q, J = 7 Hz, 1H), 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 (brs, 1H);
¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 16.78, 48.46,
119.52, 119.80, 119.97, 127.84, 130.13, 1,
32.97, 137.54, 137.60, 138.09, 141.30, 14
5.59, 147.38, 155.59, 160.54, 173.68.

Example 165B 4- (4-Chlorophenoxy) -N-[(1S) -1-methyl-2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxamide Example 165B was prepared as in Examples 165A to 92 except that L-alanine methyl ester was replaced with ammonium chloride. Intermediate ester,
This was converted to the title compound according to the procedure of Example 171 using methanolic methylamine.

HPLC: Supelco C-18 column, elution gradient of water: acetonitrile 0: 90-90: 0 over 30 minutes, detection at 254 nm, flow rate 0.8 mL /
Min, RT17.48 _{^{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 (br d, 1H), 8.18 (s, 1H), 8.36 (
s, 1H), 9.12 (br d, 1H), 9.19 (s, 1H).

Example 166 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide The title compound was prepared as in Example 164B using D-serine methyl ester. HPLC: Supelco C-18 column, eluent gradient of water: acetonitrile 0: 90-90: 0 was introduced in 30 minutes, detection 254 nm, flow rate 0.8 mL / min, retention time 16.10 minutes. MS (APCI) m / e: 404 (M-H) < ^- >. ¹ H NMR (300 MHz, 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, 1H), 8.18 (s,
1H), 8.49 (s, 1H), 9.01 (br d, 1H), 9.19 (s, 1H).
1H).

Example 167 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide The title compound was prepared in a similar manner to Example 164B using L-serine methyl ester. HPLC: Supelco C-18 column, eluent gradient of water: acetonitrile 0: 90-90: 0 was introduced in 30 minutes, detection 254 nm, flow rate 0.8 mL / min, retention time 16.18. MS (APCI) m / e: 404 (M-H) < ^- >. ¹ H NMR (300 MHz, 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, 1H), 8.18
(S, 1H), 8.49 (s, 1H), 9.01 (br d, 1H), 9.19
(S, 1H).

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. Obtained. _{MS (DCI / NH 3) m} / e: 272 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.50 (m, 2H), 7
. 85 (m, 1H), 8.20 (s, 2H), 8.45 (dd, 2H), 8.5
5 (d, 1H), 9.20 (s, 1H). Elemental _analysis: Calculated for _{C 13 H 9 N 3 O 2} S0.25H 2 O; C 56.61, H 3.47, N 15.24. Obtained: C 57.01, H 3.50, N 1
5.16.

Example 171 Methyl 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 73A (2 g, 5.5 mmol) was prepared by dissolving methylamine in a methanol solution of methylamine (2
M solution, 15 mL) and refluxed under a nitrogen atmosphere for 1 hour. The solvent was then removed and the residue was purified by flash chromatography on silica gel, eluting with 30% acetone in hexane, to give the title compound (1.96 g, 98%). Melting point: 78-80C. _{MS (DCI / NH 3) m} / e: 363,365 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 7.06 (d, 2H, J = 8.8 Hz), 7.59 (d, 2H,
J = 8.8 Hz), 8.06 (s, 1H), 8.20 (s, 1H), 8.96 (
q, 1H, J = 4.8 Hz), 9.17 (s, 1H).

Example 172 4- (4-Bromophenoxy) -N, N-dimethylthieno [2,3-c] pyridine-2-carboxamide Methyl 4- (4-bromophenoxy) -thieno [2 in Example 61A , 3-c]
Example 172 was prepared according to the procedure of Example 104, substituting pyridine-2-carboxylate. Melting point: 93-95C. _{MS (DCI / NH 3) m} / e: 377,379 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.02 (br s, 3H
), 3.13 (brs, 3H), 7.09 (d, 2H, J = 8.8 Hz), 7
. 5 (d, 2H, J = 8.8 Hz), 7.60 (s, 1H), 8.19 (s, 1
H), 9.15 (s, 1H) ppm.

Example 173 N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2
, 3-c] Pyridine-2-carboxamide In Example 61A, methyl 4- (4-trifluoromethylphenoxy) -thieno [
Example 173 was prepared according to the procedure of Example 104, substituting 2,3-c] pyridine-2-carboxylate. Melting point: 74-76 [deg.] C. _{MS (DCI / NH 3) m} / e: 367 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.17 (brs, 6H),
7.11 (d, 2H, J = 8.0 Hz), 7.45 (s, 1H), 7.63 (d
, 2H, J = 8.0 Hz), 8.24 (brs, 1H), 9.01 (brs
, 1H).

Example 174 4- (4-Chloro-3-fluorophenoxy) -N-methylthieno [2,3-c
Pyridine-2-carboxamide Example 174 was prepared as in Example 103, but replacing 4-chlorophenol with 4-chloro-3-fluorophenol, to give the title compound. Melting point: 62-64 [deg.] C. _{MS (DCI / NH 3) m} / e: 337 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.05 (d, 3H, J =
4.7 Hz), 6.24 (brs, 1H), 6.77 (d, 1H, J = 9.8)
Hz), 6.84 (dd, 1H, J = 2.4, 9.5 Hz), 7.26 (s, 2
H), 7.37 (t, 1H, J = 8.5 Hz), 7.69 (s, 1H), 8.2
1 (s, 1H), 9.00 (s, 1H). Elemental _analysis: Calculated for _{C 15 H 10 N 2 ClFO 2} S; 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 Example 175 was prepared as in Example 61, but replacing 4-chlorophenol with 4-chloro-3-fluorophenol, to give the title compound. Melting point: 227-228 ° C. _{MS (DCI / NH 3) m} / e: 323 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.94 (m, 1 H), 7
. 34 (dd, 1H, J = 3.0, 10.5 Hz), 7.60 (t, 1H, J =
8.7 Hz), 7.87 (s, 1H), 8.11 (s, 1H), 8.26 (s, 1H)
1H), 8.44 (s, 1H), 9.19 (s, 1H). Elemental _analysis: Calculated for _{C 14 H 8 N 2 ClFO 2} S; C 52.10, H 2.5
0, 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 Example 17A and 4-chloro-3-ethylphenol were treated as in Example 61 to give the title compound. Melting point: 185-187 ° C. _{MS (DCI / NH 3) m} / e: 333 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.15 (t, 3H), 2
. 70 (q, 2H), 6.95 (dd, 1H), 7.20 (d, 1H), 7.4
5 (d, 1H), 7.85 (brs, 1H), 8.15 (s, 1H), 8.4
5 (m, 1H), 9.15 (s, 1H).

Example 177 4- (3-Fluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 177 was performed according to the procedure of Example 61, substituting 3-fluorophenol for 4-chlorophenol. Prepared. Melting point: 215-216 ° C. _{MS (DCI / NH 3) m} / e: 289 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.90 (m, 1 H), 7
. 05 (m, 2H), 7.43 (q, 1H, J = 8.6 Hz), 7.86 (br
s, 1H), 8.14 (s, 1H), 8.20 (s, 1H), 8.45 (br
s, 1H), 9.17 (s, 1H).

Example 178 4- (2,3-Difluorophenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 178 was prepared by following the procedure of Example 61 and converting 4-chlorophenol to 2,3-difluoro Prepared in place of phenol. Melting point: 207-209 [deg.] C. _{MS (DCI / NH 3) m} / e: 307 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.97 (t, 1 H, J =
8.5 Hz), 7.22 (q, 1H, J = 8.5 Hz), 7.32 (q, 1H,
J = 8.5 Hz), 7.87 (brs, 1H), 8.18 (s, 1H), 8.
21 (s, 1H), 8.43 (brs, 1H), 9.17 (s, 1H).

Example 179 4- (2,3-Difluorophenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 179 was converted to 2-chlorophenol with 3-
Prepared in place of difluorophenol. Melting point: 169-171 [deg.] C. _{MS (DCI / NH 3) m} / e: 321 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.88 (d, 3H, J =
4.4 Hz), 6.94 (t, 1H, J = 8.5 Hz), 7.21 (q, 1H,
J = 8.5 Hz), 7.31 (q, 1H, J = 8.5 Hz), 8.14 (s, 1
H), 8.21 (s, 1H), 8.95 (q, 1H, J = 4.5 Hz), 9.1
7 (s, 1H).

Example 180 4- (3-Fluorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-Carboxamide Example 180 was prepared according to the procedure of Example 103, substituting 3-fluorophenol for 4-chlorophenol. Melting point: 194-195 [deg.] C. _{MS (DCI / NH 3) m} / e: 303 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 6.87 (d, 1 H, J = 8.5 Hz), 7.05 (m, 2 H)
, 7.42 (q, 1H, J = 8.5 Hz), 8.05 (s, 1H), 8.23 (
s, 1H), 8.95 (q, 1H, J = 4.4 Hz), 9.17 (s, 1H).

Example 181 N-methyl-4- (2,3,4-trifluorophenoxy) thieno [2,3-c
Pyridine-2-carboxamide Example 181 was prepared according to the procedure of Example 103 by converting 4-chlorophenol to 2,3
Prepared in place of 4-trifluorophenol. Melting point: 170-171 ° C. _{MS (DCI / NH 3) m} / e: 339 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.82 (d, 3H, J =
4.4 Hz), 7.13 (m, 1H), 7.35 (q, 1H, J = 8.5 Hz)
, 8.16 (s, 1H), 8.17 (s, 1H), 8.97 (q, 1H, J = 4)
. 5 Hz), 9.16 (s, 1H).

Example 182 4- (2,3,4-trifluorophenoxy) thieno [2,3-c] pyridine-
2-Carboxamide Example 182 was prepared according to the procedure of Example 61 by converting 4-chlorophenol to 2,3,4
-Prepared in place of trifluorophenol. Melting point: 218-219 ° C. _{MS (DCI / NH 3) m} / e: 325 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.15 (m, 1 H), 7
. 38 (q, 1H, J = 8.5 Hz), 7.89 (brs, 1H), 8.15
(S, 1H), 8.23 (s, 1H), 8.45 (br s, 1H), 9.15
(S, 1H).

Example 183 N-methyl-4- [4- (trifluoromethyl) phenoxy] thieno [2,3-
c] Pyridine-2-carboxamide Example 183 was prepared according to the procedure of Example 103, substituting 4-trifluorophenol for 4-chlorophenol. Melting point: 157-158 [deg.] C. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.76 (d, 2H,
J = 8.5 Hz), 8.01 (s, 1H), 8.34 (s, 1H), 8.92 (
q, 1H, J = 4.4 Hz), 9.24 (s, 1H).

Example 184 4- [3- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 17A and 3-trifluoromethylolophenol were prepared in the same manner as in Example 183. Workup provided the title compound. Melting point: 175-176 ° C. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H), 7
. 35 (d, 1H), 7.20 (d, 1H), 7.60 (m, 3H), 8.10
(S, 1H), 8.30 (s, 1H), 9.00 (b, 2H), 9.25 (s, 1H)
1H). Elemental _analysis: Calculated for _{C 16 H 11 F 3 N 2} O 2 S0.25H 2 O; C 53.8
6, 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 Example 185 was converted to 4-chlorophenol according to the procedure of Example 104 to give 4-chlorophenol. -Prepared in place of vinylphenol. Melting point: 80-81 ° C. _{MS (DCI / NH 3) m} / e: 325 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.02 (br s, 3H
), 3.13 (brs, 3H), 5.24 (d, 1H, J = 11.4 Hz),
5.78 (d, 1H, J = 17.3 Hz), 6.74 (dd, 1H, J = 11.
4,17.3 Hz), 7.09 (d, 2H, J = 8.5 Hz), 7.53 (d,
2H, J = 8.5 Hz) 7.61 (s, 1H), 8.16 (s, 1H), 9.1
3 (s, 1H).

Example 186 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 186 was prepared as in Example 103, but replacing 4-chlorophenol with 4-cyanophenol, to give the title compound. _{MS (ESI / NH 3) m} / e: 310 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.89 (d, 2H,
J = 8.8 Hz), 7.97 (s, 1H), 8.37 (s, 1H), 8.94 (
q, 1H, J = 4.4 Hz), 9.26 (s, 1H). Elemental _{analysis: C 16 H 11 N 3 O} 2 S0.05CH 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 Same as in example 61 but substituting 4-cyanophenol for 4-chlorophenol. Was prepared to give the title compound. Melting point: 255-257 ° C. _{MS (ESI / NH 3) m} / e: 296 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.20 (d, 2H, J =
8.8 Hz), 7.84 (s, 1H), 7.89 (d, 2H, J = 8.8 Hz)
, 8.05 (s, 1H), 8.36 (s, 1H), 8.41 (q, 1H, J = 4)
. 4 Hz), 9.26 (s, 1H). Elemental _{analysis: C 15 H 9 N 3 O} 2 S. Calculated 1.5CH ₃ OH; C 57.71
, H 3.08, N 12.24. Obtained: 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- (t-butyloxycarbonyl) amino) phenoxy-
Literature method (A. Vigroux, M. Bergon) in 4-pyridinecarboxaldehyde DMF (30 mL).
, C.I. Zedde; Med. Chem. 1995, 38, 3983), prepared according to Example 17A (2.0 g, 11.4 mmol) and t-butyl N- (
A solution of 4-hydroxyphenyl) carbamate (2.38 g, 11.4 mmol) was treated with CsCO ₃ (3.70 g, 11.4 mmol) at room temperature for 1 hour and then at 70 ° C.
It processed at 30 degreeC and 30 minutes. Brine (150 mL) was added and the mixture was extracted with ether / ethyl acetate (2 × 200 mL). The combined organic phases are dried (MgSO ₄ )
Concentrated. Flash chromatography of the residue on silica gel with 1: 6 ethyl acetate / hexane provided the specified compound (2.65 g, 67%). _{MS (ESI / NH 3) m} / e: 349 (M + H) +.

Example 188B Methyl 4-((4-t-butyloxycarbonylamino) phenoxy) thieno [
2,3-c] Pyridine-2-carboxylate 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 hour. After further treatment at room temperature for 1 hour, Cs ₂ CO ₃ (2.47 g, 7.58 mmol
) Was added. The reaction mixture was stirred at room temperature for 1 hour and further at 70 ° C. for 0.5 hour.
Brine (150 mL) was added and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 20% ethyl acetate in hexane to give the specified 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 Example 18 as in example 44 but substituting example 188B for example 43.
8C was prepared to give the title compound. _{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. The residual oil was treated with a mixture of ethyl acetate and aqueous NaHCO ₃ solution.The solid formed was collected by filtration, ethyl acetate, aqueous Na.
Washed sequentially with HCO ₃ solution, water, methanol and ethyl acetate and dried to give the title compound (492 mg, 86% from Example 188B) as a yellow solid. Melting point> 250 ° C. _{MS (DCI / NH 3) m} / e: 286 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 5.62 (br s, 2H
), 6.65 (d, 2H, J = 8.8 Hz), 6.93 (d, 2H, J = 8.8)
Hz), 7.86 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H)
, 9.00 (br s, 1H). Elemental _{analysis: C 14 H 11 N 3 O} 2 S. Calculated 0.5CH ₃ OH; C 57.7
9, 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 as in example 188C, but with t-butyl N- (4-hydroxyphenyl)
Example 189 was prepared by substituting 4- (acetylamino) phenol for the carbamate to give the title compound. _{MS (DCI / NH 3) m} / e: 328 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.04 (s, 3H), 7
. 10 (d, 2H, J = 8.8 Hz), 7.65 (d, 2H, J = 8.8 Hz)
, 7.82 (brs, 1H), 7.99 (s, 1H), 8.20 (s, 1H)
, 8.43 (br s, 1H), 9.06 (s, 1H), 9.99 (s, 1H)
. Elemental _{analysis: C 16 H 13 N 3 O} 3 S. Calculated 1.0CH ₃ OH; C 56.8
1, H 3.93, N 11.69. Measured value: C 56.51, H 3.93,
N 11.57.

Example 190 N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide Example 190A Methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-2-carboxylate Same as in Example 61A, except that 4-chlorophenol is used. Example 190A was prepared in place of 4-iodophenol to give the specified compound. _{MS (DCI / NH 3) m} / e: 412 (M + H) +.

Example 190B N-methyl-4- [4- (4-iodophenoxy)] thieno [2,3-c] pyridine-2-carboxamide Methylamine of Example 190A (1.4 g, 3.4 mmol) /methanol(
(2.0 M solution, 70 mL) The solution was stirred at 45 ° C. for 15 hours and then concentrated in vacuo.
The residue was flash chromatographed on silica gel with EtOAc / hexane (1.5 / 1) to give the specified compound (1.3 g, 93%). _{MS (DCI / NH 3) m} / e: 411 (M + H) +.

Example 190C N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
Example 190B (150 mg, 0.37 mmol), NaOB
ut (71 mg, 0.74 mmol), Pd ₂ (dba) ₃ (14 mg, 0.
014 mmol), BINAP (27 mg, 0.044 mmol) and 18-
Filled with crown-6 (196 mg, 0.74 mmol) and purged with nitrogen.
Anhydrous degassed THF (10 mL) and morpholine (64 mg, 0.74 mmol) were added sequentially. The clear dark red solution was heated at 60 ° C. for 70 hours and quenched with brine. The mixture was extracted with methylene chloride. The organic phase was dried (MgSO _4), and concentrated. To the crude subjected to flash chromatography on silica gel (EtOAc / hexanes) to obtain the title compound further _{HPLC (C-18, CH 3} CN / H 2 O) (26mg). _{MS (DCI / NH 3) m} / e: 370 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.81 (d, 3H, J =
4.5 Hz), 3.1 (m, 2H), 3.74 (m, 2H), 6.99 (d, 2
H, J = 8.8 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7.92 (s)
, 1H), 8.20 (s, 1H), 8.98 (q, 1H, J = 4.8 Hz), 9
. 04 (s, 1H).

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-2-carboxylate As in Example 61A, but 4-chlorophenol was prepared according to the literature method (Frank
, R .; Doring, R .; , Tetrahedron 1988, 44, 60.
Example 1 in place of 4-trityloxymethylphenol prepared according to 31)
91A was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 558 (M + H) +.

Example 191B 4- {4-[(Trityloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide As in Example 61 but 4-chlorophenol was converted to 4-trityl Example 191A was prepared in place of oxymethylphenol to give the title compound. _{MS (DCI / NH 3) m} / e: 543 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 4.10 (s, 2H), 7
. 11 (d, 2H, J = 8.5 Hz), 7.26 to 7.46 (m, 17H), 7
. 87 (br s, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8
. 46 (br s, 1H), 9.12 (s, 1H) ppm. Elemental _analysis: Calculated for _{C 34 H 26 N 2 O 3} S; 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 Example 191A (5.05 g, 9 mmol) in chloroform (20 mL) and methanol ( 8 mL) with trifluoroacetic acid (10 mL) at 0 ° C.
After time processing, it poured into a mixture of ice and saturated NaHCO _3. The mixture was extracted with methylene chloride (2 × 200 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 66% EtOAc / hexane to give the specified 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 As in Example 61, but substituting Example 191C for Example 191C, Example 191D was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 301 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 4.50 (d, 2H, J =
5.8 Hz), 5.19 (t, 1H, J = 5.8 Hz), 7.10 (d, 2H,
J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 7.82 (br
s, 1H), 8.03 (s, 1H), 8.20 (s, 1H), 8.43 (br
s, 1H), 9.09 (s, 1H). Elemental _analysis: Calculated for _{C 15 H 12 N 2 O 3} S; 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 Example 192 was prepared as in Example 103, but substituting Example 191C for Example 61A, to give the title compound. Melting point: 195-196 ° C. _{MS (DCI / NH 3) m} / e: 315 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.5 Hz), 4.49 (d, 2H, J = 4.5 Hz), 5.19 (t, 1H,
J = 4.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H)
H, J = 8.5 Hz), 8.07 (s, 1H), 8.11 (s, 1H), 8.9
4 (q, 1H, J = 4.5 Hz), 9.10 (s, 1H). Elemental _{analysis: C 16 H 14 N 2 O} 3 S. Calculated 0.75CH ₃ OH; C 59.
45, H 4.39, N 8.28. Obtained: C 59.31, H 4.35,
N 8.49.

Example 193 4- [4- (Methoxymethyl) phenoxy] -N-methylthieno [2,3-c]
Pyridine-2-carboxamide As in Example 188C, but preparing Example 193, substituting 4-methoxymethylphenol for 4-t-butyloxycarbonylaminophenol and methylamine for ammonia, to give the title compound. Was. Melting point: 163-164C. _{MS (DCI / NH 3) m} / e: 329 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 3.29 (s, 3H), 4.40 (s, 2H), 7.08 (d,
2H, J = 8.5 Hz), 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 (s, 1H). Elemental _analysis: Calculated for _{C 17 H 16 N 2 O 3} S; 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 as in example 188C, but substituting 4- (2-methoxyethoxymethyl) phenol for 4-t-butyloxycarbonylaminophenol, Example 19
4 was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 359 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.40 (s, 3H), 3.6
0 (m, 2H), 3.65 (m, 2H), 4.56 (s, 2H), 7.02 (d
, 2H, J = 8.5 Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.80
(S, 1H), 8.13 (s, 1H), 8.94 (s, 1H). Elemental _analysis: Calculated for _{C 18 H 18 N 2 O 4} S; 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 As in Example 188C, but with 4-t Example 195 was prepared by substituting 4- (2-methoxyethoxymethyl) phenol for -butyloxycarbonylaminophenol and methylamine for ammonia to obtain the title compound. Melting point: 133-134 [deg.] C. _{MS (DCI / NH 3) m} / e: 373 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.01 (d, 3H, J = 5.
1 Hz), 3.40 (s, 3H), 3.60 (m, 2H), 3.65 (m, 2H)
), 4.54 (s, 2H), 6.51 (q, 1H, J = 5.1 Hz), 7.00
(D, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.
73 (s, 1H), 8.14 (s, 1H), 8.94 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 20 N 2 O 4} S; C 61.27, H 5.41,
N 7.52. Found: C, 61.28; H, 5.35; N, 7.46.

Example 196 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
Thieno [2,3-c] pyridine-2-carboxamide As in Example 188C, but replacing 4-t-butyloxycarbonylaminophenol with 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol. Example 196 was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 403 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.38 (s, 3H), 3.5
7 (m, 2H), 3.63 to 3.70 (m, 6H), 4.55 (s, 2H), 7
. 02 (d, 2H, J = 8.5 Hz), 7.36 (d, 2H, J = 8.5 Hz)
, 7.71 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H).

Example 197 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
-N-methylthieno [2,3-c] pyridine-2-carboxamide Same as in Example 188C, except that 4-t-butyloxycarbonylaminophenol was converted to 4- {2- (2-methoxyethoxy) ethoxymethyl} phenol. Example 197 was prepared by substituting methylamine for ammonia, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 417 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.02 (d, 3H, J = 4.
8 Hz), 3.38 (s, 3H), 3.57 (m, 2H), 3.63 to 3.70
(M, 6H), 4.54 (s, 2H), 6.45 (m, 1H), 7.00 (d,
2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.72 (
s, 1H), 8.15 (s, 1H), 8.94 (s, 1H).

Example 198 4- {4-[(2,3,4,5-tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 198A Methyl 4- {4-} [(2,3,4,5-tetrahydro-2H-pyran-2-yl) oxy] methyl} phenoxy} thieno [2,3-c] pyridine-2-carboxylate 188B, but 4-t-butyloxycarbonylaminophenol is converted to 4-[(2,3,4,5-tetrahydro-2H-pyran-2-yl)
Oxy] methylphenol (PA Grieco, et al, J. Org.
Chem. Example 198A was prepared in place of 1977, 42, 3772) to give the specified compound. _{MS (DCI / NH 3) m} / e: 400 (M + H) +.

Example 198B 4- {4-[(2,3,4,5-tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example Example 198B was prepared as in Example 61, but substituting Example 198A for Example 61A, to give the specified compound. Melting point: 95-96C. _{MS (DCI / NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.49 (m, 4H), 1
. 69 (m, 2H), 3.49 (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), 7.10 (d, 2H, J = 8.8 Hz), 7.41 (d
, 2H, J = 8.8 Hz), 7.87 (s, 1H), 8.08 (s, 1H), 8
. 20 (s, 1H), 8.46 (s, 1H), 9.12 (s, 1H). Elemental _{analysis: C 20 H 20 N 2 O} 4 S. Calculated value for CH ₃ OH; C 60.56, H
5.08, N 6.73. Obtained value: C 60.51, H 5.07, N6.
59.

Example 199 N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide As in Example 103 Similarly, Example 199 was prepared substituting Example 198A for Example 61A to give the specified compound. Melting point: 195-196 ° C. _{MS (DCI / NH 3) m} / e: 399 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.49 (m, 4H), 1
. 69 (m, 2H), 2.79 (d, 3H, J = 4.8 Hz), 3.50 (m, 2H)
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), 7.09 (d
, 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 8.11
(S, 1H), 8.12 (s, 1H), 8.97 (q, 1H, J = 4.8 Hz)
, 9.13 (s, 1H). Elemental _analysis: Calculated for _{C 21 H 22 N 2 O 4} S; 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 Example 191D (40 mg, 0.133 mmol) in DMF (5 mL) was treated with 2-furancarboxylic acid (45 mg, 0.4 mmol) and HOBt (54 mg, 0
. 4 mmol), EDC (77 mg, 0.4 mmol) 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 flash chromatographed on silica gel with 65% EtOAc / hexane,
The specified compound was obtained. Melting point: 180-182 [deg.] C. _{MS (DCI / NH 3) m} / e: 395 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 5.31 (s, 2H), 6
. 70 (dd, 1H, J = 1.7, 3.4 Hz), 7.14 (d, 2H, J = 8
. 5 Hz), 7.36 (d, 1H, J = 3.4 Hz), 7.50 (d, 2H, J
= 8.5 Hz), 7.84 (s, 1H), 8.00 (dd, 1H, J = 1.1,
3.7 Hz), 8.13 (s, 1H), 8.17 (s, 1H), 8.44 (s, 1H)
1H), 9.14 (s, 1H).

Example 201 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 201A Methyl 4- [4-({[(2R, 4R, 5S, 6R) -4,5-diacetoxy-
6- (acetoxymethyl) tetrahydro -2H- pyran-2-yl] oxy} methyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate Dry _CH 2 _Cl 2 (10 mL) Example in 191C ( 200mg, 0.63m
mol) and tri-O-acetyl-D-glycal (520 mg, 1.92 mmol)
1) with Sc (OTf) ₃ (380 mg, 0.75 mmol) at room temperature, 12
Temporation and flash chromatography directly on silica gel with 40% EtOAc / hexane provided the specified compound. _{MS (DCI / NH 3) m} / e: 528 (M-OAc) +.

Example 201B 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Example 201A (167) in a methanol solution (10 mL) of phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide methylamine 2M.
mg)) was heated at 45 ° C. for 12 hours and concentrated. 8 residue on silica gel
% MeOH / CH ₂ Cl ₂ to give the specified compound (120 m
g, 91%). _{MS (ESI / NH 3) m} / e: 443 (M-OH) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.53 (m, 3H), 3.67 (m, 1H), 3.87 (m,
1H), 4.50 (d, 1H, J = 11.5 Hz), 4.64 (t, 1H, J =
5.4 Hz), 4.76 (d, 1H, J = 11.5 Hz), 5.06 (m, 2H)
), 5.70 (dt, 1H, J = 10.2, 2.4 Hz), 5.86 (d, 1H)
, J = 10.2 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.40 (d
, 2H, J = 8.5 Hz), 8.10 (s, 1H), 8.11 (s, 1H), 8
. 95 (q, 1H, J = 4.8 Hz), 9.12 (s, 1H).

Example 202 4- (4-acetylphenoxy) -N-methylthieno [2,3-c] pyridine-
Example 190B (500 mg, 1.2 mmol) in a flask purged with 2-carboxamide nitrogen
, Pd (OAc)₂(27 mg, 0.12 mmol), (Tol)₃P (110
mg, 0.36 mmol), dry degassed DMF (20 mL), tributylethoxy
Vinyltin (810 mL, 2.4 mmol) and triethylamine (835 ml)
, 6 mmol). This suspension was stirred at 80 ° C. for 14 hours. Ethyl acetate
After dilution with water, the reaction mixture is washed with 1% aqueous HCl and water and dried (MgSO 4). ₄ ) And concentrated. The residue was purified by HPLC (C-18, CH containing 0.1% TFA).₃CN
/ H₂O) to give the title compound (476 mg, 89%). MS (DCI / NH₃) M / e: 327 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆): Δ2.56 (s, 3H), 2
. 78 (d, 3H, J = 4.8 Hz), 7.15 (d, 2H, J = 8.8 Hz)
, 8.00 (d, 2H, J = 8.8 Hz), 8.03 (s, 1H), 8.36 (
s, 1H), 8.98 (q, 1H, J = 4.8 Hz), 9.28 (s, 1H).
Elemental analysis: C₁₇H₁₄N₂O₃S. 1.35CF₃CO₂Calculated value of H; C 4
9.25, H 3.45, N 5.83. Found: C, 49.31; H, 3.6.
0, N 5.93.

Example 203 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3-c]
A mixture of pyridine-2-carboxamide Example 203A Methyl 4- [4- (4-carboxy) phenoxy] thieno [2,3-c] pyridine-2-carboxylate THF (15 mL) and _H 2 O (15 mL), 4-bromophenoxythieno [2,3-c] pyridine-2-carboxylate (1.0 g, 2.74 m
_mol), suspension CO atmosphere (400 psi) below the _{PdCl 2 DPPFCH 2 Cl 2 (0.284g} ) and triethylamine (0.55g), 130 ℃, 1
Heat for 9 hours. EtOAc (200 ml) was added and the mixture was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 5% CH ₃ OH / CH ₂ Cl ₂ to give the specified compound (311 mg).
, 34%). _{MS (DCI / NH 3) m} / e: 330 (M + H) +.

Example 203B Methyl 4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [2,3
Mixture of -c] pyridine-2-carboxylate DMF (5 mL) and _CH 2 _Cl 2 (15mL), Example 203A (
200 mg, 0.61 mmol) of morpholine (80 mg, 0.91 mm)
ol), PyBOP (474 mg, 0.91 mmol) and DIPEA (29
6 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 flash chromatographed on silica gel with 90% EtOAc / hexane to give the specified 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 As in example 61 but substituting example 203B for example 203A, preparing example 203C to give the title compound. Melting point:> 260 ° C. _{MS (DCI / NH 3) m} / e: 401 (M + NH 4) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.50 (m, 4H), 3
. 60 (m, 4H), 7.14 (d, 2H, J = 8.5 Hz), 7.48 (d,
2H, J = 8.5 Hz), 7.86 (s, 1H), 8.15 (s, 1H), 8.
22 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 17 N 3 O 4} S; C 59.52, H 4.47,
N 10.96. Found: C, 59.64; H, 4.52; N, 10.90.

Example 204 N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 204 was prepared as in Example 103, but substituting Example 203B for Example 61A, to give the title compound. Melting point: 173-175 [deg.] C. _{MS (DCI / NH 3) m} / e: 415 (M + NH 4) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.4 Hz), 3.50 (m, 4H), 3.60 (m, 4H), 7.12 (d,
2H, J = 8.5 Hz), 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 (s, 1H). Elemental _{analysis: C 20 H 19 N 3 O} 4 S. Calculated 1.5CH ₃ OH; C 57.9
6, H 4.64, N 9.43. Obtained: C 57.99, H 4.86, N
9.63.

Example 206 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 206A methyl 4- [4 -({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxylate A solution of Example 203A (200 mg, 0.61 mmol) in DMF (11 mL) was prepared. 4- (2-aminoethyl) morpholine (158 mg, 1.21 mmol), E
DC (232 mg, 1.21 mmol), HOBt (164 mg, 1.21 mm)
ol) and triethylamine (122 mg, 1.21 mmol) at room temperature, 18
Time processed. After dilution with EtOAc, the reaction mixture was washed with brine and dried (MgSO4).
O ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 10% MeOH / EtOAc to give the specified compound (239 mg, 89%).
_{MS (DCI / NH 3) m} / e: 442 (M + H) +.

Example 206B 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Same as in Example 61, Example 206B was prepared substituting Example 206A for Example 61A to give the title compound. Melting point: 214-216 ° C. _{MS (DCI / NH 3) m} / e: 427 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.41 (t, 4H, J =
4.8 Hz), 3.37 (q, 2H, J = 6.1 Hz), 3.56 (t, 4H,
J = 4.8 Hz), 7.14 (d, 2H, J = 8.8 Hz), 7.84 (s, 1
H), 7.87 (d, 2H, J = 8.8 Hz), 8.11 (s, 1H), 8.2
2 (s, 1H), 8.39 (t, 1H, J = 6.0 Hz), 8.43 (s, 1H)
), 9.17 (s, 1H).

Example 207 N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 103 Same as in Example 207, but substituting Example 61A for Example 206A, preparing Example 207 to give the title compound. Melting point: 226-228 [deg.] C. _{MS (DCI / NH 3) m} / e: 441 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.42 (m, 4H), 2
. 78 (d, 3H, J = 4.4 Hz), 3.36 (q, 2H, J = 6.1 Hz)
, 3.56 (t, 4H, J = 4.8 Hz), 7.12 (d, 2H, J = 8.5H)
z), 7.89 (d, 2H, J = 8.5 Hz), 8.03 (s, 1H), 8.2
6 (s, 1H), 8.41 (t, 1H, J = 6.0 Hz), 8.95 (q, 1H)
, J = 4.4 Hz), 9.20 (s, 1H).

Example 208 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 208A Methyl 4- {4-[(E) -3- (t-butyloxy) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxylate Performed on flasks purged with nitrogen Example 73 (50 mg, 1.37 mmol), P
_{d 2 (dba) 3 (63mg} , 0.069mmol), tri -o- tolyl phosphine (64mg, 0.21mmol), DMF ( 20mL), t- butyl acrylate (602mL, 4.11mmol) and triethylamine (575 mL,
4.11 mmol). The suspension was stirred at 100 ° C. for 12 hours under nitrogen. After dilution with ethyl acetate, the reaction mixture is washed with brine and water and dried (MgSO4).
O ₄ ) and concentrated. The residue was flash chromatographed on silica gel with 20% EtOAc / hexane to give the title compound (323 mg, 57%). _{MS (DCI / NH 3) m} / e: 412 (M + H) +.

Example 208B Methyl 4- {4-[(E) -propenoic acid-1-yl] phenoxy} thieno [2,
3-c] pyridine-2-carboxylate Example 208A (1.76 g, 4.2 mmol) in chloroform (50 mL)
The solution was treated with trifluoroacetic acid (10 mL) at room temperature for 4 hours, followed by ice-cold aqueous
NaHCO₃Poured in. The white solid formed was collected by filtration, and water, MeOH, CH ₂ Cl₂And dried to give the specified compound (1.38 g, 100%). MS (DCI / NH₃) M / e: 356 (M + H)⁺.

Example 208C Methyl 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxylate DMF (5 mL) and CH ₂ Cl ₂ (10 mL) in a mixture of Example 208B (
260 mg, 0.73 mmol) in morpholine (127 mg, 1.46 m).
mol), PyBOP (760 mg, 1.46 mmol) and DIPEA (3
(80 mg, 2.92 mmol) at room temperature for 12 hours. After diluted with CH ₂ Cl _2, the solution was washed with brine, dried (MgSO _4), and concentrated. The residue was flash chromatographed on silica gel with 90% EtOAc / hexane,
The specified compound was obtained. _{MS (DCI / NH 3) m} / e: 425 (M + H) +.

Example 208D 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl] phenoxy} thieno [2,3-c] pyridine-2-carboxamide Example 61 Example 208D was prepared in the same manner as in Example 208, except that Example 208A was replaced with Example 208C to obtain the title compound. _{MS (DCI / NH 3) m} / e: 410 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.59 (m, 6H), 3
. 70 (m, 2H), 7.13 (d, 2H, J = 8.5 Hz), 7.20 (d,
1H, J = 15.5 Hz), 7.52 (d, 1H, J = 15.5 Hz), 7.7
9 (d, 2H, J = 8.5 Hz), 7.86 (s, 1H), 8.16 (s, 1H)
), 8.18 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H).

Example 209 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide Example 209A Methyl 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine -2-Carboxylate Example 209A was prepared as in Example 208C, but substituting 4- (2-aminoethyl) morpholine for morpholine, to give the specified compound. _{MS (DCI / NH 3) m} / e: 468 (M + H) +.

Example 209B 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide As in Example 61, but Example 209B was prepared in place of Example 209A, substituting Example 209A to give the title compound. _{MS (DCI / NH 3) m} / e: 453 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.44 (m, 4H), 3
. 30 (m, 4H), 3.59 (t, 4H, J = 4.8 Hz), 6.60 (d,
1H, J = 15.8 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.42
(D, 1H, J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7
. 87 (s, 1H), 8.06 (t, 1H, J = 4.8 Hz), 8.16 (s, 1H)
1H), 8.21 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H)
.

Example 210 N-methyl-4- [4-((E) -3-{[2- (4-morpholinyl) ethyl]]
Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide As in Example 103, but Example 210 is prepared by substituting Example 209A for Example 61A. To give the title compound. _{MS (DCI / NH 3) m} / e: 467 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.38 (m, 4H), 2
. 79 (d, 3H, J = 4.4 Hz), 3.59 (m, 8H), 6.58 (d,
1H, J = 15.8 Hz), 7.11 (d, 2H, J = 8.8 Hz), 7.42
(D, 1H, J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 8
. 05 (s, 1H), 8.23 (s, 1H), 8.95 (q, 1H, J = 4.4)
Hz), 9.17 (s, 1H).

Example 211 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-carboxamide Example 211A Methyl 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino]
-3-oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-
2-Carboxylate Example 208B (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 m)
mol) and triethylamine (142 mg, 1.41 mmol) at room temperature, 1
Treated for 8 hours. After dilution with EtOAc, the reaction mixture was washed with brine and dried (Mg
SO ₄ ) and concentrated. The residue was flash chromatographed on silica gel to give the specified compound (189 mg, 63%). _{MS (DCI / NH 3) m} / e: 429 (M + H) +.

Example 211B 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-carboxamide As in Example 61, but preparing Example 211B, substituting Example 211A for Example 61A, and substituting the title compound. Obtained. Melting point: 185-187 ° C. _{MS (DCI / NH 3) m} / e: 414 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 3.10 (m, 1 H), 3
. 30 (m, 2H), 3.54 (m, 1H), 4.60 (t, 1H, J = 5.9)
Hz), 4.84 (d, 1H, J = 4.8 Hz), 6.66 (d, 1H, J = 1)
5.8 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.42 (d, 1H,
J = 15.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.86 (s,
1H), 8.08 (t, 1H, J = 5.5 Hz), 8.16 (s, 1H),
21 (s, 1H), 8.45 (s, 1H), 9.17 (s, 1H). Elemental _analysis: Calculated for _{C 20 H 19 N 3 O 5} S; C 58.10, H 4.63,
N 10.16. Found: C, 57.99; H, 4.54; N, 10.08.

Example 212 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide As in example 103, but example 212 was prepared by substituting example 211A for example 61A. The title compound was obtained. Melting point: 225-226 ° C. _{MS (DCI / NH 3) m} / e: 428 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.10 (m, 1H), 3.30 (m, 2H), 3.54 (m, 1H)
1H), 4.60 (t, 1H, J = 5.5 Hz), 4.84 (d, 1H, J = 4
. 8 Hz), 6.66 (d, 1H, J = 15.8 Hz), 7.11 (d, 2H,
J = 8.8 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.61 (d,
2H, J = 8.8 Hz), 8.06 (s, 1H), 8.08 (t, 1H, J = 5)
. 5Hz), 8.23 (s, 1H), 8.97 (q, 1H, J = 4.8 Hz),
9.18 (s, 1H). Elemental analysis: Calcd. For C ₂₁ H ₂₁ N ₃ O ₅ S; C 59.00, H 4.95,
N 9.83. Found: C, 58.85; H, 4.90; N, 9.58.

Example 213 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [2
, 3-c] pyridine-2-carboxamide Same as in Example 212, except that 3-amino-1,2-propanediol was converted to 2
Example 213 was prepared in place of-(1H-imidazol-5-yl) ethylamine to give the title compound. _{MS (DCI / NH 3) m} / e: 448 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.5 Hz), 2.85 (t, 2H, J = 6.6 Hz), 3.49 (q, 2H,
J = 6.0 Hz), 6.53 (d, 1H, J = 15.8 Hz), 7.11 (d,
2H, J = 8.5 Hz), 7.42 (d, 1H, J = 15.8 Hz), 7.47
(S, 1H), 7.61 (d, 2H, J = 8.5 Hz), 8.07 (s, 1H)
, 8.24 (s, 1H), 8.27 (t, 1H, J = 5.5 Hz), 8.97 (
q, 1H, J = 4.8 Hz), 9.01 (s, 1H), 9.21 (s, 1H).

Example 214 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] ethyl} amino) -3-oxo-1-propenyl] phenoxy} -N- Methylthieno [2,3-c] pyridine-2-carboxamide Same as in Example 212, except that 3-amino-1,2-propanediol was replaced with 2
Example 214 instead of-[bis (2-hydroxyethyl) amino] ethylamine
Was prepared to give the title compound. _{MS (DCI / NH 3) m} / e: 485 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.79 (d, 3H, J =
4.8 Hz), 3.34 (m, 6H), 3.58 (q, 2H, J = 6.1 Hz)
, 3.77 (t, 4H, J = 5.1 Hz), 6.55 (d, 1H, J = 15.6)
Hz), 7.13 (d, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 1)
5.6 Hz), 7.64 (d, 2H, J = 8.5 Hz), 8.07 (s, 1H)
, 8.24 (s, 1H), 8.43 (t, 1H, J = 4.8 Hz), 8.97 (
q, 1H, J = 4.8 Hz), 9.20 (s, 1H).

Example 215 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] ethyl} amino) -3-oxo-1-propenyl] phenoxy} thieno [2 , 3-
c] Pyridine-2-carboxamide As in Example 211, but substituting 3-amino-1,2-propanediol for bis (2-hydroxyethyl) aminoethylamine, preparing Example 215, to give the title compound Was. _{MS (DCI / NH 3) m} / e: 471 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.56 (m, 4H), 3
. 21 (m, 2H), 3.41 (m, 4H), 4.37 (t, 2H, J = 5.6
Hz), 6.56 (d, 1H, J = 15.4 Hz), 7.13 (d, 2H, J =
8.8 Hz), 7.42 (d, 1H, J = 15.4 Hz), 7.61 (d, 2H)
, J = 8.8 Hz), 7.86 (s, 1H), 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: C 23 H 26 N 4 O} 5 S. Calculated _{CH 3 OH; C 56.36, H} 5.41, N 11.15. Obtained: C 56.40, H 5.76, N 1
1.40.

Example 216 4- (4- {3-hydroxy-3- [4-({2-[(methylamino) carbonyl] 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, 0.55mm
ol) at −50 ° C. for 30 minutes and slowly warmed to room temperature in 10 minutes. Aqueous NH ₄ Cl solution was added and the mixture was extracted with ether. The combined organic phases were washed with brine and water, dried (MgSO _4), and concentrated. Residue on silica gel, 5
Flash chromatography with% MeOH / EtOAc afforded the title compound (60 mg, 40%). _{MS (ESI / NH 3) m} / e: 653 (M + H) +. _{^{1 H NMR (300MHz, DMSO-}} d 6): δ1.58 (s, 3H), 2
. 77 (d, 3H, J = 4.8 Hz), 2.80 (d, 3H, J = 4.8 Hz)
, 3.35 (d, 1H, J = 13.0 Hz), 3.49 (d, 1H, J = 13.0 Hz).
0 Hz), 5.27 (s, 1H), 7.02 (d, 2H, J = 8.8 Hz), 7
. 08 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz)
, 7.96 (d, 2H, J = 8.8 Hz), 7.99 (s, 2H), 8.13 (
s, 1H), 8.30 (s, 1H), 8.94 (m, 2H), 9.08 (s, 1)
H), 9.21 (s, 1H). Elemental _{analysis: C 34 H 28 N 4 O} 6 S 2. Calculated CH ₃ OH; 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
] Pyridin-2-carboxamide Example 217A Methyl 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,
Example 17A (0.88 g, 3-c] pyridine-2-carbosylate in THF (15 mL) and DMF (5 mL).
5 mmol) with 4- (1-imidazolyl) phenol and potassium t-butoxide (1N in THF, 5.0 mL, 5 mmol) at 70 ° C. for 4 hours, followed by 0
After cooling to ℃, methyl thioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 mmol) were added, and the mixture was refluxed for 1 hour. The reaction mixture was poured into water, diluted with brine and extracted with ethyl acetate. Then add 1N ethyl acetate solution
NaOH (2 × 20 mL) then brine (3 × 20 mL) and dry (M
gSO ₄ ) to give the title compound. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.25 (d, 2H), 9.25 (s, 1H)
1H).

Example 217B 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide Example 217A was dissolved in 2M ammonia in methanol and placed in a sealed tube at 50 ° C.
Heated for 4 hours. Then the reaction mixture was evaporated and crystallized from methanol to give the title compound. Melting point: 310-312 ° C. _{MS (DCI / NH 3) m} / e: 337 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.10 (s, 1 H), 7
. 28 (m, 2H), 7.68 (t, 1H), 7.25 (dd, 2H), 7.8
5 (br s, 1H), 8.15 (s, 1H), 8.20 (d, 2H), 8.4
5 (br s, 1H), 9.15 (s, 1H). Elemental _{analysis: C 17 H 12 N 4 O} 2 S. Calculated 0.50H ₂ O; C 59.12
, H 3.79, N 16.22. Found: C, 59.40; H, 3.63; N, 16.30.

Example 218 N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 218A Methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [2,
3-c] Pyridine-2-carboxylate Example 17A (0.8 g, 5 mmol) in THF (15 mL) was refluxed for 4 hours.
Time, 4- (1H-pyrazol-1-yl) phenol and cesium carbonate (1
. 6 g, 5 mmol) and then cooled to 0 ° C., then methyl thioglycolate (0.4 mL, 5 mmol) and cesium carbonate (1.62 g, 5 m
mol) was added and the mixture was refluxed for 1 hour. The mixture was poured into water, diluted with brine and extracted with ethyl acetate. Then, the ethyl acetate was added to 1N NaOH
(2 × 20 mL), then with brine (3 × 20 mL) and dried (MgSO ₄ )
To give the title compound. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.50 (d,
1H), 9.22 (s, 1H).

Example 218B N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide Example 218A was dissolved in 2M methylamine in methanol and heated in a round bottom flask at 50 ° C. for 4 hours. Then the reaction mixture was evaporated and crystallized from methanol to give the title compound. Melting point: 192-194 [deg.] C. _{MS (DCI / NH 3) m} / e: 351 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.70 (d, 3H), 6
. 55 (m, 1H), 7.25 (d, 2H), 7.75 (brs, 1H), 7
. 90 (d, 2H), 8.12 (s, 1H), 8.20 (s, 1H), 8.50
(D, 1H), 9.00 (m, 1H), 9.18 (s, 1H). Elemental _{analysis: C 18 H 14 N 4 O} 2 S. Calculated 0.25H ₂ O; C 60.15
, H 4.21, N 15.59. Found: C 60.30, H 3.93, N
15.73.

Example 219 N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Examples 17A and 4 -(1H-1,2,4-Triazol-1-yl) phenol was treated as in Example 218 to give the title compound. Melting point: 214-215 [deg.] C. _{MS (DCI / NH 3) m} / e: 352 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 9.00 (q, 1H), 9.30 (s, 1H)
1H).

Example 220 N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenoxy} thieno [2,3-c] pyridine- 2-carboxamide Example 220A N-methyl-4- [4- (N-hydroxyaminedino) phenoxy] thieno [2
Example 186 (50) in a mixture of DMF (10 mL) and EtOH (10 mL).
0 mg, 1.62 mmol) in 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 dried to give the specified compound (376mg, 68%). _{MS (ESI / NH 3) m} / e: 343 (M + H) +.

Example 220B N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenoxy} thieno [2,3-c] pyridine- 2-Carboxamide 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 hour. The resulting yellow solution was heated at 120 ° C. for 18 hours and then concentrated. The residue was separated by HPLC (C-18,0.1% TFA containing _{CH 3 CN / H 2 O)} ,
The title compound was obtained (169 mg, 69%). Melting point: 174-176 [deg.] C. _{MS (ESI / NH 3) m} / e: 421 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 7.26 (d, 2H, J = 8.8 Hz), 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: Calculated for _{C 18 H 11 N 4 O 3} SF 3; C 51.43, H 2.6
4, N 13.33. Obtained: C 51.56, H 2.76, N 13.32
.

Example 221 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy]
-N- methylthieno [2,3-c] pyridine-2-carboxamide MeOH ₍₃₀ mL), in a mixture of _{Et 2 O (20mL), CH} 2 Cl 2 (30mL), Example 186 (800 mg, 2.6 mmol) Hydrogen chloride gas was introduced into the solution at 0 ° C. for 1.5 hours, and the solution was stirred at room temperature for 24 hours and concentrated. Residue is M
Dissolved in MeOH (30 mL) and ethylenediamine (3 mL) and heated at 70 ° C. for 2 hours. After cooling the reaction mixture, the resulting white solid was collected by filtration, washed with methanol and dried to give the title compound (804 mg, 88%). Melting point:> 280 [deg.] C. _{MS (ESI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.78 (d, 3 H, J =
4.4 Hz), 3.32 (brs, 4H), 6.88 (brs, 1H), 7
. 11 (d, 2H, J = 8.8 Hz), 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 (s, 1H). Elemental _analysis: Calculated for _{C 18 H 16 N 4 O 2} S; C 59.36, H 4.46,
N 14.57. Found: C, 59.60; H, 4.55; N, 14.40.

Example 222 N-Methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide A flask purged with nitrogen was charged to Example 190B (200 mg, 0.48 mmol).
), Pd (OAc) ₂ (11 mg, 0.048 mmol), tri-o-tolylphosphine (44 mg, 0.14 mmol), dry degassed DMF (10 mL), 2-
Filled with tributylstannylthiophene (305 mL, 0.96 mmol) and triethylamine (334 mL, 2.4 mmol). This suspension is heated at 80 ° C.
Stir for 15 hours. After dilution with ethyl acetate, the reaction mixture was washed brine, then with water, dried (MgSO _4), and concentrated. The residue was purified by HPLC (C-18, 0.1% TF
A-containing CH ₃ CN / H ₂ O) to give the title compound (212 mg, 90%).
). _{MS (ESI / NH 3) m} / e: 367 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.4 Hz), 7.13 (m, 1H), 7.17 (d, 2H, J = 8.8 Hz)
, 7.48 (d, 1H, J = 3.7 Hz), 7.54 (d, 1H, J = 5.1 H)
z), 7.71 (d, 2H, J = 8.8 Hz), 8.15 (s, 1H), 8.2
4 (s, 1H), 9.02 (q, 1H, J = 4.4 Hz), 9.22 (s, 1H)
).

Example 223 4-[(1,1′-biphenyl) -4-yloxy] -N-methylthieno [2,
3-c] pyridine-2-carboxamide Example 223 was prepared as in Example 222, except that (tributylstannyl) thiophene was replaced with tributylphenyltin, to give the title compound. _{MS (ESI / NH 3) m} / e: 361 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.80 (d, 3H, J =
4.5 Hz), 7.19 (d, 2H, J = 8.8 Hz), 7.36 (t, 1H,
J = 7.4 Hz), 7.47 (t, 2H, J = 7.3 Hz), 7.66 (d, 2
H, J = 7.3 Hz), 7.72 (d, 2H, J = 8.8 Hz), 8.15 (s
, 1H), 8.23 (s, 1H), 9.00 (q, 1H, J = 4.4 Hz), 9
. 19 (s, 1H).

Example 224 N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide Example 224 is a title compound. In place of 2-tributylstannylthiophene to provide
. 1993, 47, 57) except that 1-methyl- (5-tributylstannyl) imidazole was used. mp 256-258 ° C. _{MS (ESI / NH 3) m} / e365 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 2
. 1 Hz), 3.67 (s, 3H), 7.03 (s, 1H), 7.17 (d, 2
H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz), 7.69 (s)
, 1H), 8.12 (s, 1H), 8.22 (s, 1H), 9.00 (q, 1H)
, J = 2.1 Hz), 9.16 (s, 1H). Elemental _analysis: Calculated for _{C 19 H 16 N 4 O 2} S: C, 62.62; H, 4.43;
N, 15.37. Theory: 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-hydroxymethylcyclo) Propyl) anisole 1- (4-methoxyphenyl) -1-cyclopropane-carboxylic acid (5.0 g)
, 26 mmol) in THF (100 mL) was added to LiAlH ₄ (0.95 g, 2
(5 mmol) at −20 ° C. for 0.5 h, then warmed to room temperature for 2 h. Excess LiAlH ₄ was consumed by slow addition of EtOH. After dilution with ether, the reaction mixture is washed with 2% HCl brine, water, dried (MgSO ₄ ) and concentrated to provide the specified compound (5.0 g, 100%). _{MS (DCI / NH 3) m} / e: 196 (M + NH 4) +.

Example 225B 4- (1-Hydroxymethylcyclopropyl) phenol NaH (60% in mineral oil, 392 mg, 9.8 mmol) in DMF (10 mL)
To the suspension was added neat ethanethiol (610 mg, 9.8 mmol) slowly at room temperature. Then Example 225A (500 mg, 2.8 mmol) was added and the mixture was heated at 145 ° C. for 4 hours. After dilution with ether, the reaction mixture is
HCl, brine, dried (MgSO ₄ ) and concentrated. Residue is 50% Et
Flash chromatography on silica gel with OAc / hexane provided the specified 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 added to triphenylmethyl chloride (1.87 g, 6.7 mmol). At room temperature for 18 hours. After dilution with ether, the reaction mixture was washed with 1% aqueous HCl, water and dried (M
gSO ₄₎ was. The residue was subjected to flash chromatography on silica gel with 12% EtOAc / hexane to provide the specified compound. _{MS (DCI / NH 3) m} / e: 407 (M + H) +.

Example 225D Methyl 4- [4- (1-triphenylmethoxymethyl) cyclopropyl] phenoxy- [2,3-c] pyridine-2-carboxylate Example 225D was converted to 4 to provide the designated compound. -Prepared as in Example 61A except for using Example 225C instead of chlorophenol. _{MS (DCI / NH 3) m} / e: 598 (M + H) +.

Example 225E Methyl 4- [4- (1-hydroxymethyl) cyclopropyl] phenoxy- [2
, 3-c] pyridine-2-carboxylate Example 225D (230mg, 0.38mmol) in _CH 2 _Cl 2 (10mL
) And MeOH (5 mL) were treated with trifluoroacetic acid (1 mL) at 0 ° C. for 1 hour, allowed to warm to room temperature, stirred for 1 hour, and poured into an aqueous solution of NaHCO ₃ . This mixture was extracted with methylene chloride. Wash the combined organic layers with water and dry (
MgSO ₄ ). The residue was subjected to flash chromatography on silica gel with 65% EtOAc / hexane to provide the specified 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 Example 225F was prepared to provide the specified compound. Prepared similarly to Example 103 except that Example 225E was used instead of 61A. _{^{MS (ESI / NH 3) m}} / e: 355 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ0.72 (m, 2H), 0.
82 (m, 2H), 2.80 (d, 3H, J = 4.7 Hz), 3.51 (d, 2
H, J = 5.8 Hz), 4.66 (t, 1H, J = 5.8 Hz), 7.01 (d
, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.8 Hz), 8.06
(S, 1H), 8.13 (s, 1H), 8.96 (q, 1H, J = 4.7 Hz)
, 9.10 (s, 1H).

Example 226 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide 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 prepared.
Treat with NaH (60% in mineral oil, 312 mg, 7.8 mmol) and 15-crown-5 (1.33 mL, 6.7 mmol) at room temperature for 15 minutes to obtain the literature method (
C. 2- (2-ethoxyethoxy) ethyl tosylate (1.9) prepared according to Almansa et al., Tetrahedron 1991, 47, 5867).
(3 g, 6.7 mmol). The brown slurry was stirred at room temperature for 5 hours,
Poured into saline. The mixture was extracted with CH ₂ Cl ₂ and the combined organic layers were dried (
MgSO ₄ ) and concentrated. The residue was subjected to flash chromatography on silica gel with 25% EtOAc / hexane to give the specified 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 ° C. for 5 hours. After cooling to room temperature, methylene chloride (100 mL) was added and the mixture was
Washed with Cl saline. Dry the organic layer (MgSO ₄ ) and concentrate to 35% residue.
Silica gel flash chromatography with EtOAc / hexane provided the specified compound (1.33 g, 93%). _{MS (ESI / NH 3) m} / e: 298 (M + NH 4) +.

Example 226C Methyl 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}
Cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2
-Carboxylate Example 226C was prepared as Example 61A except that Example 226B was used in place of 4-chlorophenol to provide the designated compound. _{MS (ESI / NH 3) m} / e: 472 (M + H) +.

Example 226D 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclopropyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 226D was prepared as Example 103 except that Example 226C was used in place of Example 61A to provide the title compound. _{MS (ESI / NH 3) m} / e: 471 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.84 (m, 2H), 0.
87 (m, 2H), 1.06 (t, 3H, J = 6.7 Hz), 2.82 (d, 3
H, J = 4.4 Hz), 3.37 (t, 2H, J = 6.7 Hz), 3.39-3
. 55 (m, 10H), 7.07 (d, 2H, J = 8.8 Hz), 7.36 (d
, 2H, J = 8.8 Hz), 8.13 (s, 1H), 8.26 (s, 1H), 9
. 10 (q, 1H, J = 4.4 Hz), 9.28 (s, 1H). Elemental _analysis: Calculated for _{C 25 H 30 N 4 O 5} S: C, 59.22; H, 6.16;
N, 5.52. Theory: C, 59.50; H, 6.16; N, 5.26.

Example 227 N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3-
c] Pyridine-2-carboxamide Example 227 was prepared as in Example 103 except that 4-trifluorophenol was used instead of 4-chlorophenol to provide the title compound. _{mp 132~133 ℃; MS (ESI /} NH 3) m / e: 368 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 4
. 4 Hz), 7.20 (d, 2H, J = 9.2 Hz), 7.41 (d, 2H, J
= 9.2 Hz), 8.08 (s, 1H), 8.21 (s, 1H), 8.95 (q
, 1H, J = 4.4 Hz), 9.18 (s, 1H). Elemental _analysis: Calculated for _{C 16 H 11 N 2 O 3} SF 3: C, 52.17; H, 3.0
1; N, 7.61. Theory: C, 52.21; H, 3.26; N, 7.29.

Example 228 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}}
Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl} -1
, 3,4-oxadiazol-2-amine Example 22 was replaced with Example 22A to provide the title compound.
Except using 6C, it prepared like Example 275 and Example 756. mp 113-114 ° C. _{MS (ESI / NH 3) m} / e: 497 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ0.82 (m, 2H), 0.
85 (m, 2H), 1.05 (t, 3H, J = 7.1 Hz), 3.40 (t, 2H)
H, J = 7.1 Hz), 3.42 to 3.54 (m, 10H), 7.00 (d, 2
H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz), 7.55 (s
, 1H), 7.58 (s, 2H), 8.18 (br s, 1H), 9.15 (b
rs, 1H).

Example 229 4- [4- (1,1-Difluoro-2-hydroxyethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229A 4- [4- ( 1,1-Difluoro-2-ethoxy-2-oxoethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide A suspension of active copper (512 mg, 8 mmol) in dry DMSO (5 mL) was prepared. The mixture was treated with ethyl iododifluoroacetate (1.0 g, 4 mmol) at room temperature for 10 minutes. Then phenol (188 mg, 2 mmol) and Example 190B were added.
The reaction mixture was stirred at room temperature for 20 hours. After dilution with 1: 1 ether / EtOAc, the mixture was washed with 1% HCl brine, water, dried (MgSO ₄ ) and concentrated. The residue was purified by a silica gel flash chromatography with 65% EtOAc / hexanes, further purified by _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA) specifying the compound (85 mg, 15%) Provided. _{MS (ESI / NH 3) m} / e: 407 (M + H) +.

Example 229B 4- [4- (1,1-Difluoro-2-hydroxyethyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229A (40 mg, 0.1 mmol) ) In MeOH (5 mL)
The mixture was treated with aBH ₄ (50 mg) at room temperature for 2 hours. Brine was added and the mixture was added to EtO
Extracted with Ac. And the combined organic layers dried _(Na 2 SO ₄₎ and concentrated. The residue was purified by _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA) designated compound (44.4mg, 94%) was subjected to. _{MS (ESI / NH 3) m} / e: 365 (M + H) +. ¹ H NMR (300 MHz, CD ₃ OD) δ 2.94 (s, 3H), 3.93
(T, 2H, J = 13.5 Hz), 7.27 (d, 2H, J = 9.2 Hz), 7
. 65 (d, 2H, J = 9.2 Hz), 8.15 (s, 2H), 9.24 (s,
1H). Elemental _{analysis: C 17 H 14 N 2 O} 3 SF 2. Calculated TFA: C, 47.70; H
, 3.16; N, 5.86. Theory: C, 47.67; H, 3.10; N, 5.
76.

Example 230 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1 difluoroethyl} phenoxy) -N-methylthieno [2,3-c] pyridine-2-carboxamide Example 229B (40 mg, 0.11 mmol) in THF (3 mL)
NaH (60% in mineral oil, 7 mg, 0.16 mmol) and 15-crown-5
(35 mg, 0.16 mmol) at room temperature for 15 minutes. Next, literature methods (C. Almansa et al., Tetrahedron 1991, 47, 5867).
2- (2-ethoxyethoxy) ethyl tosylate (46)
mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 15 hours and then subjected the isolated title compound (46 mg, 81%) in _{HPLC (CH 3 CN / H 2} O containing C-18,0.1% TFA). _{MS (ESI / NH 3) m} / e: 481 (M + H) +. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.16 (t, 3 H, J = 7.1
Hz), 2.97 (s, 3H), 3.49 (q, 2H, J = 7.1 Hz), 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)
. 8Hz), 8.22 (s, 1H), 8.33 (s, 1H), 9.46 (s, 1H)
H).

Example 231 4- (4-Chlorophenoxy) -6-{[(2,2-dimethylpropanoyl) oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pyridine-6-ium, was dissolved in trifluoroacetic acid salt example 103 (47.4 mg, 0.149 mmol) and 1.5mL dry acetonitrile (warmed) of _{(N 2} atmosphere), chloromethyl pivalate (
(25 mg, 0.167 mmol) at room temperature. The reaction was stirred for 16 hours, then tetraammonium iodide (1 mg) was added and warmed for 48 hours to perfuse the solution. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (C-18, 20-70).
(A gradient of 100% acetonitrile-0.1% aqueous TFA, elution 60 minutes) to give 24 mg (34%) of the title compound as a foam. MS (APCI +) m / e: 433 (M) ^<+> . HPLC: Supelco C-18 column, 0.1% TFA aqueous solution over 30 minutes: gradient elution with acetonitrile from 0:90 to 90: 0, detection at 254 nm, 0.
8 mL / min flow rate, RT 20.0 min. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.18 (s, 9H);
01 (s, 3H), 6.4 to 6.6 (brs, 2H), 7.1 to 7.3 (brs
, Aprox. 2H), 7.49 (brs, 2H), 7.74 (brs, 1H
), 8.41 (brs, 1H), 8.64 (brs, 1H), 9.3-9.9 (
vbrs, 1H). Elemental analysis: Calculated for C ₂₃ H ₂₂ F ₃ Cl ₂ O ₆ S: C, 45.43; H, 3.
51; N, 4.24. Theory: C, 45.93; H, 3.70; N, 4.34.

Example 232 4- (4-bromophenoxy) -6-{[(2,2-dimethylpropanoyl) oxy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] Pyridine-6-ium Example 171 (69.4 mg, 0.191 mmol) was dissolved in 2 mL of acetonitrile, then tetraammonium iodide (1 mg) was added under N2 atmosphere, and chloromethyl pivalate (22 mg, 0.146 mmol) was added. added. The reaction solution was heated and perfused for 24 hours. Additional chloromethyl pivalate (11 mg, 0.0
73 mmol) was added and the reaction was perfused for an additional 72 hours. The reaction was concentrated under reduced pressure and the solid was partitioned between 15 mL of water and 15 mL of EtOAc. 2 x 15 mL aqueous layer
Of EtOAc and then the aqueous layer was concentrated in vacuo to a yellow material (93.5 mg).
I got HPLC purification (C-18 column, 20-75% acetonitrile-0.1
% TFA aqueous solution) provided the pure title compound (55.9 mg, 49%).
HPLC: Supelco C-18 column, 0.1% TFA aqueous solution over 30 minutes: gradient elution with acetonitrile from 0:90 to 90: 0, detection at 254 nm, 0.
8 mL / min flow rate, RT 20.3 min. MS (APCI-) m / e: 475, 477 (MH) ^- . ^{2. 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.17 (s, 9H);
02 (brm, 3H), 6.0 to 6.7 (vbrs, 2H), 7.14 (brd
, 2H), 7.64 (brd, 2H), 7.78 (s, 1H), 8.07-8.
17 (brs, 1H), 8.34 (s, 1H), 9.44 to 9.65 (vbrs
, 1H). Elemental _{analysis: 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. Theory: C, 40.94; H, 3.25
N, 3.76.

Example 233 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(isopropoxycarbonyl) oxy] methyl} thieno [2,3-c] pyridine-6-ium Nitrogen atmosphere Below, sodium tetraphenylboronate (387 mg, 1.13) was added to a solution of Example 61 (300 mg, 0.94 mmol) in acetonitrile (15 mL).
mmol), sodium iodide (169 mg, 1.13 mmol), and [isopropoxycarbonyl) oxy] methyl chloride (172 mg, 1.13 mm)
ol) was added. The reaction mixture was heated and perfused for 4 hours, cooled to room temperature, and celite (
(Celite) before diluting with acetonitrile (100 mL). The filtrate was concentrated, trityled with methanol to a foam, and provided pyridinium tetraphenylborate (550 mg) as a yellow solid. Tetraphenyl _borates, CH 3 CN: i-PrOH 1: dissolved in 1, was passed through an ion exchange column using 50-100 mesh Dowex 1X2 chloride. The eluent was concentrated and the residue was trityled with ether to give Example 233 as a white solid (210 mg, 49 mg).
%). MS (FAB) m / e: 421 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26 (d, J = 7 Hz,
6H), 4.81 (q, J = 7 Hz, 1H), 6.44 (s, 2H), 7.41
(M, 2H), 7.62 (m, 2H), 8.31 (brs, 1H), 8.59 (
s, 1H), 8.68 (s, 1H), 8.80 (brs, 1H), 9.98 (s
, 1H); Elemental _{Analysis: C 19 H 18 Cl 2 N} 2 O 5 Calculated S: C, 49.90
H, 3.96; N, 6.13. Theory: C, 49.74; H, 3.95; N,
6.14.

Example 234 4- (cyclopentyloxy) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide Example 234A Example except 5-chloro-3-cyclopentyloxypyridine uses the title compound (5.91 g, 77%) instead of benzyl alcohol with cyclopentanol (4.2 mL, 46.31 mmol). 2
Prepared as described in 36A. MS (APCI) m / e: 198 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53 to 1.76 (m, 6
H), 1.86-2.02 (m, 2H), 4.92-4.99 (m, 1H), 7
. 55 (t, J = 2.25 Hz, 1H), 8.18 (d, J = 2.25 Hz, 1
H), 8.22 (d, J = 3 Hz, 1H). Example 234B 5-Chloro-3-cyclopentyloxypyridine-4-carboxaldehyde The title compound (5.22 g, 77%) was prepared using Example 23 instead of Example 236A.
Prepared as described in Example 236B except using 4A (5.9 g, 30 mmol). MS (APCI) m / e: 226 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55 to 1.85 (m, 6
H) 1.93 to 2.04 (m, 2H), 5.14 to 5.22 (m, 1H), 8
. 36 (s, 1H), 8.63 (s, 1H), 10.31 (s, 1H). Example 234C Methyl 4- [cyclopentyloxy] thieno [2,3-c] pyridine-2-carboxylate The title compound (4.31 g, 67%) was prepared using Example 23 instead of Example 236B.
Prepared as described in Example 236C except using 4B (5.2 g, 23.11 mmol). MS (APCI) m / e: 278 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.59 to 1.69 (m, 2
H) 1.74 to 1.81 (m, 2H), 1.83 to 1.90 (m, 2H), 1
. 97 to 2.07 (m, 2H), 3.93 (s, 3H), 5.12 to 5.17 (
m, 1H), 8.05 (s, 1H), 8.24 (s, 1H), 8.94 (s, 1H)
H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 23.63 (CH ₂ ), 3
_{2.30 (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] pyridine-2-N-methylamide Example 234C (1.6 g, 61%) was replaced with Example 23A instead of Example 73A.
Prepared as described in Example 171 except using 4C (2.6 g, 9.4 mmol). mp 216-217 ° C. MS (APCI) m / e: 277 (M + H) ^<+> , 244 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.60 to 1.69 (m, 2
H) 1.73-1.90 (m, 4H), 1.97-2.08 (m, 2H), 2
. 83 (d, J = 4 Hz, 3H), 5.10 to 5.17 (m, 1H), 8.11
(S, 1H), 8.19 (s, 1H), 8.85 (s, 1H), 8.93 (d,
J = 4 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 23.60 (CH ₂ ), 2
_{6.14 (NCH 3), 32.34 (} CH 2), 80.14 (CH), 119.
68 (CH), 126.91 (CH), 135.73 (C), 137.17 (C
H), 144.2 (C), 149.02 (C), 161.18 (C).

Example 235 4- (2-cyclohexene-1-yloxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 235A Methyl 4- [2-cyclohexene-3-oxy] thieno [2,3-c] pyridine-2-carboxylate The title compound (158 mg, 57%) was substituted for 3-hydroxytetrahydrofuran Prepared as described in Example 99A, except using 2-cyclohexenol (0.113 mL, 0.115 mmol). The pure product is
Obtained by flash chromatography on silica gel using 10% acetone-hexane. MS (APCI) m / e: 290 (M + H) ^<+> , 288 (M-H) < ^{- >} , 324 (
M + Cl) ⁻ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.95 to 1.62 (m, 1
H), 1.66~2.14 (m, 5H ), 3.92 (s, 3H, OCH 3), 5
. 22-5.26 (m, 1H), 5.91-5.99 (m, 2H), 8.03 (
s, 1H, CH), 8.36 (s, 1H, CH), 8.95 (s, 1H, CH)
.

Example 235B 4- (2-cyclohexene-1-yloxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 235 (59 mg, 40%) of 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) ^<+> , 287 (M-H) < ^{- >} , 323 (
M + Cl) ⁻ . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.62 to 1.70 (m, 1
H) 1.78-1.91 (m, 2H), 1.96-2.17 (m, 3H), 2
. 82 (d, J = 5 Hz, 3H), 5.21 (brs, 1H), 5.93-5.
98 (m, 1H), 6.01 to 6.05 (m, 1H), 8.14 (s, 1H),
8.30 (s, 1H), 8.87 (s, 1H), 8.75 (d, J = 5 Hz, 1
H). ¹³ C NMR (75 MHz, 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 5-chloro-3-pyridinol at 0 ° C. under nitrogen atmosphere (10 g, 77.19 m
benzyl alcohol (9.6 mL, 92.63 mmol) and triphenylphosphine (26.mol) in a stirred solution of anhydrous tetrahydrofuran (155 mL).
32 g, 100.35 mmol) and diethyl azodicarboxylate (15
. 8 mL, 100.35 mmol) was added. The reaction mixture was stirred at room temperature overnight,
The solvent was removed under reduced pressure. The obtained residue (70 g) was treated with diethyl ether (2 × 30).
0 mL) and the solids were removed by filtration. The resulting filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 5% acetone and hexane to give the title compound in 36% (5.8 g) yield.
MS (APCI) m / e: 220 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.22 (s, 2H), 7.
33-7.49 (m, 5H), 7.77 (d, J = 5 Hz, 1H), 8.23 (
d, J = 5 Hz, 1H), 8.34 (d, J = 5 Hz, 1H).

Example 236B 5-Chloro-3-benzyloxypyridine-4-carboxaldehyde Diisopropylamine (4.5 mL, 31.78 mm) at -5 ° C under a nitrogen atmosphere.
ol) in anhydrous tetrahydrofuran (20 mL).
N-BuLi in hexane (2.5 M solution, 12.8 mL, 31
. 78 mmol) was added dropwise. The reaction mixture was stirred at −10 ° C. for 10 minutes, then at 0 ° C. for 30 minutes. This was cooled to −78 ° C. and Example 236A (5.8 g, 26
. (5 mmol) in anhydrous tetrahydrofuran (30 mL) was added slowly. −
Stirring at 78 ° C. was continued for 1 hour. The reaction was then run in anhydrous THF (15 mL)
Quenched by dropwise addition of methyl formate (5 mL, 79.5 mmol) in
The mixture was stirred at -78 ° C for 3.5 hours. During this reaction, the internal temperature of the reaction mixture was maintained at or below -74C. After 3.5 hours, the reaction mixture was poured into ice-cold saturated aqueous NaHCO ₃ (200 mL) and stirred for 15 minutes. The mixture was treated with ethyl acetate (2
(50 mL) and the organic layer was separated and washed with brine (2 × 60 mL). The dried (MgSO ₄ ) organic layer was concentrated under reduced pressure to obtain a crude product (8.5 g). The title compound was obtained in 75% (4.2 g) yield by flash chromatography on silica gel, eluting with 6% acetone-hexane. MS (APCI) m / e: 248 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ5.42 (s, 2H), 7.
33 to 7.45 (m, 3H), 7.48 to 7.52 (m, 2H), 8.41 (s
, 1H), 8.72 (s, 1H), 10.39 (s, 1H).

Example 236C Methyl 4-benzyloxythieno [2,3-c] pyridine-2-carboxylate To a ice-cooled solution of Example 236B (4.2 g, 17 mmol) in tetrahydrofuran (42 mL) under a nitrogen atmosphere. Methyl thioglycolate (1.83 mL, 20
. 4 mmol) followed by powdered cesium carbonate (6.65 g, 20.4 mmol). The reaction mixture is then allowed to warm to room temperature while stirring under nitrogen.
After 30 minutes, the reaction is refluxed for 15 minutes and cooled to room temperature. The reaction mixture was added to ice (5
0 mL) and partitioned with ethyl acetate (250 mL). The separated organic layer was washed with an ice-cold solution of saturated NaCl (3 × 60 mL) and dried (Na ₂ SO ₄ )
After concentration under reduced pressure, the obtained crude product was recrystallized from methanol. The mother liquor was purified by flash chromatography on silica gel eluting with 7% acetone-hexane. The combined fractions gave the title compound in 55% (3.07 g) yield. MS (APCI) m / e: 300 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ3.92 (s, 3H), 5.
42 (s, 2H), 7.35 to 7.47 (m, 3H), 7.52 to 7.57 (m
, 2H, Ar-CH), 8.12 (s, 1H), 8.36 (s, 1H), 8.9
8 (s, 1H).

Example 236D Methyl 4-hydroxythieno [2,3-c] pyridine-2-carboxylate 10% by weight Pd / activated carbon (38 mg, 10% w / w) in anhydrous ethanol (3 mL) Example 236C (380 mg, 1.3 mmol) under a nitrogen atmosphere
A cold ethanol solution of (82 mL) was added. The reaction solution was then degassed and stirred at room temperature under a hydrogen atmosphere. After one night, the reaction mixture was treated with 10 wt% Pd / activated carbon (190
mg, 50% w / w), and the mixture was stirred under a hydrogen atmosphere. Additional catalyst (10
(0 mg, 26% w / w) was added to the reaction mixture after 48 hours. The reaction mixture was stirred for a further 24 hours under a hydrogen atmosphere and filtered through Celite. The filtrate was evaporated to dryness under reduced pressure to obtain a crude product (320 mg). Example 23 of the title compound
6E was obtained in 75% yield (200 mg) by flash chromatography on silica gel eluting with 5% acetone-hexane followed by 40% acetone-hexane. MS (APCI) m / e: 210 (M + H) ⁺ , 208 (M−H) ⁻ , 244 (
M + Cl) ⁻ . 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.93 (s, 3H), 8.
08 (s, 1H), 8.21 (s, 1H), 8.81 (s, 1H), 10.66
-10.90 (br, s, 1H).

Example 236E 4-benzyloxythieno [2,3-c] pyridine-2-carboxamide The title compound (50 mg, 67%) was prepared in Example 236C (75 mg, 0.25 m
mol) was prepared as described in Example 44. MS (APCI) m / e: 285 (M + H) ^<+> , 319 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.43 (s, 2H), 7.
49-7.50 (m, 3H), 7.58-7.63 (m, 2H), 7.79 (b
rs, 1H), 8.30 (s, 1H), 8.36 (s, 1H), 8.48 (br
s, 1H), 8.93 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 70.13 (CH ₂ ), 1
20.56 (CH), 126.21 (CH), 127.5 (CH), 128.1
4 (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-carboxamide Example 17A (15.00 g, 85.22 mmol) was dissolved in THF (80 mL) and cesium carbonate (27.77 g, 85 .22 mmol). THF
Methyl thioglycolate (7.62 mL, 85.2) diluted in (20 mL).
2 mmol) was added dropwise over 20 minutes. The reaction was stirred for 1.5 hours and then heated to 40 ° C. for 1 hour. The reaction mixture was poured into 850 mL of stirring water. After 10 minutes, the precipitate was collected by filtration and washed twice with water. The product was dried in a desiccator to yield the title compound (15.2 g, 78%) as a solid. _{MS (DCI / NH 3) m} / e: 228 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ3.96 (s, 3H), 8.
15 (s, 1H), 8.65 (s, 1H), 9.38 (s, 1H).

Example 237B 4-Chlorothieno [2,3-c] pyridine-2-carboxylic acid Example 237A (15.17 g, 66.63 mmol) was added in MeOH / water (50
0 mL) in a 1: 4 solution and LiOH hydrate (4.34 g, 103.50).
mmol). The reaction was stirred for 1.5 hours and concentrated (100 m
L). The aqueous layer was washed with Et ₂ O, then acidified to pH 5 with 1N HCl (aq). The precipitate was isolated by filtration and washed once with water and then twice with acetonitrile. The product was dried in a desiccator and 4-chlorothieno [2,3-
c] Pyridine-2-carboxylic acid (12.10 g, 85%) was produced. _{MS (DCI / NH 3) m} / e: 214 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H);
62 (s, 1H), 9.34 (s, 1H).

Example 237C Dimethylethyl 4-chlorothieno [2,3-c] pyridine-2-carboxylate Example 237B (12.07 g, 56.50 mmol) in THF (200 mL)
) The suspension was added at 0 ° C with t-butyl 2,2,2-trichloroacetamidodate (25
. 00 g, 114.41 mmol), followed by dropwise addition of boron trifluoride-diethyl etherate (2.14 mL, 16.95 mmol). The reaction was warmed to room temperature and stirred for 18 hours. Additional t-butyl 2,2,2-trichloroacetamidodate (12.50 g, 57.21 mmol) was added and stirred for 3 hours. The stirring reaction was treated with NaHCO ₃ (14 g) and then water (300 mL)
Diluted. The reaction was partitioned between 50% EtOAc / Et ₂ O water (300 mL). The organic layer was washed with saturated NaHCO ₃ , brine, partially dried (Na ₂ SO ₄ ), filtered and concentrated. The residue using EtOAc / hexanes as eluent was purified by silica gel flash chromatography neutralized with Et 3 _N. The compound was isolated as a solid (10.04 g, 66%). _{MS (DCI / NH 3) m} / e: 270 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.59 (s, 9H),
04 (s, 1H), 8.64 (s, 1H), 9.35 (s, 1H).

Example 237D Dimethylethyl 4- (ethoxycarbonyl) thieno [2,3-c] pyridine-2
-Carboxylate Example 237C (1.00 g, 3.71 mmol), 1,3-bis (diphenylphosphino) propane (0.46 g, 1.11 mmol), triethylamine (1.55 mL, 11.13 mmol) 2: 3 EtOH / DMF (25 mL
)) To the solution was added palladium (II) acetate (0.25 g, 1.11 mmol). The reaction was inhaled with a stream of CO (g) for 15 minutes. A balloon of CO (g) was attached and heated at 105 ° C. for 16 hours, then cooled to room temperature. This reaction is converted to water (
(400 mL). The aqueous layer was washed with brine (25 mL) and saturated NaHCO ₃ (25 mL
) And then extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with 20% saturated NaHCO ₃ (2 × 200 mL), brine (2 × 100 mL), partially dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the title compound as a solid (0.60 g, 53%). MS (APCI) m / e: 308 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.44 (t, J = 7.1 Hz)
, 3H), 1.59 (s, 9H), 4.44 (q, J = 7.1 Hz, 2H), 8
. 65 (s, 1H), 8.65 (s, 1H), 9.12 (s, 1H), 9.25
(S, 1H).

Example 237E Dimethylethyl 4-formylthieno [2,3-c] pyridine-2-carboxylate NaBH ₄ (0.18 g, 4.89 mmol) in anhydrous 50% MeOH / THF
To a stirred solution of at 0 ° C. was added powdered CaCl ₂ (0.54 g, 4.89 mmol). The suspension was stirred for 20 minutes and the solution of Example 237D (0.50 g, 1.63) was obtained.
mmol) in 50% MeOH / THF was added slowly over 10 minutes. The reaction was stirred at 0 ° C. for 1 hour, followed by stirring at room temperature for 16 hours. The reaction is diluted A
Quenched in cOH (aq) / ice slurry. After completing all the gas in occasional stirring, basified with saturated NaHCO _3. The aqueous layer was washed with methylene chloride (3 × 40
mL), and the extracts were combined. The organic layer was dried _(Na 2 SO _4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the dimethylethyl 4- (hydroxymethyl) -thieno [2,3-c] pyridine-2-carboxylate compound as a solid (0. 14 g, 32%). MS (APCI) m / e: 266 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.54 (s, 9H), 4.9
4 (s, 2H), 8.08 (s, 1H), 8.40 (s, 1H), 9.02 (s)
, 1H).

To a stirred solution of oxalyl chloride (0.10 mL. 1.17 mmol) in anhydrous methylene chloride (1 mL) at −78 ° C. was added DMSO (0.19 mL, 2.65 mmol).
l) was added. After 20 minutes, dimethylethyl 4- (hydroxymethyl) -thieno [
2,3-c] pyridine-2-carboxylate (0.28 g, 1.06 mmol
)) In anhydrous methylene chloride (4 mL). The reaction was stirred at -78 <0> C for 1 hour, then treated with triethylamine (0.74 mL, 5.30 mmol). After 5 minutes, the reaction was warmed to room temperature over 30 minutes. The reaction was quenched with water (5 mL) and methylene chloride (50 mL) and 50% saturated aqueous NaHCO ₃ (50 m
L). The organic phase was washed with 50% saturated aqueous NaHCO ₃ (1 × 50 mL)
And dried (Na ₂ SO ₄ ), filtered, concentrated and dried in a desiccator to yield the title compound as a solid (0.25 g, 90%). MS (APCI) m / e: 264 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.59 (s, 9H), 8.7
4 (s, 1H), 8.91 (s, 1H), 9.31 (s, 1H), 10.24 (
s, 1H).

Example 237F Dimethylethyl 4-[(4-chlorophenyl) (hydroxy) methyl] thieno [
2,3-c] Pyridine-2-carboxylate To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) at −5 ° C. is a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether ( 2.85 mL, 2.85 mmol) was added. 10 minutes later, water (1m
L) was added dropwise to quench, methylene chloride (25 mL) and 50% saturated N
aHCO ₃ (50 mL). The aqueous phase was washed with methylene chloride (25 mL
), The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to provide the title compound as a foam which was crushed and dried in a desiccator to yield a powder (0.36 g, 100%). MS (APCI) m / e: 376 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 1.52 (s, 9H), 6.1
8 (d, 1H), 7.25 to 7.34 (continuous m, 4H), 7.96 (s, 1
H), 8.47 (s, 1H), 9.03 (s, 1H).

Example 237G Methyl 4-[(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-
c] pyridine-2-carboxylate Example 237F (0.12g, 0.32mmol) and _{10% H 2} SO 4 / Me
Dissolve in OH (10 mL) solution and heat to 50 ° C. for 18 hours. The reaction was run with saturated NaH
Quenched in CO ₃ (100 mL). The aqueous phase was washed with methylene chloride (2 × 50 mL
) And the organic extracts were combined. The organic layer was washed with a saturated aqueous solution of NaHCO ₃ (1 × 10
0 mL), washed with brine (1 × 100 mL) and partially dried (Na ₂ SO ₄ )
Then, the mixture was filtered and concentrated. The product is dried in a desiccator to give the title compound as a solid (
0.10 g, 94%). MS (APCI) m / e: 334 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 3.85 (s, 3H), 6.1
7 (d, 1H), 7.23 to 7.33 (continuous m, 4H), 8.05 (s, 1
H), 8.48 (s, 1H), 9.05 (s, 1H).

Example 237H Methyl 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2-carboxylate oxalyl chloride (0.023 mL. 0.26 mmol) in anhydrous methylene chloride (1 mL) ) In DMSO (0.045 mL, 0.63 m
mol) was added. After 15 minutes, Example 237G (0.07 g, 0.21 mmol)
) In anhydrous DMSO / methylene chloride (5 mL) was added dropwise. The reaction was stirred at -78 ° C for 1 hour, then triethylamine (0.15 mL
, 1.05 mmol). After 5 minutes, the reaction was warmed to room temperature over 1 hour. The reaction was quenched with water (2 mL), EtOAc (50 mL) and sat.
Partitioned with aqueous O ₃ (50 mL). Wash the organic layer with 50% saturated aqueous NaHCO ₃ (2 × 50 mL), brine (1 × 50 mL) and dry (Na ₂ SO ₄ )
, Filtered and concentrated. Dry in a desiccator to give the title compound as a white solid (0.
(07 g, 100%). MS (APCI) m / e: 332 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) 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)) ^<+> . IR (KBr) 3208, 2959, 1719, 1657, 1585, 1567
, 1434, 1308, 1268 cm ^-1 .

Example 237I 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 237H (70 mg, 0.21 mmol) was suspended in MeOH (5 mL) and chloroform was added until the solid dissolved. Heated at 50 ° C. for 20 hours with an ammonia balloon attached. The reaction solution was concentrated, and the residue was eluted with EtOA.
Purified by flash chromatography on silica gel using c / hexane.
The resulting title compound was dried in a desiccator to yield a white solid (35 mg, 53%). mp 216-218 ° C. MS (APCI) m / e: 317 (M + H) ^<+> . _{^{1 H NMR (DMSO-d 6}} ) δ7.68 (m, 2H), 7.86 (brs,
1H), 7.88 (m, 2H), 8.38 (s, 1H), 8.53 (brs, 1H)
H), 8.67 (s, 1H), 9.55 (s, 1H). ¹³ C NMR (DMSO-d ₆ ) δ 123.4, 128.0, 129.3, 1
32.0, 135.9, 137.9, 138.9, 143.2, 145.1, 1
48.8, 148.9, 162.7, 193.6. IR (KBr) 3289, 3145, 1681, 1655, 1399, 1270
cm ^-1. Elemental _{analysis: C 15 H 9 ClN 2 O} 2 S, Calculated for _{0.1C 6 H 14: C, 57} .
59; H, 3.22; N, 8.61. Theory: 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 Example 94 was treated according to the method of Example 237D to provide the title compound.

Example 238B 4- (Carboxy) thieno [2,3-c] pyridine-2-carboxamide Example 238A was treated according to the method of Example 159A to provide the title compound.

Example 238C N-4- (4-Chlorophenyl) thieno [2,3-c] pyridine-2,4-dicarboxamide Example 238B was treated according to the method of Example 24 to provide the title compound. . mp> 270 ° C. MS (ESI) m / e: 332 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.46 (m, 2H), 7.
84 (brs, 1H), 7.85 (m, 2H), 8.52 (m, 1H), 8.5
6 (brs, 1H), 8.90 (m, 1H), 9.47 (m, 1H), 10.7
9 (brs, 1H).

Example 239 [4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl] methanol Example 239 (900 mg, 97%) is replaced by Example 73 instead of Example 61A.
(1 g, 2.74 mmol), but prepared as described in Example 90. MS (APCI) m / e: 336; 338 (M + H) ^<+> , 370; 372 (M +
Cl) ⁻ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.78 (d, J = ₆ Hz,
2H), 5.88 (t, J = 6 Hz, 1H), 6.98 (d, J = 9 Hz, 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 Example 240 (400 mg, 80%) was replaced with Example 239 in place of Example 90.
(500 mg, 1.49 mmol), but prepared as described in Example 91A. MS (APCI) m / e: 334; 336 (M + H) ^<+> , 333; 335 (M-
H) ^- . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J = 9 Hz,
2H), 7.62 (d, J = 9 Hz, 2H), 8.26 (s, 1H), 8.40
(S, 1H), 9.27 (s, 1H), 10.21 (s, 1H).

Example 241 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde oxime The title compound was prepared from Example 91A in a similar manner to Example 30. HPLC: Supelco C-18 column, water: acetonitrile 0: 90-
90: 0, 30 min elution, flow rate 0.8 mL / min, rt: 19.61 min and 20.
28 minutes. _{MS (DCI / NH 3) m} / e: 305 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 8.16 (m, 3H)
), 8.51 (s, 1H), 9.05 (s, 1H), 9.14 (s, 1H), 1
1.91 (s, 1H), 12.66 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 119.28, 119.3
3, 120.58, 122.21, 125.25, 127.51, 128.13
, 128.82, 129.99, 133.03, 133.84, 135.37,
136.10, 137.11, 139.40, 139.95, 140.83, 1
41.28, 143.24, 143.66, 146.31, 146.58, 15
5.69. Elemental _{analysis: C 14 H 9 ClN 2 O} 2 S, 0.4 Calculated toluene: C, 59.0
7; H, 3.60; N, 8.20. Theory: C, 59.15; H, 3.65; N
, 8.25.

Example 242 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbaldehyde O-methyloxime Example 242 was prepared from Example 91A as in Example 26. . E-Isomer spectral data: HPLC: Supelco C-18 column, gradient elution of water: acetonitrile 0: 90-90: 0 over 30 minutes, flow rate of 0.8 mL / min, RT 22.72 minutes and 23. 60 minutes. ^{MS (ESI) m / e:} 319 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ3.94 (s, 3H), 7.
12 (m, 2H), 7.47 (m, 2H), 7.65 (s, 1H), 8.18 (
s, 1H), 8.61 (s, 1H), 9.08 (s, 1H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 62.29, 119.35.
, 122.26, 124.01, 127.60, 130.01, 133.77,
136.85, 140.91, 141.38, 144.34, 146.46, 1
55.58.

Example 243A Mike Steager 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone O-methyloxime Example 159A was The treatment was performed in the same manner as in Example 22. The derived amide was treated according to the method of Example 33 to produce the corresponding methyl ketone. This ketone was treated according to the method of Example 26 to provide the title compound as a mixture of E- and Z-isomers. Both isomers were separated by column chromatography on type H (Sigma) silica gel, eluting with 25% EtOAc: hexane. Spectral data for Z-isomer: mp 126-128 ° C. MS (APCI) m / e: 333 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 1H), 9.01 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 12.18, 62.32,
118.85, 119.88, 127.77, 130.01, 132.98, 1
36.94, 136.98, 140.32, 145.60, 146.94, 15
0.84, 155.40. Elemental _{analysis: C 16 H 13 ClN 2 O} 2 Calculated S: C, 57.74; H, 3.9
4: N, 8.42. Theory: C, 58.03; H, 3.92; N, 8.14.

Example 243B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone O-methyloxime E-isomer is a preparation of Example 243A. MS (APCI) m / e: 333 (M + H) ^<+> . 3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H);
04 (s, 3H), 7.18 (m, 2H), 7.48 (m, 2H), 7.82 (
s, 1H), 8.11 (s, 1H), 9.12 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 19.25, 62.16,
119.88, 120.17, 121.60, 127.95, 130.04, 1
31.98, 134.49, 136.52, 138.85, 140.68, 14
6.21, 147.39, 155.22.

Example 244A 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime Example 244A was prepared using hydroxyl hydrochloride in place of methoxyamine hydrochloride. Prepared similarly as in Example 243A using an amine. ^{MS (APCI) m / e:} 319 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ2.23 (s, 3H), 7.
15 (m, 2H), 7.48 (m, 2H), 7.62 (s, 1H), 8.10 (
s, 1H), 9.02 (s, 1H), 11.89 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 11.41, 117.45
, 119.73, 124.45, 127.65, 129.97, 133.14,
136.78, 137.17, 140.28, 146.72, 147.39, 1
49.85, 155.51. Elemental _analysis: C ₁₅ H 11 ClNO ₂ Calculated S: C, 54.96; H, 3.69
N, 8.55. Theory: C, 55.37; H, 3.47; N, 8.37.

Example 244B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime Z-isomer was isolated from Example 244A. Was. MS (APCI) m / e: 319 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 7.
15 (d, J = 9 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 7.73
(S, 1H), 8.10 (s, 1H), 9.12 (s, 1H), 12.35 (s
, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 19.32. 118.36
, 119.96, 120.01, 127.81, 130.02, 132.08,
134.60, 136.99, 138.95, 140.73, 145.08, 1
47.18, 155.40.

Example 245 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-propanone The title compound was obtained by using ethyl magnesium bromide instead of methyl magnesium bromide. And prepared in the same manner as in Example 33. mp 101-102 ° C. MS (APCI) m / e: 318 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.11 (t, J = 8 Hz,
3H), 3.18 (d, J = 8 Hz, 2H); 7.21 (m, 2H), 7.51
(M, 2H), 8.13 (s, 1H), 8.32 (s, 1H), 9.19 (s,
1H).

Example 246 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1-ethanone oxime The title compound was prepared in Example 26 using hydroxylamine hydrochloride using hydroxylamine hydrochloride. Example 2 as in
Prepared from 45 and provided a mixture of E- and Z-oxime isomers. mp 195-198 ° C (decomposition). MS (APCI) m / e: 333 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.10 (m, 6H), 2.
77 (m, 4H), 7.17 (m, 4H), 7.48 (m, 4H), 7.61 (
s, 1H), 7.71 (s, 1H), 8.09 (s, 1H), 8.11 (s, 1H)
H), 9.00 (s, 1H), 9.12 (s, 1H), 11.88 (s, 1H)
, 12.42 (s, 1H). HPLC: Supelco C-18 column, water: acetonitrile 0: 90-
Elution at 90: 0 for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, RT = 20
. 20 minutes and 21.10 minutes (E- and Z-alien). Elemental _{analysis: C 16 H 13 ClN 2 O} 2 Calculated S: C, 57.74; H, 3.9
4: N, 8.42. Theory: C, 57.51; H, 4.12; N, 8.22.

Example 247 2- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N-methoxy-N-methyl-2-oxoacetamide Example 88 (0. 38 mmol) is prepared as described in Example 42;
Then at -78 ° C combined with THF (1.0 mL) and LDA (0.92 mL of a freshly prepared 0.5 M solution in THF, 0.46 mmol). The clear, pale yellow solution was transferred to a solution of bis (N, O-dimethylhydroxyl) oxamide (88 mg, 0.50 mmol) in THF (1.0 mL) at −78 ° C. before being cannulated at −78 ° C. at 1.25 ° C. Stirred for hours. The solution was gradually warmed to room temperature, diluted with 2N aqueous hydrochloric acid (20 mL) and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were washed with brine (1 × 10 mL), dried (MgSO ₄ ) and concentrated to a yellow solid. Silica gel flash column chromatography (15% acetone in hexane) as a yellow solid (25 mg, 17%
Yield). mp 135.0-137.8 ° C. ^{_{MS (DCI / NH 3) m}} / e: 377 (35 Cl) / 379 (37 Cl). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.31 (s, 3H);
64 (s, 3H), 7.27 (d, J = 8.8 Hz, 2H), 7.52 (d, J
= 8.8 Hz, 2H), 8.15 (s, 1H), 8.22 (s, 1H), 9.2
6 (s, 1H).

Example 248 4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carbonitrile The pyridine of the compound obtained from Example 61B (500 mg, 1.64 mmol)
7 mL) solution at −78 ° C. under nitrogen under trifluoroacetic anhydride (1 mL, 6.6 mmol).
1), stirred at -78 ° C for 40 minutes, gradually warmed to room temperature and stirred for another 2 hours. The mixture was diluted with ethyl acetate, washed with saturated NaHCO _3, brine and dried (MgSO ₄₎ and concentrated. The resulting pale purple solid was dissolved in a minimum amount of ethyl acetate, filtered through a silica plug, washed with 50/50 hexane / ethyl acetate and concentrated to give 395 mg (84%) of the title compound as a white solid. Was. _{mp140~142 ℃; MS (APCI-NH} 3) m / e: 287 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.04 (d, 2H), 7.40
(D, 2H), 8.00 (s, 1H), 8.14 (s, 1H), 8.96 (s,
1H). Elemental _analysis: C ₁₄ H 7 _ClN 2 OS Calculated: C, 58.64; H, 2.46 ;
N, 9.77. Theory: C, 58.45; H, 2.62; N, 9.52.

Example 249 4- (4-Chlorophenoxy) -N′-hydroxythieno [2,3-c] pyridine-2-carboxymidamide Ethanol of compound obtained from Example 248 (100 mg, 0.35 mmol) (2 mL) solution at room temperature under nitrogen under triethylamine (90 mL, 0.6 mmol)
), Hydroxylamine hydrochloride (40 mg, 0.53 mmol) and stirred for 18 h. The resulting white heterogeneous mixture was dissolved in ethyl acetate and saturated NaHC
Washed with O ₃ , brine, dried (MgSO ₄ ) and concentrated to give 120 mg of an off-white foam. The foam was dissolved in ethyl acetate, filtered through a plug of silica and concentrated to give the title compound as a white solid (110 mg, 98%). _{mp194~196 ℃; MS (APCI-NH} 3) m / e: 320 (M + H) +. ¹ H NMR (300 MHz, 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, 2H), 6.26 (brs, 2H). Elemental _{analysis: C 14 H 10 ClN 3 O} 2 Calculated S: C, 52.59; H, 3.1
5; N, 13.14. Theory: C, 52.72; H, 3.05; N, 12.82.
.

Example 250 4- (4-chlorophenoxy) -N′-cyanothieno [2,3-c] pyridine-
2-Carboximidamide THF (2 mg) of the compound obtained from Example 248 (100 mg, 0.35 mmol).
mL) solution at ambient temperature under nitrogen, cyanamide (74 mg, 1.75 mmol), 1,
8-diazabicyclo [5.4.0] undec-7-ene (52 mL, 0.35 m
mol) and stirred for 24 hours. The resulting yellow homogeneous solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated,
This gave a pale yellow solid which was tritylated with CH ₂ Cl ₂ to give 123 mg of a white powder. This was dissolved in ethyl acetate and THF, washed with distilled water and saline, and dried (M
gSO ₄ ) and concentrated to give 99 mg of a white powder (MgSO ₄ ), which was tritylated with CH ₂ Cl ₂ and then placed in a vacuum oven at 60 ° C. overnight to afford the title compound (78 mg, 69%). mp 265-268 ° C. _{MS (APCI-NH 3) m} / e: 329 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.58 (brs, 1H),
9.17 (s, 1H), 9.05 (brs, 1H), 8.41 (s, 1H), 8
. 19 (s, 1H), 7.48 (d, 2H), 7.15 (d, 2H). Elemental _analysis: C ₁₅ H 9 _ClN 4 OS Calculated: C, 54.80; H, 2.76 ;
N, 17.04. Theory: C, 54.50; H, 3.01; N, 17.16.

Example 251 (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone Example 251A [4- (4-Chlorophenoxy) thieno [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) was added a suspension of 1.3 M s-butyllithium in cyclohexane at −78 ° C. (3
. 52 mL, 4.58 mmol) were added dropwise over 10 minutes. After 40 minutes, the reaction was cooled at -48 ° C to 2-nitrobenzaldehyde (1.43 g, 9.55 mmol).
) Was cannulated into a stirred solution of THF (10 mL). After 20 minutes, the reaction was
OH (6 mL) was added slowly to quench. The reaction was treated with EtOAc (125 m
L) and the organic layer was washed with 1: 1 saturated aqueous NaHCO ₃ (1 × 75 mL), brine (1 × 75 mL), partially dried (Na ₂ SO ₄ ) and concentrated.

The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound as a solid (1.49 g, 95%). mp 85-90 ° C. MS (APCI) m / e: 413 (M + H) ^<+> . 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.54 (s, 1H);
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)
H), 7.98 (m, 1H), 8.12 (s, 1H), 9.02 (s, 1H).
Elemental _{analysis: C 20 H 13 ClN 2 O} 4 S, 0.3H 2 O Calculated: C, 57.4
3; H, 3.28; N, 6.70. Theory: C, 57.42; H, 3.45; N
, 6.42.

Example 251B (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol Example 251A (0.10 g, 0.24 mmol) was treated with EtOH (1.7 mL).
, And a solution of tin (II) chloride dihydrate (0.43 g, 1.92 mmol) in concentrated hydrochloric acid (0.70 mL) was gradually added. The reaction was stirred for 18 hours and then CH
Partitioned between Cl ₃ (50 mL) and saturated NaHCO ₃ (75 mL). Et water layer
Extract with OAc (1 × 50 mL), combine all organic extracts and partially dry (N
a ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound as a pale colored solid (0.08 g, 87%). mp 92-96 ° C. MS (APCI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.08 (brs, 2H),
6.10 (d, J = 4.3 Hz, 1H), 6.54 (d, J = 4.3 Hz, 1H)
), 6.55 (m, 1H), 6.61 (m, 1H), 6.98 (m, 1H), 7
. 05 (m, 2H), 7.13 (m, 1H), 7.19 (m, 1H), 7.42
(M, 2H), 8.09 (s, 1H), 8.98 (s, 1H). Elemental _{analysis: C 20 H 15 ClN 2 O} 2 Calculated S: C, 62.74; H, 3.9
5; N, 7.32. Theory: C, 63.09; H, 4.05; N, 7.06.

Example 251C (2-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone silica gel (0.13 g) and celite (0.13 g) in dichloromethane (
Pyridinium chlorochromate (0.13 g, 0. 6 mL) in an anhydrous stirred solution.
59 mmol) was added. A solution of Example 251B (0.15 g, 0.39 mmol) in anhydrous dichloromethane (9 mL) was slowly added dropwise. One hour later, saturated NaHCO ₃ (5 mL) was added, and the mixture was stirred for one hour. The reaction was filtered and the black solid was crushed and washed with 5% MeOH / dichloromethane (3 × 20 mL). The combined organic filtrate and washings were combined with saturated NaHCO ₃ (2 × 100 mL), brine (1 × 75 mL)
), Partially dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to yield the title compound (45 mg, 39%) as a light colored solid. mp 152-154 ° C. MS (APCI) m / e: 381 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ6.54 (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, 1H), 7.5
8 (m, 1H), 8.24 (s, 1H), 9.21 (s, 1H). ¹³ C NMR (300 MHz, 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
, 1552, 1483, 1409, 1267, 1245, 1219, 1155c
m- ¹ . Elemental _{analysis: C 20 H 13 ClN 2 O} 2 Calculated S: C, 63.08; H, 3.4
4: N, 7.36. Theory: C, 62.94; H, 3.51; N, 7.25.

Example 252 (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252A [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
3-Nitrophenyl) methanol Example 251A was used, substituting 3-nitrobenzaldehyde for 2-nitrobenzaldehyde. mp 79-83 ° C. MS (APCI) m / e: 413 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.33 (d, J = 4.4 H
z, 1H), 6.99 (d, J = 4.4 Hz, 1H), 7.07 (m, 2H),
7.27 (m, 1H), 7.43 (m, 2H), 7.66 (m, 1H), 7.9
2 (m, 1H), 8.13 (s, 1H), 8.15 (m, 1H), 8.34 (m
, 1H), 9.01 (s, 1H). Elemental _{analysis: C 20 H 13 ClN 2 O} 4 Calculated S: C, 58.19; H, 3.1
7; N, 6.79. Theory: C, 57.97; H, 3.23; N, 6.70.

Example 252B (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252A was treated according to the method of Example 251B to provide the title compound. mp 73-78 ° C. MS (APCI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.03 (s, 2H), 5.
88 (s, 1H), 6.45 (continuous m, 2H), 6.57 (m, 1H), 6
. 64 (m, 1H), 6.96 (m, 1H), 7.06 (m, 2H), 7.11
(M, 1H), 7.42 (m, 2H), 8.08 (s, 1H), 8.97 (s,
1H). Elemental _{analysis: C 20 H 15 ClN 2 O} 2 Calculated S: C, 62.74; H, 3.9
5; N, 7.32. Theory: C, 63.06; H, 4.22; N, 6.92.

Example 252C (3-Aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Example 252B was treated according to the method of Example 251C to provide the title compound. mp 174-178 ° C. MS (APCI) m / e: 481 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.47 (brs, 2H),
6.86 to 6.96 (continuous m, 2H), 7.06 (m, 1H), 7.16 to
7.23 (continuous m, 3H), 7.48 (m, 2H), 7.77 (s, 1H)
, 8.20 (s, 1H), 9.22 (s, 1H).

Example 253 4- (4-Bromophenoxy) -2-vinylthieno [2,3-c] pyridine methyltriphenylphosphonium bromide (113 mg, 0.314 mmol
) Was added to a stirred solution of anhydrous tetrahydrofuran (2 mL) at -78 ° C under a nitrogen atmosphere under n-BuLi (2.5 M solution in hexane, 0.125 mL, 0.314 mmol).
l) The solution was added dropwise. The reaction mixture was then stirred for 40 minutes at 0 ° C.,
Cooled to 8 ° C. While maintaining the internal temperature at -72 ° C or lower, the solution was added to Example 24.
A solution of 0 (100 mg, 0.3 mmol) in anhydrous tetrahydrofuran (2 mL) was added. Upon completion of the addition, the reaction mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 1 hour. Next, the reaction mixture was partitioned between ethyl acetate (60 mL) and brine (20 mL). The organic layer was washed with brine (2 × 20 mL), dried (MgSO ₄ ) and evaporated to dryness under reduced pressure to give a crude (145 mg). The title compound is 26% by silica gel flash chromatography eluting with 25% acetone-hexane.
In a yield of 26 mg. MS (APCI) m / e: 332, 334 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.53 (d, J = 10 Hz)
, 1H), 5.86 (d, J = 16 Hz, 1H), 7.02 (d, J = 9 Hz,
2H), 7.06 to 7.14 (m, 1H), 7.37 (s, 1H), 7.57 (
d, J = 9 Hz, 1H), 8.17 (s, 1H), 9.04 (s, 1H).

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 254A (70 mg, 10%) was replaced with Example 91 in place of Example 240.
Prepared as in Example 253 except using A (700 mg, 2.42 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.53 (d, J = 10.5
Hz, 1H), 5.86 (d, J = 18 Hz, 1H), 7.04 to 7.14 (m
, 1H), 7.10 (d, J = 9 Hz, 2H), 7.38 (s, 1H), 7.4
5 (d, J = 9 Hz, 2H), 8.16 (s, 1H), 9.04 (s, 1H).

Example 254B 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol Example 254A (22 mg, 28%) was prepared. Example 25 Instead of Example 253
Prepared as in Example 255 except using 4A (70 mg, 0.26 mmol). MS (APCI) m / e: 322 (M + H) ⁺ , 356 (M + Cl) ⁻ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.50 to 3.64 (m, 2
H), 4.86-4.91 (m, 1H), 5.0 (t, J = 6 Hz, 1H), 6
. 04 (d, J = 4 Hz, 1H), 7.07 (d, J = 9 Hz, 2H), 7.2
1 (s, 1H), 7.43 (d, J = 9 Hz, 2H), 8.14 (s, 1H),
9.04 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 66.52 (CH ₂ ), 7
0.24 (CH), 114.60 (CH), 119.06 (CH), 127.2
2 (C), 129.91 (CH), 133.36 (CH), 137.16 (C)
, 137.42 (C), 140.79 (CH), 145.79 (C), 155.
91 (C), 156.59 (C).

Example 255 1- [4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2-ethanediol Tetrahydrofuran of Example 253 (90 mg, 0.271 mmol) (2m
L) To the solution was added 4-methylmorpholine N-oxide (63.5 mg, 0.542 m
mol) and osmium tetroxide (14 mg, 0.054 mmol) in water (0.
(5 mL) was added at room temperature. The reaction mixture was stirred for 48 hours and the solvent was removed. The resulting residue was purified by flash chromatography on silica gel, eluting directly with 20% acetone-hexane to give the title compound (52 mg, 53%). MS (APCI) m / e: 366; 368 (M + H) ^<+> , 402 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.50 to 3.64 (m, 2
H), 4.89 (m, 1H), 5.01 (t, J = 6 Hz, 1H), 6.05 (
d, J = 4 Hz, 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
(S, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 66.52 (CH ₂ ), 7
0.25 (CH), 114.60 (CH), 115.08 (C), 119.24
(CH), 132.84 (CH), 133.49 (CH), 137.18 (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 diethyl azodicarboxylate (180 mL, 1.13 mmol) was prepared in Example 90 (
220 mg, 0.750 mmol), THF (7.5 mL), triphenylphosphine (297 mg, 1.13 mmol) and phthalimide (166 mg,
1.13 mmol). After 16 hours, the orange solution was concentrated under reduced pressure to obtain an orange solid. Silica gel flash column chromatography (20% acetone in hexane) provided one compound (100% yield) as the main product, which was combined with hydrazine hydrate (230 mL, 7.50 mmol) and ethanol (75 mL). Heated to reflux. After 4 hours, the solution was cooled to room temperature, concentrated, 5N HCl
(30 mL) and filtered through a fritted glass funnel. Filtrate is 3NN
Added to pH> 12 with aOH and extracted with EtOAc (3 × 30 mL).
The organic extracts were combined, washed once with brine (30 mL), dried (MgSO ₄ ),
Filter and concentrate under reduced pressure to give the title compound as a white solid (190 mg, 87% yield). mp 78.6-79.8 <0> C. _{MS (DCI / NH 3) m} / e: 321 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.24 (brs, 2H),
4.02 (s, 2H), 7.03 (d, J = 9.1 Hz, 2H), 7.15 (s
, 1H), 7.42 (d, J = 9.1 Hz, 2H), 8.14 (s, 1H), 9
. 01 (s, 1H). Elemental _{analysis: C 14 H 11 ClN 2 OS} , 0.25H 2 O Calculated: C, 56.9
5; H, 3.93; N, 9.49. Theory: C, 56.86; H, 3.81; N
, 9.62.

Example 257 [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methylcarbamate Example 90 (50 mg, 0.17 mmol) in CH ₂ Cl ₂ (0.5 mL) ),
Sodium cyanate (22 mg, 0.34 mmol) and trifluoroacetic acid (4
0 mL, 0.34 mmol), and gas generation was observed. After 24 hours, the mixture was partitioned distilled water (15mL) _CH 2 _Cl 2 and (50 mL). The layers were separated and the organic layer dried (MgSO _4), filtered and concentrated. Silica gel column chromatography (30% acetone in hexane) gave the title compound as a white solid (21 mg).
, 37% yield). mp 113-115 ° C. ^{_{MS (DCI / NH 3) m}} / e: 335 (35 Cl) / 337 (37 Cl). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.30 (s, 2H), 6.
80 (brs, 2H), 7.06 (d, J = 9.2 Hz, 2H), 7.37 (s
, 1H), 7.45 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H), 9
. 10 (s, 1H).

Example 258 N-{[4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] methyl} urea Potassium cyanate (41 mg, 0.50 mmol) was prepared according to Example 256 ( 130m
g, 0.45 mmol), distilled water (2.0 mL) and concentrated hydrochloric acid (40 mL, 0.1 mL).
45 mmol) and the solution was heated at 50 ° C. After 3 hours, the solution was cooled slowly to 0 ° C. and the resulting precipitate was isolated by filtration. Silica gel flash column chromatography (20% acetone in hexane to 1% in EtOAc)
(Change to 0% MeOH) to give the title compound as a white solid (63 mg, 42% yield).
Was provided. mp 202-204 ° C. ^{_{MS (DCI / NH 3) m}} / e: 334 (35 Cl) + / 336 (37 Cl) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.47 (d, J = 6.1 H
z, 2H), 5.68 (s, 2H), 6.68 (t, J = 6.1 Hz, 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: C 15 H 12 ClN 3 O} 2 Calculated S: C, 53.97; H, 3.6
2: N, 12.59. Theory: C, 53.80; H, 3.67; N, 12.37.
.

Example 259 (E) -3- [4- (4-Bromophenoxy) thieno [2,3-c] pyridine-
2-yl] propenamide Example 259A Methyl 3- (4- (4-bromophenoxy) thieno [2,3-c] pyridine-2
-Yl) propenoate Example 259A (590 mg, 57%) was replaced by Example 2 instead of Example 91A.
Prepared as in Example 91B except using 40 (890 mg, 2.67 mmol). MS (APCI) m / e: 390; 392 (M + H) ⁺ , 389; 391 (M-
H) ^- . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.75 (s, 3H), 6.
58 (d, J = 16 Hz, 1H), 7.07 (d, J = 9 Hz, 2H), 7.5
9 (d, J = 9 Hz, 2H), 7.89 (s, 1H), 8.02 (d, J = 16
Hz, 1H), 8.17 (s, 1H), 9.12 (s, 1H).

Example 259B 3- (4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl) propenonic acid Example To provide the title compound (270 mg, 93%) 259A and the method of Example 88 were used. MS (APCI) m / e: 376; 378 (M + H) ^<+> . _{^{1 H NMR (300MHz, DMSO-}} d 6) d: 6.45 (d, J = 16H
z, 1H), 7.07 (d, J = 9 Hz, 2H), 7.58 (d, J = 9 Hz,
2H), 7.81 (s, 1H), 7.90 (d, J = 16 Hz, 1H), 8.1
6 (s, 1H), 9.10 (s, 1H).

Example 259C 3- (4- (4-Bromophenoxy) thieno [2,3-c] pyridin-2-yl) propenamide Example 259B instead of Example 91c to provide the title compound. The methods of Example 259B (222 mg, 81%) and Example 92 were used except that mp 195-196 ° C. MS (APCI) m / e: 375; 377 (M + H) ⁺ , 409; 411 (M +
Cl) ^- . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.62 (d, 16 Hz, 1
H), 7.04 (d, J = 9 Hz, 2H), 7.26 (s, 1H), 7.56 (
d, J = 9 Hz, 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 (100 MHz, DMSO-d ₆ ) δ 115.55 (C), 11
9.98 (CH), 122.11 (CH), 126.68 (CH), 131.8
0 (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-2-yl] propenamide Example 260 (25 mg, 50%) Prepared from Example 259A (50 mg, 0.13 mmol) as described in 171. ^{MS (APCI) m / e:} 389 (M + H) +; 1 H NMR (400MHz, DMSO-d 6) δ2.71 (d, J = 4.5H
z, 3H), 6.62 (d, J = 16 Hz, 1H), 7.06 (d, J = 9 Hz)
, 2H), 7.58 (d, J = 9 Hz, 2H), 7.69 (s, 1H), 7.7
4 (d, J = 16 Hz, 1H), 8.15 (s, 1H), 8.27 (d, J = 4
. 5 Hz, 1H), 9.08 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 25.7 (CH ₃ ), 11
5.6 (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] pyridine-
2-yl] -2,3-dihydroxypropanamide To provide the title compound, Example 260 (90 mg, 0.2
Example 2 as described in Example 255 except that 32 mmol) was used.
60 (52 mg, 53%) was prepared. MS (APCI) m / e: 423; 425 (M + H) ^<+> , 456 (M + Cl) < ^- >. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.61 (d, J = 4.5H)
z, 3H), 4.09 (brd, J = 3 Hz, 1H), 5.27 (brd, J =
3 Hz, 1 H), 5.68 (d, J = 6 Hz, 1 H), 6.09 (d, J = 6 H)
z, 1H), 7.00 (d, J = 9 Hz, 2H), 7.23 (s, 1H), 7.
56 (d, J = 9 Hz, 2H), 7.77 (d, J = 4.5 Hz, 1H), 8.
14 (s, 1H), 9.04 (s, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 25.5 (CH ₃ ), 70.
3 (CH), 75.1 (CH), 115.0 (CH), 115.1 (C), 11
9.5 (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 Example to prepare the title compound 261 and the product from Example 259C may be used.

Example 263 4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-ylamine Example 159A (0.500 g, 1.64 mmol) and 1,8-bis (dimethylamino) naphthalene A mixture of N, N, N ′, N′-tetramethyl-1,8-naphthalenediamine (0.350 g, 1.64 mmol) in 90 mL of anhydrous THF was warmed until all solids were in solution. The solution was stirred for 15 minutes and diphenylphosphoryl azide (0.450 g, 1.64 mmol) was added. The solution was heated at 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 / hexane,
422 mg of the intermediate isocyanate were provided as a light orange solid. The resulting product was dissolved in 100 mL of toluene and heated at reflux for 6 hours. The product was evaporated to dryness. The resulting dark orange solid was dissolved in 20 mL of a 2.0 M solution of hydrogen chloride in dioxane. The solution was evaporated, leaving 313 mg (84.9%) of the title compound. MS (APCI) m / e: 277 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ6.91 (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 ° C. for 3 hours. . The solution was cooled and the amine from Example 263 (32 mg, 0.1
2 mmol) was added. The mixture was stirred for 4 days and poured into 50 mL of HCl. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated sodium carbonate, then with water, dried (MgSO ₄ ) and evaporated. Purification of the product by preparative HPLC using a gradient of 30% -70% acetonitrile / water + 0.1% TFA over 40 minutes gave 18 mg (49%) of the title compound. MS (APCI) m / e: 305 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₃ OD) δ 7.16 (s, 1H), 7.24
(D, 2H), 7.46 (d, 2H), 8.08 (s, 1H), 8.61 (s,
1H), 9.13 (s, 1H).

Example 265 N- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] urea Hydroxidation of the Isocyanate Obtained from Example 263 (110 mg, 0.364 mmol) The mixture in 10 mL of ammonium was stirred vigorously for 18 hours. The resulting red solid was collected and dried under reduced pressure to give 60.7g (52.2%) of the title compound. MS (APCI) m / e: 320 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (d, 2H), 7.
34 (s, 1H), 7.50 (d, 2H), 7.65 to 7.79 (m, 4H),
8.06-8.16 (m, 2H), 9.18 (s, 1H).

Example 266 N- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N′-methylthiourea Obtained from Example 263 (150 mg, 0.542 mmol). 5 mL of a pyridine solution of the prepared amine in methyl isothiocyanate (198 mg, 2.71 mmol)
Processed. The solution was heated at 100 ° C. for 5 days under a nitrogen atmosphere. All volatiles were removed under reduced pressure. The resulting product was purified by flash column chromatography on silica gel, eluting with chloroform / NH ₄ OH to give 110 mg (58.
1%) of the title compound. MS (APCI) m / e: 350 (M + H) ^<+> . ¹ H NMR (300 MHz, 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), 8.67 (s, 1H).

Example 267 Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfonamide To a solution of Example 124A (261 mg, 1 mmol) in THF (2 mL) was added -7.
N-BuLi (2.5 M solution in hexane, 0.60 mL
, 1.5 mmol). This was stirred at −78 ° C. for 2 hours and a rapid flow of SO ₂ was introduced to the surface of the reaction mixture. After 15 minutes, the reaction mixture was warmed to 0 ° C. while continuing to introduce SO ₂ . After 10 minutes at 0 ° C., the flow of SO ₂ was stopped and the reaction mixture was
Warmed to 0 ° C. Then, the solvent and excess SO ₂ gas were removed under reduced pressure to obtain a cream-colored solid lithium sulfinate. This material was dissolved in saturated aqueous NaHCO ₃ (1 mL) and N-chlorosuccinimide (200 mg, 1.
5 mmol). The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The product formed was extracted into CH ₂ Cl ₂ (2 × 50 mL) and water (2 × 20
mL). The dried (Na ₂ SO ₄ ) organic layer was evaporated to dryness under reduced pressure to obtain a sulfonyl chloride derivative. Part of this material (143 mg, 0.398 mmol)
Was dissolved in CH ₂ Cl ₂ (1 mL) at −5 ° C. and treated with diisopropylethylamine (0.083 mL, 0.478 mmol) and a 2M solution of methylamine in methanol (0.239 mL, 1.2 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. This was purified by flash chromatography on silica gel eluting directly with 10% acetone-hexane followed by 25% acetone-hexane to give the title compound (19 mg, 13.5%). MS (APCI) m / e: 355 (M + H) ^<+> , 353 (M-H) < ^{- >} . _6. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.57 (s, 3H),
19 (d, J = 9 Hz, 2H), 7.49 (d, J = 9 Hz, 2H), 7.76
(S, 1H), 8.16 (br, d, J = 3 Hz, 1H), 8.24 (s, 1H)
), 9.24 (s, 1H).

Example 268 2,3-Dihydroxypropyl 4- (4-chlorophenoxy) thieno [2,3-
c] Pyridine-2-sulfonamide Example 268 (8.6 mg, 7.5%) except that methylamine was replaced with 3-amino-1,2-propanediol (0.086 mL, 1.12 mmol) Was prepared as described in Example 267. MS (APCI) m / e: 415 (M + H) ⁺ , 413 (MH) ⁻ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.76 (d, J = 7.5 H).
z, 1H), 2.81 (d, J = 7.5 Hz, 1H), 3.02 (d, J = 4.
5 Hz, 1H), 3.08 (d, J = 4.5 Hz, 1H), 3.44 to 3.55
(M, 1H), 4.47 to 4.64 (m, 1H), 4.80 (d, J = 6 Hz,
1H), 7.17 (d, J = 9 Hz, 2H), 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 Example 269 (25 mg, 16%) was prepared by substituting 2- Example 26 except that hydroxyethylamine (0.072 mL, 1.2 mmol) was used.
Prepared as described in 7. MS (APCI) m / e: 385 (M + H) ^<+> , 383 (M-H) < ^{- >} . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.97 (t, J = ₆ Hz,
2H), 3.38-3.45 (m, 2H), 4.69-4.78 (m, 1H),
7.18 (d, J = 9 Hz, 2H); 7.48 (d, J = 9 Hz, 2H);
78 (s, 1H), 8.23 (s, 1H), 9.21 (s, 1H). ¹³ C NMR (75 MHz, 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- (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 s-butyllithium in cyclohexane was added at -78 ° C in THF.
(10 mL). T of Example 124A (1.00 g, 3.82 mmol)
An HF (5 mL) solution was added dropwise. The reaction was stirred for 30 minutes and tributyl borate (1.55 mL, 5.73 mmol) was added slowly. The mixture was stirred for 45 minutes while removing the cooling bath and warming to room temperature. A 2N NaOH (15 mL) solution was added. After 10 minutes, the reaction was diluted with hexane (15 mL) and the aqueous layer was collected. Organic layer is 2NNa
Extracted with OH (2 × 5 mL), combined all aqueous layers with 6N HCl to pH 2 and extracted with 10% MeOH / CH ₂ Cl ₂ (4 × 25 mL). The organic extracts were combined and concentrated. The resulting solid was washed with acetonitrile (1 × 25 mL) and dried in a desiccator to yield the title compound as a tan solid (0.83 g, 71%). MS (APCI) m / e: 262 (M + H-B (OH) ₂ ) ^<+> , m / e: 340
(M + Cl ⁻ ) ⁻ . ¹ H NMR (300 MHz, 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] anisole Example 270A (0.25 g, 0.82 mmol), 4-iodoanisole (
0.19 g, 0.82 mmol), [1,1′-bis (triphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1: 1) (
0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.46 mm)
ol), triethylamine (0.11 mL, 0.82 mmol) in DME (7 m
The mixture in L) was sucked with dry nitrogen for 10 minutes. The reaction was heated at 75 ° C. for 18 hours, then partitioned between EtOAc (100 mL) and saturated NaHCO ₃ (100 mL). The organic layer was washed with saturated NaHCO ₃ (100 mL), brine (75 mL),
Partially dried (Na ₂ SO ₄ ) and concentrated to a colored, wet solid. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to produce a colored solid. The title product was crystallized from hot acetonitrile (0.11 g, 37%). mp 121-123 ° C. MS (APCI) m / e: 368 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 2H), 8.13 (s, 1H), 9.05 (s, 1H)
H). Elemental _analysis: C ₂₀ H 14 ClNO ₂ Calculated S: C, 65.30; H, 3.84
N, 3.81. Theory: C, 65.06; H, 3.69; N, 4.05.

Example 270C 4- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] phenol Anhydrous CH ₂ Cl _{2 of} Example 270B (0.09 g, 0.24 mmol) (4m
L) To the solution was added a 1 M solution of boron tribromide in CH ₂ Cl ₂ (0.96 mL, 0.9
6 mmol) was added. After 2 hours, 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) and partially dried (
Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using ETOAc / hexane as eluent to give the solid title compound (0
. 08g, 96%). mp 213-215 ° C. MS (RSI) m / e: 354 (M + H) ^<+> . _{^{1 H NMR (300MHz, DMSO-}} d 6) 6.86 (m, 2H), 7.1
1 (m, 2H), 7.45 (m, 2H), 7.56 (s, 1H), 7.68 (m
, 2H), 8.13 (s, 1H), 9.03 (s, 1H), 9.99 (s, 1H)
). Elemental _{analysis: C 19 H 12 ClNO 2 S} , 0.5H 2 O Calculated: C, 62.90
H, 3.61; N, 3.86. Theory: 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- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] nitrobenzene Example 170A (0.25 g, 0. 82 mmol), 1-iodo-4-nitrobenzene (0.20 g, 0.82 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1:
1) (0.10 g, 0.12 mmol), cesium fluoride (0.37 g, 2.4
A mixture of 6 mmol) and triethylamine (0.11 mL, 0.82 mmol) was aspirated with anhydrous nitrogen in DME (8 mL) for 10 min. The reaction was heated at 70 ° C. for 18 hours, and EtOAc (100 mL) and saturated NaHCO ₃ (100 mL)
). The organic layer was saturated NaHCO ₃ (100 mL), brine (75 mL)
, Partially dried (Na ₂ SO ₄ ) and concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent to give the title compound as a colorless solid (0.15
g, 48%). Melting point 193-195 [deg.] C. MS (ESI) m / e: 383 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 2H), 9.17 (s, 1H). Elemental _{analysis: C 19 H 11 ClN 2 O} 3 Calculated S: C, 59.61; H, 2.9
0; 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 Example 272A (0.13 g, 0.34 mmol) in EtOH (3.5 mL) )
To the suspension was added tin (II) chloride dihydrate (0.31 g, 1.36 mmol) in concentrated HC.
1 (0.68 mL) solution was added slowly. 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 1N NaOH (1 × 50 mL), brine (1 × 50 mL), partially dried (Na ₂ SO ₄ ), and concentrated to give a colored solid (0.13 g). Crystallization from acetonitrile gave the desired product as colored crystals (0.08 g, 6
8%). MP 178-182 [deg.] C MS (APCI) m / e: 353 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.68 (brs, 2H),
6.62 (m, 2H), 7.09 (m, 2H), 7.39 (s, 1H), 7.4
4 (m, 2H), 7.51 (m, 2H), 8.11 (s, 1H), 8.97 (s
, 1H). Elemental _analysis: 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] -3-pyridinamine Example 273A 6- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -3-nitropyridine Example 273A (in the same manner as in Example 272A) using 2-bromo-5-nitropyridine instead of 1-iodo-4-nitrobenzene. 120 mg, 32%). Melting point 221-223 [deg.] C MS (APCI) m / e: 384 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (m, 2H), 7.
49 (m, 2H), 8.16 (s, 1H), 8.50 (s, 1H), 8.61 (
d, J = 8.8 Hz, 1H), 8.70 (dd, J = 8.8, 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] -3-pyridinamine Example 273B (0.07 g, 59) as in Example 272B. %) Was prepared.
MP 225-227 ° C MS (APCI) m / e: 354 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.82 (broads, 2
H), 6.92 (dd, J = 8.5, 2.6 Hz, 1H), 7.05 (m, 2H
), 7.39 (m, 2H), 7.60 (m, 1H), 7.79 (d, J = 8.5)
Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 8.04 (s, 1H)
, 8.39 (s, 1H). Elemental _analysis: 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 Example 270A (0.20 g, 0.65 mmol), 2-amino-5-bromo
Pyridine (0.11 g, 0.65 mmol), [1,1'-bis (diphenylphosphine)
Sufino) ferrocene] dichloropalladium (II) dichloromethane complex (1:
1) (0.11 g, 0.13 mmol), cesium fluoride (0.30 g, 1.9)
5 mmol), a mixture of triethylamine (0.09 mL, 0.65 mmol)
Was sucked with anhydrous nitrogen in DME (6 mL) for 20 minutes. Heat the reaction to reflux for 4 hours
And concentrated. 10% residueⁱPrOH / CHCl₃(100mL)
And filtered, and the organics are washed with saturated NaHCO₃(2 x 100 mL)
Partially dried (Na₂SO₄) And concentrated to give a crude colored solid (0.2
5g). 25% to 65% acetonitrile / water + 0.1% T over 40 minutes
Purification was performed by preparative HPLC using a concentration gradient of FA. The product is saturated NaHCO ₃ And the precipitate is filtered off and dried in a desiccator to give a pale colored solid.
To give the title compound (54 mg, 23%). 208-210 ° C MS (APCI) m / e: 254 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 6.50 (brs, 2H),
6.53 (dd, J = 8.9, 0.9 Hz, 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.
9Hz, 1H), 9.00 (s, 1H). Elemental analysis: C₁₈H₁₂ClN₃OS calc: 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-oxadiazol-2-amine Example 156 (0 .15 g, 0.47 mmol) in 1,4-dioxane (3 m
L) and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.5
0 mmol) was added. The reaction was stirred for 10 minutes and NaHCO ₃ (0.04 g
, 0.50 mmol) in water (1.4 mL) was added dropwise. 2 colored reactants
Stirred for hours and poured into saturated NaHCO ₃ (75 mL). 10% aqueous phase
Extracted with isopropanol / CHCl ₃ (4 × 25 mL). The organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated to give a solid (0.13 g). A portion of the crude was purified by HPLC using a gradient of 30% to 70% acetonitrile / water + 0.1% TFA over 40 minutes to give the title compound as a tan solid.
MP 262-263 [deg.] C MS (APCI) m / e: 345 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (m, 2H), 7.
47 (m, 2H), 7.52 (s, 1H), 7.60 (broads, 2H),
8.24 (s, 1H), 9.17 (s, 1H). _{^{13 C NMR (DMSO-d 6}} ) δ164.3,155.6,153.1,1
46.6, 141.2, 137.0, 136.9, 134.0, 131.4, 1
30.1 (2C), 127.7, 119.5 (2C), 117.5. IR (KBr) 3325, 3234, 3080, 1665, 1578, 1547
, 1486, 1411, 1287, 1257, 1229, 1203 cm ^-1 . Elemental _{analysis: C 15 H 9 ClN 4 O} 2 Calculated S: 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-2-ylamine Example 157 (0 .15 g, 0.41 mmol) in 1,4-dioxane (4 m
L), and a 5 M solution of cyanogen bromide in acetonitrile (0.10 mL, 0.1 mL).
50 mmol) was added. The reaction was stirred for 10 minutes and NaHCO ₃ (0.04
g, 0.50 mmol) in water (1.4 mL) was added dropwise. The color reaction was stirred for 3 hours and poured into saturated NaHCO ₃ (75 mL). 10 aqueous phases
Extracted with% IPA / CHCl ₃ (4 × 25 mL). The organic extracts were combined, partially dried (Na ₂ SO ₄ ), and concentrated to give a solid. 40 parts of crude
Purification by HPLC using a gradient of 30% to 70% acetonitrile / water + 0.1% TFA over a minute to afford the title compound as a tan solid. 270-273 ° C MS (APCI) m / e: 389 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.08 (m, 2H), 7.
52 (s, 1H), 7.56 (brs, 2H), 7.59 (m, 2H), 8.2
7 (s, 1H), 9.19 (s, 1H). Elemental _{analysis: C 15 H 9 BrN 4 O} 2 Calculated S: C, 46.29; H, 2.33
N, 14.39. Found: C, 46.08; H, 2.59; N, 14.12.

Example 277 5- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -4H-1,2,4-triazol-3-amine 61A (0.33 g) , 1.03 mmol) and aminoguanidine hydrochloride (3
. 45 g, 31.20 mmol) in a dry flask containing 25 wt.
A Me / MeOH (7.13 mL, 34.32 mmol) solution was added slowly. The reaction was stirred at ambient temperature for 1 hour and at 50 ° C. for 20 hours, then at 70 ° C. for 2 hours.
Heat for 4 hours. The reaction was poured into water (200 mL) and 3N HCl (
10 mL). The precipitate was collected by filtration, washed with water (2 × 20 mL) and dried in a desiccator. Crude the crude for 40 minutes from 25% to 65% acetonitrile /
Purified by preparative HPLC using a concentration gradient of water + 0.1% TFA. The product is neutralized with saturated NaHCO ₃ , the precipitate is filtered off and dried in a desiccator,
The title compound was obtained as a white solid (0.16 g, 45%). Melting point> 270 ° C MS (APCI) m / e: 344 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.46 (brs, 2H),
7.27 (m, 2H), 7.58 (m, 2H), 7.67 (s, 1H), 8.3
1 (s, 1H), 9.21 (s, 1H). Elemental _analysis: 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-Thiadiazol-2-amine Example 88 (0.36 g, 1.18 mmol) was suspended in thionyl chloride (4 mL).
It became cloudy and the suspension was heated at 45 ° C. for 2 hours. The reaction was concentrated and the residue was₂Cl ₂ (2 × 5 mL) and concentrated to give a colored solid. DM the crude solid
F (5 mL) and thiosemicarbazide (2.69 g, 29.50 mmol)
) Was added and the reaction was stirred for 24 hours. Pour the reaction into water (250 mL)
And the aqueous suspension was washed with saturated NaHCO₃PH> 7 with aqueous solution (10 mL)
Processed. Collect the precipitate, wash with water (2 × 20 mL) and desiccator
Dried in to give the corresponding acyl semicarbazate as a solid (0.30 g
) [MS (APCI) m / e: 377 (M + H)⁺]. Crude (0.20 g)
Suspended in toluene (2 mL), methanesulfonic acid (0.10 mL, 1.60 mm
ol) was added. The reaction was heated at reflux for 4 hours and cooled to room temperature. Uneven
Dilute one mixture with hexane (5 mL) and remove solvent by decantation
Thus, a colored residue was obtained. Triturate the residue with hexane (2 × 10 mL) and dry under vacuum
did. The solid is suspended in water (15 mL) and NH 9 until pH 9₄Treated with OH
. The precipitate was collected and washed with water (2 × 5 mL). Use acetone as eluent
Crude was partially purified on silica gel by flash chromatography
. 25% -65% acetonitrile / water + 0.1% TF over 40 minutes
Further purification by preparative HPLC using a concentration gradient of A. The product is saturated NaHC
O₃Neutralize with aqueous solution, filter precipitate and dry in desiccator, tan
The title compound was obtained as a solid (0.04 mg, overall yield 14%). Melting point> 270 ° C MS (APCI) m / e: 361 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆6.) δ 7.15 (m, 2H);
46 (m, 2H), 7.68 (s, 1H), 7.75 (brs, 2H), 8.1
1 (s, 1H), 9.06 (s, 1H). Elemental analysis: C_FifteenH₉ClN₄OS₂Calculated: C, 49.93; H, 2.51
N, 15.53. Found: C, 49.82; H, 2.64; N, 15.58.

Example 279 4- (4-Chlorophenoxy) -2- (5-methyl-1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Obtained from Example 249 A solution of the obtained compound (160 mg, 0.5 mmol) in pyridine (2.0 mL) was added to acetyl chloride (50 mL, 0.55 mm) in nitrogen at ambient temperature.
ol) and heated to reflux for 15 hours. The resulting dark yellow homogeneous solution was diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ), filtered through silica and concentrated to give 169 mg of an off-white powder Was.
This solid was flash chromatographed on silica gel using 30-50% ethyl acetate / hexane to give the title compound (150 mg, 87%). _{Mp: 120~121 ℃ MS (APCI-NH} 3) m / e: 344 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (s, 1 H), 8.
27 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.16 (
d, 2H), 2.69 (s, 3H). Elemental _{analysis: C 16 H 10 ClN 3 O} 2 Calculated S: C, 55.90; H, 2.9
3; N, 12.22. Found: C, 56.10; H, 3.16; N, 12.01.
.

Example 280 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridin-2-yl] -1,3,4-oxadiazol-2-amine Example 158 was treated according to the method of Example 275 to give the title compound. MS (APCI) m / e: 358.9 (M + H) ^<+> . ^{1 H NMR (300MHz, DMSO-} d 6) δ7.22 (d, 2H), 7.
51 (s, 1H), 7.60 (s, 2H), 7.79 (d, 2H), 8.40 (
s, 1H), 9.25 (s, 1H).

Example 281 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
4-oxadiazol-2-yl] thieno [2,3-c] pyridine Example 281A 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1, 3,4-oxadiazole-2-thiol The compound from Example 156 (100 mg, 0.31 mmol) was treated with ethanol (
2 mL) and cooled to 0 ° C. Carbon disulfide (0.04 mL, 0.71 m
mol), followed by potassium hydroxide (20 mg, 0.31 mmol).
The reaction was stirred for 1 hour and the cold bath was removed. After 1 hour at ambient temperature, the reaction was refluxed for 3 hours and concentrated to a solid. The crude solid was added to chloroform (1 × 5 m
Triturated in l) and concentrated. The residue was dissolved in water (15ml) and acidified with formic acid.
The resulting precipitate was filtered off, washed with water (2 × 15 ml) and dried in a desiccator to give the title compound (106 mg, 94%). Melting point: 236-240 ° C MS (ESI) m / e: 362 (M + H) ⁺ . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 7.15 (m, 2H), 7.4
6 (m, 2H), 7.65 (m, 1H), 8.24 (s, 1H), 9.18 (s
, 1H). Elemental _{analysis: C 15 H 8 ClN 3 O} 2 S 2 Calculated: C, 47.89; H, 2.5
7; N, 11.17. Found: C, 47.89; H, 2.49; N, 10.97.
.

Example 281B 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
To a suspension of 4-oxadiazol-2-yl] thieno [2,3-c] pyridine 281A (100 mg, 0.28 mmol) in THF (1 ml) at 0 ° C. with stirring, was added a 1M aqueous sodium hydroxide solution (0%). .28ml, 0.28mmo
l) was added. After 30 minutes all solids dissolved and iodomethane (0.02 ml,
0.31 mmol) was slowly added dropwise. The reaction was stirred for 30 minutes and water (8
ml) was added. The solid was collected by filtration, washed with water (2 × 15 ml) and dried in a desiccator to give 80 mg of a pale 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 (41mg, 39%). Melting point: 158-160 <0> C MS (ESI) m / e: 376 (M + H) ^<+> . ¹ H NMR (300 MHz, CD ₂ Cl ₂ ) δ 2.75 (s, 3H), 7.0
1 (m, 2H), 7.33 (m, 2H), 7.91 (s, 1H), 8.12 (s
, 1H), 8.93 (s, 1H). Elemental _{analysis: 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, 10.8.
9.

Example 282 4- (4-Chlorophenoxy) -2- (2-methyl-1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Example 282A 4- (4-Chlorophenoxy) -2- (1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Toluene of the compound (90 mg, 0.314 mmol) obtained in Example 248 (1.5 mL) solution at room temperature under nitrogen with dibutyltin oxide (8 mg, 0.1 mL).
031 mmol), trimethylsilyl azide (125 mL, 0.942 mmol)
), Heated to reflux for 24 hours and stirred at room temperature for another 2.5 days. The resulting yellow heterogeneous mixture was concentrated and flash chromatographed with 20% methanol / dichloromethane to give 105 mg of a pale yellow powder. This powder was dissolved in ethyl acetate and extracted with 10% NaHCO ₃ (twice), the aqueous extracts were combined,
Acidify to pH 2 with N HCl, extract with ethyl acetate, dry (Na ₂ SO ₄ ) and concentrate to give the title compound as a white powder (63 mg, 61%).
. ^{_{Mp: 250~254 ℃ MS (APCI-NH}} 3) m / e: 330 (M + H) + 1 H NMR (300MHz, DMSO-d 6) δ9.26 (s, 1H), 8.
27 (s, 1H), 8.01 (s, 1H), 7.48 (d, 2H), 7.19 (
d, 2H). Elemental _{analysis: 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 4- (4-Chlorophenoxy) -2- (2-methyl-1,2,3,4-tetrazol-5-yl] thieno [2,3-c] pyridine Obtained according to Example 282A. A solution of the compound obtained (100 mg, 0.3 mmol) in methanol (4 mL) was treated with diazomethane (
Treatment with diethyl ether and N-methyl-N'-nitro-N-nitrosoguanidine in 40% KOH) until the yellow color persists for more than 5 minutes, stir for an additional 15 minutes, until the yellow color disappears (gassing vigorously). Glacial acetic acid (as evolved) was quenched by slow dropwise addition and concentrated. Reverse phase silica gel pale yellow solid thus obtained was with 5% methanol / dichloromethane and filtered through silica gel and using a 25 to 65% _CH 3 CN in 0.1% TFA / water with 0.1% TFA (Dy
Flash chromatography was performed on a C.I. namax 21.4 mm C-18 column) to give the title compound as a white powder (40 mg, 39%). ^{_{Mp: 131~133 ℃ MS (APCI-NH}} 3) m / e: 344 (M + H) + 1 H NMR (300MHz, DMSO-d 6) δ9.25 (s, 1H), 8.
28 (s, 1H), 7.89 (s, 1H), 7.48 (d, 2H), 7.18 (
d, 2H), 4.47 (s, 3H). Elemental _{analysis: C 15 H 10 ClN 5 OS} 0.25H 2 O Calculated: C, 51.7
H; 3.04; N, 20.11. Found: C, 51.74; H, 2.93;
N, 19.93.

Example 283 5- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -4-methyl-4H-1,2,4-triazol-3-amine water Sodium oxide (60% in oil, 0.02 g, 0.42 mmol) at 0 ° C
Was suspended in DMF (1 mL). Example 277 (0.11 g, 0.32 mm
ol) 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 minutes the reaction was quenched with water (
75 mL). The resulting precipitate was collected by filtration and washed with water (1 × 20 mL) and 50% EtOAc / hexane (2 × 25 mL). The crude solid was dried to give a colored solid (0.11 g). The title compound was isolated by preparative HPLC using a gradient of 25% to 65% acetonitrile / water + 0.1% TFA over 40 minutes. The product was neutralized with saturated aqueous NaHCO ₃ and the precipitate was collected by filtration and dried in a desiccator (31 mg, 27%). ^{Mp: 233~235 ℃ MS (APCI) m} / e: 358 (M + H) + 1 H NMR (300MHz, DMF-d 7) δ3.75 (s, 3H), 6.5
8 (brs, 2H), 7.23 (m, 2H), 7.54 (m, 2H), 7.61
(S, 1H), 8.27 (s, 1H) 9.18 (s, 1H). Elemental _analysis: 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 4- (4-Chlorophenoxy) -2- [5- (trifluoromethyl) -1,2,2
4-oxadiazol-3-yl] thieno [2,3-c] pyridine Pyridi of the compound obtained from Example 249 (100 mg, 0.31 mmol)
Trifluoroacetic anhydride (50 mL, 0.1 mL) in nitrogen at room temperature.
31 mmol), stirred for 20.5 hours and heated to reflux for 3 hours.
Dilute the brown solution with ethyl acetate and add saturated NaHCO 3₃, Washed with saline and dried (
MgSO₄), Concentrate and concentrate with 50/50 hexane / ethyl acetate.
Filter through Kagel and concentrate to give 120 mg of a yellow residue. This residue
20-33% ethyl acetate / hexane and 0-1% methanol / CH₂Cl₂To
Chromatography on silica gel twice using as a white solid
The title compound was obtained (67 mg, 54%). Melting point: 52-54 ° C MS (APCI-NH₃) M / e: 398 (M + H)⁺, 416 (M + NH₄) ⁺ .¹ 1 H NMR (300 MHz, DMSO-d₆7.) δ 9.30 (s, 1H);
29 (s, 1H), 8.10 (s, 1H), 7.48 (d, 2H), 7.20 (
d, 2H). Elemental analysis: C₁₆H₇ClF₃N₃O₂S 0.25 H₂Calculated value of O: C, 4
7.77; 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-Oxadiazol-3-amine Methanol of the compound (100 mg, 0.3 mmol) obtained from Example 250
(1.5 mL) solution in hydroxylamine hydrochloride (40 m
g, 0.45 mmol) and triethylamine (70 mL, 0.5 mmol).
And stirred for 18 hours, added 4 mL of THF and stirred for 2 days,
Conversion to 0/50 dichloromethane / methanol, followed by hydroxylamine hydrochloride
(100 mg, 1.4 mmol) and triethylamine (200 mL, 2.7
mmol) was added, stirred at ambient temperature for 24 hours and refluxed for 8 hours. Anti
The reaction mixture was diluted with ethyl acetate and diluted with NaHCO₃, Washed with saline and dried (M
gSO₄) And concentrated to give 105 mg of an off-white solid. Get
0.1% TFA / H containing 0.1% TFA₂25-65% CH in O ₃ CN followed by 0.1% TFA / H with 0.1% TFA₂20-80% in O
CH₃Reversed phase silica gel using CN (Dynamax 21.4 mm C-18)
Column) twice to give the title compound as a white powder.
(26 mg, 25%). Melting point: 217-219 ° C MS (APCI-NH₃) M / e: 345 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆7.) δ 9.26 (s, 1H);
25 (s, 1H), 8.02 (s, 1H), 7.49 (d, 2H), 7.14 (
d, 2H), 6.62 (brs, 2H). Elemental analysis: C_FifteenH₉ClN₄O₂Calculated value of S: C, 52.25; H, 2.63
N, 16.25. Found: C, 51.94; H, 2.88; N, 15.98.

Example 286 of 5- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -N-methyl-1,3,4-thiadiazol-2-amine thiosemicarbazide The title compound (4% overall yield) was prepared in the same manner as in Example 278 using 4-methylthiosemicarbazide instead. Melting point: 226-229 [deg.] C MS (APCI) m / e: 375 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.95 (d, J = 1.7 H
z, 3H), 7.14 (m, 2H), 7.45 (m, 2H), 7.69 (s, 1
H), 8.17 (s, 1H), 8.19 (brm, 1H), 9.07 (s, 1H)
). Elemental _{analysis: C 16 H 11 ClN 4 OS} 2 Calculated: C, 51.27; H, 2.9
6; N, 14.95. Found: C, 51.24; H, 3.03; N, 14.85.
.

Example 287 4- (4-Chlorophenoxy) -2- (1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Example 287A 4- (4-chloro) Phenoxy) -N ′-(diethoxymethoxy) thieno [2,3
-C] Pyridine-2-carboximimidamide A solution of the compound obtained in Example 249 (100 mg, 0.31 mmol) in triethyl orthoformate (1.3 mL) was placed in nitrogen at 140 ° C. for 5 hours and 160 ° C. for 2 hours.
And stirred at room temperature for 14 hours. The obtained pale yellow oil (110 mg) was added to 2
Flash chromatography on silica gel using 0-70% ethyl acetate / hexane provided 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) δ9.05 (s, 1H), 8.
15 (s, 1H), 7.97 (s, 1H), 7.46 (d, 2H), 7.10 (
d, 2H), 6.65 (brs, 2H), 5.66 (s, 1H), 3.62-3
. 71 (m, 4H) 1.15 (t, 6H).

Example 287B 4- (4-Chlorophenoxy) -2- (1,2,4-oxadiazol-3-yl) thieno [2,3-c] pyridine Compound obtained from Example 287A ( A solution of 50 mg (0.119 mmol) in toluene (6 mL) was heated to reflux in nitrogen for 20 hours and cooled and concentrated. The yellow residue (46 mg) was flash chromatographed on silica gel using 25-50% ethyl acetate / hexane to give the title compound as a white solid (
39 mg, 100%). Analytical HPLC: 4.6 x 250 mm C-18 column, 0.8 mL / min, 254
nm, _CH containing _{0.1% TFA 3 CN: H 2} O, 0: 100 (0~3 minutes), 9
Slope to 0:10 (3-30 minutes), 90:10 (30-35 minutes), 0:10
Slope to 0 (35-40 minutes), Rt = 22.47 minutes (100% peak area)
_{Mp: 151~152 ℃ MS (APCI-NH} 3) m / e: 330 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.86 (s, 1 H), 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 Example 183 (100 mg) , 0.283 mmol) of triethyl orthoformate (
15 mL) solution was heated to reflux under a nitrogen atmosphere for 28 hours. All volatiles were removed under reduced pressure. The resulting oil was purified by flash column chromatography using hexane / ethyl acetate (2: 1) as eluent to give the title compound as a colorless oil (65 mg, 63%). This oil solidified on standing. MS (ESI) m / e: 364 (M + H) ^<+> . ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.14 (d, 2H), 7.66
(D, 2H), 8.05 (s, 1H), 8.24 (s, 1H), 8.50 (s, 1H)
1H), 9.07 (s, 1H). Elemental _analysis: Calculated for _{C 16 H 8 N 3 F 3} O 2 S: C, 52.89; H, 2.22
N, 11.57. Found: C, 53.03; H, 2.25; N, 11.48.

Example 289 3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine Example 289A 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -5- (trichloromethyl-1,2,4-oxadiazole The compound obtained from Example 249 (50 mg, 0.156 mmol) in trichloroacetyl chloride (20 mL) in nitrogen at ambient temperature.
, 0.17 mmol), heated to reflux for 1.5 hours, cooled to room temperature, stirred overnight, further treated with trichloroacetyl chloride (100 mL, 0.86 mmol) and stirred for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated. The resulting brown residue was flash chromatographed on silica gel using 25-50% ethyl acetate / hexane to give the title compound as a clear residue (37m
g, 53%). _{MS (APCI-NH 3) m} / e: 448 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1 H),
24 (s, 1H), 8.09 (s, 1H), 7.46 (d, 2H), 7.18 (
d, 2H).

Example 289B 3- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,2,4-oxadiazol-5-amine Obtained from Example 289A. Of the obtained compound (30 mg, 0.067 mmol).
A 0 M ammonia solution in methanol (6 mL) was heated to 60 ° C. under a pressure tube for 15 hours and cooled to ambient temperature, washing the flask with methanol and distilled water. Most of the methanol was removed under vacuum, the cloudy mixture was filtered and washed with distilled water. The resulting 25 to 65% and reverse phase silica gel using 20 to 80% _CH 3 CN in a yellow brown solid in 0.1% TFA / water containing 0.1% TFA (Dyn
flash chromatography twice on an Amax C-18 21.4 mm column) to give the title compound as a white solid (4 mg, 17%). Analytical HPLC: 4.6 x 250 mm C-18 column, 0.8 mL / min, 254
nm, _CH containing _{0.1% TFA 3 CN: H 2} O, 0: 100 (0~3 minutes), 9
Slope to 0:10 (3-30 minutes), 90:10 (30-35 minutes), 0:10
Slope to 0 (35-40 minutes), Rt = 19.44 minutes (100% peak area)
_{Mp: 268~270 ℃ MS (APCI-NH} 3) m / e: 345 (M + H) +. 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (s, 1 H),
27 (s, 1H), 8.22 (brs, 2H), 7.67 (s, 1H), 7.4
7 (d, 2H), 7.15 (d, 2H).

Example 290 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4- (
The title compound was prepared as described in Example 288 using triethyl orthoacetate as the solvent. Reflux was maintained for 5 days, giving a 29% yield. MS (APCI) m / e: 377 (M + H) ^<+> . ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.65 (s, 3H), 7.13
(D, 2H), 7.65 (d, 2H), 7.94 (s, 1H), 8.27 (s,
1H), 9.06 (s, 1H).

Example 291 4- (4-Chlorophenoxy) -2- (2-furyl) thieno [2,3-c] pyridine Example 270A (0.30 g, 0.98 mmol), 2,5-dibromofuran (0.66 g, 2.94 mmol), cesium fluoride (0.45 g, 2.94 m)
mol), triethylamine (0.14 mL, 0.98 mmol)
In ME (9 mL), the mixture was sucked with anhydrous nitrogen for 25 minutes, and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1
: 1) (0.16 g, 0.20 mmol) was added. The reaction was heated at reflux for 4 hours and stirred at ambient temperature overnight. The reaction was diluted with EtOAc (100 mL) and filtered. The organic layer was washed with saturated NaHCO ₃ (3 × 50 mL), brine (75 mL)
Washed with), partially dried _(Na 2 SO _4), and concentrated to give a colorless 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 is called EtO
H (10 mL) and 5% Pd / C (3 mg, 0.02 mmol) was added. A balloon of hydrogen gas was attached and the reaction 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 combined filtrate and washings were concentrated to give a colored wet foam. Run the crude for 40 minutes 30% -70% acetonitrile / water + 0
. Purified by preparative HPLC using a concentration gradient of 1% TFA. The product is saturated with N
Neutralized with aHCO ₃ , the precipitate was collected by filtration and dried in a desiccator to give the title compound as a pale colored solid (15 mg, 5% overall yield). Melting point: 75-77 [deg.] C MS (APCI) m / e: 328 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.70 (dd, J = 3.4)
, 1.7 Hz, 1H), 7.12 (m, 2H), 7.24 (d, J = 3.4 Hz)
, 1H), 7.46 (m, 2H), 7.59 (s, 1H), 7.88 (d, J =
1.7 Hz, 1H), 8.16 (s, 1H) 9.08 (s, 1H).

Example 292 4- (4-Chlorophenoxy) -2- (2-thienyl) thieno [2,3-c] pyridine Example using 2-iodothiophene instead of 1-iodo-4-nitrobenzene. Example 292 (50 mg, 22%) was prepared as for 272A. Melting point: 101-103C MS (APCI) m / e: 344 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (m, 2H), 7.
19 (dd, J = 5.0, 3.4 Hz, 1H), 7.46 (m, 2H), 7.5
4 (d, J = 0.9 Hz, 1H), 7.67 (dd, J = 3.4, 1.3 Hz,
1H), 7.73 (dd, J = 5.0, 1.3 Hz, 1H) 8.14 (s, 1H)
) 9.05 (s, 1H). Elemental _{analysis: 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-4-carboxamide Example 293A 2- [4- ( Ethyl 4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazole-4-carboxylate Ethyl bromopyruvate (390 mL, 2.30 mmol) was prepared in Example 146 (
672 mg, 2.09 mmol) and absolute ethanol (100 mL) and the orange homogeneous solution was heated to 60 ° C. After 48 hours, the mixture was cooled to ambient temperature and concentrated in vacuo. Purification was done by flash silica gel chromatography (15% acetone in hexane) to give the title compound as a white solid (297 mg, 34% yield). ^{_{MS (DCI / NH 3) m}} / e: 417 (35 Cl) / 419 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.94 (s, 1 H), 8.24
(S, 1H) 8.12 (s, 1H) 7.88 (s, 1H) 7.36 (d, J = 8
. 8 Hz, 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-4-carboxamide Example 293A (32 mg, 77 mmol) Methanol (2.0M solution 4m
L) Combined with the ammonia in and the solution was heated to 40 ° C. in a sealed tube. After 16 hours, the homogeneous solution was cooled to room temperature and concentrated to give a brown solid which was dry-packed on flash silica gel eluting with 20% acetone in hexane followed by 40% acetone in hexane to afford the title compound. Was recovered (8 mg, 27% yield). Mp _{215~218 ℃ MS (DCI / NH 3} ) m / e: 388 (M + H) / 405 (M + NH 3), 4
_{^{07 (37 Cl + NH 3)}} . ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.67 (brs, 2H), 7.
06 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H),
8.09 (s, 1H), 8.25 (s, 1H), 8.94 (s, 1H).

Example 294 tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] -1,3-thiazol-4-ylcarbamate Example 293 Conversion to the corresponding carboxylic acid was performed in a similar manner as described in Example 18. To a mixture of carboxylic acid (40 mg, 0.10 mmol), tert-butanol (10 mL) and triethylamine (20 μL, 0.10 mmol) was added diphenylphosphoryl azide (25 μL, 0.10 mmol),
The solution was heated to 80C. After 18 hours, the solution was cooled and concentrated. The yellow residue was dissolved in CH ₂ Cl ₂ (30 mL), 0.5N aqueous HCl (40 mL), saturated Na
Washed sequentially with an aqueous HCO ₃ solution (25 mL) and brine (25 mL). The combined aqueous washes were back-extracted with CH ₂ Cl ₂ (2 × 25 mL). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated to give a yellow residue. Flash silica gel flash column chromatography (15% acetone in hexane)
Gave the title compound as a lighter yellow solid (13 mg, 28% yield). ^{MS (APCI) m / e:} 460 (35 Cl) / 462 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.91 (s, 1 H), 8.11
(S, 1H), 7.71 (s, 1H), 7.35 (d, J = 8.9 Hz, 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-4-amine trifluoroacetic acid (0.5 mL) Example 294 (9.0 mg, 20 μmol) was added at 0 ° C. in CH ₂ Cl ₂ (1.5 mL). After 1 hour, remove volatiles,
The organic residue was dissolved in 0.5N aqueous HCl (35 mL). The aqueous phase was extracted with Et ₂ O (
10 mL) and the ether washes were extracted with 1N HCl (2 × 20 mL). The acidic layers are combined, and a saturated aqueous solution of potassium carbonate is made basic (pH> 12).
). The basic phase was extracted with EtOAc (3 × 40 mL), the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give a dark brown solid (9 mg). Purification by flash silica gel column chromatography (20% acetone in hexane) provided the title compound as a bright yellow solid (
6.8 mg, 97% yield). Mp 168-170 ° C. ^{(decomposition) MS (APCI) m / e} : 360 (35 Cl) / 362 (37 Cl). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.90 (s, 1 H), 8.11
(S, 1H), 7.68 (s, 1H), 7.35 (d, J = 9.2 Hz, 2H)
, 7.02 (d, J = 8.9 Hz, 2H), 6.07 (s, 1H), 3.89 (
brs, 2H).

Example 296 4- (4-chlorophenoxy) -2- (4,5-dihydro-1,3-oxazoline
Ru-2-yl) thieno [2,3-c] pyridine Example 150 (0.14 g, 0.38 mmol) in anhydrous dichloromethane (4 m
L) In the solution, 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU
) (0.09 mL, 0.57 mmol) was added. The reaction was stirred for 24 hours,
An excess of morpholine (0.2 mL) was added to react with the remaining starting material.
The reaction was stirred for 4 hours and EtOAc (100 mL) and H₂O (100 mL
) And liquid separation. The organic layer is diluted with NaH₂PO₄(100 mL), saturated NaHCO ₃ (100 mL), washed with brine (100 mL) and partially dried (Na₂SO ₄ ) And concentrated to give a solid. EtOAc / hexane as eluent of crude product
Purification by flash chromatography using the title compound as a solid
(0.07 g, 55%). 158-160 ° C (decomposition) MS (APCI) m / e: 331 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 4.01 (t, J = 9.6H)
z, 2H), 4.48 (t, J = 9.6 Hz, 2H), 7.14 (m, 2H),
7.47 (m, 2H), 7.62 (s, 1H), 8.24 (s, 1H), 9.1
9 (s, 1H). Elemental analysis: C₁₆H₁₁ClN₂O₂Calculated S: C, 58.09; H, 3.3
5; N, 8.47. Found: C, 58.16; H, 3.31; N, 8.27.

Example 297 4- (4-Chlorophenoxy) -2- (1,3-oxazol-2-yl) thieno [2,3-c] pyridine The method of Ishibashi et al. (Tetrahedron Lett. 1996, 3
7 (17), pp. 2997-3000) to give the title compound from Example 296.

Example 298 4- (4-Chlorophenoxy) -2- (4,5-dihydro-1H-imidazol-2-yl) thieno [2,3-c] pyridine Example 154 (0.15 g, 0 .43 mmol) and calcium oxide (0.4%).
12 g, 2.15 mmol) of a phenyl ether (10 mL) suspension
Heated to 250 ° C. The reaction was stirred for 45 minutes, during which time the reaction volume decreased due to evaporation of the solvent. The reaction was cooled to room temperature and 10% MeOH / dichloromethane (2
5 mL) and filtered. Concentrate the filtrate and concentrate the residue in 40 minutes for 30%
Preparative HPLC using a concentration gradient of ９０90% acetonitrile / water + 0.1% TFA
And purified. The fractions containing the product were combined, neutralized with saturated NaHCO _3. The product crystallized on standing for 3 days, was filtered off and dried in a desiccator,
The title compound was obtained as tan needles (23 mg, 16%). Melting point: 154-155 [deg.] C MS (APCI) m / e: 330 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.46 (td, J = 9.9)
, 1.7 Hz, 2H), 3.83 (t, J = 9.9 Hz, H), 7.12 (m,
2H), 7.34 (brs, 1H), 7.46 (m, 2H), 7.81 (s, 1
H), 8.17 (s, 1H), 9.11 (s, 1H). Elemental _analysis: 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 4- (4-Chlorophenoxy) -2- (1H-imidazol-2-yl) thieno [2,3-c] pyridine Zimmerman, S.A. C. The title compound can be synthesized from Example 298 according to the method of J. Org. Chem. 1989, 54 (6), 1256-1264.

Example 300 4-Chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide Method of Example 125 from the corresponding 4-chloromethyl ester isolated as a by-product of Example 125A To prepare Example 300. _{MS (DCI / NH 3) m} / e: 227 (M + H) +. 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H),
95 (d, 2H), 7.57 (d, 2H), 7.90 (b, 1H), 8.00 (
b, 1H), 8.27 (s, 1H), 9.15 (s, 1H).

Example 301 3-Amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide From the crude mixture of Example 131B, 3-amino-4-chlorothieno [2,3-c
] Methyl pyridine-2-carboxylate was isolated. The mixture was hydrolyzed as described in Example 18 and the resulting acid was reacted with ammonium chloride using the method in Example 92. After the reaction mixture was poured into 5% aqueous sodium bicarbonate and precipitated, 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 ) δ 7.01 (brs, 2H),
7.49 (brs, 2H), 8.42 (s, 1H), 9.11 (s, 1H).

Example 302 9- (4-Chlorophenoxy) pyrido [4 ′, 3 ′: 4,5] thieno [3,2-
d] Pyrimidine-2,4 (1H, 3H) -dione Example 131D (70 mg, 0.22 mmol) in anhydrous tetrahydrofuran (
5 mL) was added to a suspension of 1,1-carbonyldiimidazole (71
mg, 0.44 mmol) and triethylamine (60 μL, 0.44 mmol)
l) was added. The reaction mixture was stirred at reflux for 48 hours and at ambient temperature for a further 24 hours. The reaction mixture was poured into a 1: 1 solution of water: sat. NH ₄ Cl and the resulting solid was collected by filtration. This material was purified by flash chromatography on silica gel eluting with 20% acetone-hexane. The desired fractions were combined, evaporated and suspended in hot EtOAC to give the title compound (39m
g) was obtained in 51% yield. MS (APCI) m / e: (M-H) - 344. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.32 (m, 2H), 7.
55 (m, 2H), 7.92 (s, 1H), 9.09 (s, 1H), 11.22
(Brs, 1H), 11.72 (brs, 1H). HPLC: Supelco C-18 column, water: acetonitrile 0: 90-9
0: 0, 30 minutes elution, flow rate 0.8 mL / min, room temperature 20.33 minutes.

Example 303 4- (4-Chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridine-2-carboxamide Example 125A was prepared in the same manner as in Example 218 to obtain the title compound. Was. _{MS (DCI / NH 3) m} / e: 333 (M + H) +. ¹ H NMR (300 MHz, 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, 1H), 9.18 (s, 1H).

Example 304 4- (4-Bromophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Carboxamide Example 17A and 4-bromophenol were treated as in Example 125,
The title compound was obtained. Mp _{177~178 ℃ MS (DCI / NH 3} ) m / e: 364 (M + H) +. 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H),
95 (d, 2H), 7.57 (d, 2H), 7.90 (m, 1H), 8.00 (
m, 1H), 8.27 (s, 1H), 9.15 (s, 1H). Elemental _{analysis: C 15 H 11 BrN 2 O} 2 Calculated S: C, 49.60; H, 3.0
5; N, 7.71. Found: C, 49.36; H, 3.24; N, 7.61.

Example 305 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 305A 4- (4-chlorophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Methyl carboxylate, N-oxide Example 125A was prepared according to the method of Example 123A to give the title compound.
_{MS (DCI / NH 3) m} / e: 350 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.78 (s, 3H), 3.
88 (s, 3H), 7.28 (m, 2H), 7.51 (m, 2H), 7.68 (
brs, 1H), 8.92 (brs, 1H).

Example 305B 7-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Example 305A was prepared according to the method of Example 1C to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 31.64 minutes. _{MS (DCI / NH 3) m} / e: 368 (M + H) +. ¹ H NMR (300 MHz, 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-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Example 305B was prepared according to the method of Example 18 using tetrahydrofuran instead of isopropanol pyridine-2-carboxylate to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 27.25 min. MS (APCI) m / e: 354 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.72 (s, 3H), 7.
16 (m, 2H), 7.49 (m, 2H), 8.01 (s, 1H).

Example 305D 7-Chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 305C was prepared according to Example 92 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 24.75 min. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. _6. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.58 (s, 3H),
10 (m, 2H), 7.47 (m, 2H), 8.0 (brs, 1H), 8.02
(S, 1H), 8.03 (brs, 1H).

Example 306 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Tert-Butyl pyridine-3-carboxylate Example 306A tert-butyl 3,5-dichloropyridine-4-oxalate Example 17A except for using t-butyl chlorooxalate instead of methyl formate.
To give the title compound. _{MS (DCI / NH 3) m} / e: 241 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.5 (s, 9H), 8.8
5 (s, 2H).

Example 306B 2- (methoxycarbonyl) -4- (4-chlorophenoxy) thieno [2,3-
c] tert-Butyl pyridine-3-carboxylate treating Example 306A and 4-chlorophenol analogously to Example 61,
The title compound was obtained. _{MS (DCI / NH 3) m} / e: 420 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42 (s, 9H);
95 (s, 3H), 7.18 (d, 2H), 7.50 (d, 2H), 8.05 (
s, 1H), 9.20 (s, 1H).

Example 306C 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Tert-Butyl pyridine-3-carboxylate Example 306B was prepared in the same manner as in Example 217 to obtain the title compound. _{MS (DCI / NH 3) m} / e: 405 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.35 (s, 9H), 7.
10 (d, 2H), 7.45 (d, 2H), 7.95 (m, 1H), 8.08 (
s, 1H), 8.14 (m, 1H), 9.18 (s, 1H).

Example 306D 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridine-3-carboxylic acid Example 306C (0.08 g, 0.2 mmol) was treated with trifluoroacetic acid (0.5
mL) and a cold solution of methylene chloride (0.5 mL) and stirred for 1 hour.
The solution was concentrated, treated slowly with a cold solution of sodium bicarbonate (20 mL), and the mixture was extracted with ethyl acetate (3 × 20 mL). The ethyl acetate extract was dried and concentrated to give the title compound. _{MS (DCI / NH 3) m} / e: 349 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 4- (4-Toluidino) thieno [2,3-c] pyridine-3-carboxamidomethyl Example 93C (271 mg, 1 mmol), 4-methylaniline (150 mg)
, 1.4 mmol), sodium t-butoxide (134.5 mg, 1.4 mm)
ol), 18-crown _{-6 (370mg, 1.4mmol), Pd} 2 (dba
) ₃ (46mg, 5mol%) and BINAP (31 mg, a mixture of 5 mol%), a reflux condenser was adjusted to 3 neck round bottom flask equipped with an internal temperature probe and _{N 2} inlet. This was evacuated under nitrogen and anhydrous tetrahydrofuran (5 mL) was added. The reaction mixture was warmed at 45 ° C. for 3 days, and the solid was filtered through celite and washed with a mixture of ethyl acetate and acetone. The filtrate was washed with ethyl acetate (100 m
L), washed with brine (2 × 50 mL), dried (MgSO ₄ ), concentrated and dried under reduced pressure. Flash chromatography on silica gel eluting with 30% acetone-hexane gave the title compound in 29% yield (86 mg).
I got it. _{MS (DCI / NH 3) m} / e: 298 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), 2.
80 (d, J = 6 Hz, 3H), 7.02 (d, J = 9 Hz, 2H), 7.10
(D, J = 9 Hz, 2H), 8.13 (s, 1H), 8.26 (s, 1H), 8
. 36 (m, 1H), 8.76 (brs, 1H). ¹³ C NMR (75 MHz, 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 4-chloroaniline instead of 4-methylaniline (510 mg, 4 mmol
), And the title compound (500 mg, 84%) was prepared in the same manner as in Example 307 except that the reaction was heated to 60 ° C for 20 hours. MS (APCI) m / e: 318 (M + H) ^<+> , 352 (M + Cl) < ^- >. _{^{1 H NMR (400MHz, DMSO-}} d 6) d: 2.83 (d, J = 4Hz
, 3H), 7.07 (d, J = 9 Hz, 2H), 7.32 (d, J = 9 Hz, 2H)
H), 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 (100 MHz, DMSO-d ₆ ) δ 26.3 (CH ₃ ), 11
8.1 (2 × CH), 121.7 (CH), 123.6 (C), 129.1 (2
× CH), 133.0 (CH), 134.4 (C), 137.1 (C), 137
. 2 (C), 138.2 (CH), 142.6 (C), 143.2 (C), 16
1.4 (C).

Example 309 Example 308 except that morpholine (0.175 mL, 2 mmol) was used instead of 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamidomethyl 4-chloroaniline The title compound (105 mg, 38%) was prepared in the same manner as described above. MS (APCI) m / e: 278 (M + H) ^<+> , 312 (M + Cl) < ^- >. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.91 (d, J = 4 Hz,
3H), 3.23 (m, 4H), 3.91 (m, 4H), 8.14 (s, 1H)
, 8.18 (s, 1H), 8.96 (s, 1H), 8.99 (d, J = 4 Hz,
1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 26.1 (CH ₃ ), 51
. 6 (2 × CH 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 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 311A 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Methyl carboxylate Example 61A was prepared as in Example 1C to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 30.35 min. _{MS (DCI / NH 3) m} / e: 354 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
14 (m, 2H), 7.45 (m, 2H), 7.91 (s, 1H), 8.24 (
s, 1H), 9.21 (s, 1H).

Example 311B 7-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 311A was prepared according to the method of Example 44 to give the title compound. _{MS (DCI / NH 3) m} / e: 339 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.20 (m, 2H), 74
8 (m, 2H), 7.94 (brs, 1H), 8.04 (s, 1H), 8.22
(S, 1H), 8.49 (brs, 1H). Elemental _{analysis: C 14 H 8 Cl 2 N} 2 O 2 Calculated S: C, 56.42; H, 3.2
8; 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 prepared as described in Example 171 to give the title compound. _{MS (DCI / NH 3) m} / e: 353 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3H), 7.
16 (m, 2H), 7.49 (m, 2H), 8.05 (s, 1H), 8.17 (
s, 1H), 9.04 (brs, 2H).

Example 313 7-Chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3-c] pyridine-2-carboxamide Example 311A was prepared according to the method of Example 114. Prepared to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 23.49 minutes. Mp _{129~132 ℃ MS (DCI / NH 3} ) m / e: 382 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.33 (m, 2H);
51 (m, 2H), 4.82 (t, 1H), 7.19 (m, 2H), 7.48 (
m, 2H), 8.08 (s, 1H), 8.27 (s, 1H), 9.12 (brt
, 1H), 9.18 (s, 1H), 12.81 (brs, 1H).

Example 314 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 314A 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Methyl carboxylate Example 123A was prepared in a similar manner to Example 1C using phosphorus oxybromide instead of phosphorus oxychloride to give the title compound. MS (ESI) m / e: 400 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
22 (m, 2H), 7.48 (m, 2H), 8.19 (s, 1H), 8.20 (
s, 1H).

Example 314B 7-bromo-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 314A was prepared according to Example 44 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 24.95 minutes. _{MS (DCI / NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.22 (m, 2H), 7.
44 (m, 2H), 7.95 (s, 1H), 8.02 (s, 1H), 8.29 (
s, 1H), 8.51 (brs, 1H).

Example 315 7-bromo-4- (4-chlorophenoxy) -N-methylthieno [2,3-c]
Pyridine-2-carboxamide Example 314A was prepared according to the method of Example 171 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 25.40 min. _{MS (DCI / NH 3) m} / e: 397 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.81 (d, 3H);
97 (s, 3H), 7.19 (m, 2H), 7.48 (m, 2H), 8.04 (
s, 1H), 8.21 (s, 1H), 9.05 (brs, 1H).

Example 316 4- (4-bromophenoxy) -7-chlorothieno [2,3-c] pyridine-2
-Carboxamide Example 316 was prepared in the same manner as in Example 311, except that 4-bromophenol was used instead of 4-chlorophenol, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 383,385 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.14 (d, 2H, J = 8)
. 9 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.98 (brs, 1H)
), 8.05 (s, 1H), 8.22 (s, 1H), 8.52 (brs, 1H).
. Elemental _{analysis: 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]
Example 317 was prepared in the same manner as in Example 312 except that 4-bromophenol was used instead of pyridine-2-carboxamide 4-chlorophenol to obtain the title compound. _{MS (DCI / NH 3) m} / e: 397,399 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.80 (d, 3 H, J = 4
. 7 Hz), 7.13 (d, 2H, J = 9.2 Hz), 7.60 (d, 2H, J
= 9.2 Hz), 8.07 (s, 1H), 8.13 (s, 1H), 9.03 (q
, 1H, J = 4.7 Hz). Elemental _{analysis: 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 Example 17A and 4-trifluoromethylphenol were treated in the same manner as in Example 311 to obtain the title compound. Mp _{^{175~176 ℃ MS (DCI / NH 3}} ) m / e: 373 (M + H) +; 1 H NMR (300MHz, DMSO-d 6) δ7.30 (d, 2H), 7.
80 (d, 2H), 8.00 (s, 1H), 8.20 (s, 1H), 8.25 (
s, 1H), 8.55 (s, 1H). Elemental _{analysis: C 16 H 10 ClF 3 N} 2 O 2 Calculated S: 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-2-carboxamide Example 17A and Example 17A Treatment of 4-trifluoromethylphenol gave the title compound. Mp _{178~179 ℃ MS (DCI / NH 3} ) m / e: 387 (M + H) +. ¹ H NMR (300 MHz, 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: C 16 H 10 ClF 3 N} 2 O 2 Calculated S: 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 amino in place of methylamine Example 320 was prepared according to the method of Example 319 using ethanol. Mp _{96~97 ℃ MS (ESI / NH 3} ) m / e: 415 (M + H) +. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.66 (t, 2H, J = 4.8)
Hz), 3.87 (t, 2H, J = 4.8 Hz), 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 4- (4-chlorophenoxy) -N, 7-dimethyl Methyl thieno [2,3-c] pyridine-2-carboxylate Methyl boric acid instead of 4- (trifluoromethyl) phenyl boric acid, dichlorobis (tricyclohexylphosphine) palladium instead of tetrakis (triphenylphosphine) palladium, Then, Example 311A was prepared in the same manner as in Example 95A, except that NMP was used instead of DME, to obtain the title compound. _{MS (DCI / NH 3) m} / e: 334 (M + H) +. ^{1 H NMR (300MHz, DMSO-} d 6) δ2.74 (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 Example 321A is prepared according to the method of Example 171 to give the title compound. Was. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, 30 min elution, detection at 254 nm, flow rate 0.8 mL / min, room temperature 20.70 min. _{MS (DCI / NH 3) m} / e: 334 (M + H) +. ¹ H NMR (300 MHz, 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 (brs, 1H).

Example 322 4- (4-Chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxamide Example 322A 4- (4-Chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxylic acid Example 311A (100 mg, 0.28 mmol) was dissolved in a 25% solution of sodium methoxide in methanol (10 mL) and heated to 60 ° C. in a pressure tube for 3 days. The solvent was removed under reduced pressure, the residue was redissolved in methylene chloride and acidified with formic acid. The organic layer was washed with _{H 2} O and brine, dried _(Na 2 SO _4), and the solvent was removed under reduced pressure to give the title compound as an off-white solid (50mg, 54%). MS (DCI) m / e: 336 (M + H) ^<+> . ¹ H NMR (300 MHz, 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 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-Carboxamide Example 322A (40 mg, 0.12 mmol) was treated according to the method of Example 92 to give the title compound (23 mg, 0.58 mmol) as a white solid. _{Mp> 250 ℃ MS (DCI / NH} 3) m / e: 335 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.08 (s, 3H), 7.
01 (m, 2H), 7.38 (m, 2H), 7.82 (brs, 1H), 7.9
0 (s, 1H), 8.04 (s, 1H), 8.43 (s, 1H).

Example 323 4- (4-Chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] pyridine-2-carboxamide Example 323A 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] Methyl pyridine-2-carboxylate Example 311A (200 mg, 0.597 mmol) in acetic anhydride (20 mL)
The solution was heated at reflux for 18 hours. The reaction was cooled and poured on ice. Mix 1
Time stirring _was added CH ₂ Cl ₂ (100mL). The organic extract was washed with 1N Na
Washed with OH (100 mL), H ₂ O (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and rotary evaporated to give a crude brown residue. The residue was dissolved directly in DMF (20 mL) and H ₂ O (3 mL), treated with K ₂ CO ₃ and warmed at 60 ° C. for 2 hours. The reaction was cooled to room temperature and rotoevaporated. The crude residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate / hexane gradient to 50% ethyl acetate / hexane to give the title compound. _{MS (DCI / NH 3) m} / e: 336 (M + H) +. ¹ H NMR (300 MHz, 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 (brs, 1H).

Example 323B 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] Pyridine-2-carboxamide Example 323A was prepared according to Example 44 to give the title compound. HPLC: Supelco C-18 column, concentration gradient eluent 0.1% TFA
Aqueous solution: acetonitrile 0: 90-90: 0, elution for 30 minutes, detection at 254 nm, flow rate 0.8 mL / min, room temperature 18.61 minutes. M.p.> 250 [deg.] C MS (APCI) m / e: 321 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.04 (m, 2H), 7.
38 (m, 2H), 7.40 (s, 1H), 7.75 (s, 1H), 8.32 (
brs, 1H).

Example 324 4- (4-Chlorophenoxy) -N-methyl-7- (methylamino) thieno [2
, 3-c] pyridine-2-carboxamide Barraclough et al. (J. Med. Chem. 1990, 33
Example 311A (27 mg, 76 mmol) was treated according to the procedure described in Example 1 (27 mg, 76 mmol) to give the title compound (12 mg, 45% yield). ^{_{MS (DCI / NH 3) m}} / e: 348 (35 Cl) / 350 (37 Cl). ¹ H NMR (CDCl ₃ , 300 MHz) 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, 1H), 7.86 (s, 1H)
.

Example 325 N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4-c]
Pyridine-2-carboxamide Example 142D (10 mg, 33 mmol) was treated according to the method of Example 96 to give the title compound as a white solid (1.5 mg, 75%). ^{_{MS (DCI / NH 3) m}} / e: 300 (M + H) +, 317 (M + NH 3) +. ¹ H NMR (CDCl ₃ , 300 MHz) δ 2.39 (s, 3H), 3.07
(D, J = 5.1 Hz, 3H), 7.06 (d, J = 8.8 Hz, 2H), 7.
23 (d, J = 8.5 Hz, 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-carboxami
Example 327A 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxylic acid
Cyl 4-chlorophenol (1.08 g, 8.7 mmol) in anhydrous tetrahydroph
A potassium t-butoxide solution (T) was added to a run (25 mL) solution at 0 ° C. under a nitrogen atmosphere.
A 1.0 M solution in HF, 8.7 mL, 8.7 mmol) was added dropwise. And anti
The reaction mixture was heated and stirred at 65 ° C for 2 hours, cooled to 0 ° C, and
Treated with Example 17A (1.0 g, 5.7 mmol) in furan (10 mL), 6
Heated to 5 ° C. for 2 hours. The reaction was cooled to 0 ° C. and ethyl glycolate (1.07
mL, 11.4 mmol) and cesium carbonate (3.0 g, 9.2 mmol).
Was added and the mixture was heated at 65 ° C. for 3 hours. Cool and concentrate the reaction,
The residue was diluted with ethyl acetate (50 mL) and washed with brine (3 × 50 mL).
And dried (MgSO 4)₄)did. Then, ethyl acetate was concentrated to obtain an oil.
Flash chromatography on silica gel with 10% ethyl acetate-hexane as eluent
Purification by chromatography gave 0.110 g of the title compound as a glassy residue (6.
1%). MS (DCI / NH₃) M / e: 318 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 1.35 (t, 2H, CH₂ ), 4.4 (q, 3H, CH₃), 7.2, (d, J = 9 Hz, 2H), 7.5
(D, J = 9 Hz, 2H), 8.09 (s, 1H), 8.23 (s, 1H), 9
. 25 (s, 1H) Example 327B 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carboxylic acid tetrahydrate of lithium hydroxide monohydrate (0.0113 g, 0.5 mmol)
To a solution of furan (5 mL) and water (1 mL) was added Example 327A (0.1 g, 0.1 g).
3 mmol) was added and the mixture was heated at 50 ° C. for 2 hours. Allow the mixture to cool and
Formic acid until acidic (pH?). The mixture is then added to ethyl acetate (5
0 mL), the extract is washed with brine (2 × 20 mL) and dried (MgSO 4). ₄ ) And concentrated. On silica gel with 20% acetone-hexane as eluent
Purification by flash chromatography gave the title compound 0 as a glassy residue.
. 710 g (81.6%) were obtained. MS (DCI / NH₃) M / e: 290 (M + H)⁺.¹ 1 H NMR (300 MHz, DMSO-d₆) Δ 3.4 (brs, 1H), 7
. 2 (d, J = 9 Hz, 2H), 7.5 (d, J = 9 Hz, 2H), 8.09 (
s, 1H), 8.23 (s, 1H), 9.25 (s, 1H).

Example 327C 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide A solution of Example 327B (0.15 g, 0.5 mmol) in DMF (10 mL) was added to 1-hydroxy Benzotriazole hydrate (0.104 g, 0.66 mmol
_), And treated with NH 4 Cl (0.0948g, 0.017mmol) and 4-methylmorpholine (0.141 g, 0.14 mmol). Cool the solution to 0 ° C., treat with 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.115 g, 0.6 mmol), warm to room temperature, stir overnight, Pour into saturated NaHCO ₃ , filter, wash with brine (3 × 20 mL) and dry (M
gSO ₄ ) and concentrated. 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 NMR (300 MHz, DMSO-d ₆ ) δ 7.18 (d, 2H), 7.
29 (s, 1H), 7.5 (d, 2H), 7.82 (brs, 1H), 8.25
(S, 1H), 8.35 (brs, 1H), 8.95 (s, 1H).

Example 328 4- (4-Chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide A solution of Example 327 (0.06 g, 0.2 mmol) in toluene (5 mL) was treated with Lawesson's reagent ( (0.1 g, 0.2 mmol). The reaction was then refluxed for 1 hour, cooled, concentrated, and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (3 × 15 mL), dried (MgSO ₄ ) and concentrated. Purification by flash chromatography on silica gel eluting with 20% acetone-hexane gave 0.022 g (37%) of the title compound as a pale yellow solid. _{MS (DCI / NH 3) m} / e: 305 (M + H) +. ¹ H NMR (300 MHz, 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 E- and Z-4- (2-phenylethenyl) thieno [2,3 -C] pyridine-
To a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene (0.2 mL) was added a solution of diethyl tert-butyl 2-carboxylate (0.08 mL, 0.38 mmol) in dichloromethane (2 mL) at −78 ° C. while stirring. 84 mL, 0.42 mmol) was added dropwise. After 45 minutes, a solution of Example 237E (0.10 g, 0.38 mmol) in dichloromethane (3 mL) was slowly added dropwise, and the reaction was stirred for 1 hour. The cooling bath was removed and the reaction was stirred for 20 minutes. The reaction was quenched by pouring into dilute aqueous NaHCO ₃ . The aqueous solution was extracted with dichloromethane (2 × 25 mL) and ethyl acetate (2 × 25 mL). Combine all organic phases and dry (Na ₂ SO ₄ )
And concentrated to give a colored oil. The residue was purified by flash chromatography on silica gel using EtOAc / hexane as eluent. The mixture of stereoisomers was dried in a desiccator to give a solid (0.07 g, 55%). MS (APCI) m / e: 338 (M + H) ^<+> .

Example 329B E-4- (2-phenylethenyl) thieno [2,3-c] pyridine-2-carboxamide Example 329A (0.07 g, 0.21 mmol) was added to 10% H ₂ SO ₄ / Me
Dissolved in OH (10 mL) solution. The solution was heated at reflux for 6 hours and stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and saturated NaHCO ₃ (50 mL)
Basified with. The aqueous phase was extracted with dichloromethane (2 × 50 mL) and the organic extracts were combined. The organic layer was washed with dilute brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a colored residue. The residue was treated with methanol (8 mL
)) And chloroform (1 mL). A balloon of ammonia gas was attached and the reaction was heated at 35 ° C. for 24 hours. The reaction was concentrated and the residue was purified by HPLC using 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 further the corresponding Z-isomer (14 mg, 24%).
I got Mp _{257~258 ℃ MS (DCI / NH 3} ) m / e: 281 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.34 (dd, J = 7.6)
, 7.2 Hz, 1H), 7.46 (dd, J = 7.6, 7.2 Hz, 2H), 7
. 55 (d, J = 16.5 Hz, 1H), 7.64 (d, J = 16.5 Hz, 1
H), 7.73 (d, J = 7.2 Hz, 2H), 7.88 (brs, 1H), 8
. 37 (brs, 1H), 8.62 (s, 1H), 8.85 (brs, 1H),
9.18 (s, 1H). Elemental _{analysis: C 16 H 12 N 2 OS} 0.2H 2 O Calculated: C, 67.68; H
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-carboxamide Rate The title compound was prepared in the same manner as in Example 95A except that 4-chlorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (160 mg,
53%). MS (APCI) m / e: 304 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
69 (m, 4H), 8.30 (s, 1H), 8.60 (s, 1H), 9.42 (
s, 1H).

Example 330B 4- (4-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 330A was prepared in a similar manner to Example 44 to give the title compound (60 mg).
, 60%). MS (APCI) m / e: 289 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8 Hz,
2H), 7.69 (d, J = 8 Hz, 2H), 7.77 (s, 1H), 8.19
(S, 1H), 8.41 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H)
1H).

Example 331 4- [3- (Trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxalamide Example 331A 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxylate The title compound was prepared in the same manner as in Example 95A, except that 4- (trifluoromethyl) phenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (100 mg, 30%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 3H), 7.
81-7.93 (m, 4H), 8.01 (s, 1H), 8.67 (s, 1H),
9.46 (s, 1H).

Example 331B 4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-Carboxalamide Example 331A was prepared in a similar manner to Example 44 to give the title compound (90 mg).
, 94%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (s, 1 H), 7.
90-7.97 (m, 4H), 8.25 (s, 1H), 8.46 (s, 1H),
8.69 (s, 1H), 9.38 (s, 1H).

Example 332 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 332A 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxa The title compound was prepared in the same manner as in Example 95A, except that 3-chlorophenylboric acid was used instead of 4-chlorophenylboric acid (130 mg, 43%). MS (APCI) m / e: 304 (M + H) ^<+> . ¹ H NMR (300 MHz, 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, 1H).

Example 332B 4- (3-Chlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 332A was prepared in a similar manner to Example 44 to give the title compound (82 mg).
, 86%). MS (APCI) m / e: 288 (M + H) ^<+> . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.58-7.62 (m, 3
H), 7.62 (s, 1H), 7.69 (s, 1H), 8.19 (s, 1H),
8.49 (s, 1H), 8.51 (s, 1H), 9.31 (s, 1H).

Example 333 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 333A 4- (4-bromophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 4-bromophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (148 mg,
42%). MS (APCI) m / e: 305 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 7.
61 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 7.5 Hz, 2H),
8.02 (s, 1H), 8.57 (s, 1H), 9.40 (s, 1H).

Example 333B 4- (4-Bromophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 333A was prepared in a similar manner to Example 44 to give the title compound (118m).
g, 88%). MS (APCI) m / e: 333, 335 (1: 1) (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 7.5 H
z, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.84 (s, 1H),
8.22 (s, 1H), 8.46 (s, 1H) 9.33 (s, 1H).

Example 334 4- (3-Aminophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 334A 4- (3-Aminophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 3-aminophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (90 mg, 3
2%). MS (APCI) m / e: 285 (M + H) ^<+> . ¹ H NMR (300 MHz, 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 = 7.5 Hz, 1H), 8.07 (s, 1H), 8.53 (s
, 1H), 9.36 (s, 1H).

Example 334B 4- (3-Aminophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 334A was prepared in a similar manner to Example 44 to give the title compound (83 mg).
, 98%). MS (APCI) m / e: 270 (M + H) ^<+> . 5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.30 (s, 2H),
67-6.82 (m, 3H), 7.22 (t, J = 7.5 Hz, 1H), 7.7
9 (s, 1H), 8.23 (s, 1H), 8.43 (s, 1H), 8.51 (s
, 1H), 9.25 (s, 1H).

Example 335 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 335A 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine- The title compound was prepared in the same manner as in Example 95A, except that 3,5-dichlorophenylboric acid was used instead of 2-carboxalate 4- (trifluoromethyl) phenylboric acid (90 m
g, 27%). MS (APCI) m / e: 338 (M + H) ^<+> .

Example 335B 4- (3,5-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 335A was prepared in the same manner as in Example 44 to obtain the title compound (21 mg).
, 24%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (d, J = 2.25)
Hz, 2H), 7.80 (m, 1H), 7.88 (s, 1H), 8.20 (s,
1H), 8.53 (s, 1H), 8.56 (s, 1H), 9.36 (s, 1H)
.

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-carboxalate The title compound was prepared in the same manner as in Example 95A, except that 2,4-dichlorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid.
mg, 30%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.38 (s, 3H), 7.
59 (s, 1H), 7.61 (d, J = 2.25 Hz, 1H), 7.70 (s, 1H)
1H), 7.86 (d, J = 2.25 Hz, 1H), 8.49 (s, 1H), 9
. 45 (s, 1H).

Example 336B 4- (2,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 336A was prepared in the same manner as in Example 44 to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.60 (s, 1 H), 7.
64 (m, 1H), 7.81 (brs, 1H), 7.87 (s, 1H), 7.9
1 (m, 1H), 8.37 (brs, 1H), 8.45 (s, 1H), 9.37
(S, 1H).

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-carboxalate The title compound was prepared in the same manner as in Example 95A, except that 3,4-dichlorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (130).
mg, 39%). MS (APCI) m / e: 338 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.94 (s, 3H), 7.
67-7.76 (m, 1H), 7.85 (m, 1H), 7.79 (d, J = 2.
25 Hz, 1H), 8.06 (s, 1H), 8.63 (s, 1H), 9.44 (
s, 1H).

Example 337B 4- (3,4-Dichlorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 337A was prepared in the same manner as in Example 44 to obtain the title compound (44 mg).
, 46%). MS (APCI) m / e: 323 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65-7.68 (m, 1
H), 7.84-7.87 (m, 2H), 8.96 (d, J = 2.25 Hz, 1
H), 8.21 (s, 1H), 8.47 (s, 1H), 8.56 (s, 1H),
9.35 (s, 1H).

Example 338 4- (2,4-Difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 338A 4- (2,4-Difluorophenyl) thieno [2,3-c] The title compound was prepared in the same manner as in Example 95A, except that 2,4-difluorophenylboric acid was used in place of pyridine-2-carboxalate 4- (trifluoromethyl) phenylboric acid (13
0 mg, 42%). MS (APCI) m / e: 306 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.90 (s, 3H), 7.
26 (m, 1H), 7.45 (m, 1H), 7.63 (m, 1H), 7.81 (
d, J = 3 Hz, 1H), 8.55 (s, 1H), 9.44 (s, 1H).

Example 338B 4- (2,4-Difluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 338A was prepared in the same manner as in Example 44 to obtain the title compound. MS (APCI) m / e: 291 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.30 (m, 1 H), 7.
49 (m, 1H), 7.66 (m, 1H), 7.77 (s, 1H), 7.99 (
s, 1H), 8.39 (s, 1H), 8.47 (s, 1H), 9.34 (s, 1)
H).

Example 339 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 339A 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2- Carboxarate The title compound was prepared in the same manner as in Example 95A, except that 4-fluorophenylboric acid was used instead of 4- (trifluoromethyl) phenylboric acid (100 mg).
, 35%). MS (APCI) m / e: 288 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 7.
38-7.48 (m, 2H), 7.55-7.64 (m, 1H), 7.78 (d
, J = 3 Hz, 1H), 8.57 (s, 1H), 9.44 (s, 1H).

Example 339B 4- (4-Fluorophenyl) thieno [2,3-c] pyridine-2-carboxamide Example 339A was prepared in the same manner as in Example 44 to obtain the title compound. MS (APCI) m / e: 273 (M + H) ^<+> . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.40-7.50 (m, 2
H), 7.57-7.65 (m, 2H), 7.81 (s, 1H), 8.01 (s
, 1H), 8.47 (s, 1H), 8.51 (s, 1H), 9.36 (s, 1H)
).

Example 340 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide Example 340A Lithium 2,3,5-trichloro-4-formylpyridine diisopropylamine (7.3 mL, 1.5 M in cyclohexane,
1 mmol) in dry THF (10 mL) at −78 ° C. under nitrogen for 30 minutes
Solution of 2,3,5-trichloropyridine (2 g, 11 mmol) in THF (20 mL)
The solution was stirred for a further 30 minutes, and methyl formate (1.
4 mL, 1.3 g, 22 mmol) was slowly added to the brown solution over 15 minutes.
Slowly warmed to room temperature and stirred overnight. The resulting dark brown solution is washed with ice and
And saturated NaHCO₃, Extracted with ethyl acetate, washed with brine and dried (
Na₂SO₄) And concentrated. 20-33% ethyl acetate / hexa brown oil
Flash chromatography on silica gel using the title compound afforded the title compound.
(1.7 g, 74%). MS (APCI-NH₃) M / e: 211 (M + H)⁺, 229 (M + NH₄) ⁺ .¹ 1 H NMR (300 MHz, DMSO-d₆) 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 is passed through a syringe through potassium t-butoxide ( (4 mL, 1 M in THF, 4 mmol), warmed to room temperature, stirred for 1 hour, and cooled to 0 ° C. Example 340A (390 mg, 2 mmol) in 2 mL THF was added, the reaction was heated at 60 ° C. for 2 hours and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and 1N NaOH
Washed with brine, dried (Na ₂ SO ₄ ) and concentrated. 1-2% of brown residue
Flash chromatography on silica gel twice with methanol / dichloromethane and 5-20% ethyl acetate / hexane gave the title compound (235).
mg, 24%). _{MS (APCI-NH 3) m} / e: 483 (M-H) -, 517 (M + Cl) -. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.20 (s, 1 H), 8
. 24 (s, 1H) 7.63 (m, 2H), 7.53 (m, 2H), 7.24 (
m, 2H), 6.99 (m, 2H).

Example 340C 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-A 2 mL THF solution of methyl carboxylate 340B (227 mg, 0.47 mmol) was added to methyl thioglycolate (50 μL, 0.52 mmol) followed by Cs ₂ CO ₃ powder (17
9 mg, 0.55 mmol), stirred at room temperature for 21 hours, heated at 60 ° C. for 15 minutes, and cooled to room temperature. Dilute the reaction with ethyl acetate and distilled water,
Washed with 1M K ₂ CO ₃ , brine, dried (MgSO ₄ ) and concentrated. The residue was flash chromatographed on silica gel using 5-20% ethyl acetate / hexanes, followed by HPLC purification _{30~90% CH 3 CN / H 2} O with 0.1% TFA as gradient eluent ( C-18) to give the title compound (6
mg, 3%). _{MS (APCI-NH 3) m} / e: 400 (M + H) +. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.20 (s, 1 H), 7.
78 (s, 1H) 7.51 (d, 2H), 6.93 (d, 2H), 3.90 (s
, 3H).

Example 340D 5-Chloro-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide 340C (5 mg, 0.013 mmol) in 1 mL methanol and 1 mL dichloromethane was added to a 2M ammonia / methanol solution (3 mL, 6 mL) in a pressure tube.
mmol), heated at 60 ° C. for 4 hours, cooled to room temperature and concentrated. 95
/ 5 dichloromethane / methanol and filtered and the residue through silica with, concentrated, and purified by reverse-phase H using _{20~75% CH 3 CN / H 2} O containing 0.1% TFA
Purification by PLC (C-18) provided the title compound (4.2 mg, 84%).
. HPLC (C-18, 4.6 × 250 mm), 0.8 mL / min, λ = 254 nm
, _CH 3 containing _{0.1% TFA CN: H 2 O} 0~90%, rt 23.3 min (9
8.52% area). _{MS (APCI-NH 3) m} / e: 385 (M + H) +. ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.98 (s, 1 H), 7.
9 (s, 1H), 7.49 (d, 2H), 6.83 (d, 2H).

The above are merely specific examples, and the present invention is not limited to the compounds described. Variations and modifications which are obvious to one skilled in the art are included within the scope and nature of the invention as defined in the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 31/4545 A61K 31/4545 31/497 31/497 31/519 31/519 31/5377 31/5377 A61P 29/00 A61P 29/00 C07D 491/048 C07D 491/048 495/04 105 495/04 105Z 105A 498/04 105 498/04 105 513/04 343 513/04 343 // (C07D 498/04 (C07D 498) / 04 263: 00 263: 00 221: 00) 221: 00) (C07D 513/04 (C07D 513/04 277: 00 277: 00 (81) Designated country EP (AT, BE, CH, CY, DE, DK) , ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR) , NE, SN, TD, T ), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72 ) Inventor Alendsen, David Elder United States, Illinois 60048, Libertyville, Illinois Bastia, Pramira United States, Illinois 60048, Libertyville, Marvelly Drive 1602 (72) Inventor Kondoroski, Kevin Earl United States of America, Illinois 60202, Evanston, Oak Avenille 1112 (72) Inventor Freeman, Dienifer Sea United States, Illinois 60030, Gladeslake, Country Drive Number 303, 1908 (72) Inventor Gunawadana, Indalani Dubrillo Illinois, Illinois · 60048, Libertyville, Nodizk Court · 622 (72) Inventor Chew, Coy-Tong United States of America, Illinois 60031; Gurney, Olmaden Lane 622 (72) Inventor: Ratei, Craig United States of America, Illinois 60085, Woo -Keegan, Gran Le Avenille 3170 (72) Inventor Matsukatei, Kyasarin M. United States, Massachusetts 02446, Wurzklein, Freeman Street No. 1, 231 (72) Inventor Mote, Nicholas A. United States of America, Illinois 60085, Walkiegan, North Avenue 721 (72) Inventor Patel, Mina Buoy United States, Illinois 60661, Chicago, West Madison Street No. 3703-605, Tower 3 (72) Inventor Stager, Michael・ A. United States, Wisconsin 53211, Greenfield, South Thirty fifth Street 4919 (72) Inventor Stout, David M. United States, Illinois 60048, Libertyville, Elm Drive 416 F-term (reference) BB07 CC16 EE01 FF01 GG03 GG04 HH01 4C071 AA01 BB01 CC01 CC02 CC21 DD13 EE13 FF05 FF06 GG01 GG03 GG05 HH01 HH05 HH11 JJ04 JJ05 JJ06 JJ08 LL01 4C072 AA01 BB02 CC02 CC11 CC16 DD10 EE03 A03 EA13 U03 A03 BC BC71 BC73 BC82 BC85 CB05 CB22 CB26 GA10 MA01 MA04 NA15 ZB11

Claims (23)

[Claims] 1. A compound having the formula I:Or a pharmaceutically acceptable salt or prodrug thereof, wherein-----Is a single bond or a double bond, provided that one bond is a double bond
In the case of a bond, the adjacent bond is a single bond; E, F, and G are: (1) carbon, (2) nitrogen, and (3) N⁺-O⁻Independently selected from, wherein at least one of E, F or G is nitrogen or N⁺-O⁻And more
Wherein at least one of E, F or G is carbon, and Y and Z are (1) carbon, (2) nitrogen, (3) oxygen, and (4) S (O)_t(T is an integer from 0 to 2), independently selected from the group consisting of: wherein at least one of Y or Z is other than carbon;_AIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆− (R₆Is optionally substituted with one or two substituents independently selected from: (a) hydrogen, (b) (i) aryl and (ii) cycloalkyl of 3 to 10 carbons. (C) alkanoyl wherein the alkyl moiety is 1 to 10 carbons, and (d) cycloalkyl of 3 to 10 carbons), (5) -C (W X) is selected from: (a) O and (b) S, and (6) alkenylene;_A(1) halo, (2) (a) oxo, (b) cycloalkyl of 3 to 10 carbons, (c) -CO₂R₇(R₇Is selected from: (i) hydrogen and (ii) aryl and cycloalkyl of 3 to 10 carbons, 1 to 10 carbons optionally substituted with one or two substituents independently selected from And (d) -NR₈R₉(R₈And R₉Is selected from: (i) hydrogen, (ii) -OH, aryl, heterocycle, cycloalkyl of 3 to 10 carbons, and -NR_AR_B(R_AAnd R_BIs independently selected from alkyl of 1 to 6 carbon atoms, optionally substituted with one or two substituents selected from hydrogen and -OH), independently selected from 1-6 alkyl optionally substituted with one or two substituents, (iii) alkanoyl wherein the alkyl moiety is 1-10 carbon atoms, (iv) cycloalkyl of 3-10 carbons. Alkyl, (v) alkoxy, (vi) heterocycle, and (vii) aryl, wherein (vi) and (vii) are alkyl of 1 to 6 carbon atoms And halo, substituted with one or two substitutions independently selected from:), (e) -C (W) R₁₀(W is as defined above, and R₁₀Represents 1 to 10 carbon atoms optionally substituted with one or two substituents independently selected from: (i) hydrogen, (ii) aryl and cycloalkyl of 3 to 10 carbons Alkyl of (iii) -NR₈R₉And (iv) -OR₇(F) —OH, (g) aryl, and (h) heterocycle, 1 to 10 optionally substituted with 1, 2 or 3 substituents independently selected from Wherein (g) and (h) are: (i) alkyl of 1 to 20 carbons, (ii) -NR₈R₉(Iii) alkoxy of 1 to 10 carbons, (iv) thioalkoxy of 1 to 10 carbons, (v) halo, (vi) perfluoroalkyl of 1 to 3 carbons, (vii) 2 to 10 Alkenyl of 1 carbon, (viii) alkoxy of 1 to 10 carbons and alkyl of 1 to 10 carbons optionally substituted with 1 or 2 substituents independently selected from -OH, (Ix) -CO₂R₇, (X) aryl, and (xi) -CHO, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: (10) cycloalkyl of 10 carbons, (4) aryl, (5) heterocycle, wherein (4) and (5) are (a) alkyl of 1 to 20 carbons, (b) (i) -OR₁₁(R₁₁Is hydrogen, -C (W) R₁₂(R₁₂Is selected from alkyl of 1 to 10 carbons, cycloalkyl of 3 to 10 carbons, aryl, and heterocycle), and 1 or 2 substituents selected from -OH and -OH Selected from alkyl of 1 to 6 carbons, optionally substituted with; heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from: ii) alkoxy and alkoxyalkoxy, 1 to 10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (iii) 3 to 10 carbon spiroalkyl, And (iv) alkyl of 1 to 10 carbons, optionally substituted with 1, 2, or 3 substituents independently selected from halo, (c) (i) alkoxy and (ii) alkyl Xyalkoxy, 1-10 carbon alkoxy optionally substituted with one or two substituents independently selected from: (d) 1-10 carbon thioalkoxy, (e) halo, (F) perfluoroalkyl of 1 to 3 carbons, (g) (i) -C (W) R₁₀And (ii) -C (W) R₁₂Alkenyl of 2 to 10 carbons optionally substituted with one or two substituents independently selected from: (h) -CO₂R₇, (I) -NR₈R₉, (J) aryl, (k) -C (W) R₁₂, (L) -CHO, (m) -C (O) NR₈R₉(N) -CN, (o) (i) alkyl of 1 to 10 carbons and (ii) perfluoroalkyl of 1 to 3 carbons, with one or two substituents independently selected from Optionally substituted heterocycle, (p) -C (W) R₁₀, (Q) ethylenedioxy, and (r) -OCF₃, Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from), (6) -OR₇, (7) hydrogen, and (8) -NR₈R₉L is selected from_BIs (1) a covalent bond, (2) -O-, (3) -S (O)_t-, (4) -NR₆-, (5) C (W)-, and (6) -C (= NR₁₃)-(R₁₃Are (a) hydrogen, (b) -NO₂, (C) -CN, and (d) -OR₁₄(R₁₄Is selected from: (i) hydrogen, (ii) aryl, and (iii) aryl and -C (O) R_Fifteen(R_FifteenIs hydrogen, -OH, alkoxy, and NR_AR_BX selected from 1 to 10 alkyls optionally substituted with 1 to 2 substituents, independently selected from_BAre (1) hydrogen, (2) (a) -CO₂R₇, (B) -NR₈R₉, (C) -C (W) NR₈R₉(D) heterocycle, (e) (i) alkyl of 1 to 10 carbons, (ii) -NO₂And (iii) -NR_AR_BAryl optionally substituted with one or two substituents independently selected from:, (f) -OR₁₆(R₁₆Is (i) hydrogen and (ii) -C (W) NR_AR_BAnd (g) -NR_AC (W) NR₈R₉1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (3) (a) -C (W) NR_AR_B, (B) -CO₂R₇And (c) a heterocycle, an alkenyl of 2 to 6 carbons optionally substituted with one or two substituents independently selected from: (4) -NR₁₇R₁₈(R₁₇And R₁₈(A) hydrogen, (b) (i) -OH, (ii) -C (W) R₁₀, (Iii) -NR_AC (= NR₁₃) NR_BR₁₉(R_A, R_B  And R₁₃Is already defined and R₁₉Is hydrogen, alkyl of 1 to 10 carbons, and -NO₂  (Iv) heterocycle, (v) aryl, (vi) halo, and (vii) -NR_AR_B(C) alkoxy; (d) (i) halo; (ii) 1-alkyl of 1 to 10 carbons optionally substituted with 1, 2 or 3 substituents independently selected from (Iii) 1 to 10 carbon alkoxy, and (iv) 1 to 3 carbon perfluoroalkyl, 1, 2, or 3 substitutions independently selected from: Aryl optionally substituted with a group, (e) heterocycle, (f) -NR_AR_B, (G) -C (O) R₂₀(R₂₀Is (i) hydrogen, (ii) alkyl of 1 to 10 carbons, (iii) -OR₁₂And (iv) -NR_AR_B(H) cycloalkyl of 3 to 10 carbons, and (i) independently selected from -OH), (5) alkoxy, (6) -OH, (7) -NR_AC (= NR₁₃) NR_BR₁₉, (8) -C (W) NR₈R₉(9) aryl, (10) heterocycle, wherein (9) and (10) are (a) halo, (b) (i) halo, (ii) alkoxy of 1 to 10 carbons, iii) -NR_AR_B, (Iv) -OH, (v) -CO₂R₇, (Vi) -C (W) NR_AR_BAnd (vii) aryl, 1 to 10 carbon alkyl optionally substituted with 1, 2, or 3 substituents independently selected from: (c) -NR_AR_B(D) alkoxy of 1 to 10 carbons, (e) thioalkoxy of 1 to 10 carbons, (f) perfluoroalkyl of 1 to 3 carbons, (g) -OH, (h) -C (W) NR₈R₉, (I) -CO₂R₇, (J) -NR_AC (W) OR₂₁(R_AIs already defined and R₂₁Is (i) aryl and 1-10 carbon alkyl optionally substituted with one or two substituents selected from 3-10 carbon cycloalkyl, (ii) aryl, and (iii) (K) cycloalkyl of 3 to 10 carbons, (k) alkenyl of 1 to 10 carbons, (l) heterocycle, (m) aryl, and (n) -NO₂Optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(11) -CN, (12) -CHO, (13) halo, and (14) -B (OR_A) (OR_B), Where R₁, R₂, R₃, R₄, And R₅Is hydrogen or lacking
, -L_A-Is a covalent bond, -L_B-Is a covalent bond, X_AOr X_BOne of them is
Other than hydrogen, R₁, R₂, R₃, R₄, And R₅Is missing or (1) hydrogen, (2) (a) -OC (O) R₂₂(R₂₂Is (i) alkyl, (ii) alkoxy, and (iii) NR_AR_B(B) alkoxy, (c) -OH, (d) -NR_AR_B(E) a heterocycle, and (f) aryl, alkyl of 1 to 6 carbons optionally substituted with one or two substituents independently selected from: (3) -CO₂R₇, (4) -C (O) NR_AR_B, (5) -SR₂₃(R₂₃Is one or two substituents selected from: (a) hydrogen, (b) alkyl of 1 to 6 carbons, (c) (i) alkyl of 1 to 6 carbons, and (ii) halo. Selected from aryl optionally substituted with), (6) -NR_AR_B(7) halo, (8) alkoxy, (9) perfluoroalkyl of 1 to 3 carbons, (10) -OH and (11) heterocyclic ring, with the proviso that E, F, and When Y is carbon, G is nitrogen and Z is sulfur
, -L_A-Is a covalent bond, X_AIs halo and R₁Is -CO₂R₇Other than
]. Wherein F and Y are carbon, E and G independently nitrogen or ^N + -O ^- is, Z is S _{(O) t,} A compound according to claim 1. 3. 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-carboxylate, 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidin-4-amine, 6-ethyl-N- (5-methyl-1,3,4-thiadiazole- 2-yl) thieno [2,3-d] pyrimidin-4-amine, 4-[(5-amino-1,3,4-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 4-[(5-amino-1,3,4-thiadiazole) The compound of claim 2, wherein the compound is selected from the group consisting of: -2-ylthio) -6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine. Wherein F and Z are carbon, nitrogen or ^N + -O E and G are independently ^- a, and Y is S _{(O) t,} A compound according to claim 1. 5. A method for preparing 7-methyl-4-[(4-methylphenyl) thio] thieno [
3,2-d] pyrimidine, 7-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [3,2-d] pyrimidine, 7-methyl-4- [[5- (methylthio) -1,3,4-thiadiazole-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-amine and 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2- 5. The compound according to claim 4, wherein the compound is selected from the group consisting of: d] pyrimidine-6-carboxamide. 6. E, G and Y are carbon, F is nitrogen or ^N + -O ^- and is, Z is A compound according to claim 1 is S (O). 7. Methyl 4-[(4-methylphenyl) thio] thieno [2,3
-C] pyridine-2-carboxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boric acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2-carboxami
, 4-[(4-chlorophenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, N-methoxy-N-methyl-4-[(4-methylphenyl) thio] thieno [2,
3-c] pyridine-2-carboxamide, N-methoxy-4-[(4-methylphenyl) thio] thieno [2,3-c] pyri
Gin-2-carboxamide, N- (4-chlorophenyl) -4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxaldehyde, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxaldehyde, O-methyloxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxaldehyde, O- (phenylmethyl) oxime, 2-[[[4- (4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-ylmethylene] amino] oxy] acetic acid, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxaldehyde, O-phenyloxime, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxaldehyde, oxime, 2-[[[4- (4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-ylmethylene] amino] oxy] acetamide, (E) -3-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] -2-propenamide, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] ethanone, 2-benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pi
Lysine, 2-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] ethanone, oxime, N- (2,3-dihydroxypropyl) -4-[(4-methylphenyl) thio]
Thieno [2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boric acid, hydrazide, N ² -4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] carbonyl] -N ⁶ -[(Nitroamino) iminomethyl] -L-lysine
, Methyl ester, N- (aminoiminomethyl) -4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Bothioamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine, methyl 4-[(2-methoxy-2-oxoethyl) thio] thieno [2,3-c]
Pyridine-2-carboxylate, 4-[(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine
-2-carboxamide, 4-[(4-bromophenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide, 4-[[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pi
Lysine-2-carboxamide, 4-[(2-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 4-[(3-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 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-ca
Luboxamide, 4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxami
, 4-[(4-methylphenyl) thio] -N- [3- (4-morpholinyl) propyl
Ru] thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl
Acetate, 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine-
2-carboxamide, methyl 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyri
Gin-2-carboxylate, 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-cal
Boxylate, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine
-2-carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2-carboxyl
Samide, 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-carboxa
Mido, 4- (4-ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c]
Pyridine-2-carboxamide, 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, 4- [2- (2,3-dihydroxypropyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (trifluoromethyl) 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-carboxa
Mido, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-4-
Yl] oxy] benzoate, 4-phenoxythieno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4- (methoxymethyl) phenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid
N- (4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
) -O- (3-tetrahydrofuranyl) carbamate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-methanol
(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenonic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Aldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenamide, 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] pyri
Gin-2-carboxylate, N-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] pyridi
2-Carboxamide, 4- (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2-cal
Boxamide, ethyl 4-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-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-carboxa
Mido, methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-cal
Boxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-meta
Nor, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N, N-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -N, N-diethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyri
Gin-2-carboxamide, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] pyrrolidine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] piperidine, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] morpholine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -4-methylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -4-phenylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] carbonyl] -4- (phenylmethyl) piperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] carbonyl] -4- (2-pyridinyl) piperazine, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-carboxamide, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide,
Trifluoroacetate, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1,1-bis (hydroxymethyl) ethyl
Ru] thieno [2,3-c] pyridine-2-carboxamide, (D, L) -4- (4-chlorophenoxy) -N- (2-hydroxypropyl)
Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thie
No [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfone
Mido, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamide
4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Amide, N-oxide, methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Acid, N-oxide, 4- (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] pyridi
2-carboxylate, 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridi
2-carboxylate, 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxylic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbothio
Amide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-carboxamide, N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-carboxamide, 4- (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thio
Eno [2,3-c] pyridine-2-carboxamide, N- (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, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydride
Razide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydride
Razide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine
-2-carbohydrazide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine
-2-carboxamide, 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl @ amino) acetic acid, N- (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno
[2,3-c] pyridine-2-carboxamide, N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno
[2,3-c] pyridine-2-carboxamide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl @ amino) -3-hydroxypropanoic acid, N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl]
-4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl {amino) -3-hydroxypropanoic acid, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methyla
Mino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxami
, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl @ amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1S) -1-methyl-2- (methyla
Mino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxami
, 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyridi
2-Carboxamide, N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2
, 3-c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c
Pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, N-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, N-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] pyridi
2-Carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] -N-methylthieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (methoxymethyl) phenoxy] -N-methylthieno [2,3-c]
Pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-
c] pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} -N-methylthiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
-N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] pheno
Xythithieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy) meth
Tyl] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4-{[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl]
Oxydibenzyl 2-furoate, 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Phenoxy] -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, N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) fe
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} cal
Bonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl
] Phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-} [2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide, N-methyl-4- [4-((E) -3-} [2- (4-morpholinyl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pi
Lysine-2-carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [2
, 3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] e
Tyl {amino) -3-oxo-1-propenyl] phenoxy} -N-methylthiye
No [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] e
Tyl {amino) -3-oxo-1-propenyl] phenoxy} thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide, N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) pheno
Xy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadi
Azol-3-yl] phenoxydithieno [2,3-c] pyridine-2-carbo
Oxamide, 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy]
-N-methylthieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pi
Lysine-2-carboxamide, 4-([1,1′-biphenyl] -4-yloxy) -N-methylthieno [2,
3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) pheno
Xy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] phenoxy} -N-meth
Tilthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclo
Propyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-cal
Boxamide, N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3
-C] pyridine-2-carboxamide, 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}
Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl} -1
, 3,4-oxadiazol-2-amine, 4- [4- (1,1-difluoro-2-hydroxyethyl) phenoxy] -N-
Methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1-diflu
(Oroethyl @ phenoxy) -N-methylthieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (4-chlorophenoxy) -6-{[(2,2-dimethylpropanoyl)
[Xy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pi
Lysine-6-ium, 4- (4-bromophenoxy) -6-{[(2,2-dimethylpropanoyl)
[Xy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pi
Lysine-6-ium, 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(isoprop
[Ropoxycarbonyl) oxy] methyl}] thieno [2,3-c] pyridine-6-
Ium, 4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide,
4-[(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pi
Lysine-2-carboxamide, 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, N ⁴ -(4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dical
Boxamide, [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] me
Tanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde oxime, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde O-methyloxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-Ethanone O-methyloxime, 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-Ethanone O-methyloxime, 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-propanone, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-propanone oxime, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonit
Ryl, 4- (4-chlorophenoxy) -N′-hydroxythieno [2,3-c] pyridi
2-carboxyimidamide, 4- (4-chlorophenoxy) -N′-cyanothieno [2,3-c] pyridine-
2-carboximidamide, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
2-nitrophenyl) methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
(2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
(3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol, 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2-Il
] -1,2-ethanediol, 1- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2-ethanediol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] meth
Tanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] me
Tyl carbamate, N-{[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
[Methyl] urea, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenamide, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-
2-yl] -N-methyl-2-propenamide, 3- [4- (4-bromophenoxy) thieno [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-ylform
Amide, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Urea, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Sulfonamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-sulfonamide, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Phenol, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] Aniline, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Aniline, 4- (4-chlorophenoxy) -2- (5-nitro-2-pyridinyl) thieno [
2,3-c] pyridine, 6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -3-pyridinamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -2-pyridinamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-oxadiazol-2-amine, 5- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-oxadiazol-2-ylamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -4H-1,2,4-triazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-thiadiazol-2-amine 4- (4-chlorophenoxy) -2- (5-methyl-1,2,4-oxadiazo
Yl-3-yl) thieno [2,3-c] pyridine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pi
Lysin-2-yl {-1,3,4-oxadiazol-2-amine, 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
4-oxadiazol-2-yl] thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (2-methyl-2H-1,2,3,4-te
Tolazol-5-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -4-Methyl-4H-1,2,4-triazol-3-amine, 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) -1,2,2
4-oxadiazol-3-yl] thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2,4-oxadiazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N-methyl-1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (1,2,4-oxadiazole-3-i
Ru) thieno [2,3-c] pyridine, 2- (1,3,4-oxadiazol-2-yl) -4- [4- (trifluoro
Methyl) phenoxy] thieno [2,3-c] pyridine, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2,4-oxadiazol-5-amine, 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4- (
Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] -1,3-thiazole-4-carboxylate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3-thiazole-4-carboxamide, tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] -1,3-thiazol-4-ylcarbamate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
-1,3-thiazol-4-amine, 4-chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide,
3-amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide,
4- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Carboxamide, 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide, tert-butyl 2- (aminocarbonyl) -4- (4-chlorophenoxy) thio
Eno [2,3-c] pyridine-3-carboxylate, N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide, N-methyl-4- (4-morpholinyl) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 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-chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thio
Eno [2,3-c] pyridine-2-carboxamide, 7-bromo-4- (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, 7-chloro-N-methyl-4- [4- (trifluoromethyl) phenoxy] thiye
No [2,3-c] pyridine-2-carboxamide, 7-chloro-N- (2-hydroxyethyl) -4- [4- (trifluoromethyl
) Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -N-methyl-7- (methylamino) thieno [2
, 3-c] pyridine-2-carboxamide, 4-[(E) -2-phenylethenyl] thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2-carboxami
4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxa
And 4- (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-2
The compound of claim 6, wherein the compound is selected from the group consisting of: -carboxamide. 8. E, an F, and Y is carbon, G is nitrogen or ^N + -O ^- is, Z is S _{(O) t,} A compound according to claim 1. 9. 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-5-
Carboxamide, ethyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio] thieno [2,3-b] pyridine-5-carboxylate, methyl 6-[(4-methylphenyl) Thio] thieno [2,3-b] pyridine-2
9. The compound of claim 8, wherein the compound is selected from the group consisting of: -carboxylate, and methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxylate. 10. E, an F, and Z are carbon, G is nitrogen or ^N + -O ^- is, Y is S _{(O) t,} A compound according to claim 1. 11. 7-[(4-methylphenyl) thio] thieno [3,2-b
] The compound according to claim 10, which is pyridine-2-carboxamide. 12. F, G and Y are carbon and E is nitrogen or N⁺-O ⁻ And Z is S (O)_tThe compound of claim 1, wherein 13. A 2-bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine, a 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine. -2-carboxamide, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-carbonitrile, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2 13. The compound of claim 12, wherein the compound is selected from the group consisting of: -carboxamide, and 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonitrile. 14. is E and G are carbon, nitrogen or ^N + -O F and Y is independently ^- and, Z is S _{(O) t,} A compound according to claim 1. 15. Methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-2-carboxylate, 7- (4-methylphenoxy) [1,3] thiazolo [5] , 4-c] pyridine-2
-Carboxamide, and N-methyl-7- (4-methylphenoxy) [1,3] thiazolo [5,4-c]
15. The compound of claim 14, wherein the compound is selected from the group consisting of: pyridine-2-carboxamide. 16. E and G are carbon, F is nitrogen or N ⁺ -O ^- and is, Y and Z is nitrogen, compounds of claim 1. 17. G and Y are carbon, E and F are independently nitrogen or ^N + -O ^- is, Z is S _{(O) t,} A compound according to claim 1. 18. E, wherein G and Z are carbon, F is nitrogen or ^N + -O ^- is, Y is S _{(O) t,} A compound according to claim 1. 19. E and G are carbon, F is nitrogen or N ⁺ -O ^- is, Y is nitrogen, Z is oxygen, compounds of claim 1. 20. E, wherein G and Y are carbon, F is nitrogen or ^N + -O ^- is, Z is O, and A compound according to claim 1. 21. 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxamide and 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothioamide 21. The compound according to claim 20, selected from the group consisting of: 22. Methyl 2-[(6-ethylthieno [2,3-d] pyrimidi
N-4-yl) thio] acetate, 6-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-d] pyrimi
Gin, 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
E] thieno [2,3-d] pyrimidine, ethyl 6-ethyl-4- [4- (methylphenyl) thio] thieno [2,3-d]
Pyrimidine-6-carboxylate, 6-ethyl-N- (phenylmethyl) thieno [2,3-d] pyrimidine-4-a
Min, 6-ethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) thiye
No [2,3-d] pyrimidin-4-amine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-e
Tyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 4-chloro-6-ethyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine
Gin, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -6-e
Tyl-2- (phenylmethyl) thieno [2,3-d] pyrimidine, 7-methyl-4-[(4-methylphenyl) thio] thieno [3,2-d] pyrimidine
Gin, 7-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio
E] thieno [3,2-d] pyrimidine, 7-methyl-4-[[5- (methylthio) -1,3,4-thiadiazole-2-
Yl] thio] thieno [3,2-d] pyrimidine, 4-[(5-amino-1,3,4-thiadiazol-2-yl) thio] -7-me
Thithieno [3,2-d] pyrimidine, 7-methyl-N-[(4- (methylthio) phenyl] thieno [3,2-d] pyrimidine
Midine-7-amine, 7-methyl-4-[(4- (methylphenyl) thio] thieno [3,2-d] pyri
Midine-6-carboxamide, methyl 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-
2-carboxylate, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Rubonic acid, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (2-pyridinylthio) thieno [2,3-c] pyridine-2-carboxami
, 4-[(4-chlorophenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, N-methoxy-N-methyl-4-[(4- (methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, N-methoxy-4-[(4- (methylphenyl) thio] thieno [2,3-c] pi
Lysine-2-carboxamide, N- (4-chlorophenyl) -4-[(4- (methylphenyl) thio] thieno [
2,3-c] pyridine-2-carboxamide, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-methyl oxime, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O- (phenylmethyl) oxime, 2-[[[4-[(methylphenyl) thio] thieno [2,3-c] pyridine-2
-Ylmethylene] amino] oxy] acetic acid, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, O-phenyloxime, 4-[(4- (methylphenyl) thio] thieno [2,3-c] pyridine-2-ca
Ruboxaldehyde, oxime, 2-[[[4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine
-2-ylmethylene] -amino] oxy] acetamide, (E) -3-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-
2-yl] -2-propenamide, 1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] ethanone, 2-benzoyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pi
Lysine, 2-ethyl-4-[(4-methylphenyl) thio] thieno [2,3-c] pyridi
1- [4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] ethanone, oxime, N- (2,3-dihydroxypropyl) -4-[(4-methylphenyl) thio]
Thieno [2,3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boric acid, hydrazide, N ² -4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2
-Yl] carbonyl] -N ⁶ -[(Nitroamino) iminomethyl] -L-lysine
, Methyl ester, N- (aminoiminomethyl) -4-[(4-methylphenyl) thio] thieno [2
, 3-c] pyridine-2-carboxamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Bothioamide, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine, methyl 4-[(2-methoxy-2-oxoethyl) thio] thieno [2,3-c]
Pyridine-2-carboxylate, 4-[(2-amino-2-oxoethyl) thio] thieno [2,3-c] pyridine
-2-carboxamide, 4-[(4-bromophenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (phenylthio) thieno [2,3-c] pyridine-2-carboxamide, 4-[[4- (trifluoromethyl) phenyl] thio] thieno [2,3-c] pi
Lysine-2-carboxamide, 4-[(2-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 4-[(3-methylphenyl) thio] thieno [2,3-c] pyridine-2-cal
Boxamide, 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-ca
Luboxamide, 4- (cyclohexylthio) thieno [2,3-c] pyridine-2-carboxami
, 4-[(4-methylphenyl) thio] -N- [3- (4-morpholinyl) propyl
Ru] thieno [2,3-c] pyridine-2-carboxamide, trifluoromethyl
Acetate, 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyridine-
2-carboxamide, methyl 4-[(4-methylphenyl) sulfinyl] thieno [2,3-c] pyri
Gin-2-carboxylate, 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, methyl 4- (4-methylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxylate, 4 (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxami
Methyl 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-cal
Boxylate, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine
-2-carboxamide, 4- (4-octylphenoxy) thieno [2,3-c] pyridine-2-carboxyl
Samide, 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-carboxa
Mido, 4- (4-ethenylphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- [4- (1,2-dihydroxyethyl) phenoxy] thieno [2,3-c]
Pyridine-2-carboxamide, 4- [2- (2-propenyl) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, 4- [2- (2,3-dihydroxypropyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (trifluoromethyl) 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-carboxa
Mido, 4- (3-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-t-butylphenoxy) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (4-chloro-3-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chloro-2-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-methoxyphenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, ethyl 3-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-4-
Yl] oxy] benzoate, 4-phenoxythieno [2,3-c] pyridine-2-carboxamide, 4- (3-bromophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-fluorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (3,5-dimethylphenoxy) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (3-chloro-4-methylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-iodophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4- (methoxymethyl) phenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 2- (aminocarbonyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridinium, iodide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxylic acid
N- (4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
) -O- (3-tetrahydrofuranyl) carbamate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-methanol
(E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenoic acid, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Aldehyde, (E) -3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenamide, 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] pyri
Gin-2-carboxylate, N-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] pyridi
2-Carboxamide, 4- (5-formyl-2-furanyl) thieno [2,3-c] pyridine-2-cal
Boxamide, ethyl 4-[[2- (aminocarbonyl) thieno [2,3-c] pyridine-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-carboxa
Mido, methyl 4- (1-phenylethenyl) thieno [2,3-c] pyridine-2-cal
Boxylate, 4-[(4-methylphenyl) thio] thieno [2,3-c] pyridine-2-meta
Nor, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N, N-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -N, N-diethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -N-cyclopropylthieno [2,3-c] pyri
Gin-2-carboxamide, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] pyrrolidine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] piperidine, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] morpholine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -4-methylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -4-phenylpiperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] carbonyl] -4- (phenylmethyl) piperazine, 1-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-i
L] carbonyl] -4- (2-pyridinyl) piperazine, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-carboxamide, 4-[[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
L] carbonyl] -N- (1-methylethyl) -1-piperazineacetamide,
Trifluoroacetate, 4- (4-chlorophenoxy) -N- [1- (hydroxymethyl) ethyl] thiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N- [1,1-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, 4- (4-chlorophenoxy) -N- [2- (4-morpholinyl) ethyl] thie
No [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-sulfone
Mido, 4- (4-morpholinyl) thieno [2,3-c] pyridine-2-carboxamide
4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxa
Amide, N-oxide, methyl (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Acid, N-oxide, 4- (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] pyridi
2-carboxylate, 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, methyl 3-amino-4- (4-chlorophenoxy) thieno [2,3-c] pyridi
2-carboxylate, 3-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-5-cal
Boxamide, 4-chloro-N- (4-chlorophenyl) thieno [2,3-b] pyridine-5-
Carboxamide, ethyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl) thio] thio
Eno [2,3-b] pyridine-5-carboxylate, 7-[(4-methylphenyl) thio] thieno [3,2-b] pyridine-2-cal
Boxamide, methyl 6-[(4-methylphenyl) thio] thieno [2,3-b] pyridine-2
-Carboxylate, methyl 3-amino-6-chlorothieno [2,3-b] pyridine-2-carboxy
Rate, 2-bromo-4-[(4-methylphenyl) thio] thieno [3,2-c] pyridi
4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-cal
Boxamide, 4-[(4-methylphenyl) thio] thieno [3,2-c] pyridine-2-cal
Bonitrile, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carboxa
Mido, 4- (4-methylphenoxy) thieno [3,2-c] pyridine-2-carbonit
Ryl, 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridine-2
-Carboxamide, methyl 7- (4-methylphenoxy) [1,3] thiazolo [5,4-c] pyridi
2-carboxylate, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbothio
Amide, 4- (4-chlorophenoxy) -N-ethylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-carboxamide, N- (2-chloroethyl) -4- (4-chlorophenoxy) thieno [2,3-c
Pyridine-2-carboxamide, 4- (4-bromophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-carboxamide, 4- (2-bromo-4-chlorophenoxy) -N- (2-hydroxyethyl) thio
Eno [2,3-c] pyridine-2-carboxamide, N- (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, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine
-2-carboxamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbohydride
Razide, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbohydride
Razide, 4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pyridine
-2-carbohydrazide, 4- (4-chlorophenoxy) -N-hydroxythieno [2,3-c] pyridine
-2-carboxamide, 2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-
Yl] carbonyl @ amino) acetic acid, N- (2-amino-2-oxoethyl) -4- (4-chlorophenoxy) thieno
[2,3-c] pyridine-2-carboxamide, N- (2-amino-2-oxoethyl) -4- (4-bromophenoxy) thieno
[2,3-c] pyridine-2-carboxamide, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl @ amino) -3-hydroxypropanoic acid, N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl]
-4- (4-Chlorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl {amino) -3-hydroxypropanoic acid, (2R) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1R) -1-methyl-2- (methyla
Mino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxami
, (2S) -2-({[4- (4-chlorophenoxy) thieno [2,3-c] pyri
Zin-2-yl] carbonyl {amino) propanoic acid, 4- (4-chlorophenoxy) -N-[(1S) -1-methyl-2- (methyla
Mino) -2-oxoethyl] thieno [2,3-c] pyridine-2-carboxami
, 4- (4-chlorophenoxy) -N-[(1R) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-chlorophenoxy) -N-[(1S) -1- (hydroxymethyl)-
2- (methylamino) -2-oxoethyl] thieno [2,3-c] pyridine-2
-Carboxamide, 4- (3-pyridinyloxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-bromophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-bromophenoxy) -N, N-dimethylthieno [2,3-c] pyridi
2-Carboxamide, N, N-dimethyl-4- [4- (trifluoromethyl) phenoxy] thieno [2
, 3-c] pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) -N-methylthieno [2,3-c
Pyridine-2-carboxamide, 4- (4-chloro-3-fluorophenoxy) thieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chloro-3-ethylphenoxy) thieno [2,3-c] pyridine-2
-Carboxamide, 4- (3-fluorophenoxy) thieno [2,3-c] pyridine-2-carboxy
Samide, 4- (2,3-difluorophenoxy) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 4- (2,3-difluorophenoxy) -N-methylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- (3-fluorophenoxy) -N-methylthieno [2,3-c] pyridine-
2-carboxamide, N-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, N-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] pyridi
2-Carboxamide, 4- (4-cyanophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, 4- (4-cyanophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- (4-aminophenoxy) thieno [2,3-c] pyridine-2-carboxa
Mido, 4- [4- (acetylamino) phenoxy] thieno [2,3-c] pyridine-2
-Carboxamide, N-methyl-4- [4- (4-morpholinyl) phenoxy] thieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] thieno [2,3-c] pyridine-
2-carboxamide, 4- [4- (hydroxymethyl) phenoxy] -N-methylthieno [2,3-c
] Pyridine-2-carboxamide, 4- [4- (methoxymethyl) phenoxy] -N-methylthieno [2,3-c]
Pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} thieno [2,3-
c] pyridine-2-carboxamide, 4- {4-[(2-methoxyethoxy) methyl] phenoxy} -N-methylthiye
No [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
Thieno [2,3-c] pyridine-2-carboxamide, 4- (4-{[2- (2-methoxyethoxy) ethoxy] methyl} phenoxy)
-N-methylthieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(tetrahydro-2H-pyran-2-yloxy) methyl] pheno
Xythithieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4-[(tetrahydro-2H-pyran-2-yloxy) meth
Tyl] phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4-{[2- (aminocarbonyl) thieno [2,3-c] pyridin-4-yl]
Oxydibenzyl 2-furoate, 4- [4-({[(2R, 4R, 5S, 6R) -4,5-dihydroxy-6- (
Hydroxymethyl) tetrahydro-2H-pyran-2-yl] oxydimethyl)
Phenoxy] -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, N-methyl-4- [4- (4-morpholinylcarbonyl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, 4- [4-({[2- (4-morpholinyl) ethyl] amino} carbonyl) fe
Nonoxy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4-({[2- (4-morpholinyl) ethyl] amino} cal
Bonyl) phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3- (4-morpholinyl) -3-oxo-1-propenyl
] Phenoxy {thieno [2,3-c] pyridine-2-carboxamide, 4- [4-((E) -3-{[2- (4-morpholinyl) ethyl] amino} -3
-Oxo-1-propenyl) phenoxy] thieno [2,3-c] pyridine-2-
Carboxamide, N-methyl-4- [4-((E) -3-{[2- (4-morpholinyl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] thieno [2,3-c] pi
Lysine-2-carboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-{(E) -3-[(2,3-dihydroxypropyl) amino] -3-
Oxo-1-propenyl {phenoxy) -N-methylthieno [2,3-c] pyri
Gin-2-carboxamide, 4- [4-((E) -3-{[2- (1H-imidazol-4-yl) ethyl]
Amino {-3-oxo-1-propenyl) phenoxy] -N-methylthieno [2
, 3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] e
Tyl {amino) -3-oxo-1-propenyl] phenoxy} -N-methylthiye
No [2,3-c] pyridine-2-carboxamide, 4- {4-[(E) -3-({2- [bis (2-hydroxyethyl) amino] e
Tyl {amino) -3-oxo-1-propenyl] phenoxy} thieno [2,3-
c] pyridine-2-carboxamide, 4- [4- (1H-imidazol-1-yl) phenoxy] thieno [2,3-c
Pyridine-2-carboxamide, N-methyl-4- [4- (1H-pyrazol-1-yl) phenoxy] thieno [
2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1H-1,2,4-triazol-1-yl) pheno
Xy] thieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- {4- [5- (trifluoromethyl) -1,2,4-oxadi
Azol-3-yl] phenoxydithieno [2,3-c] pyridine-2-carbo
Oxamide, 4- [4- (4,5-dihydro-1H-imidazol-2-yl) phenoxy]
-N-methylthieno [2,3-c] pyridine-2-carboxamide, N-methyl-4- [4- (2-thienyl) phenoxy] thieno [2,3-c] pi
Lysine-2-carboxamide, 4-([1,1′-biphenyl] -4-yloxy) -N-methylthieno [2,
3-c] pyridine-2-carboxamide, N-methyl-4- [4- (1-methyl-1H-imidazol-5-yl) pheno
Xy] thieno [2,3-c] pyridine-2-carboxamide, 4- {4- [1- (hydroxymethyl) cyclopropyl] phenoxy} -N-meth
Tilthieno [2,3-c] pyridine-2-carboxamide, 4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl} cyclo
Propyl) phenoxy] -N-methylthieno [2,3-c] pyridine-2-cal
Boxamide, N-methyl-4- [4- (trifluoromethoxy) phenoxy] thieno [2,3
-C] pyridine-2-carboxamide, 5- {4- [4- (1-{[2- (2-ethoxyethoxy) ethoxy] methyl}
Cyclopropyl) phenoxy] thieno [2,3-c] pyridin-2-yl} -1
, 3,4-oxadiazol-2-amine, 4- [4- (1,1-difluoro-2-hydroxyethyl) phenoxy] -N-
Methylthieno [2,3-c] pyridine-2-carboxamide, 4- (4- {2- [2- (2-ethoxyethoxy) ethoxy] -1,1-diflu
Oroethyl @ phenoxy-N-methylthieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-chlorophenoxy) -6-{[(2,2-dimethylpropanoyl)
[Xy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pi
Lysine-6-ium, 4- (4-bromophenoxy) -6-{[(2,2-dimethylpropanoyl)
[Xy] methyl} -2-[(methylamino) carbonyl] thieno [2,3-c] pi
Lysine-6-ium, 2- (aminocarbonyl) -4- (4-chlorophenoxy) -6-{[(isoprop
[Ropoxycarbonyl) oxy] methyl} thieno [2,3-c] pyridine-6-i
, 4- (benzyloxy) thieno [2,3-c] pyridine-2-carboxamide,
4-[(4-chlorophenyl) (hydroxy) methyl] thieno [2,3-c] pi
Lysine-2-carboxamide, 4- (4-chlorobenzoyl) -N-methylthieno [2,3-c] pyridine-2
-Carboxamide, N ⁴ -(4-chlorophenyl) thieno [2,3-c] pyridine-2,4-dical
Boxamide, [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl] me
Tanol, 4- (4-bromophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Dehyde, oxime, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbal
Aldehyde, O-methyl oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-Ethanone O-methyloxime, 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-Ethanone O-methyloxime, 1- [4- (4-Chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-ethanone oxime, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-propanone, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1-propanone oxime, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N-methoxy-N-methyl-2-oxoacetamide, 4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-carbonit
Ryl, 4- (4-chlorophenoxy) -N′-hydroxythieno [2,3-c] pyridi
2-carboxyimidamide, 4- (4-chlorophenoxy) -N′-cyanothieno [2,3-c] pyridine-
2-carboximidamide, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
2-nitrophenyl) methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
(2-nitrophenyl) methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone, (2-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] (
(3-nitrophenyl) methanol, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanone, (3-aminophenyl) [4- (4-chlorophenoxy) thieno [2,3-c]
Pyridin-2-yl] methanol, 4- (4-bromophenoxy) -2-vinylthieno [2,3-c] pyridine, 1- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine- 2-Il
] -1,2-ethanediol, 1- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2-ethanediol, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] meth
Tanamine, [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl] me
Tyl carbamate, N-{[4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2-i
[Methyl] urea, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-
2-yl] -2-propenamide, (E) -3- [4- (4-bromophenoxy) thieno [2,3-c] pyridine-
2-yl] -N-methyl-2-propenamide, 3- [4- (4-bromophenoxy) thieno [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-ylform
Amide, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Urea, N- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N'-methylthiourea, 4- (4-chlorophenoxy) -N-methylthieno [2,3-c] pyridine-2
-Sulfonamide, 4- (4-chlorophenoxy) -N- (2,3-dihydroxypropyl) thieno
[2,3-c] pyridine-2-sulfonamide, 4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thieno [2,3
-C] pyridine-2-sulfonamide, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Phenol, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] Aniline, 4- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
Aniline, 4- (4-chlorophenoxy) -2- (5-nitro-2-pyridinyl) thieno [
2,3-c] pyridine, 6- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -3-pyridinamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -2-pyridinamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-oxadiazol-2-amine, 5- [4- (4-bromophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-oxadiazol-2-ylamine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -4H-1,2,4-triazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3,4-thiadiazol-2-amine 4- (4-chlorophenoxy) -2- (5-methyl-1,2,4-oxadiazo
Yl-3-yl) thieno [2,3-c] pyridine, 5- {4- [4- (trifluoromethyl) phenoxy] thieno [2,3-c] pi
Lysin-2-yl {-1,3,4-oxadiazol-2-amine, 4- (4-chlorophenoxy) -2- [5- (methylsulfanyl) -1,3,3
4-oxadiazol-2-yl] thieno [2,3-c] pyridine, 4- (4-chlorophenoxy) -2- (2-methyl-2H-1,2,3,4-te
Tolazol-5-yl) thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -4-Methyl-4H-1,2,4-triazol-3-amine, 4- (4-chlorophenoxy) -2- [5- (trifluoromethyl) -1,2,2
4-oxadiazol-3-yl] thieno [2,3-c] pyridine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2,4-oxadiazol-3-amine, 5- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -N-methyl-1,3,4-thiadiazol-2-amine, 4- (4-chlorophenoxy) -2- (1,2,4-oxadiazole-3-i
Ru) thieno [2,3-c] pyridine, 2- (1,3,4-oxadiazol-2-yl) -4- [4- (trifluoro
Methyl) phenoxy] thieno [2,3-c] pyridine, 3- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,2,4-oxadiazol-5-amine, 2- (5-methyl-1,3,4-oxadiazol-2-yl) -4- [4- (
Trifluoromethyl) phenoxy] thieno [2,3-c] pyridine, methyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridine-2
-Yl] -1,3-thiazole-4-carboxylate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
] -1,3-thiazole-4-carboxamide, tert-butyl 2- [4- (4-chlorophenoxy) thieno [2,3-c] pi
Lysin-2-yl] -1,3-thiazol-4-ylcarbamate, 2- [4- (4-chlorophenoxy) thieno [2,3-c] pyridin-2-yl
-1,3-thiazol-4-amine, 4-chloro-3-methylthieno [2,3-c] pyridine-2-carboxamide,
3-amino-4-chlorothieno [2,3-c] pyridine-2-carboxamide,
4- (4-chlorophenoxy) -N, 3-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-bromophenoxy) -3-methylthieno [2,3-c] pyridine-2
-Carboxamide, 7-chloro-4- (4-chlorophenoxy) -3-methylthieno [2,3-c]
Pyridine-2-carboxamide, tert-butyl 2- (aminocarbonyl) -4- (4-chlorophenoxy) thio
Eno [2,3-c] pyridine-3-carboxylate, N-methyl-4- (4-toluidino) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-chloroanilino) -N-methylthieno [2,3-c] pyridine-2-
Carboxamide, N-methyl-4- (4-morpholinyl) thieno [2,3-c] pyridine-2-ca
Ruboxamide, 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-chloro-4- (4-chlorophenoxy) -N- (2-hydroxyethyl) thio
Eno [2,3-c] pyridine-2-carboxamide, 7-bromo-4- (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, 7-chloro-N-methyl-4- [4- (trifluoromethyl) phenoxy] thiye
No [2,3-c] pyridine-2-carboxamide, 7-chloro-N- (2-hydroxyethyl) -4- [4- (trifluoromethyl
) Phenoxy] thieno [2,3-c] pyridine-2-carboxamide, 4- (4-chlorophenoxy) -N, 7-dimethylthieno [2,3-c] pyridi
2-Carboxamide, 4- (4-chlorophenoxy) -7-methoxythieno [2,3-c] pyridine-
2-carboxamide, 4- (4-chlorophenoxy) -7-oxo-6,7-dihydrothieno [2,3
-C] pyridine-2-carboxamide, 4- (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-2-carboxamide, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carboxami
, 4- (4-chlorophenoxy) furo [2,3-c] pyridine-2-carbothioa
Imide, 4-[(E) -2-phenylethenyl] thieno [2,3-c] pyridine-2-ca
Luboxamide, 4- (4-chlorophenyl) thieno [2,3-c] pyridine-2-carboxami
4- [3- (trifluoromethyl) phenyl] thieno [2,3-c] pyridine-
2-carboxamide, 4- (3-chlorophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (4-bromophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (3-aminophenyl) thieno [2,3-c] pyridine-2-carboxami
, 4- (3,5-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (3,4-dichlorophenyl) thieno [2,3-c] pyridine-2-carbo
Oxamide, 4- (2,4-difluorophenyl) thieno [2,3-c] pyridine-2-cal
Boxamide, 4- (4-fluorophenyl) thieno [2,3-c] pyridine-2-carboxa
And 4- (4-bromophenoxy) -5-chlorothieno [2,3-c] pyridine-2
-A compound selected from the group consisting of carboxamide. 23. A method for treating reperfusion injury and inflammatory disease, comprising administering an effective amount of the compound of claim 1.